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NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2015 Sep 29.
Published in final edited form as: Curr Pharm Des. 2014;20(19):3178–3197. doi: 10.2174/13816128113196660690

Interaction Between Bone and Muscle in Older Persons with Mobility Limitations

L Ferrucci 1, M Baroni 2, A Ranchelli 2, F Lauretani 3, M Maggio 3, P Mecocci 2, C Ruggiero 2,*
PMCID: PMC4586132  NIHMSID: NIHMS716728  PMID: 24050165

Abstract

Aging is associated with a progressive loss of bone-muscle mass and strength. When the decline in mass and strength reaches critical thresholds associated with adverse health outcomes, they are operationally considered geriatric conditions and named, respectively, osteoporosis and sarcopenia. Osteoporosis and sarcopenia share many of the same risk factors and both directly or indirectly cause higher risk of mobility limitations, falls, fractures and disability in activities of daily living. This is not surprising since bones adapt their morphology and strength to the long-term loads exerted by muscle during anti-gravitational and physical activities. Non-mechanical systemic and local factors also modulate the mechanostat effect of muscle on bone by affecting the bidirectional osteocyte-muscle crosstalk, but the specific pathways that regulate these homeostatic mechanisms are not fully understood. More research is required to reach a consensus on cut points in bone and muscle parameters that identify individuals at high risk for adverse health outcomes, including falls, fractures and disability. A better understanding of the muscle-bone physiological interaction may help to develop preventive strategies that reduce the burden of musculoskeletal diseases, the consequent disability in older persons and to limit the financial burden associated with such conditions. In this review, we summarize age-related bone-muscle changes focusing on the biomechanical and homeostatic mechanisms that explain bone-muscle interaction and we speculate about possible pathological events that occur when these mechanisms become impaired. We also report some recent definitions of osteoporosis and sarcopenia that have emerged in the literature and their implications in clinical practice. Finally, we outline the current evidence for the efficacy of available anti-osteoporotic and proposed anti-sarcopenic interventions in older persons.

Keywords: Bone-muscle, sarcopenia, osteoporosis, disability, aging

1. INTRODUCTION

The ability of humans to move in their environment mainly depends upon the interaction of bone and muscle. The skeleton provides the framework that supports the body, it gives its characteristic shape and provides the mechanical integrity for locomotion and protection. The muscles, which make up 50% of the body mass, act on bones and joints to generate the many different coordinated movements necessary for human life, as we know it.

The bone mass and architecture are adjusted to control the strains produced by mechanical load and muscular activity. Bone is made up of specific bone cells, collagen proteins and minerals (calcium and phosphate) both including in the matrix that provides maximal strength in a lightweight form. Collagen fibers are incredibly strong, but too flexible and elastic to support the body. The minerals give to the bone its hardness and rigidity. The structural units of the bone are called Haversian systems. Each system consists of concentrically arranged layers of hard, inorganic material surrounding a microscopic Haversian canal. Blood vessels and nerves pass through this canal. Materials are exchanged between the living cells and the blood vessels in the Haversian canal by the way of canaliculi. The living bone cells (osteocytes) lie along the interfaces between contiguous concentric layers of the matrix and live as long as 50 years, in contrast to osteoclasts and osteoblasts, which are relatively short-lived and transiently present on a small fraction of the bone surface [1,2]. Osteocytes are the orchestrators of the remodeling process. They sense the sites of old bone and direct the homing of osteoclasts (and perhaps osteoblasts) to the site that is in need of remodeling. In addition, they produce factors that influence osteoblast and osteoclast generation as well as mineral homeostasis, they mediate the homeostatic adaptation of bone to mechanical loading and control or modify the mineralization of the matrix produced by osteoblasts [35].

Skeletal muscle is made up of many multinucleate cells, called fibers, which run the entire length of the muscle. Each muscle fiber contains a large number of parallel tube-like structures, called myofibrils, which in turn contain units called sarcomeres. This is where the contraction occurs with the thin filaments (actin) sliding between the thick filaments (myosin dimers), along with numerous other regulatory proteins. The force generated by the muscle fiber is proportional to the number of myofibrils it contains. Muscles are innervated by motor neurons. The motor unit is the combination of a single motor neuron and the muscle fibers innervated by its branches. Acetylcholine released from the axon end of the motor neuron branch binds to receptors on the fiber cell surface and causes the release of calcium from the sarcoplasmic reticulum. Thus, in the presence of calcium, the myosin component attaches the actin within the sarcomere generating power. After a sequence of chemical transformations via actin-induced breakdown of adenosine triphosphate (ATP), free energy is released to generate both force production and movement of actin within the sarcomere, thereby causing the whole muscle to generate force and movement [6]. Motor units are differentiated into three main classes based on the specific type of myosin dimers expressed in the fibers. Slow motor units contain type I myosin that is rich in mitochondria and myoglobin, has high capacity for sustained delivery of ATP from oxidative metabolism and, is able to transduce energy at a relatively slow rate for long periods of time. Fast fatigable motor units express type IIx myosin that transduces energy from the glycolysis of glycogen at a faster rate than type I myosin, thus providing considerable energy over a relatively short time period and generating more force at higher velocity than slow motor units. Fast fatigue-resistant motor units contain type Ha myosin, that transduces energy at a rate which is intermediate between slow and fast fatigable motor units. These motor units are intermediate in cross-sectional area (CSA) between type I and type IIx and are also intermediate in term of the number of fibers and the velocity of contraction [6].

The interaction between muscles and bones generates movements. The mechanical properties of both skeletal and muscle systems, i.e. musculoskeletal system, and the complexity of their physical interfacing and molecular signaling clearly influence the forces transmitted to the surroundings, the speed of motion of the bones that the muscles attach to, and the stresses involved within the bones.

Aging is accompanied by changes in the musculoskeletal system including a decrease in lean mass and bone, and an increase in fat mass [7]. In the Delmonico et al. longitudinal study, men aged 85+ years have significantly lower body weight and lean mass than those aged 65–69 years and experience cross-sectional and longitudinal losses of muscle mass and strength that are twice what is observed in women [8]. Women, on the other hand, experience over 50% larger lifetime loss of bone mass and strength, driven by loss of estrogens [9]. Even if weight is maintained constant over life, with aging the body becomes relatively fatter due to the gradual replacement of many tissues, including bone marrow and muscle, by fat. Furthermore, the musculoskeletal system undergoes inevitable physiological changes of its structure, in terms of mass, geometry and composition, that changes gradually impair functionality and at certain impoverishment threshold they promote the onset of pathological conditions, named osteoporosis and sarcopenia [1012]. Both conditions co-exist in older people and share genetic, environmental and health-related intrinsic and extrinsic factors [1315]. For instance, many pathological conditions, i.e. diabetes, use of steroids, being bedridden, may accelerate the progression of musculoskeletal age-related changes and the onset of their disabling consequences. Indeed, age-related sarcopenia and osteoporosis when not recognized and treated, increase the risk for falls and fractures, thereby making older individual more susceptible to mobility limitations and, ultimately, to severe disability [16, 17].

Within this framework, we aim to review the current literature in order to I) summarize the age-related bone and muscle changes; II) examine the interactions between muscle and bone from mechanical to biological levels; III) analyze the pathways through which age-related musculoskeletal changes, osteoporosis and sarcopenia negatively impact mobility; IV) outline the current evidence for the efficacy of the pharmacological and non-pharmacological countermeasures for age-related musculoskeletal changes and their disability burden.

2. MUSCULOSKELETAL AGE-RELATED MODIFICATIONS

The progressive loss of musculoskeletal mass and strength, commonly named osteopenia for bone and sarcopenia for muscle, is considered an universal phenomenon with structural and functional features secondary to a complex and multifactorial etiology. Bone undergoes loss of density, changes in the geometry, i.e. their cortical and medullary area, and modifications in the architectural characteristics, i.e. trabecular thickness and cortical pororsity, as well as in the number and activity of osteoprogenitor cells within the bone marrow (BM) environment. Muscle shows myogenic and neurogenic adaptations in the composition and the contractile properties of the fibers, loss of motor neurons, less muscle cell recruitment at the neuromuscular junction, unbalance in muscle protein turnover, increased cell signaling pathways leading to apoptosis, and decreased muscle regeneration. Several morphological aspects of age-related bone-muscle changes are known, but the triggers and the many factors accelerating them are still to be defined. Recognizing the age-related changes and the underlying causes and mechanisms is expected to facilitate the development of agents to blunt these processes and to design intervention trials that target one or more of such underlying mechanisms.

2a. Bone

Bone density

Both sexes lose areal bone mineral density (aBMD) at relatively slow rates starting at around age 40, approximately 0.5% per year. Women experience an accelerated loss of aBMD in their 50s, approximately 3% to 5% per year, at the onset and during menopause. Postmenopausal women lose trabecular BMD rapidly in their vertebrae, pelvis, and ultradistal wrist, while less rapid is the cortical bone loss in long bones and vertebrae. About 8–10 years after menopause, a slower age-related bone loss becomes prominent and continues for the rest of life [18]. Men, who do not experience sudden loss of gonadal sex steroid secretion, have slower age-related bone loss through their adult life past about age 40 [19, 20]. However, the age-related reduction in bone mass is disproportionally related to skeletal weakening, thus suggesting that architectural changes are important determinants of bone quality and strength.

Bone geometry

Both sexes have a specific age-related rate of periosteal apposition and endocortical reabsorption. A steeper periosteal apposition in men than in women increases the total bone area at both central and peripheral sites, while a larger endocortical reabsorption, much higher in women than men, widens the medullary cavity [21, 22]. In humans and mice alike, the rate of endosteal bone loss is comparable between males and females, whereas periosteal apposition is substantially more pronounced in males, leading to different patterns of cortical expansion [23]. Periosteal apposition in men occurs mostly at younger ages, whereas in women it is evident across the entire lifespan. Endocortical reabsorption in women occurs over the aging process and may considerably exceed the effect of periosteal apposition as compared to men. In spite of specific sex- and age-related geometric changes, the cross-sectional moment of inertia—a derived parameter that summarizes how parallel changes in bone material and in bone geometry translate into changes in bone mechanical properties—declines over the lifespan in both sexes, but in women more steeply as compared to men [24].

Cortical and trabecular bone

Both cortical and trabecular bone undergo age- and sex-related physiological changes, albeit to a lesser extent in the cortical area. The most evident modifications in cortical bone are the decreased cortical BMD and cortical thickness, the increased cortical porosity and the widening of the medullary cavity [25, 26]. Cortical age-related changes are not generalized even at the same cortical envelope, but the magnitude of cortical porosity increases with proximity to the endosteal surface, particularly in women, thus contributing to their enhanced severity of osteoporosis [27]. Cortical porosity results from a negatively balanced osteonal remodeling, which leads to a progressive increase in the size of osteonal canals that merge each other and become superosteons. The number of osteonal canals decreases from the sixth decade and onward [28], resulting in a significant deficit of cortical mineralized matrix and minor resistance to fracturing. Advanced porosity combined with concomitant endosteal and periosteal bone loss results in marked focal thinning and apparent weakening of the cortex.

The most pronounced age-related modifications in bone architecture are the reduction in trabecular thikness, number and connectivity density. The thinning processes equally shift down the thickness of all trabeculae, leading to the clearance of the smallest interconnecting struts and removal of a higher percentage of the thin struts compared with the thicker trabeculae. In males, with aging the rate of bone loss is inversely related to the thickness of individual trabeculae, with the thickest struts remaining unaffected [29, 23]. The thickest trabeculae are probably those in direct continuation (with no branching) with the cortex and, as observed primarily in males, it appears that they benefit from the relative cortical resistance to age-related thinning [30, 31]. It is well documented that age-related thinning and/or loss of interconnecting struts precedes the deterioration of the main struts, which in part explains the discrepancy between the age-related decreases in bone density and bone strength [32]. The thinning and clearance of interconnecting struts make the trabecular bone more susceptible to buckling under normal compression loads and vulnerable to unusual or off-axis loads.

Bone cells, matrix and microcracks

With aging the bone turnover becomes attenuated and unbalanced, such that the amount of deposited bone is less than that removed. The half-life of the bone matrix is extended, as is its exposure to fatigue damage and microfracture, resulting in inferior material properties [33]. The major bone cell population consists of osteoclasts, terminally differentiated myeloid cells that are uniquely adapted to remove mineralized bone matrix, osteoblasts, developed from pluripotent mesenchymal stem cells in bone marrow, and osteocytes, which are osteoblasts terminally differentiated and surrounded by un-mineralized osteoid matrix. The signals that lead to differentiation of osteoblast precursors decrease, while those promoting their apoptosis increase with age. Both mechanisms may contribute to the loss in osteoblast numbers and may account for a significant reduction in bone formation.

Rather than having a fixed lifespan, osteocytes die by a stochastic process occurring at a fractional rate of about 2.5% per year. In deep bone (more than 45 µm from the surface) that is rarely or never remodeled, osteocyte density declines exponentially with age, approaching an asymptotic value which at the age of 75 years is about 40% of the value at age 20 [34]. Osteocyte death is a major contributor to the decline of bone mass and strength with age, and the likely mechanisms are the autophagy failure and nuclear pore “leakiness” associated with oxidative stress damage [35]. Therefore, osteocyte death is evidently dependent on the biological age of the bone, not on the chronological age of the subject. Another aspect observed in elderly individuals is the decline in osteocytic lacunae, the increased amount of hypermineralized calcium phosphate inclusions and deprivation in osteocytic canaliculi. The age-related deprivation in osteocytic canaliculi is more pronounced in the endosteal than in the periosteal part of the cortical envelope. The progressive accumulation of hypermineralized inclusions is sometimes referred to as micropetrosis. Based on the size and distribution of the inclusions it has been suggested that they are hypermineralized occluded lacunae. It is yet unclear how the lacunar occlusion affects bone function [36].

The rate of bone remodeling and the amount of bone deposited with each cycle of remodelling decrease with aging, possibly due to a reduction in the number of cell precursors of osteoblasts, stem cells from which these precursors are derived and osteoblasts’s lifespan. The net result is a decrease in the amount of bone with age, starting fairly early in life [37, 38].

The process of mineralization is also affected by reduced age-related bone remodeling. Mineralization is the percent of the solid phase of bone that is mineral; a related measure is tissue mineral density (TMD) which is mineral content per volume of solid tissue [39], and is not the same as BMD, which is defined as mineral content per total area (aBMD) or volume (vBMD), and is thus influenced by porosity in bone. Data suggest an age-dependent increase in average mineralization of cancellous and cortical tissue in women and men (18–96 years), partly due to accumulation of elderly tissue fragments [40, 41].

Microcrack, a rather new micro structural feature that dramatically increases with age, consists of microscopic damage that accumulates in bone tissue due to mechanical stress associated with physiologic loading [42]. The microdamages result in part from the embrittlement of bone collagen due to advanced glycation end products (AGEs) and the detrimental changes in the collagen protein network [4345]. The cracks propagate easier through old bone tissue; therefore, bone becomes more brittle as it ages and less capable of absorbing energy before it fractures [46]. Microdamages are thought to have a marked impact on bone strength and are associated with bone fragility fractures [23].

Bone marrow

Age-related bone changes may depend on the structure and function of BM that contains mesenchimal stem cells (MSCs) [47]. MSCs give rise to several different phenotypes, including osteogenic and myogenic cells, hematopoiesis-supportive cells and adipocytes. Although the cell population size in the BM remains relatively constant, with aging there is a shift in balance from a stroma that actively supports osteogenesis and exuberant hematopoiesis to one that is primarily adipogenic and supports an altered form of hematopoiesis. The BM of young individuals is virtually devoid of adipocytes. In osteoporotic and older subjects, an adipose replacement in BM and an increased adipogenic differentiation of MSCs at the expense of osteoblast differentiation have been demonstrated [48, 49]. The cause for this age-related shift in phenotypic expression might be due to coexisting changes in systemic and local factors to which the bone precursors are exposed. Among factors intrinsic to stromal cells and BM environment are somatic mutations, altered gene expression and cellular differentiation, reduced mitochondrial activity and/or mitochondrial dysfunction with increased reactive oxygen species (ROS) generation, altered response to growth factors, accumulation of AGEs and increased expression of pro-inflammatory cytokines, such as interleukin (IL)-6, tumor necrosis factor (TNF)- α.

Hormones

Among systemic factors that influence bone remodeling, a major role is played by age-related declines in sex steroids, i.e. estrogens and testosterone, growth hormones, vitamin D and PTH. Several lines of evidence show that low estrogen levels contribute to bone loss and fracture risk later in life [50, 51]. In postmenopausal women, a threshold level of serum bioavailable (non-sex hormone binding globulin [SHBG]-bound) estradiol below 11 pg/mL leads to trabecular bone loss, whereas a threshold level below 3 pg/mL to cortical bone loss [52]. Estrogens contribute to bone health by modulating several pathways: decreasing the differentiation of osteoclast precursors by blocking RANKL/M-CSF-induced activator protein-1-dependent transcription [53, 54]; suppressing RANKL production by osteoblastic cells, T- and B-lymphocytes; inhibiting the activity of mature osteoclasts by direct receptor-mediated mechanisms [55]; modulating the production of IL-1, IL-6, TNF-α, macrophage colony-stimulating factor (M-CSF), and prostaglandins [56]; enhancing osteoblast differentiation [57]; inducing osteoclasts apoptosis mediated by transforming growth factor (TGF)-β [58]; and increasing osteoprotegerin (OPG) and TGF-β production by osteoblastic cells [59]. Therefore, estrogen deficiency favors bone resorption by increasing osteoclast recruitment and activity, probably by decreasing their apoptosis. Longstanding estrogen deficiency leads to chronic negative calcium balance due to reduced intestinal calcium absorption [60] and renal tubular calcium resorption [61]. Unless negative calcium balance is compensated with adequate calcium supplementation in presence of sufficient levels of vitamin D, secondary hyperparathyroidism develops, leading to an increased bone resorption. Indeed, the increase of PTH as a compensatory response to low calcium levels, stimulates osteoclast activity, which maintains normal serum calcium levels at the expense of bone mineralization. Other multiple factors may increase the PTH secretion with age, including vitamin D deficiency which is common in postmenopausal women [62] and in older men [63]. Although PTH secretion increases in aging men similar to what is seen in aging women [19, 52], it has been more difficult to demonstrate a direct role for PTH in causation of age-related bone loss in men [64].

For many years it was assumed that decreased serum testosterone, a dominant gonadal steroid in men, is responsible for male age-related bone loss. It likely contributes to a reduced fracture risk in men because of its influence on increasing bone size during growth and development [10] and favoring bone periosteal apposition, at least in rodents [65]. Recent data clearly suggest that the age-related decline of free testosterone levels might play a role in bone loss of older men mainly because it is the substrate for aromatase, which converts testosterone to estrogen. Therefore, decreasing levels of bioavailable estrogen may play a significant role in mediating age-related bone loss in men, similar to women [66]. Cross-sectional observational studies show that age-related bone loss at various skeletal sites in men correlates better with serum estradiol than testosterone, and serum total or bioavailable estradiol positively correlates with BMD [6769].

Ultimately, with aging bone remodeling and formation might be blunted by the low production of growth factors, i.e. GH and IGF-I, necessary for osteoblast differentiation and function. The age-related decrease in amplitude and frequency of GH production by the pituitary gland leads to decreased liver production of IGF-I. Both IGF-I and IGF-2 levels decrease with age, but IGF-2 less rapidly. Decreased systemic and local skeletal production of IGF-I and -2 as well as increased levels of growth factor binding proteins might down-regulate bone modeling and up-regulate remodeling in older persons which is not adequate to maintain BMD [70, 71].

2b. Skeletal Muscle

Muscle mass, strength and tissue composition

Lean muscle mass and strength decline starting approximately at 40 years of age to become 25% of body weight at 75–80 years old. Skeletal muscle CSA and muscle circumference decrease by 40% from the age of 30 to 60 years and by 25–40% per decade after 60 years, with a steeper trend in men compared to women [110112]. The loss of muscle strength is as great as 20–40% by the 7th decade and greater after 80 years [113]. The velocity at maximal power decreases by roughly 18% between ages 20–29 and 50–59, and by a further 20% between 60–69 and 80–89 [113]. Overall, the loss of muscle mass, strength and power appears greater in men as compared to women, steeper in older as compared to younger persons and superior in the lower limbs than in the upper limbs [72, 73].

The age-related decline of muscle mass is associated with an accelerated loss of the type IIx (fast) as compared to type I (slow) fibers, and a decrease of the myosin content per half-sarcomere. At the microstructural level, the average CSA of type I fibers slightly declines and the percentage of the total muscle CSA occupied by type I oxidative fibers tends to increase with age, whereas type IIx fast glycolytic fibers become thinner and atrophic. However, the muscle atrophy does not explain entirely the age-related decline in muscle strength. A deficit in contractile force (force normalized to muscle CSA) in aging skeletal muscle has been described and the loss in specific force is a widespread phenomenon involving fast-and slow-twitch fiber. Impairment in the mechanism of excitation-induced elevation of intracellular calcium and energy conversion from ATP into mechanical response might lead to decrease in muscle tension, clinically manifested as muscle weakness [74,75].

Furthermore, as the muscle mass decrease with aging, the area previously occupied by muscle fibers is replaced by fat and connective tissue. Even the residual muscle tissue components might be infiltrated by lipids, which can be contained within the adipocytes as well as deposited within the muscle fibers. The intra-myocellular lipids might result from net buildup of lipid due to reduced oxidative capacity of muscle fibers with aging [77, 76, 77].

Ultimately, as with precursor cells in BM, muscle satellite cells might express both adipocytic and myocytic phenotypes. The expression of the adipocytic phenotype increases with aging [78]. From a biological perspective, this process is still relatively poorly understood in terms of its extent and spatial distribution. However, from a functional point of view, it has been demonstrated that the fat content of skeletal muscle is inversely associated with bone strength at both trabecular and cortical level of the tibia and the femur, increasing the risk for fragility fractures [79, 80].

Motor unit structure and properties

According to some authors, neurogenic mechanisms might drive the age-related changes in muscle tissue and performance. These include the reduction in the number and size of the spinal cord motor neurons, alterations in axonal flow and in the neuromuscular junction. As the motor units are lost via neurodegeneration of the multiple levels of nervous system involved in their control, remaining motor units tend to recruit denervated fibers and to cluster similar fiber types changing the fiber type into that of the motor unit. As the type II fibers are recruited into slow motor units, there is a net conversion of type II fibers into type I fibers, with an increase in hybrid type I and II fibers. The reinnervation of fast fibers by axonal sprouting from slow fibers causes the final motor units to lose the mosaic-like appearance typically of young muscle tissue [81, 82]. Although the functional significance of motor unit remodeling still needs to be determined, the single fiber intrinsic force and the aggregate power-generating capacity of the remaining or clustering fibers decline with aging. Several factors might explain these findings: the increased noncontractile area within the motor units, the actin-myosin cross-bridge instability between the fibers, and the alterations of the excitation-contraction coupling process [83, 84]. Other findings suggest alterations of the myelin sheaths, reduced number of spinal cord motor neurons, increased size of terminal areas and few synaptic vesicles in the neuromuscular junction, high amount of neurotransmitters released in nerve impulses. However, the loss of motor neurons and the changes in conduction velocity in peripheral nerves might be irrelevant with aging and they often occur after the eighth decade when the loss in muscle mass and strength are already established [85].

Muscle regeneration

From a different prospective, the poor muscle regeneration by satellite cells in response to injury is considered the cause of impaired reinnervation of the myofibers [86]. The satellite cells are resident progenitors, located beneath the basal lamina of myofibers, responsible for postnatal growth, repair, and maintenance of skeletal muscle. They are generally considered as unipotent stem cells with the ability to differentiate into myogenic cell linage. In normal condition and undamaged muscle, satellite cells are maintained in a quiescent status, while muscle injury activates them. In humans, the number of satellite cells declines with aging, the response of satellite cells to activating stimuli is delayed and the secondary proliferative expansion reduced [8789]. These age-related changes might be enhanced by modifications of the niche environment, i.e. thickening of the interstitium, reduced blood supply and remodeling of neuromuscular junction, and by the expression of local diffusible molecular regulators, called myogenic regulatory factors (MRF) [90].

Pre-clinical studies have found that the expression of MRFs, such as myogenic determination factor (myoD), myogenic regulatory factor 5 and myogenin, is decreased in older compared to younger skeletal muscle. A reduced or delayed expression of MRFs in humans might impair the proliferation and differentiation of myoblasts more than their number [91, 92]. Myostatin, a member of the transforming growth factor-beta superfamily, is a negative regulator of the differentiation and the proliferation of myogenesis by reducing myoD and myogenin. The effect of age on myostatin expression is still under investigation. A cross-sectional study does not report changes between young and older men in myostatin expression in the vastus lateralis muscle, while a similar study in older women find a 56% increase in myostatin expression at the same site [9395]. Ultimately, the age-related impairment of muscle cellular regeneration has been attributed to modifications of Notch and Wnt signaling pathways. Notch receptor activation usually controls myoblast proliferation, but in aged muscle there is a decreased Notch expression. The increased Wnt signaling with aging might promote the conversion of the satellite cells from a myogenic to a fibroblastic lineage, thus inhibiting myogenicity and contributing to muscle fibrosis and impaired muscle repair [9698].

Protein unbalance

A long-term unbalance between the rate of protein synthesis and the rate of their breakdown might sustain age-related loss of muscle tissue. The muscle protein unbalance is due to nutritional, hormonal, local, systemic and environmental factors. The anorexia of aging and its underlying mechanisms contribute to muscle impoverishment by reducing total and essential amino acid intake. In addition, the decreased expression of anabolic hormones with aging does not support adequate protein synthesis, while the increased expression of endocrine and inflammatory factors usually sustain protein degradation. The ubiquitin-proteasome pathway is the most important mechanism for protein degradation in skeletal muscle cells. This system involves a series of enzymatic steps in which the proteins are targeted by an enzyme system that binds them to a polypeptide ubiquitin. The ubiquitinized proteins are then transferred to the proteasome complex and degraded into short peptides which are finally recycled as free intracellular amino acids. This pathway is promoted by inflammatory cytokines, such as TNF-α and IL-6, by hormones such as Cortisol and angiotensin, as well as by ROS [99].

Hormones

Several studies have shown that age-related decrease in anabolic hormones, i.e. GH, IGF-I, insulin and sex-steroids, and the increase in catabolic hormone, i.e. Cortisol, and angiotensin might affect skeletal muscle by causing fiber atrophy. At molecular level, anabolic hormones stimulate muscle protein synthesis through the activation of the phosphatidyl inosito13 kinase/serine-threonine kinase AKT system and the mammalian target of rapamycin and SGKI. Anabolic hormones might also inhibit muscle atrophy by phosphorylating the forkhead protein FOXO and inactivating FOXO, which reduces the expression of the E3 ligase, atrogin I, and subsequently prevents protein degradation by shrinking the expression of the ubiquitin-proteasome system [100,101].

GH and IGF-I are well-known promoters of protein synthesis in skeletal muscle fibers. GH-induced muscle growth might be mediated in endocrine manner by circulating IGF-I, but also in autocrine-paracrine manner by direct expression of IGF-I and GH receptors on target muscle. Their effects on muscle are mediated by a set of transmembrane receptors that bind insulin and IGF-I. They regulate proliferation, differentiation and fusion of skeletal muscle precursor cells by activating a complex array of cell signaling pathways which are anabolic, anticatabolic and antiapoptotic. The age-related loss of IGF-I has been linked to low protein synthesis, low muscle cell activity and motor neuron function, alteration of the pathways controlling the calcium-induced contractility of muscle fibers, impaired proliferation of muscle progenitor cells and weakened integration with the existing fibers during the muscle repair process [102104].

The epidemiological findings concerning the effects of estrogens and testosterone on age-related muscle changes are still controversial. Estrogens might have a direct effect on muscle mass since it has been shown that skeletal muscle has estrogen α-receptors (ER-α) on the cell membrane. The detrimental effects of low estrogen levels on muscle mass might be mediated by an increase of proinflammatory cytokines, such as TNF-α and IL-6. Age-related decline in testosterone levels might also impair muscle protein synthesis, but its effects on muscle might be modulated by several other factors, including genetic background, nutrition and exercise [105108].

Although insulin resistance has been associated with detrimental muscle tissue features, i.e. mass loss, fiber atrophy, intramyocellular fat mass deposition and mitochondrial dysfunctions, the role of insulin in the onset and progression of sarcopenia is still controversial [109].

Regarding catabolic hormones, Cortisol is known to stimulate degradation and to inhibit synthesis of muscle proteins [110]. Long-term exposure to high Cortisol levels has negative effect on muscle strength and mass mainly through detrimental effects on type II muscle fibers, as demonstrated by glucocorticoid-mediated atrophy [111]. In clinical setting, high levels of Cortisol have been found in sarcopenic older persons as compared to those not sarcopenic [112]; low muscle density, atrophy and weakness in patients with Cushing's syndrome as compared to those without such a condition; and in older individuals with poorer physical performance [113,114].

Other hormonal factors might modulate age-related sarcopenia. Low levels of vitamin D are associated with low muscle mass, low muscle strength and increased risk for falls. The nuclear effects of 1,250H vitamin D have been described in muscle cells and low levels of vitamin D impair muscle anabolism. The PTH might also modulate the muscle tissue functioning through an increase in intracellular calcium or an induced pro-inflammatory pathway [115].

Inflammation

Several lines of evidence point to inflammation as a chronic age-related condition associated with loss of muscle mass and strength, and weakness in the elderly. Low grade inflammation increases the expression of pro-inflammatory cytokines and higher levels of IL-6, TNF-α, IL-1β and /or IL1β have been associated with sarcopenia. Comparison of skeletal muscle biopsies from younger and older subjects showed increased expression of genes up-regulated by inflammatory factors. Age-related subclinical inflammation might promote muscle atrophy by accelerating muscle cell protein degradation and weakening muscle protein synthesis. Both increased IL-6 and TNF-α levels are linked with higher concentration of Cortisol, cause DNA fragmentation and apoptosis by stimulating NFkB to produce caspase 8. Pro-inflammatory cytokines may also stimulate MRF-1, which activates the ubiquitin-proteasome system. In older men and women, higher levels of IL-6 and C-reactive protein (CRP) are associated with a two- to threefold greater risk for losing more than 40% of grip strength over 3 years [116120]. In animal studies, the administration of IL-6 or TNF-α increases skeletal muscle breakdown, decreases the rate of protein synthesis, and reduces plasma concentrations of IGF-I. However, blood IL-6 should be differentiated from the muscle-derived form of IL-6 produced during exercise. The former is considered proinflammatory playing an intimate role with IL-1β and TNF-α in the induction of sickness behavior, the latter might have anti-inflammatory effects by inhibiting TNFα and the apoptotic pathway. In addition, evidence suggests that disease-related inflammation (congestive heart failure, renal failure, rheumatoid arthritis or cachexia secondary acquired immunodeficiency or cancer) might contribute to the debilitating muscle atrophy [121123].

Oxidative stress

Age-related deterioration of muscle function may involve damage of muscle proteins by ROS and nitrogen oxidative species (NOS) generated during oxidative metabolism. Muscle contraction implies rapid changes in oxygen flux and energy supply, thus increasing the electron leakage from the mitochondrial electron transport chain and the exposure of muscle protein to oxidative stress. Fast-twitch glycolytic fibers might be more susceptible to oxidative stress than slow-twitch aerobic fibers. These fibers produce more ROS via mitochondrial oxidative phosphorylation but have higher antioxidant capacities that prevent or attenuate oxidative damage [124], Post-translational chemical modification of proteins induced by ROS and NOS might affect their structural and functional integrity up to impair the muscle contraction [125, 126]. Furthermore, the high concentration of heme-containing protein, i.e. myoglobin, and the accumulation of ROS over time might damage cell components, including mitochondria and DNA sequences, both conditions conferring greater sensitivity to oxidative damage. Alteration of mitochondrial DNA (mtDNA) increases with age in skeletal muscle, and the frequency of abnormal mitochondrial regions is higher in muscles strongly affected by sarcopenia. The mtDNA modifications induced by ROS might prompt muscle cell apoptosis, mitochondrial structural changes and electron transport chain uncoupling until to impair cell respiration and metabolic functions [127129].

Apoptosis

That is a programmed cell death contributing to the loss of myonuclei and theoretically of the complete muscle fibers. Intrinsic and extrinsic stimuli might be responsible for the induction of apoptosis which is ultimately mediated by signals as ligands for the death receptors and calcium regulators. Intrinsic pathways to apoptosis are those initiated by ROS and activated by disturbances in intracellular calcium homeostasis, which involves caspase-12. Since accelerated apoptosis of myocytes has been associated with mtDNA mutations in the muscle tissue, it has been postulated that apoptosis can be the link between mitochondria dysfunction and loss of muscle mass. Extrinsic stimuli or ligand-induced apoptosis are mediated by the TNF-α receptor which causes the activation of initiator caspase-8 and then the executor caspase-3, -6 and -7. The role of extrinsic factors might be more relevant within aging and associated with an increased level of several caspases [130].

3. EVIDENCE FOR BONE-MUSCLE INTERACTION

The relationship between muscle and bone has been regarded as self-evident for many years, but confirmed through direct measurement of muscle and bone mass in recent decades. Appendicular skeletal muscle mass and muscle CSA positively correlate with BMD at several body sites [131137]. Handgrip strength reveals the strongest positive correlation with the forearm and upper limb BMD [138141], but a weak association with femoral [142, 143] and lumbar BMD [144]. Based on these findings a site-specific muscle-bone relationship has been postulated. Muscle area is positively associated with cortical bone area in children, young and adult persons, with a higher endosteal apposition in women while a greater periosteal expansion in men [145]. Muscle volume and estimated torque of lower leg have been suggested to explain differences in structural bone strength [146]. Except one study that shows a positive association between walking parameters and higher bone stiffness index, no further observational data support correlation between measures of physical performance and leg or lumbar spine BMD [147,148].

Exercise interventions in postmenopausal women produce a small but significant increase in the trabecular and cortical vBMD, especially among those in longer duration exercise programs (12 months) and within 10 years from menopause [149]. In men, exercise interventions positively impact hip BMD with changes almost superimposed to that caused by unsupervised 30 minute walking [150]. On the contrary, microgravity by decreasing the muscle stimuli on bone may induce substantial and significant loss of trabecular and cortical bone in the hip and somewhat smaller losses in the spine [151]. Six month bed rest, used to simulate the effects of microgravity and disuse, is associated with a reduction in bone density of tibia and trabecular density of radius, a loss in the trabecular number and increase in trabecular separation at both sites, independent of nutritional and physical exercise countermeasures [152]. Conversely, a positive association has been demonstrated between BMD of various skeletal sites and marker of physical performance, i.e. walking speed and distance, step length, one-leg-stance time [153].

Few studies investigate the coexistence of advanced bone and muscle loss. Middle-aged and elderly community-dwelling men with sarcopenia are more likely to have osteoporosis than those with normal skeletal muscle mass (Odds Ratio = 3.0; 95% CI=1.6–5.8) [154]. Hip fractured men have higher probability to be sarcopenic than women, but in both sexes sarcopenia is significantly associated with osteoporosis [155,156].

The close coupling between muscle and bone systems has been largely discussed in the context of the “bone-muscle unit” proposed within the mechanostat theory [157]. Bone adapts its morphology and strength to the long-term loads exerted by muscle contraction, as a result of physical activity and gravitational forces. Bone responds to the varying strains imposed by increases or decreases of mechanical loading conferred by muscles, with sharp losses or modeling effects triggered when strains fall below or exceed set-points. The set-points are gender-specific and might depend on the interaction with systemic factors [158].

Osteocytes are the mechanosensors of modifications of fluid flow within bone canaliculi occurring during deformation of bone microarchitecture secondary to loading forces. Osteocytes initiate the bone remodeling cycle thought the recruitment of osteoclasts to the bone surface [159]. Although the exact mechanisms by which osteocytes act as a mechanosensor is yet to be revealed, the sensing of mechanical strain leads to changes of ion channel activities, stimulation of mitogen-activated protein kinase (MAPK) and transcription of gene patterns depending on the target cells. Individual mechano-responsiveness have been shown to depend on genetics and gender, while controversial remains the role of age [160].

Emerging research points to a bidirectional signaling between muscle and bone, broadening the relationship beyond that of a purely mechanical perspective. Systemic and local non-mechanical factors may also modulate the skeletal mechano-responsiveness per se with direct effects ("help or hinder") on the mechanosensitivity threshold. Anabolic hormones influence loading related bone formation in a permissive manner by lowering the modeling set point, thus promoting bone gain, and raising the remodeling set points, reducing bone loss. Estrogen, GH and IGF-I that decline as a function of age, are critical factors for the maintaining of the mechano-sensing and -responsiveness threshold in the bone-muscle unit [161].

According to in vitro and early-stage loading-induced in vivo responses, estrogens hold a permissive role on the osteogenic effects of mechanical loading. At the cellular level, bones respond to mechanical loading by a series of molecular events that depend on the presence of functional ER-α and -β Prompted by the findings that the number of ER-α declines with aging and after menopause, postmenopausal osteoporosis perse would be attributable to the de-sensibilizzation of bones to loading stimuli and the amplified action of pro-resorption cytokines induced by estrogen-withdrawal [162, 163].

Along with in vivo animal models, GH and its downstream effector IGF-I, seems to potentiate the effect of muscle loading due to exercise, as demonstrated on periosteal bone formation at several sites (vertebrae, femoral diaphysis, neck and distal metaphysis) [164]. In older men, those with higher IGF-I circulating levels have increased femoral neck density [165]. The reduced expression of IGF-I in muscle, which remains lower in the older as compared to the younger men, might let down the mechanosensitivity of osteocytes. In addition, animal and co-colture models confirm that skeletal muscle is a local source of IGF-I and fibroblast growth factor 2 (FGF-2). Both molecules act as osteogenic-related factors by binding their receptors localized at the periosteum.

A paracrine mechanism for increasing mechanosensitivity has been also hypothesized. Since bone receives anabolic stimuli from muscle in the form of paracrine signals, then it is also possible that catabolic changes in muscle produce anti-osteogenic modifications in bone. Such a relationship has been revealed between myostatin and bone. In spite of its inhibitory effects on muscle, myostatin is considered an important myokine for bone. Myostatin deficiency or loss of myostatin function increases osteogenic differentiation of BM-derived stem cells, bone mass and bone repair [166]. Thus, conditions up-regulating myostatin secretion would cause muscle atrophy and suppress bone formation through its antiosteogenic effects.

More recently, the possibility of a relationship between bone and fat has also been acknowledged. With respect of aging, changes in body composition mainly consist of fat gain and muscle loss, which are accompanied by loss of muscle quality. Independent of BMD, muscle CSA and strength, fatty infiltration of muscle fibers increases the risk for fractures in the Health-ABC participants [167, 168]. Direct and indirect feedback loops link adipose tissue to bone, at least in part mediated by the effects of leptin. This is a cytokine-like hormone secreted by adipocytes via central and peripheral means. Centrally, leptin prevents bone mass accrual through the combined action of the sympathetic nervous system (SNS) and cocaine- and amphetamine-regulated transcript (CART) activation. In the brainstem leptin inhibits the synthesis and release of serotonin from the raphe nuclei. Brain-derived serotonin binds to HTR2C receptors of ventro-medial neurons of the hypothalamus, decreases signaling of the SNS, and thus increases bone mass accrual [169]. On one hand, leptin reduces serotonin synthesis and increases SNS signaling on the osteoblasts via β2 adrenergic receptors. The SNS activity might support bone resorption and loss through the inhibition of osteoblast proliferation and the promotion of RANKL expression. On the other hand, leptin binds to receptors on the neurons of the arcuate nuclei and increases the expression of CART gene, that decreases RANKL expression by osteoblasts and inhibits bone resorption. Whether CART affects gene expression in osteoblasts via a direct or indirect mechanism remains currently unknown [170].

Peripherally, leptin interacts with BM stromal cells increasing the expression of osteogenic genes, directing the MSC to the osteogenic instead of the adipogenic pathway and inhibiting the expression of the receptor activator of nuclear factor-κB-ligand, the major downstream cytokine controlling osteoclastogenesis. Leptin might also enhance osteoblastic differentiation and activity by inhibiting their apoptosis, stimulating de novo collagen synthesis and mineralization [171174].

Intriguing studies have linked leptin to osteoprotegerin (OPG) expression and bone derived osteocalcin (OC). Leptin might stimulate stromal cells to increase expression of OPG and ESP gene in osteoblasts. ESP gene encodes for the intracellular protein tyrosine phosphatase (OST-PTP), favoring the maturation of undercarboxylated OC. Undercarboxylated OC acts as a hormonal factor modulating the pancreatic β-cell proliferation, the secretion of insulin by β-cells and the insulin sensitivity in muscle, liver, and adipose tissue via the expression of an insulin sensitizing adipokine (the adiponectin gene), and the production of testosterone by the Leydig cells [175]. On the contrary, the insulin signaling causes a decrease in osteoprotegerin (OPG) expression and OPG/RANKL ratio, enhancing bone resorption, stimulating OC decarboxylation and inhibiting osteoblast differentiation [173,176].

However, interventional studies suggest that leptin may play a more important role in patients with leptin deficiency. Despite the fact that patients with congenital leptin deficiency have age- and gender- appropriate bone mineral content and bone mineral density, leptin treatment increases their skeletal maturation [177]. In women with hypothalamic amenorrhea, a significant increase in bone-formation markers after leptin administration has been described [178]. However, whether the increase in bone-formation markers is a direct effect of leptin or mediated by restoration of estradiol and IGF-I levels remains unknown. More research is needed to fully elucidate the role of leptin in central regulation of bone metabolism, since it is unclear if the data derived from rodent studies will apply to humans.

A common multigenetic control on the muscle-bone system may also contribute to the development and preservation of lean mass, BMD and muscle-bone strength. It is becoming apparent that there are several genes involved in the genetic control of maturation, development, and decline of musculoskeletal systems [179181]. The heritability of lean mass, measured with DXA, has been estimated to vary between 56% and 84% [182] as well as those of bone strength, measured with section modulus of femoral neck, has been reported to be 40 to 55% [183]. However, whether and how these genetic traits interact in order to maintain or promote muscle and bone mass and quality over the lifespan is unknown.

4. OSTEOPOROSIS AND SARCOPENIA: FROM DEFINITION TO THE IMPACT ON MOBTLITY LIMITATION

4a. Osteoporosis, Fragility Fractures and Disability

Definition

Osteoporosis is a skeletal disorder in which the reduction in bone strength predisposes to an increased risk for fractures. It is often referred to as a silent disease, as many individuals do not realize they are affected by it until a fracture occurs [184]. According to the World Health Organization (WHO) criteria, the diagnosis of osteoporosis is officially made based exclusively on BMD that lies 2.5 standard deviations (SD) or more below the average value for young healthy women (a T-score of <-2.5 SD). Although the BMD is considered a good predictor of absolute risk for fracture (absolute risk for hip fracture and for any fracture increase 2.6-fold and 1.6-fold, respectively, per SD decrease in BMD), with aging there is a progressive loss of the power of BMD on predicting hip fracture risk [185,186].

Despite the T-score is still considered the key characteristic diagnostically and it provides an intervention threshold, it has been clear for long time that the risk for fracture increases with age at any given T-score. At the same threshold of 2.5 SD, the risk for fracture rises dramatically from 50 to 80 years of age and most fragility fractures occur in individuals with T-scores greater than >2.5 SD. To date, the combination of clinical factors, such as age, previous fractures, chronic diseases and drug treatment, with bone density estimation seems to better identify subject with high risk of fractures [187,188].

Epidemiology

Osteoporosis affects more than 75 million people in the United States, Europe and Japan and it causes more than 8.9 million fractures annually worldwide. All osteoporotic fractures are more likely to occur in women, mainly due to their lower BMD, different bone geometry, higher life expectancy and an increased risk for falling compared with men. Men lose about half as much bone with aging as women, and suffer one-third the number of fragility fractures as women [189,190].

Disability associated with osteoporosis

Fragility fractures, usually occurring after a low energy trauma at the distal radius, proximal femur, vertebral body or proximal humerus, mainly depend on a compromised bone strength even in the absence of low BMD. Indeed, bone fragility is a function of the “quantity” of bone, estimated by measuring BMD, and the “quality” of bone, a complex and multidimensional set of bone properties including microarchitecture, turnover, mineralization, and damage accumulation [191193].

Forearm fractures tend to occur at earlier ages than hip and vertebral ones with a peak incidence in women between 40 and 65 years of age. A prior wrist fracture increases the risk of a future wrist fracture about threefold and doubles the risk of any osteoporotic fracture [194]. In developed countries, one-fifth of Colle’s fracture results in hospitalization and only 50% of patients report a good functional outcome after 6 months [195].

Vertebral fractures cause pain and limitation of the spinal movement, affecting considerably the overall quality of life. Spinal mobility is impaired even in the absence of significant pain (one-third of the vertebral fractures are asymptomatic), and often such undiagnosed vertebral fractures are associated with disability. Dorso-lumbar fractures have the worst impact on spinal mobility. Pain and disability become worse with each new fracture, as does mortality. The probability to suffer a new vertebral fracture increases fivefold during the first year post-fracture compared with the non-fractured patients. One-fifth of patients with vertebral fracture requires hospitalization, and some will require subsequent long-term care [196]. Co-morbidity commonly associated with vertebral fractures, particularly kyphosis, obstructive and restrictive lung disease, bed rest, may contribute to the loss of quality of life and increased mortality at older age [197].

Hip fracture often causes catastrophic disability. Although in developed countries, most hip fractured patients undergo surgical repair of the fracture or replacement of the joint, 20–25% of them die within 1-year. About half of the patients lose their prior level of physical function and many lose their independence and require long-term care [198]. Only half of the survivors will walk again and often not at the same level as prior to the fracture. Assuming no pain prior to a hip fracture, 47% of patients reported bone pain one or more years post-fracture with approximately 23% reported mild pain, 24% moderate pain and 2% severe pain [199]. About 30% of women and 22% of men with a prior history of fracture experience a new fracture during the next 5 years [200]. An official report from the Northern Sydney Area [201] showed that after a 12-month follow-up of community-dwelling patients suffering a hip fracture, 76% were unable to walk as well as before their fracture, and 22% required a new nursing home admission. These findings are similar to those found in a recent meta-analysis on the long-term disability after hip fractures [199], where 20% of subjects with a fracture were no longer able to shop independently as a result of the fracture and 42% of them had not returned to their pre-fracture mobility levels after 1 year. After an osteoporotic fracture rehabilitation is lengthy and many individuals never regain their pre-fracture level of mobility, which may have a significant impact on lifestyle, well-being and quality of life [202].

Therefore, osteoporosis and fragility fractures have a great health and social impact causing for an individual several clinical and health-related consequences, including short-term pain and mobility limitation, increased risk of fracture, chronic disability, the need for long-term care and premature death [203205]. In the Americas and Europe osteoporotic fractures account for 2.8 million disability-adjusted life years (DALYs) annually and approximately 1% of the DALYs attributable to non-communicable diseases, somewhat more than accounted for by hypertension and rheumatoid arthritis [206]. Older persons with high risk of fractures deserve more attention as an opportunity for prevention of future disability and for reducing health and social impact [207, 208]. Unfortunately, they are not recognized consistently by health care professionals and currently, prevention strategies remain suboptimal [209, 210].

4b. Sarcopenia, Falls and Disability

Definition

Sarcopenia is the term originally coined to describe progressive age-related loss in muscle mass. According to updated definition sarcopenia is a “syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk for adverse outcome, physical disability, poor quality of life and death” [211213]. Criteria for the clinical diagnosis of sarcopenia, such as the presence of low muscle mass accompanied by low muscle strength and/or low physical performance, have been defined [214]. Specifically, Evans suggests that the diagnosis of sarcopenia should be considered in all older patients who are bedridden, cannot independently rise from a chair, or who have a measured gait speed <1.0 m/s. Patients who meet these criteria should further undergo body composition assessment using dual-energy X-ray absorptiometry with sarcopenia being defined as an appendicular lean/fat mass 2 SD less than that of young adult [216]. The definition of sarcopenia should include the accompanying deterioration of muscle function or muscle weakness. However, some authors suggest that the muscle weakness is inevitable, but not proportional consequence of muscle loss, and therefore, this term should not be used interchangeably with sarcopenia [77]. Practically, this is supported by the evidence that muscle strength does not correlate directly with muscle mass, and the relationship between strength and mass may not be linear [7, 215]. Some authors have argued that with regards to terminology, dynapenia would be a better acronym to describe age-related decline in muscle strength and function [216]. This, however, has not yet been uniformly incorporated into clinical use.

Epidemiology

Within the existing literature, sarcopenia is a highly prevalent condition in older people, with 45% of the older U.S. population having a moderate degree of sarcopenia and 10% have severe sarcopenia. The prevalence of sarcopenia increases considerably with age ranging from 5% to 13% in 60 to 70 years, to 11% to 50% for the population aged 80 years and older [217, 218]. Sarcopenia seems to be more prevalent in men (68%) as compared to women (21%) as demonstrated among Italian NH residents [219]. Estimates from the WHO suggest that there are 600 million people aged 60 years or older in the year 2000 and that the number will increase to 1.2 billion by the year 2025. Conservative estimates based on the prevalence of sarcopenia and the WHO population counts suggest that sarcopenia affects more than 50 million people today and that it will affect more than 200 million people over the next 40 years [220].

Disability associated with sarcopenia

In older persons, sarcopenia is related to falls and physical disability leading to reduced quality of life [217], to increased risk for nursing home placement [221], home healthcare [214], hospitalization and overall healthcare expenditures [222, 223]. Several cross-sectional and longitudinal studies have shown that sarcopenia explains, at least in part, the high rate of functional impairment, that is a limitation in mobility performance, and physical disability, defined as difficulty or inability in performing activities of daily living, in older persons [224]. Using the definition based on height-adjusted appendicular muscle mass of 2 or more SD below the mean of young adults, sarcopenia has been associated with having difficulty walking in older men and increased risk for fracture in older women [225, 226]. The likelihood of having physical disability was estimated approximately 4 times greater (OR 3.66 IC95% 1.42–10.02 in men and OR 4.08 IC95% 1.52–11.31 in women) in sarcopenic older men and women than in older persons with a normal muscle mass participating in the New Mexico Elder Health Survey [227]. In the Health Aging and Body Composition study, older adults in the lowest skeletal muscle mass quintile (adjusted for height and fat mass) are 80% to 90% more likely to have mobility impairment than older adults in the highest quintile [228]. In the US National Health and Nutrition Examination Survey, the likelihood of functional impairment and physical disability is approximately twofold greater in older men and threefold greater in older women with severe sarcopenia than in older adults with a normal muscle mass. In the same population the relationship between muscle index and physical disability does not appear linear and the odds ratios for physical disability increase in a graded fashion when moving from the low risk to the high risk categories. Based on these findings, approximately 10% of the older American population is considerably more likely to have physical disability and 35% of them is somewhat more likely to have physical disability due to sarcopenia [229]. However, because of the lack of temporality, these early cross-sectional studies cannot infer causation about the relationship between sarcopenia and physical function. Longitudinal findings from prospective cohort studies have examined the influence of sarcopenia, as determined by muscle mass, on the development of functional limitations or disability. Among the participants in the Health, Aging and Body Composition Study, it has been showed that muscle size in the mild-thigh is a weak to modest predictor of a loss in physical function over a 2-to 3-year follow-up [230], while the risk of developing mobility limitations over 2.5 years was found 90% higher in men and 68% higher in women within the lowest muscle size than those in the highest muscle size quintile [12]. In addition, severe sarcopenia is a modest risk factor for the development of physical disability in older women, but not in older men over 8 years of follow-up [227]. Because the influence of sarcopenia on the development of disability appears to be weaker than what was suggested from cross-sectional observations, it implies that the nature of the relationship between sarcopenia and disability is bidirectional. That is, sarcopenia leads to disability, and disability in turn leads to sarcopenia. This pattern of relationship is biologically plausible. Physical disability would lead to a reduced physical activity level, a reduced physical activity level would result in decreased anabolic stimuli to skeletal muscle, and the decreased anabolic stimuli to skeletal muscle would cause significant muscle loss over time.

An additional pathway linking sarcopenia to physical disability may include falls and fear of falling. The evidence that sarcopenia is a risk factor for falls relies on small and heterogeneous studies in which data concerning falls are collected retrospectively. Both lower and upper extremity muscle weakness is a risk factor for falls, with odd ratios consistently higher for institutionalized than community-dwelling older adults [231]. Among men (mean age 74 years) those with sarcopenia have higher risk for falling (OR 2.58 CI95% 1.42–4.73) [230] as well as men aged 50–85 years without sarcopenia are less likely to report a fall in the previous year [232]. Given the increasing aging of the population, the high prevalence of sarcopenia and disability due to sarcopenia impose a significant, although modifiable, economic burden on healthcare services in the majority of industrialized nations [233]. In 2000 it was estimated that the healthcare costs in the United States associated with sarcopenia were $18.5 US billion, which were about 1.5% of total healthcare expenditure [234]. The great health and socio-economic burden of sarcopenia and its consequences clearly makes the condition a priority among the interventions of the health care systems.

5. INTERVENTION STRATEGIES TO COUNTERACT DISABILITY ASSOCIATED WITH SARCOOSTEOPOROSIS

The prevention of mobility limitation and disability associated with the progression of sarcopenia and osteoporosis is mainly based on non-pharmacological interventions, that include nutrition and physical activity, and calcium plus vitamin D supplementation. To date, pharmacological agents are available to counteract the progression of osteoporosis and the onset of fragility fractures, but still needed to be developed and tested for the prevention of sarcopenia and its consequences in humans.

5a. Non-pharmacological interventions

Nutrition

The contribution of nutritional deficiencies and anorexia of aging to the pathogenesis of osteoporosis [235] and sarcopenia has long been recognized. However, the effects of adequate nutrition has not been studied extensively and much of the research in this area is relatively new and minimally based on large intervention trials. The nutrients that have been most consistently linked to sarcopenia and osteoporosis in older adults are vitamin D, proteins, and antioxidants, including carotenoids, selenium, vitamins E and C [236].

Vitamin D

A significant proportion of older population is vitamin D deficient (< 30 ng/ml) owing to low dietary intake, reduced sunlight exposure, and impaired hydroxylation in the liver and kidneys [237]. Vitamin D deficiency is associated with bone loss due to several mechanisms, including reduced calcium absorption, secondary hyperparathyroidism, reduced muscle mechanical stimuli and complex genomic and nongenomic pathways, currently less well understood [238240]. Vitamin D supplementation may reduce bone loss by reversing secondary hyperparathyroidism and may maintain muscle strength, muscle function, and balance by enhancing at genomic level the transcription of a range of proteins, including those involved in calcium metabolism. The role of vitamin D and the extent to which it has direct effects on normal muscle strength and physical function remains controversial [241244]. Much of the epidemiological literature is consistent with the possibility that there are direct effects of vitamin D on muscle strength. Systematic review of vitamin D supplementation concludes that it can be advised in older people with low vitamin D levels to prevent sarcopenia and falls. A meta-analysis confirmed that vitamin D dietary supplementation (700–1000 IU per day) may increase muscle strength and performance and reduce the risk of falling by 19% in community-living elderly and nursing home residents with low vitamin D level [245, 246].

Supplementation with vitamin D and calcium decreases bone loss in adult and older persons [247], increases BMD at several body sites [248] and reduces the risk for non-vertebral fractures [249]. A meta-analysis of 17 trials of calcium and calcium in combination with vitamin D (52,625 participants, 46,108 receiving the combination) indicates a 12% reduction in fractures of all types (RR 0.88, 95% CI 0.83 to 0.95) [250], while a meta-analysis from Cochrane collaboration (eight trials involving 46,658 participants), confirms that the combination of vitamin D with calcium significantly reduces hip fractures (RR 0.84, 95% CI 0.73 to 0.96), particularly among older persons living in institutional care [251]. Similarly, a meta-analysis examining 11 studies including 52,915 patients shows that oral vitamin D with - but not without - calcium supplementation reduces fracture risk in adults [252]. The efficacy of supplementation with vitamin D and calcium increases with the degree of vitamin D insufficiency, with age (effect was also greater in people aged > 70 years compared with those aged 50 to 70 years, and in those living in care institutions compared with those living in the community), with a better compliance (rates > 80%). However, the protective effects of vitamin D have not been showed constantly, and in postmenopausal women with adequate vitamin D levels, calcium supplementation may be as effective as vitamin D [253,254].

Protein

Dietary proteins are considered a key nutrient at older age providing amino acids for the synthesis of muscle protein. Absorbed essential amino acids strongly stimulate muscle protein synthesis and inhibit protein breakdown, resulting in a positive net protein balance in both the young and older persons [255257]. Aging does not inevitably reduce the anabolic response to a high-quality protein meal, which occurs in the presence of low protein and carbohydrate intake. The unbalance between protein and carbohydrate intake may blunt the dose response relationship between protein synthesis and leucine plasma disposal, possibly due to the effects of insulin resistance [258261].

The majority of evidence regarding the protective effects of protein to prevent osteoporosis and sarcopenia are from observational studies. Small intervention trials have been conducted in older persons to investigate the effect of protein supplementation on muscle metabolism and sarcopenia, but no intervention trial has investigated the protective effects on bone health. A greater loss of lean mass over 3 years was found among older community-dwelling men and women who had low energy-adjusted protein intake at baseline. The differences were substantial, such that the persons with protein intakes in the top fifth of the distribution lost 40% less lean mass over the follow-up period when compared with those in bottom fifth. Protein and amino acid supplementation may have the potential to slow sarcopenic muscle loss. However, whilst some trials show that amino acid supplementation may increase lean mass and improve physical function, other trials have not been successful [262265]. To date, the daily intake of protein to prevent sarcopenia is equal to 1.2–1.5 g/kg, though the current recommended daily intake for adults is 0.8 g/kg [266]. Older adults should be encouraged to consume a diet higher in lean meat rather than vegetable-based sources or consume essential amino acid supplements particularly if they are engaging in resistance training [267]. There is a general agreement that amino acid supplements without adequate leucine content do not stimulate protein synthesis [268, 269, 264]. In addition, it is more important to ingest a sufficient amount of high-quality protein (25–30 g) with each meal rather than one large bolus, because greater than 30 g in a single meal may not further stimulate muscle protein synthesis [270]. Ultimately, interventions combining protein or amino acid supplementation with exercise training may be potentially more advantageous on skeletal muscle and physical function. The consumption of a high protein meal has been shown to increase muscle protein synthesis in older adults by >50%, combining a high protein meal with resistance exercise increases synthesis more than 100% [271]. The long-term effects of combined exercise training and high protein intakes are not clear [267].

Similarly, the role of protein intake on the maintenance of bone health and the prevention of osteoporosis and fractures remains controversial [272]. Protein might play a role in the maintenance of BMD through different mechanisms, e.g. by increasing IGF-I, calcium absorption, muscle strength and mass, which all could benefit the skeleton [273]. In a prospective study carried out on more than 40,000 women in Iowa, higher protein intake was associated with a reduced risk of hip fracture, independent of calcium and vitamin D. The association was particularly evident with protein of animal rather than vegetal origin, and the relative risk for hip fracture seemed to decrease parallel to the intake of animal protein [274]. Contradictory results have also been observed. A slightly higher risk for forearm fractures was observed in women consuming more than 95 g per day protein as compared with those consuming less 68 g per day, whereas no association was found with hip fracture [275]. Data from the 1999 to 2002 National Health and Nutrition Examination Survey did not show any protection against fractures in postmenopausal women with adequate total calcium intake in presence of inadequate dietary protein intake, suggesting that an optimal balance between calcium and protein intake is required [275]. Positive correlations were found between BMD and protein intake in a longitudinal research within the Framingham study [276], in a cohort of older men and women receiving calcium and vitamin D supplements [277], in older women consuming less than 66 g protein per day as compared to those eating more than 87 g per day [278, 279]. Conversely, a high diet ratio between animal over vegetable proteins induced a higher rate of bone loss at the femoral neck and an increased risk for hip fractures in older women [280]. It has been hypothesized that excessive protein intake (particularly animal) would create a fixed metabolic acid load due to the high sulfur amino acid content. If the kidneys and lungs are not able to completely handle this diet-induced acid load, a source of additional buffer would be necessary. The large carbonate reservoir of the skeleton would be called upon to provide this buffer, and calcium would consequently be excreted with the carbonate. The clinical consequences would be an increased calciuria potentially favoring bone loss and hip fracture [281].

Antioxidants

Whether high antioxidant intake and status are beneficial in promoting better physical performance, muscular and bone strength is still controversial. Antioxidant intake and circulating levels as well as markers of oxidative damage have been variously correlated with sarcopenia [282], bone remodeling processes, fractures and physical function in older adults [283285]. Among clinical trials, supplementation with antioxidant lycopene seems to reduce oxidative stress and bone resorption [286]; supplementation of ascorbic acid together with alpha-tocopherol may be useful in preventing or aiding in the treatment of age-related osteoporosis [287]; 6-month daily antioxidant supplements (600 mg vitamin E and 1,000 mg vitamin C daily) offered some protection against bone loss in the lumbar spine BMD similar in the extent as resistance exercise, although combining both interventions does not seem to produce synergic effects [288].

Even more controversial are the studies concerning the use of antioxidant supplementation for the prevention of sarcopenia. Studies that evaluated oxidative-stress protection showed that carotenoids or carotenoids-rich foods are protective against decline in muscle strength and walking disability among older community-dwelling adults [288]. Other antioxidants, such as α-tocopherol, ascorbic acid, selenium and polyphenols have been studied in older subjects. However, foods may be a favored source of antioxidants for their content of multiple antioxidant substances, vitamins, minerals and fibers, and more studies are needed before older persons should be advised to take antioxidant supplementation for the prevention of sarcopenia and osteoporosis [289].

Physical exercise

Inactivity causes loss of muscle mass and strength at all ages. Older adults who are less physically active are more likely to develop sarcopenia, osteoporosis and to increase the risk for fractures [15, 290294]. Exercise has been reported as one of the best non-pharmacological ways to improve muscle and bone mass throughout life, and to prevent and treat sarcopenia and osteoporosis. However, not all exercise regimens have the same positive effects. Exercise interventions such as resistance training are used in attempt to restore muscle force. Strength training in sedentary older and younger persons improves metabolic capacities, increases glycogen storage, and enhances oxidative enzyme activity. Aerobic exercise (i.e. swimming, running, walking) involving high-repetition, low-intensity muscle contractions leads to minimal strength gain in comparison to the low-repetition, high-intensity stimulus of resistance training in which strengthening and endurance activities are included. Aerobic exercise may increase muscle area, without causing hypertrophy, and may have muscle quality improving effects, even among the frail older population [295, 296]. Aerobic exercise may increase the mitochondrial volume and enzyme activity, decrease the body fat infiltration of muscle tissue, and stimulate protein synthesis and satellite cell activation [297, 298]. However, it is not clear defined the amount of training, whether aerobic or resistance type in nature, may need intensity more than typical for leisure type of physical activity in order to have significant effects [299, 300].

Data in older men and women suggest a positive association between current exercise and hip BMD, but the effects on fracture are not clear since they are not reported as an endpoint. Strength exercise seems to be a powerful stimulus to improve and maintain bone mass during the ageing process. Among regular exercisers, those who reported strenuous or moderate exercise had higher BMD at the hip than did those who reported mild or less exercise. Similar associations were seen for lifelong regular exercisers and hip BMD. Furthermore, high-intensity strength training effectively maintains femoral neck BMD as well as improves muscle mass, strength, and balance in postmenopausal women compared to nonexercising controls. Then, resistance training would be useful to maintain BMD and to reduce the risk for falls in older adults [241, 301303].

Multi-component exercise programs of strength, aerobic, high impact and/or weight-bearing training alone or in combination with nutritional or pharmacological agents, may help to increase or at least prevent decline in bone mass with ageing, especially in postmenopausal women [304, 305]. In a randomized study of women at least 10 years past menopause, the group receiving calcium supplementation plus exercise had less bone loss at the hip than did those assigned to calcium alone. The feasibility, sustainability, and safety of power resistance training in older adults and the influence of nutritional supplementation with power training need to be confirmed by larger longitudinal trials [269]. Of note, walking that provides a modest increase in the loads on the skeleton above the gravity has proved to be less effective in osteoporosis prevention [306]. Weight-bearing exercise, such as walking, can be recommended for older adults who should be encouraged to start slowly, but they should gradually increase the time walked each day.

From the clinical perspective, an important facet of the effects of exercise on muscle and bone tissue is that prevention of sarcopenia and osteoporosis with exercise may not have sufficient power to occur at short period of time, especially among the elderly [307, 311]. Consequently, it is widely accepted that prevention of both conditions should be carried out throughout the entire lifespan.

From a health-care prospective, some issues arise regarding the implementation of exercise training into the community or at home that often may be the only option for frail older people.

5b. Pharmacological interventions

A variety of drugs of proved clinical efficacy are available in the field of osteoporosis and fracture prevention. The most commonly used anti-fracture drugs are those slowing bone resorption, i.e. bisphosphonates (BPs), selective estrogen receptor modulators (SERMs), denosumab as anti-RANKL monoclonal antibody, and those stimulating bone formation, i.e. PTH and teriparatide, while strontium ranelate appears to act through both mechanisms. Despite several and large clinical trials have been conducted, the anti-fracture efficacy of these treatments in older population (>75 years old) mainly relies on subgroup or pooled analysis [308311].

Conversely, several pharmacologic agents have been proposed to prevent or counteract sarcopenia, including recombinant anabolic hormones, angiotensin II converting enzyme inhibitors (ACEIs) and anti-myostatin agents, but their use is still far from clinical practice.

Anti-osteoporotic drugs

Several randomized clinical trials and metanalysis have been conducted to evaluate the antifracture effects at several bone sites of the available anti-osteoporotic drugs [312320]. Although few data are available in older groups [321], there is acceptable evidence to recommend the BPs, strontium ranelate, or teriparatide for vertebral fracture relative risk reduction (RRR) in persons aged > 75 years [311, 322]. A significant RRR of vertebral fracture at 1 year has been demonstrated for risedronate (RRR 81%; p<0.001), teriparatide (RRR 65%; p<0.05) and strontium ranelate (RRR 59%; p=0.002), and at 3 years for risedronate (RRR 44%; p=0.003), alendronate (RRR 38%; p<0.05), strontium ranelate (RR 32%; p=0.013) and denosumab in high risk fracture women (16.6% placebo vs. 7.5% denosumab; p< 0.001) [322].

Concerning the non-vertebral fractures, there is evidence for protective effects of strontium ranelate after 1 and 3 years of treatment (RRR 41%; p=0.027 and RRR 31%; p=0.011) [311], for denosumab (HR 0.80; p=0.01) [321] and zoledronic acid (HR 0.73, p=0.002) after three years with efficacy almost superimposed to those of younger persons [325]. Risedronate demonstrated to reduce non-vertebral fracture only in a combined analysis of subjects participating in the HIP study (70–79 years and ≥80 years groups) [323].

The studies that specifically investigated hip fracture prevention as the primary outcome — the HIP study [326], the Clodronate Study [322, 324] and the FREEDOM Study (Denosumab: post-hoc analysis and 2-year extension) [321, 323, 325], suggest a weak efficacy after 3 years of treatment. Hip fracture reduction was demonstrated for risedronate in a subgroup analysis including women with osteoporosis (those 70 to 79 years old), where the incidence of hip fracture among those assigned to risedronate was 1.9%, as compared with 3.2% among those assigned to placebo (RRR 0.6; p=0.009). Clodronate showed hip fracture reduction in unselected community-dwelling older women at 1 and 3 years. Denosumab significantly reduced the risk of hip fractures in a subgroup analysis among those older than 75 years (2.3% placebo vs. 0.9% denosumab; p<0.01) or with a baseline femoral neck bone mineral density T-score of -2.5 SD or less (2.8% placebo vs. 1.4% denosumab; p= 0.02) [322, 323]. Strontium ranelate showed antifracture hip efficacy, as a secondary outcome, in the subgroup analysis of women aged ≥80 years [326] and those aged >74 years with more severe osteoporosis of the femoral neck participating in the TRO-POS study [327]. In the pooled analysis from the HORIZON study, the incidence of hip fracture was not affected by zoledronic acid, whereas a reduced incidence of all fracture types appeared in the subgroup of those younger than 75 years [325]. There is no evidence on hip fracture prevention for teriparatide and clodronate at 3 years in the older groups [311, 328, 313, 314]. Teriparatide demonstrated a reduction of low back pain and improvement in quality of life which lasted for at least 18 months after its discontinuation [329]. A critical point in the choice of treatment for osteoporosis in elderly patients is the time to onset of the efficacy. This evaluation is necessary since we know that after a vertebral fracture the risk of subsequent fracture increases fivefold in the first year [200] and these patients who sustain a first fragility fracture are at an increased risk of subsequent fractures in all sites [330, 331]. Strontium ranelate studies reported reduced morphometric and clinical vertebral fractures within 12 months in postmenopausal osteoporotic women [319, 330]. In those aged 80 and over on strontium ranelate, reduction in morphometric vertebral, non-vertebral fractures and any clinical fractures were also observed within 12 months [332]. The earliest efficacy strontium ranelate on hip fracture prevention was observed at 36 months in those aged 74 years and older with BMD T-score less than -3.0 SD [330]. A significant hip fracture reduction was found after 12 months of denosumab treatment in subjects aged ≥75 years with a baseline femoral neck T-score of -2.5 SD or less [322].

In the absence of direct treatment comparison for anti-osteoporotic drugs, some authors proposed an indirect treatment comparison (ITC) approach assessing the relative efficacy in reducing the rates of fractures in a sample of 59,209 post-menopausal women. Using a Bayesian analysis that looked at seven studies including four drugs, specifically zoledronate (1 study), alendronate (3 studies), ibandronate (1 study) and risedronate (2 studies), the ITC approach indicated that zoledronate had the highest efficacy in preventing vertebral and hip fractures, while risedronate had the highest efficacy in reducing non-vertebral non-hip fractures [333, 334]. The last updated ITC analysis in osteoporosis medications, concluded that based on the combination of effect size and probability of being most efficacious, teriparatide, zoledronate and denosumab are consistently ranked highest for reducing non-vertebral and vertebral fractures [335].

Potential anti-sarcopenic agents: hormones

Although testosterone levels positively correlate with muscle mass and strength [336], protein synthesis, the number of satellite cells [337], testosterone replacement is not recommended for the prevention or treatment of sarcopenia because of side effects, i.e. fluid retention, gynecomastia, polycythemia, sleep apnea [338], increased risk of prostate cancer, and low benefits to physical performance. Newer agents, specific androgen receptor modulators (SARMs), may hold more promise for anabolic effects on skeletal muscle without the side effects, but they are in early stages of clinical investigations [339].

Reduced levels of circulating estradiol seem to correlate with impaired muscle performance and sarcopenia in older women [340]. However, the effect of hormone replacement therapy (HRT) in women is controversial. HRT might decrease the loss of muscle mass and improve physical functioning [341], but it is also implicated with breast cancer [342] and it is not recommended in older adults. Similarly, tibolone (a synthetic steroid with estrogenic, androgenic, and progestogenic properties) is not recommended until further research is conducted to determine the long-term safety in older adults [269].

The effects of recombinant GH supplementation alone or in combination with sex steroids or exercise [343345] to counter the effects of sarcopenia in older people are weak and still under debate [346]. Some studies demonstrated an increase in muscle mass, but not in muscle strength, others have shown an increase in both muscle mass and strength after administration of GH supplementation [347, 348]. In addition, the combination of GH replacement and exercise training does not improve the effects brought by exercise alone [349]. To date, the use of rGH in older non-hypopituitary adults is not supported as it did not show efficacy, while have reported a high incidence of side effects, i.e. fluid retention, gynecomastia, orthostatic hypotension, carpel tunnel syndrome and increased risk of cancer [350].

Potential anti-sarcopenic agents: anti-myostatin and ace-inibitor

It has been hypothesized that molecules blocking my-ostatin pathway increase muscle mass and play a pivotal role in preventing sarcopenia at older age. Mutations of the myostatin gene was found to correlate with exaggerated muscle hypertrophy [351], while over expression of myostatin to induce extensive muscle loss. However, even if myostatin deficiency increases muscle mass in animal models, the structure and function of muscle tendons are impaired making them smaller, stiffer and brittle [352, 353]. One study tested the use of recombinant antibody to myostatin, i.e. MYO-29, in patients with muscular dystrophy. Initial results have shown a good safety and tolerability profile for the administration of myostatin inhibitors [354] but further studies are needed. Recently, the administration of a soluble activin type 2B receptor demonstrates to reduce the availability of myostatin by binding it and to increase muscle weight more than myostatin inhibitors [355].

With respect to ACEIs, that are drugs widely used in treating hypertension and heart failure, the results of three cohort studies report favourable changes in body composition and physical function in older adults. A randomized controlled trial of ACEIs showed higher exercise capacity and fewer falls in older participants with existing impairment of activities of daily living [356]. Conversely, a study comparing the effects of nifedipine with ACEIs in older people found no difference between treatments in muscle strength, walking distance or functional performance [357]. It is possible that frailer subjects have a tendency to more cardiovascular problems and benefit more. Then, the mechanism for ACEIs action on skeletal muscle are yet to be elucidated. However, they may involve an improved cardiac output and blood flow to muscle, a reduced proinflammatory status, an improved endothelial function and muscle glucose uptake, and a positive modulation of the IGF-I system.

CONCLUSION

For many years the relationship between muscle and bone has been regarded as self-evident among the age-related changes in body composition. Currently understanding the bone-muscle changes associatd with aging and the underlying pathophysiological processes is a priority, because of the growing of the old population and the health- and economic burden associated to the development of sarcopenia, osteoporosis and their consequences. In the clinical practice a consensus has been reached about the threshold of bone loss at that it should be considered a disease, however older persons at high risk for fractures are still not recognized consistently or systematically by health care professionals, and prevention strategies remain suboptimal despite evidence for their efficacy. In addition, osteoporosis often co-exists with sarcopenia in older persons. As regard of sarcopenia, we are still in need of specific population clinical cut scores to distinguish it as a clinical disease, instead of a condition normal for chronological ageing, and of clear definitions of its clinical outcomes. In this context, we believe that future research should focus on the simultaneous assessment of both osteoporosis and sarcopenia, for instance using the DXA which is already an essential part of the diagnosis of osteoporosis, and should concentrate on exploring and making a consensus about the clinically relevant dimensions and outcomes resulting from their interactions. Whether not recognized and treated on time, both osteoporosis and sarcopenia lead to inevitable and irreversible deterioration of the structure and function of musculoskeletal system, that impair functionality making older individuals more susceptible to falls, fractures and permanent severe disability.

Several morphological and functional aspects of bone-muscle aging are known. However, the triggers and many local or systemic factors accelerating bone-muscle loss leading to sarco-osteoporosis are still to be defined. As regard the muscle-bone interaction, for a long time it has been supported that both systems interact each other from a mechanical point of view, with bones that adapt their morphology and strength to the long-term loads exerted by muscle contraction as a result of opposing gravity and physical activities. Then, systemic and local non-mechanical factors, including hormones, cytokines and other trophic agents, have been discovered to modulate the mechanostat effect of muscle on bone strength.

Emerging evidence points to a bidirectional crosstalk between osteocytes and muscle cells mediated by biochemical and common molecular signaling. Adipokines may impact bone-muscle interaction via central and peripheral pathways, as well as other factors, including neuroendocrine age-related modifications, lifestyle changes, nutritional habits and candidate genes.

Recognizing bone-muscle changes with aging and highlighting the underlying pathophysiological mechanisms help to develop agents or interventions to blunt these processes and to design intervention trials that target one or more of such underlying mechanisms. In this scenario, older population is the most significant target group for prevention and treatment of health- and disability-related consequences of sarcopenia and osteoporosis, although it is widely accepted that their primary prevention should be carried out with multifactorial interventions throughout the entire lifespan.

To date, we are far from the development and validation of pharmacological agents to eventually counteract or treat sarcopenia. With exception of ACEIs, as a pharmaceutical intervention that can improve muscle exercise capacity in functionally impaired older people, the most compelling evidence to combat sarcopenia is resistance training either alone or in combination with nutritional supplements. As some older people are unable or unwilling to embark on exercise training programs, alternative treatment options need to be developed. Several pharmacologic approaches are under investigation and most of them hold promise for a greater understanding of the mechanisms to fight or reverse sarcopenia.

ACKNOWLEDGEMENTS

Declared none.

Footnotes

CONFLICT OF INTEREST

The authors confirm that this article content has no conflicts of interest.

REFERENCES

  • 1.Manolagas SC, Parfitt AM. What old means to bone. Trends Endocrinol Metab. 2010;21:369–374. doi: 10.1016/j.tem.2010.01.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Bonewald LF. The Amazing Osteocyte. J Bone Miner Res. 2010;26:229–238. doi: 10.1002/jbmr.320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Parfitt AM. Skeletal heterogeneity and the purposes of bone remodeling: implications for the understanding of osteoporosis. In: Marcus R, et al., editors. Osteoporosis. Elsevier; 2007. pp. 79–89. [Google Scholar]
  • 4.Matsuo K. Cross-talk among bone cells. Curr Opin Nephrol Hypertens. 2009;18:292–297. doi: 10.1097/MNH.0b013e32832b75f1. [DOI] [PubMed] [Google Scholar]
  • 5.Rochefort GY, Pallu S, Benhamou CL. Osteocyte: the unrecognized side of bone tissue. Osteoporos Int. 2010;21:1457–1469. doi: 10.1007/s00198-010-1194-5. [DOI] [PubMed] [Google Scholar]
  • 6.Gordon Linch. Sarcopenia- age related muscle wasting and weakness. 1st edition. Springer; [Google Scholar]
  • 7.Doherty TJ. Invited review: Aging and sarcopenia. J Appl Physiol. 2003;95:1717–1727. doi: 10.1152/japplphysiol.00347.2003. [DOI] [PubMed] [Google Scholar]
  • 8.Delmonico MJ, Harris TB, Visser M, Park SW, Conroy MB, Velasquez-Mieyer P, et al. Longitudinal study of muscle strength, quality, and adipose tissue infiltration. Am J Clin Nutr. 2009;90:1579–1585. doi: 10.3945/ajcn.2009.28047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Keaveny TM, Kopperdahl DL, Melton LJ, 3rd, et al. Age-dependence of femoral strength in white women and men. J Bone Miner Res. 2010;25:994–1001. doi: 10.1359/jbmr.091033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Russo CR, Lauretani F, Bandinelli S, et al. Aging bone in men and women: Beyond changes in bone mineral density. Osteoporos Int. 2003;14:531–538. doi: 10.1007/s00198-002-1322-y. [DOI] [PubMed] [Google Scholar]
  • 11.Sigurdsson G, Aspelund T, Chang M, et al. Increasing sex difference in bone strength in old age: The Age, Gene/Environment Susceptibility-Reykjavik study (AGES-REYKJAVIK) Bone. 2006;39:644–651. doi: 10.1016/j.bone.2006.03.020. [DOI] [PubMed] [Google Scholar]
  • 12.Visser M, Goodpaster BH, Kritchevsky SB, et al. Muscle mass, muscle strength, and muscle fat infiltration as predictors of incident mobility limitations in well-functioning older persons. J Gerontol A Biol Sci Med Sci. 2005;60:324–333. doi: 10.1093/gerona/60.3.324. [DOI] [PubMed] [Google Scholar]
  • 13.Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002;359:1761–1767. doi: 10.1016/S0140-6736(02)08657-9. [DOI] [PubMed] [Google Scholar]
  • 14.Mikkola TM, Sipilä S, Rantanen T, et al. Muscle cross-sectional area and structural bone strength share genetic and environmental effects in older women. J Bone Miner Res. 2009;24:338–345. doi: 10.1359/jbmr.081008. [DOI] [PubMed] [Google Scholar]
  • 15.Sirola J, Kröger H. Similarities in acquired factors related to postmenopausal osteoporosis and sarcopenia. J Osteoporos. 2011;2011:536735. doi: 10.4061/2011/536735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Visser M, Schaap LA. Consequences of sarcopenia. Clin Geriatr Med. 2011;27:387–399. doi: 10.1016/j.cger.2011.03.006. [DOI] [PubMed] [Google Scholar]
  • 17.Järvinen TL, Sievänen H, Khan KM, Heinonen A, Kannus P. Shifting the focus in fracture prevention, from osteoporosis to falls. BMJ. 2008;336:124–126. doi: 10.1136/bmj.39428.470752.AD. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Clarke BL, Khosla S. Physiology of bone loss. Radiol Clin North Am. 2010;48:483–495. doi: 10.1016/j.rcl.2010.02.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Khosla S. Update in male osteoporosis. J Clin Endocrinol Metab. 2010;95:310. doi: 10.1210/jc.2009-1740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Orwoll E, Lambert LC, Marshall LM, et al. Testosterone and estradiol among older men. J Clin Endocrinol Metab. 2006;91:1336–1144. doi: 10.1210/jc.2005-1830. [DOI] [PubMed] [Google Scholar]
  • 21.Riggs BL, Melton LJIII, 3rd, Robb RA, et al. Population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites. J Bone Miner Res. 2004;19:1945–1954. doi: 10.1359/JBMR.040916. [DOI] [PubMed] [Google Scholar]
  • 22.Lambert JK, Zaidi M, Mechanick JI. Male osteoporosis: epidemiology and the pathogenesis of aging bones. Curr Osteoporos Rep. 2011;9:229–236. doi: 10.1007/s11914-011-0066-z. [DOI] [PubMed] [Google Scholar]
  • 23.Gabet Y, Bab I. Microarchitectural changes in the aging skeleton. Curr Osteoporos Rep. 2011;9:177–183. doi: 10.1007/s11914-011-0072-1. [DOI] [PubMed] [Google Scholar]
  • 24.Lauretani F, Bandinelli S, Griswold ME, et al. Longitudinal changes in BMD and bone geometry in a population-based study. J Bone Miner Res. 2008;23:400–408. doi: 10.1359/JBMR.071103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Chen H, Zhou X, Shoumura S, Emura S, Bunai Y. Age- and gender-dependent changes in three-dimensional microstructure of cortical and trabecular bone at the human femoral neck. Osteoporos Int. 2010;21:627–636. doi: 10.1007/s00198-009-0993-z. [DOI] [PubMed] [Google Scholar]
  • 26.Ward KA, Pye SR, Adams JE, et al. Influence of age and sex steroids on bone density and geometry in middle-aged and elderly European men. Osteoporos Int. 2011;22:1513–1523. doi: 10.1007/s00198-010-1437-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Cooper DM, Thomas CD, Clement JG, Turinsky AL, Sensen CW, Hallgrimsson B. Age-dependent change in the 3D structure of cortical porosity at the human femoral midshaft. Bone. 2007;40:957–965. doi: 10.1016/j.bone.2006.11.011. [DOI] [PubMed] [Google Scholar]
  • 28.Augat P, Schorlemmer S. The role of cortical bone and its micro-structure in bone strength. Age Ageing. 2006;35:1127–1131. doi: 10.1093/ageing/afl081. [DOI] [PubMed] [Google Scholar]
  • 29.Seeman E. The growth and age-related origins of bone fragility in men. Calcif Tissue Int. 2004;75:100–109. doi: 10.1007/s00223-004-0289-4. [DOI] [PubMed] [Google Scholar]
  • 30.Christiansen BA, Kopperdahl DL, Kiel DP, Keaveny TM, Bouxsein ML. Mechanical contributions of the cortical and trabecular compartments contribute to differences in age-related changes in vertebral body strength in men and women assessed by QCT-based finite element analysis. J Bone Miner Res. 2011;26:974–983. doi: 10.1002/jbmr.287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Mueller TL, van Lenthe GH, Stauber M, Gratzke C, Eckstein F, Muller R. Regional, age and gender differences in architectural measures of bone quality and their correlation to bone mechanical competence in the human radius of an elderly population. Bone. 2009;45:882–891. doi: 10.1016/j.bone.2009.06.031. [DOI] [PubMed] [Google Scholar]
  • 32.Stauber M, Muller R. Age-related changes in trabecular bone mi-crostructures: global and local morphometry. Osteoporos Int. 2006;17:616–626. doi: 10.1007/s00198-005-0025-6. [DOI] [PubMed] [Google Scholar]
  • 33.Parfitt AM. Bone age, mineral density, and fatigue damage. Calcif Tissue Int. 1993;53:S82–S85. doi: 10.1007/BF01673408. [DOI] [PubMed] [Google Scholar]
  • 34.Qiu S, Rao DS, Palnitkar S, Parfitt AM. Relationships between osteocyte density and bone formation rate in human cancellous bone. Bone. 2002;31:709–711. doi: 10.1016/s8756-3282(02)00907-9. [DOI] [PubMed] [Google Scholar]
  • 35.D'Angelo MA, Raices M, Panowski SH, Hetzer MW. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell. 2009;136:284–295. doi: 10.1016/j.cell.2008.11.037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Busse B, Djonic D, Milovanovic P, Hahn M, Puschel K, Ritchie RO, et al. Decrease in the osteocyte lacunar density accompanied by hypermineralized lacunar occlusion reveals failure and delay of remodeling in aged human bone. Aging cell. 2010;9:1065–1075. doi: 10.1111/j.1474-9726.2010.00633.x. [DOI] [PubMed] [Google Scholar]
  • 37.Szulc P, Seeman E. Thinking inside and outside the envelopes of bone: dedicated to PDD. Osteoporos Int. 2009;20:1281–1288. doi: 10.1007/s00198-009-0994-y. [DOI] [PubMed] [Google Scholar]
  • 38.Seeman E. The growth and age-related origins of bone fragility in men. Calcif Tissue Int. 2004;75:100–109. doi: 10.1007/s00223-004-0289-4. [DOI] [PubMed] [Google Scholar]
  • 39.Wang X. Cortical bone mechanics and composition: effects of age and gender Stud Mechanobiol Tissue Eng Biomater. 2011 [Google Scholar]
  • 40.Bailey AJ, Sims TJ, Ebbesen EN, Mansell JP, Thomsen JS, Mosekilde L. Age-related changes in the biochemical properties of human cancellous bone collagen: relationship to bone strength. Calcif Tissue Int. 1999;65:203–210. doi: 10.1007/s002239900683. [DOI] [PubMed] [Google Scholar]
  • 41.Akkus O, Polyakova-Akkus A, Adar F, Schaffler MB. Aging of microstructural compartments in human compact bone. J Bone Miner Res. 2003;18:1012–1019. doi: 10.1359/jbmr.2003.18.6.1012. [DOI] [PubMed] [Google Scholar]
  • 42.Lee TC, Mohsin S, Taylor D, Parkesh R, Gunnlaugsson T, O’Brien FJ, et al. Detecting microdamage in bone. J Anat. 2003;203:161–172. doi: 10.1046/j.1469-7580.2003.00211.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Saito M, Marumo K. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int. 2010;21:195–214. doi: 10.1007/s00198-009-1066-z. [DOI] [PubMed] [Google Scholar]
  • 44.Wang X, Shen X, Li X, Mauli Agrawal CM. Age-related changes in the collagen network and toughness of bone. Bone. 2002;31:1–7. doi: 10.1016/s8756-3282(01)00697-4. [DOI] [PubMed] [Google Scholar]
  • 45.Zioupos P, Currey JD, Hamer AJ. The role of collagen in the declining mechanical properties of aging human cortical bone. J Bio-med Mater Res. 1999;45:108–116. doi: 10.1002/(sici)1097-4636(199905)45:2<108::aid-jbm5>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  • 46.Turner CH. Aging and fragility of bone. J Musculoskelet Neuronal Interact. 2007;7:342–343. [PubMed] [Google Scholar]
  • 47.Manolagas SC, Jilka RL. Bone marrow, cytokines and bone remodeling Emerging insights into the pathophysiology of osteoporosis. N Engl J Med. 1995;332:305–311. doi: 10.1056/NEJM199502023320506. [DOI] [PubMed] [Google Scholar]
  • 48.Dalle Carbonares L, Valenti MT, Zanatta M, Donatelli L, Lo Cascio V. Circulating mesenchymal stem cells with abnormal osteogenic differentiation in patients with osteoporosis. Arthritis Rheum. 2009;60:3356–3365. doi: 10.1002/art.24884. [DOI] [PubMed] [Google Scholar]
  • 49.Veronesi F, Torricelli P, Borsari V, Tschon M, Rimondini L, Fini M. Mesenchymal stem cells in the aging and osteoporotic population. Crit Rev Eukaryot Gene Expr. 2011;21:363–377. doi: 10.1615/critreveukargeneexpr.v21.i4.60. [DOI] [PubMed] [Google Scholar]
  • 50.Riggs BL, Khosla S, Melton LJ., 3rd A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type U osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res. 1998;13:763–773. doi: 10.1359/jbmr.1998.13.5.763. [DOI] [PubMed] [Google Scholar]
  • 51.Cummings SR, Browner WS, Bauer D, et al. Endogenous hormones, the risk of hip, vertebral fractures among older women. Study of Osteoporotic Fractures Research Group. N Engl J Med. 1998;339:733–738. doi: 10.1056/NEJM199809103391104. [DOI] [PubMed] [Google Scholar]
  • 52.Khosla S, Riggs BL, Robb RA, et al. Relationship of volumetric bone density and structural parameters at different skeletal sites to sex steroid levels in women. J Clin Endocrinol Metab. 2005;90:5096–5103. doi: 10.1210/jc.2005-0396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Shevde NK, Bendixen AC, Dienger KM, Pike JW. Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. Proc Natl Acad Sci USA. 2000;97:7829–7834. doi: 10.1073/pnas.130200197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Srivastava S, Toraldo G, Weitzmann MN, et al. Estrogen decreases osteoclast formation by downregulating receptor activator of NF-κB ligand (RANKL)-induced JNK activation. J Biol Chem. 2001;276:8836–8840. doi: 10.1074/jbc.M010764200. [DOI] [PubMed] [Google Scholar]
  • 55.Oursler MJ, Pederson L, Fitzpatrick LA, et al. Human giant cell tumors of the bone (osteoclastomas) are estrogen target cells. Proc Natl Acad Sci USA. 1994;91:5227–5231. doi: 10.1073/pnas.91.12.5227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Charatcharoenwitthaya N, Khosla S, Atkinson EJ, et al. Effect of blockade of TNF-alpha and interleukin-1 action on bone resorption in early postmenopausal women. J Bone Miner Res. 2007;22:724–729. doi: 10.1359/jbmr.070207. [DOI] [PubMed] [Google Scholar]
  • 57.Dang ZC, van Bezooijen RL, Karperien M, Papapoulos SE, Lowik CW. Exposure of KS483 cells to estrogen enhances osteogenesis and inhibits adipogenesis. J Bone Miner Res. 2002;17:394–405. doi: 10.1359/jbmr.2002.17.3.394. [DOI] [PubMed] [Google Scholar]
  • 58.Hughes DE, Dai A, Tiffee JC, et al. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nat Med. 1996;2:1132–1136. doi: 10.1038/nm1096-1132. [DOI] [PubMed] [Google Scholar]
  • 59.Hofbauer LC, Khosla S, Dunstan CR, et al. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. J Clin Endocrinol Metab. 1999;140:4367–4370. doi: 10.1210/endo.140.9.7131. [DOI] [PubMed] [Google Scholar]
  • 60.Gallagher JC, Riggs BL, DeLuca HF. Effect of estrogen on calcium absorption and serum vitamin D metabolites in postmenopausal osteoporosis. J Clin Endocrinol Metab. 1980;51:1359–1364. doi: 10.1210/jcem-51-6-1359. [DOI] [PubMed] [Google Scholar]
  • 61.McKane WR, Khosla S, Burritt MF, et al. Mechanism of renal calcium conservation with estrogen replacement therapy in women in early postmenopause-a clinical research center study. J Clin Endocrinol Metab. 1995;80:3458–3464. doi: 10.1210/jcem.80.12.8530583. [DOI] [PubMed] [Google Scholar]
  • 62.Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281. doi: 10.1056/NEJMra070553. [DOI] [PubMed] [Google Scholar]
  • 63.Van der Mei IA, Ponsonby AL, Engelsen O, et al. The high prevalence of vitamin D insufficiency across Australian populations is only partly explained by season and latitude. Environ Health Perspect. 2007;115:1132–1139. doi: 10.1289/ehp.9937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Kennel KA, Riggs BL, Achenbach SJ, Oberg AL, Khosla S. Role of parathyroid hormone in mediating age-related changes in bone resorption in men. Osteoporos Int. 2003;14:631–636. doi: 10.1007/s00198-003-1417-0. [DOI] [PubMed] [Google Scholar]
  • 65.Turner RT, Wakley GK, Hannon KS. Differential effects of androgens on cortical bone histomorphometry in gonadectomized male and female rats. J Orthop Res. 1990;8:612–617. doi: 10.1002/jor.1100080418. [DOI] [PubMed] [Google Scholar]
  • 66.Gennari L, Khosla S, Bilezikian JP. Estrogen and fracture risk in men. J Bone Miner Res. 2008;23:1548–1551. doi: 10.1359/jbmr.0810c. [DOI] [PubMed] [Google Scholar]
  • 67.Khosla S, Amin S, Singh RJ, Atkinson EJ, Melton LJ, 3rd, Riggs BL. Comparison of sex steroid measurements in men by immunoassay versus mass spectroscopy and relationships with cortical and trabecular volumetric bone mineral density. Osteoporos Int. 2008;19:1465–1471. doi: 10.1007/s00198-008-0591-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.van den Beld AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab. 2000;85:3276–3282. doi: 10.1210/jcem.85.9.6825. [DOI] [PubMed] [Google Scholar]
  • 69.Szulc P, Munoz F, Claustrat B, et al. Bioavailable estradiol may be an important determinant of osteoporosis in men: the MINOS study. J Clin Endocrinol Metab. 2001;86:192–199. doi: 10.1210/jcem.86.1.7126. [DOI] [PubMed] [Google Scholar]
  • 70.Boonen S, Mohan S, Dequeker J, et al. Down-regulation of the serum stimulatory components of the insulin-like growth factor (IGF) system (IGF-I, IGF-II, IGF binding protein [BP]-3, and IGFBP-5) in age-related (type II) femoral neck osteoporosis. J Bone Miner Res. 1999;14:2150–2158. doi: 10.1359/jbmr.1999.14.12.2150. [DOI] [PubMed] [Google Scholar]
  • 71.Amin S, Riggs BL, Melton LJ, 3rd, et al. High serum IGFBP-2 is predictive of increased bone turnover in aging men and women. J Bone Miner Res. 2007;22:799–807. doi: 10.1359/jbmr.070306. [DOI] [PubMed] [Google Scholar]
  • 72.Kostka T. Quadriceps maximal power and optimal shortening velocity in 335 men aged 2388 years. Eur J Appl Physiol. 2005;95:140–145. doi: 10.1007/s00421-005-1390-8. [DOI] [PubMed] [Google Scholar]
  • 73.Janssen I, Heymsfield SB, Wang ZM, Ross R. Skeletal muscle mass and distribution in 468 men and women aged 18–88 yr. J Appl Physiol. 2000;89:81–88. doi: 10.1152/jappl.2000.89.1.81. [DOI] [PubMed] [Google Scholar]
  • 74.Narici MV, Maffulli N. Sarcopenia: characteristics, mechanisms and functional significance. Br Med Bull. 2010;95:139–159. doi: 10.1093/bmb/ldq008. [DOI] [PubMed] [Google Scholar]
  • 75.Kamel HK. Sarcopenia and aging. Nutr Rev. 2003;61:157–167. doi: 10.1301/nr.2003.may.157-167. [DOI] [PubMed] [Google Scholar]
  • 76.Roth SM, Metter EJ, Ling S, Ferrucci L. Inflammatory factors in age-related muscle wasting. Curr Opin Rheumatol. 2006;18:625–630. doi: 10.1097/01.bor.0000245722.10136.6d. [DOI] [PubMed] [Google Scholar]
  • 77.Dube J, Goodpaster BH. Assessment of intramuscular triglycerides: contribution to metabolic abnormalities. Curr Opin Clin Nutr Metab Care. 2006;9:553–559. doi: 10.1097/01.mco.0000241664.38385.12. [DOI] [PubMed] [Google Scholar]
  • 78.Shefer G, Yablonka-Reuveni Z. Reflections on lineage potential of skeletal muscle satellite cells: do they sometimes go MAD? Crit Rev Eukaryot Gene Expr. 2007;17:13–29. doi: 10.1615/critreveukargeneexpr.v17.i1.20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Farr JN, Funk JL, Chen Z, et al. Skeletal muscle fat content is inversely associated with bone strength in young girls. J Bone Miner Res. 2011;26:2217–2225. doi: 10.1002/jbmr.414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Wong AK, Bhargava A, Beattie K, et al. Muscle density, a surrogate of intermuscular adipose derived from pQCT, is an independent correlate of fractures in women. J Bone Miner Res. 2011;26(Suppl 1) (Available at http://www.abstracts2view.com/asbmr/view.php?nu=ASBMR11L_A11006306-25&terms=). [Google Scholar]
  • 81.Xie Y, Yao Z, Chai H, Wong WM, Wu W. Expression and role of low-affinity nerve growth factor receptor (p75) in spinal motor neurons of aged rats following axonal injury. Developmental Neuroscience. 2003;25:65–71. doi: 10.1159/000071469. [DOI] [PubMed] [Google Scholar]
  • 82.Lexell J, Downham DY, Larsson Y, Bruhn E, Morsing B. Heavy-resistance training in older Scandinavian men and women: short-and long-term effects on arm and leg muscles. Scand J Med Sci Sports. 1995;5:329–341. doi: 10.1111/j.1600-0838.1995.tb00055.x. [DOI] [PubMed] [Google Scholar]
  • 83.Lowe DA, Thomas DD, Thompson LV. Force generation, but not myosin ATPase activity, declines with age in rat muscle fibers. Am J Physiol Cell Physiol. 2002;283:C187–C192. doi: 10.1152/ajpcell.00008.2002. [DOI] [PubMed] [Google Scholar]
  • 84.Wang ZM, Messi ML, Delbono O. L-type Ca2+ channel charge movement and intracellular Ca2+ in skeletal muscle fibers from aging mice. Biophysical Journal. 2000;78:1947–1954. doi: 10.1016/S0006-3495(00)76742-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Gordon T, Hegedus J, Tam SL. Adaptive and maladaptive motor axonal sprouting in aging and motoneuron disease. Neurol Res. 2004;26:174–185. doi: 10.1179/016164104225013806. [DOI] [PubMed] [Google Scholar]
  • 86.Edstrom E, Altun M, Bergman E, et al. Factors contributing to neuromuscular impairment and sarcopenia during aging. Physiol Behav. 2007;92:129–135. doi: 10.1016/j.physbeh.2007.05.040. [DOI] [PubMed] [Google Scholar]
  • 87.Renault V, Thornell LE, Eriksson PO, Butler-Browne G, Mouly V. Regenerative potential of human skeletal muscle during aging. Aging Cell. 2002;1:132–139. doi: 10.1046/j.1474-9728.2002.00017.x. [DOI] [PubMed] [Google Scholar]
  • 88.Lorenzon P, Bandi E, de Guarrini F, et al. Ageing affects the differentiation potential of human myoblasts. Exp Gerontol. 2004;39:1545–1554. doi: 10.1016/j.exger.2004.07.008. [DOI] [PubMed] [Google Scholar]
  • 89.Conboy IM, Conboy MJ, Smythe GM, Rando TA. Notch-mediated restoration of regenerative potential to aged muscle. Science. 2003;302:1575–1577. doi: 10.1126/science.1087573. [DOI] [PubMed] [Google Scholar]
  • 90.Gopinath SD, Rando TA. Stem cell review series: aging of the skeletal muscle stem cell niche. Aging Cell. 2008;7:590–598. doi: 10.1111/j.1474-9726.2008.00399.x. [DOI] [PubMed] [Google Scholar]
  • 91.Bigot A, Jacquemin V, Debacq-Chainiaux F, et al. Replicative aging down-regulates the myogenic regulatory factors in human myoblasts. Biol Cell. 2008;100:189–199. doi: 10.1042/BC20070085. [DOI] [PubMed] [Google Scholar]
  • 92.Hikida RS. Aging changes in satellite cells and their functions. Curr Aging Sci. 2011;4:279–297. doi: 10.2174/1874609811104030279. [DOI] [PubMed] [Google Scholar]
  • 93.Langley B, Thomas M, Bishop A, Sharma M, Gilmour S, Kambadur R. Myostatin inhibits myoblast differentiation by down-regulating MyoD expression. J Biol Chem. 2002;277:49831–49840. doi: 10.1074/jbc.M204291200. [DOI] [PubMed] [Google Scholar]
  • 94.Welle S. Cellular and molecular basis of age-related sarcopenia. Can J Appl Physiol. 2002;27:19–41. doi: 10.1139/h02-002. [DOI] [PubMed] [Google Scholar]
  • 95.Raue U, Slivka D, Jemiolo B, Hollon C, Trappe S. Myogenic gene expression at rest and after a bout of resistance exercise in young (18–30 yr) and old (80–89 yr) women. J Appl Physiol. 2006;101:53–59. doi: 10.1152/japplphysiol.01616.2005. [DOI] [PubMed] [Google Scholar]
  • 96.Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, Rando TA. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 2007;317:807–810. doi: 10.1126/science.1144090. [DOI] [PubMed] [Google Scholar]
  • 97.Buas MF, Kadesch T. Regulation of skeletal myogenesis by Notch. Exp Cell Res. 2010;316:3028–3033. doi: 10.1016/j.yexcr.2010.05.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Arthur ST, Cooley ID. The effect of physiological stimuli on sarcopenia; impact of Notch and Wnt signaling on impaired aged skeletal muscle repair. Int J Biol Sci. 2012;8:731–760. doi: 10.7150/ijbs.4262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Reid MB. Response of the ubiquitin-proteasome pathway to changes in muscle activity. Am J Physiol Regul Integr Comp Physiol. 2005;288:R1423–R1431. doi: 10.1152/ajpregu.00545.2004. [DOI] [PubMed] [Google Scholar]
  • 100.Kandarian SC, Jackman RW. Intracellular signaling during skeletal muscle atrophy. Muscle Nerve. 2006;33:155–165. doi: 10.1002/mus.20442. [DOI] [PubMed] [Google Scholar]
  • 101.Clavel S, Coldefy AS, Kurkdjian E, et al. Atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 are up-regulated in aged rat tibialis anterior muscle. Mech Ageing Dev. 2006;127:794–801. doi: 10.1016/j.mad.2006.07.005. [DOI] [PubMed] [Google Scholar]
  • 102.Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev. 2002;23:824–854. doi: 10.1210/er.2001-0033. [DOI] [PubMed] [Google Scholar]
  • 103.Machida S, Booth FW. Insulin-like growth factor 1 and muscle growth: implication for satellite cell proliferation. Proc Nutr Soc. 2004;63:337–340. doi: 10.1079/PNS2004354. [DOI] [PubMed] [Google Scholar]
  • 104.Schertzer JD, van der Poel C, Shavlakadze T, Grounds MD, Lynch GS. Muscle-specific overexpression of IGF-I improves E-C coupling in skeletal muscle fibers from dystrophic mdx mice. Am J Physiol Cell Physiol. 2008;294:C161–C168. doi: 10.1152/ajpcell.00399.2007. [DOI] [PubMed] [Google Scholar]
  • 105.Brown M. Skeletal muscle and bone: effect of sex steroids and aging. Adv Physiol Educ. 2008;32:120–126. doi: 10.1152/advan.90111.2008. [DOI] [PubMed] [Google Scholar]
  • 106.Roubenoff R. Catabolism of aging: is it an inflammatory process? Current Opinion in Clinical Nutrition and Metabolic Care. 2003;6:295–299. doi: 10.1097/01.mco.0000068965.34812.62. [DOI] [PubMed] [Google Scholar]
  • 107.Urban RJ, Bodenburg YH, Gilkison C, et al. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. American Journal of Physiology. 1995;269:E820–E826. doi: 10.1152/ajpendo.1995.269.5.E820. [DOI] [PubMed] [Google Scholar]
  • 108.Bhasin S, Woodhouse L, Storer TW. Proof of the effect of testosterone on skeletal muscle. Journal of Endocrinology. 2001;170:27–38. doi: 10.1677/joe.0.1700027. [DOI] [PubMed] [Google Scholar]
  • 109.Abbatecola AM, Paolisso G, Fattoretti P, et al. Discovering pathways of sarcopenia in older adults: a role for insulin resistance on mitochondria dysfunction. J Nutr Health Aging. 2011;15:890–895. doi: 10.1007/s12603-011-0366-0. [DOI] [PubMed] [Google Scholar]
  • 110.Marcell TJ. Sarcopenia: causes, consequences, and preventions. J Gerontol A Biol Sci Med Sci. 2003;58:M911–M916. doi: 10.1093/gerona/58.10.m911. [DOI] [PubMed] [Google Scholar]
  • 111.LaPier TK. Glucocorticoid-induced muscle atrophy. The role of exercise in treatment and prevention. J Cardiopulm Rehabil. 1997;17:76–84. doi: 10.1097/00008483-199703000-00002. [DOI] [PubMed] [Google Scholar]
  • 112.Waters DL, Quails CR, Dorin RI, Veldhuis JD, Baumgartner RN. Altered growth hormone, Cortisol, and leptin secretion in healthy elderly persons with sarcopenia and mixed body composition phenotypes. J Gerontol A Biol Sci Med Sci. 2008;63:536–541. doi: 10.1093/gerona/63.5.536. [DOI] [PubMed] [Google Scholar]
  • 113.Miller BS, Ignatoski KM, Daignault S, et al. A quantitative tool to assess degree of sarcopenia objectively in patients with hypercortisolism. Surgery. 2011;150:1178–1185. doi: 10.1016/j.surg.2011.09.020. [DOI] [PubMed] [Google Scholar]
  • 114.Peeters GM, van Schoor NM, Visser M, et al. Relationship between Cortisol and physical performance in older persons. Clin Endocrinol. 2007;67:398–406. doi: 10.1111/j.1365-2265.2007.02900.x. [DOI] [PubMed] [Google Scholar]
  • 115.Visser M, Deeg DJ, Lips P. Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab. 2003;88:5766–5772. doi: 10.1210/jc.2003-030604. [DOI] [PubMed] [Google Scholar]
  • 116.Schaap LA, Pluijm SMF, Deeg DJH, Visser M. Inflammatory markers and loss of muscle mass (sarcopenia) and strength. American Journal of Medicine. 2006;119:526.e9–526.e17. doi: 10.1016/j.amjmed.2005.10.049. [DOI] [PubMed] [Google Scholar]
  • 117.Giresi PG, Stevenson EJ, Theilhaber J, et al. Identification of a molecular signature of sarcopenia. Physiol Genomics. 2005;21:253–263. doi: 10.1152/physiolgenomics.00249.2004. [DOI] [PubMed] [Google Scholar]
  • 118.Rasmussen BB, Fujita S, Wolfe RR, et al. Insulin resistance of muscle protein metabolism in aging. Faseb J. 2006;20:768–769. doi: 10.1096/fj.05-4607fje. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 119.Kandarian SC, Jackman RW. Intracellular signaling during skeletal muscle atrophy. Muscle Nerve. 2006;33:155–165. doi: 10.1002/mus.20442. [DOI] [PubMed] [Google Scholar]
  • 120.Schiaffino S, Mammucari C. Regulation of skeletal muscle growth by the IGFl-Akt/PKB pathway: insights from genetic models. Skelet Muscle. 2011;1:4. doi: 10.1186/2044-5040-1-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 121.Degens H. The role of systemic inflammation in age-related muscle weakness and wasting. Scandinavian Journal of Medicine and Science in Sports. 2010;20:28–38. doi: 10.1111/j.1600-0838.2009.01018.x. [DOI] [PubMed] [Google Scholar]
  • 122.Wood LJ, Nail LM, Winters KA. Does muscle-derived interleukin-6 mediate some of the beneficial effects of exercise on cancer treatment-related fatigue? Oncol Nurs Forum. 2009;36:519–524. doi: 10.1188/09.ONF.519-524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 123.Yeh SS, Lovitt S, Schuster MW. Pharmacological treatment of geriatric cachexia: evidence and safety in perspective. J Am Med Dir Assoc. 2007;8:363–377. doi: 10.1016/j.jamda.2007.05.001. [DOI] [PubMed] [Google Scholar]
  • 124.Reid MB, Durham WJ. Generation of reactive oxygen and nitrogen species in contracting skeletal muscle: potential impact on aging. Ann NY Acad Sci. 2002;959:108–116. doi: 10.1111/j.1749-6632.2002.tb02087.x. [DOI] [PubMed] [Google Scholar]
  • 125.Callahan LA, She ZW, Nosek TM. Superoxide, hydroxyl radical, and hydrogen peroxide effects on single-diaphragm fiber contractile apparatus. Journal of Applied Physiology. 2001;90:45–54. doi: 10.1152/jappl.2001.90.1.45. [DOI] [PubMed] [Google Scholar]
  • 126.Lamb GD, Posterino GS. Effects of oxidation and reduction on contractile function in skeletal muscle fibres of the rat. Journal of Physiology. 2003;546:149–163. doi: 10.1113/jphysiol.2002.027896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 127.Ostdal H, Skibsted LH, Andersen HJ. Formation of long-lived protein radicals in the reaction between H2O2-activated metmyoglobin and other proteins. Free Radical Biology and Medicine. 1997;23:754–761. doi: 10.1016/s0891-5849(97)00023-3. [DOI] [PubMed] [Google Scholar]
  • 128.Chen JH, Hales CN, Ozanne SE. DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res. 2007;35:7417–7428. doi: 10.1093/nar/gkm681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 129.Wagatsuma A, Sakuma K. Molecular mechanisms for age-associated mitochondrial deficiency in skeletal muscle. J Aging Res. 2012;2012:768–304. doi: 10.1155/2012/768304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 130.Dupont-Versteegden EE. Apoptosis in skeletal muscle and its relevance to atrophy. World J Gastroenterol. 2006;12:7463–7466. doi: 10.3748/wjg.v12.i46.7463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 131.Douchi T, Oki T, Nakamura S, Ijuin H, Yamamoto S, Nagata Y. The effect of body composition on bone density in pre- and postmenopausal women. Maturitas. 1997;1:55–60. doi: 10.1016/s0378-5122(97)01112-2. [DOI] [PubMed] [Google Scholar]
  • 132.Visser M, Kiel DP, Lagois J, et al. Muscle mass and fat mass in relation to bone mineral density in very old men, women. The Framingham Heart Study. Applied Radiation and Isotopes. 1998;49:745–747. doi: 10.1016/s0969-8043(97)00101-2. [DOI] [PubMed] [Google Scholar]
  • 133.Blain H, Vuillemin A, Teissier A, Hanesse B, Guillemin F, Jeandel C. Influence of muscle strength and body weight and composition on regional bone mineral density in healthy women aged 60 years and over. Gerontology. 2001;47:207–212. doi: 10.1159/000052800. [DOI] [PubMed] [Google Scholar]
  • 134.Proctor DN, Melton LJ, Khosla S, Crowson CS, O’Connor MK, Riggs BL. Relative influence of physical activity, muscle mass and strength on bone density. Osteoporosis International. 2000;11:944–952. doi: 10.1007/s001980070033. [DOI] [PubMed] [Google Scholar]
  • 135.Walsh MC, Hunter GR, Livingstone MB. Sarcopenia in premenopausal and postmenopausal women with osteopenia, osteoporosis and normal bone mineral density. Osteoporosis International. 2006;17:61–67. doi: 10.1007/s00198-005-1900-x. [DOI] [PubMed] [Google Scholar]
  • 136.Lauretani F, Bandinelli S, Russo CR, et al. Correlates of bone quality in older persons. Bone. 2006;4:915–921. doi: 10.1016/j.bone.2006.03.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 137.Orsatti FL, Nahas EA, Nahas-Neto J, et al. Low appendicular muscle mass is correlated with femoral neck bone mineral density loss in postmenopausal women. BMC Musculoskelet Disord. 2011;12:225. doi: 10.1186/1471-2474-12-225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 138.Orwoll ES, Bauer DC, Vogt TM, Fox KM. Axial bone mass in older women. Annals of Internal Medicine. 1996;2:187–196. doi: 10.7326/0003-4819-124-2-199601150-00001. [DOI] [PubMed] [Google Scholar]
  • 139.Taaffe DR, Cauley JA, Danielson M, et al. Race and sex effects on the association between muscle strength, soft tissue, and bone mineral density in healthy elders: the health, aging, and body composition study. Journal of Bone and Mineral Research. 2001;16:1343–1352. doi: 10.1359/jbmr.2001.16.7.1343. [DOI] [PubMed] [Google Scholar]
  • 140.Bauer DC, Browner WS, Cauley JA, et al. Factors associated with appendicular bone mass in older women. Annals of Internal Medicine. 1993;118:657–665. doi: 10.7326/0003-4819-118-9-199305010-00001. [DOI] [PubMed] [Google Scholar]
  • 141.Shin H, Panton LB, Dutton GR, Ilich JZ. Relationship of Physical Performance with Body Composition and Bone Mineral Density in Individuals over 60 Years of Age: A Systematic Review. J Aging Res. 2011;2011:191896. doi: 10.4061/2011/191896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 142.Foley KT, Owings TM, Pavol MJ, Grabiner MD. Maximum grip strength is not related to bone mineral density of the proximal femur in older adults. Calcified Tissue International. 1999;64:291–294. doi: 10.1007/s002239900621. [DOI] [PubMed] [Google Scholar]
  • 143.Lindsey C, Brownbill RA, Bohannon RA, Ilich JZ. Association of physical performance measures with bone mineral density in postmenopausal women. Archives of Physical Medicine and Rehabilitation. 2005;86:1102–1107. doi: 10.1016/j.apmr.2004.09.028. [DOI] [PubMed] [Google Scholar]
  • 144.Cauley JA, Fullman RL, Stone KL, et al. Factors associated with the lumbar spine and proximal femur bone mineral density in older men. Osteoporosis International. 2005;16:1525–1537. doi: 10.1007/s00198-005-1866-8. [DOI] [PubMed] [Google Scholar]
  • 145.Schoenau E, Neu CM, Mokov E, Wassmer G, Manz F. Influence of puberty on muscle area and cortical bone area of the forearm in boys and girls. J Clin Endocrinol Metab. 2000;85:1095–1098. doi: 10.1210/jcem.85.3.6451. [DOI] [PubMed] [Google Scholar]
  • 146.Rittweger J, Beller G, Ehrig J, et al. Bone-muscle strength indices for the human lower leg. Bone. 2000;27:319–326. doi: 10.1016/s8756-3282(00)00327-6. [DOI] [PubMed] [Google Scholar]
  • 147.Martyn-St James M, Carroll S. Meta-analysis of walking for preservation of bone mineral density in postmenopausal women. Bone. 2008;43:521–531. doi: 10.1016/j.bone.2008.05.012. [DOI] [PubMed] [Google Scholar]
  • 148.Madsen OR, Lauridsen UB, Sorensen OH. Quadriceps strength in women with a previous hip fracture: relationships to physical ability and bone mass. Scandinavian Journal of Rehabilitation Medicine. 2000;32:37, 40. doi: 10.1080/003655000750045721. [DOI] [PubMed] [Google Scholar]
  • 149.Polidoulis I, Beyene J, Cheung AM. The effect of exercise on pQCT parameters of bone structure and strength in postmenopausal women-a systematic review and meta-analysis of randomized controlled trials. Osteoporos Int. 2012;23:39–51. doi: 10.1007/s00198-011-1734-7. [DOI] [PubMed] [Google Scholar]
  • 150.Whiteford J, Ackland TR, Dhaliwal SS, et al. Effects of a 1-year randomized controlled trial of resistance training on lower limb bone and muscle structure and function in older men. Osteoporos Int. 2010;21:1529–1536. doi: 10.1007/s00198-009-1132-6. [DOI] [PubMed] [Google Scholar]
  • 151.Hughes-Fulford M. To Infinity and beyond! Human spaceflight and life science. Faseb J. 2011;25:2858–2864. doi: 10.1096/fj.11-0902ufm. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 152.Armbrecht G, Belavý DL, BackstrÖm M, et al. Trabecular and cortical bone density and architecture in women after 60 days of bed rest using high-resolution pQCT: WISE 2005. J Bone Miner Res. 2011;26:2399–2410. doi: 10.1002/jbmr.482. [DOI] [PubMed] [Google Scholar]
  • 153.Shin H, Panton LB, Dutton GR, Ilich JZ. Relationship of Physical Performance with Body Composition and Bone Mineral Density in Individuals over 60 Years of Age: A Systematic Review. J Aging Res. 2011;2011:191896. doi: 10.4061/2011/191896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 154.Verschueren S, Gielen E, O'Neill TW, et al. Sarcopenia and its relationship with bone mineral density in middle-aged and elderly European men. Osteoporos Int. 2012 doi: 10.1007/s00198-012-2057-z. [Epub ahead of print]. [DOI] [PubMed] [Google Scholar]
  • 155.Di Monaco M, Castiglioni C, Vallero F, Di Monaco R, Tappero R. Sarcopenia is more prevalent in men than in women after hip fracture: A cross-sectional study of 591 inpatients. Arch Gerontol Geriatr. 2012 doi: 10.1016/j.archger.2012.05.002. [Epub ahead of print]. [DOI] [PubMed] [Google Scholar]
  • 156.Di Monaco M, Vallero F, Di Monaco R, Tappero R. Prevalence of sarcopenia and its association with osteoporosis in 313 older women following a hip fracture. Arch Gerontol Geriatr. 2011;52:71–74. doi: 10.1016/j.archger.2010.02.002. [DOI] [PubMed] [Google Scholar]
  • 157.Frost HM. Why the ISMNI and the Utah paradigm? Their role in skeletal and extraskeletal disorders. J Musculoskelet Neuronal Interact. 2000;1:5–9. [PubMed] [Google Scholar]
  • 158.Fricke O, Schoenau E. The 'Functional Muscle-Bone Unit': probing the relevance of mechanical signals for bone development in children and adolescents. Growth Horm IGF Res. 2007;17:1–9. doi: 10.1016/j.ghir.2006.10.004. [DOI] [PubMed] [Google Scholar]
  • 159.Rubin J, Rubin C, Jacobs CR. Molecular pathways mediating mechanical signaling in bone. Gene. 2006;367:1–16. doi: 10.1016/j.gene.2005.10.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 160.Lang TF. The bone-muscle relationship in men and women. J Osteoporos. 2011;2011:702735. doi: 10.4061/2011/702735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 161.Zofkova I. Hormonal aspects of the muscle-bone unit. Physiol Res. 2008;57:S159–S169. doi: 10.33549/physiolres.931501. [DOI] [PubMed] [Google Scholar]
  • 162.Lanyon L, Skerry T. Postmenopausal osteoporosis as a failure of bone's adaptation to functional loading: a hypothesis. J Bone Miner Res. 2001;16:1937–1947. doi: 10.1359/jbmr.2001.16.11.1937. [DOI] [PubMed] [Google Scholar]
  • 163.Lee KC, Lanyon LE. Mechanical loading influences bone mass through estrogen receptor alpha. Exerc Sport Sci Rev. 2004;32:64–68. doi: 10.1097/00003677-200404000-00005. [DOI] [PubMed] [Google Scholar]
  • 164.Mosekilde L, Thomsen JS, Orhii PB, McCarter RJ, Meya W, Kalu DN. Additive effect of voluntary exercise and growth hormone treatment on bone strength assessed at four different skeletal sites in an aged rat model. Bone. 1999;24:71–80. doi: 10.1016/s8756-3282(98)00169-0. [DOI] [PubMed] [Google Scholar]
  • 165.Szulc P, Joly-Pharaboz MO, Marchand F, Delmas PD. Insulin-like growth factor I is a determinant of hip bone mineral density in men less than 60 years of age: MINOS study. Calcif Tissue Int. 2004;74:322–329. doi: 10.1007/s00223-003-0090-9. [DOI] [PubMed] [Google Scholar]
  • 166.Hamrick MW, Shi X, Zhang W, et al. Loss of myostatin (GDF8) function increases osteogenic differentiation of bone marrow-derived mesenchymal stem cells but the osteogenic effect is ablated with unloading. Bone. 2007;40:1544–1553. doi: 10.1016/j.bone.2007.02.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 167.Lang T, Cauley JA, Tylavsky F, Bauer D, Cummings S, Harris TB. Computed tomographic measurements of thigh muscle cross-sectional area and attenuation coefficient predict hip fracture: the health, aging, and body composition study. J Bone Miner Res. 2010;25:513–519. doi: 10.1359/jbmr.090807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 168.Schafer AL, Vittinghoff E, Lang TF, et al. Fat infiltration of muscle, diabetes, and clinical fracture risk in older adults. J Clin Endocrinol Metab. 2010;95:E368–E372. doi: 10.1210/jc.2010-0780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 169.Yadav VK, Oury F, Suda N, Liu ZW, Gao XB, Confevreux C, et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell. 2009;138:976–989. doi: 10.1016/j.cell.2009.06.051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 170.Schwetz V, Pieber T, Obermayer-Pietsch B. The endocrine role of the skeleton: background and clinical evidence. Eur J Endocrinol. 2012;166:959–967. doi: 10.1530/EJE-12-0030. [DOI] [PubMed] [Google Scholar]
  • 171.Thomas T, Gori F, et al. Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology. 1999:1630–1638. doi: 10.1210/endo.140.4.6637. [DOI] [PubMed] [Google Scholar]
  • 172.Amelio PD, Panico A, Spertino E, Isaia GC. Energy metabolism and the skeleton: Reciprocal interplay. World J Orthop. 2012;3:190–198. doi: 10.5312/wjo.v3.i11.190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 173.Kume K, Satomura K, Nishisho S, Kitaoka E, et al. Potential role of leptin in endochondral ossification. J Histochem Cytochem. 2002;50:159–169. doi: 10.1177/002215540205000204. [DOI] [PubMed] [Google Scholar]
  • 174.Gordeladze JO, Drevon CA, Syversen U, Reseland JE. Leptin stimulates human osteoblastic cell proliferation, de novo collagen synthesis, and mineralization: Impact on differentiation markers, apoptosis, and osteoclastic signaling. J Cell Biochem. 2002;85:825–836. doi: 10.1002/jcb.10156. [DOI] [PubMed] [Google Scholar]
  • 175.Lee NK, Sowa H, Hinoi E, et al. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;30:456–469. doi: 10.1016/j.cell.2007.05.047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 176.Holloway WR, Collier FM, et al. Leptin inhibits osteoclast generation. J.Bone Miner. Res. 2002;17:200–209. doi: 10.1359/jbmr.2002.17.2.200. [DOI] [PubMed] [Google Scholar]
  • 177.Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, Hamnvik OP, Koniaris A. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab. 2011;301:E567–E584. doi: 10.1152/ajpendo.00315.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 178.Welt CK, Chan JL, Bullen J, Murphy R, Smith P, De Paoli AM, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004;351:987–997. doi: 10.1056/NEJMoa040388. [DOI] [PubMed] [Google Scholar]
  • 179.Seeman E, Hopper JL, Young NR, Formica C, Goss P, Tsalamandris C. Do genetic factors explain associations between muscle strength, lean mass, and bone density? A twin study. Am J Physiol. 1996;270:E320–E327. doi: 10.1152/ajpendo.1996.270.2.E320. [DOI] [PubMed] [Google Scholar]
  • 180.Mikkola TM, Sipilä S, Rantanen T, et al. Muscle cross-sectional area and structural bone strength share genetic and environmental effects in older women. J Bone Miner Res. 2009;24:338–345. doi: 10.1359/jbmr.081008. [DOI] [PubMed] [Google Scholar]
  • 181.Karasik D. How pleiotropic genetics of the musculoskeletal system can inform genomics andphenomics of aging. Age. 2011;33:49–62. doi: 10.1007/s11357-010-9159-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 182.Tiainen KM, Perola M, Kovanen VM, et al. Genetics of maximal walking speed and skeletal muscle characteristics in older women. Twin Res Hum Genet. 2008;11:321–334. doi: 10.1375/twin.11.3.321. [DOI] [PubMed] [Google Scholar]
  • 183.Griffith JF, Genant HK. New imaging modalities in bone. Curr Rheumatol Rep. 2011;13:241–250. doi: 10.1007/s11926-011-0174-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 184.Siris ES, Boonen S, Mitchell PJ, Bilezikian J, Silverman S. What's in a name? What constitutes the clinical diagnosis of osteoporosis? Osteoporos Int. 2012;23:2093–2097. doi: 10.1007/s00198-012-1991-0. [DOI] [PubMed] [Google Scholar]
  • 185.Kanis JA, McCloskey EV, Johansson H, Oden A, Melton LJ, 3rd, Khaltaev N. A reference standard for the description of osteoporosis. Bone. 2008;42:467–475. doi: 10.1016/j.bone.2007.11.001. [DOI] [PubMed] [Google Scholar]
  • 186.Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. Geneva: World Health Organization; 1994. (WHO Technical Report Series, No. 843). [PubMed] [Google Scholar]
  • 187.Guidelines for preclinical evaluation and clinical trials in osteoporosis. Geneva: World Health Organization; 1998. [Google Scholar]
  • 188.Siris ES, Silverman SJ. Predicting fractures in an international cohort using risk factor algorithms without BMD. Bone Miner Res. 2011;26:2770–2777. doi: 10.1002/jbmr.503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 189.Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. Geneva: World Health Organization; 1994. (WHO Technical Report Series, No. 843). [PubMed] [Google Scholar]
  • 190.Khosla S. Update in male osteoporosis. J Clin Endocrinol Metab. 2010;95:3–10. doi: 10.1210/jc.2009-1740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 191.McLellan AR. Identification and treatment of osteoporosis in fractures. Curr Rheumatol Rep. 2003;5:57–64. doi: 10.1007/s11926-003-0084-7. [DOI] [PubMed] [Google Scholar]
  • 192.van Staa TP, Leufkens HG, Cooper C. Does a fracture at one site predict later fractures at other sites? A British cohort study. Osteoporos Int. 2002;13:624–629. doi: 10.1007/s001980200084. [DOI] [PubMed] [Google Scholar]
  • 193.Wehren LE. The epidemiology of osteoporosis and fractures in geriatric medicine. Clin Geriatr Med. 2003;19:245–258. doi: 10.1016/s0749-0690(02)00072-1. [DOI] [PubMed] [Google Scholar]
  • 194.Barrett-Connor E, Sajjan SG, Siris ES, Miller PD, Chen YT, Mark-son LE. Wrist fracture as a predictor of future fractures in younger versus older postmenopausal women: results from the National Osteoporosis Risk Assessment (NORA) Osteoporosis International. 2008;19:607–613. doi: 10.1007/s00198-007-0508-8. [DOI] [PubMed] [Google Scholar]
  • 195.O’Neill TW, Cooper C, Finn JD, et al. Incidence of distal forearm fracture in British men and women. Osteoporosis International. 2001;12:555–558. doi: 10.1007/s001980170076. [DOI] [PubMed] [Google Scholar]
  • 196.Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. The Journal of the American Medical Association. 2001;285:320–323. doi: 10.1001/jama.285.3.320. [DOI] [PubMed] [Google Scholar]
  • 197.Kado DM, Browner WS, Palermo L, et al. Vertebral fractures and mortality in older women: a prospective study. Archives of Internal Medicine. 1999;159:1215–1220. doi: 10.1001/archinte.159.11.1215. [DOI] [PubMed] [Google Scholar]
  • 198.Melton LJ., 3rd Adverse outcomes of osteoporotic fractures in the general population. Journal of Bone and Mineral Research. 2003;18:1139–1141. doi: 10.1359/jbmr.2003.18.6.1139. [DOI] [PubMed] [Google Scholar]
  • 199.Bertram M, Norman R, Kemp L, Vos T. Review of the long-term disability associated with hip fractures. In j Prev. 2011;17(6):365–370. doi: 10.1136/ip.2010.029579. [DOI] [PubMed] [Google Scholar]
  • 200.Bliuc D, Nguyen ND, Milch VE, et al. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. The Journal of the American Medical Association. 2009;301:513–521. doi: 10.1001/jama.2009.50. [DOI] [PubMed] [Google Scholar]
  • 201.March L, Chamberlain A, Cameron I, et al. Prevention, treatment and rehabilitation of fractured neck of femur. Report from the Northern Sydney Area. 1996 [Google Scholar]
  • 202.Lips, et al. Quality of life in patients with Osteoporosis. Osteoporos Int. 2005;16:447–455. doi: 10.1007/s00198-004-1762-7. [DOI] [PubMed] [Google Scholar]
  • 203.Fransen M, Woodward M, Norton R, Robinson E, Butler M, Campbell AJ. Excess mortality or institutionalization after hip fracture: men are at greater risk than women. J Am Geriatr Soc. 2002;50:685–690. doi: 10.1046/j.1532-5415.2002.50163.x. [DOI] [PubMed] [Google Scholar]
  • 204.Trombetti A, Herrmann F, Hoffmeyer P, Schurch MA, Bonjour JP, Rizzoli R. Survival and potential years of life lost after hip fracture in men and age-matched women. Osteoporos Int. 2002;13:731–737. doi: 10.1007/s001980200100. [DOI] [PubMed] [Google Scholar]
  • 205.Dempster DW. Osteoporosis and the burden of osteoporosis-related fractures. Am J Manag Care. 2011;17:S164–S169. [PubMed] [Google Scholar]
  • 206.The world health report 2004: changing history. Geneva: World Health Organization; 2004. [Google Scholar]
  • 207.Raisz LG. Clinical practice Screening for osteoporosis. N Engl J Med. 2005;353:164–171. doi: 10.1056/NEJMcp042092. [DOI] [PubMed] [Google Scholar]
  • 208.Meadows LM, Mrkonjic L, Lagendyk L. Women's perceptions of future risk after low-energy fractures at midlife. Ann Fam Med. 2005;3:64–69. doi: 10.1370/afm.258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 209.Papaioannou A, Giangregorio L, Kvern B, Boulos P, Ioannidis G, Adachi JD. The osteoporosis care gap in Canada. BMC Musculoskelet Disord. 2004;5:11. doi: 10.1186/1471-2474-5-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 210.Siris ES, Bilezikian JP, Rubin MR, et al. Pins and plaster aren't enough: a call for the evaluation and treatment of patients with osteoporotic fractures. J Clin Endocrinol Metab. 2003;88:3482–3486. doi: 10.1210/jc.2003-030568. [DOI] [PubMed] [Google Scholar]
  • 211.Cruz-Jentoft AJ, Baeyens JP, Bauer JM. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010;39:412–423. doi: 10.1093/ageing/afq034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 212.Muscaritoli M, Anker SD, Argiles J, et al. Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) "cachexia-anorexia in chronic wasting diseases" and "nutrition in geriatrics". Clin Nutr. 2010;29:154–159. doi: 10.1016/j.clnu.2009.12.004. [DOI] [PubMed] [Google Scholar]
  • 213.Evans WJ. Skeletal muscle loss: cachexia, sarcopenia, and inactivity. The American Journal of Clinical Nutrition. 2010;91:1123S–1127S. doi: 10.3945/ajcn.2010.28608A. [DOI] [PubMed] [Google Scholar]
  • 214.Jassen I, Heymsfield SB, Ross R. Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. Journal of the American Geriatrics Society. 2002;50:889–896. doi: 10.1046/j.1532-5415.2002.50216.x. [DOI] [PubMed] [Google Scholar]
  • 215.Goodpaster BH, Park SW, Harris TB, et al. The loss of skeletal muscle strength, mass, quality in older adults. The Health, Aging and Body Composition Study. Journal of Gerontology Series A. 2006;61:1059–1064. doi: 10.1093/gerona/61.10.1059. [DOI] [PubMed] [Google Scholar]
  • 216.Clark BC, Manini TM. Sarcopenia dynapenia. Journals of Gerontology Series A. 2008;63:829–834. doi: 10.1093/gerona/63.8.829. [DOI] [PubMed] [Google Scholar]
  • 217.Janssen I, Shepard DS, Katzmarzyk PT, Roubenoff R. The healthcare costs of sarcopenia in the United States. Journal of the American Geriatrics Society. 2004;52:80–85. doi: 10.1111/j.1532-5415.2004.52014.x. [DOI] [PubMed] [Google Scholar]
  • 218.Morley JE. Sarcopenia: diagnosis and treatment. J Nutr Health Aging. 2008;12:452–456. doi: 10.1007/BF02982705. [DOI] [PubMed] [Google Scholar]
  • 219.Landi F, Liperoti R, Fusco D, et al. Sarcopenia and mortality among older nursing home residents. J Am Med Dir Assoc. 2012;13:121–126. doi: 10.1016/j.jamda.2011.07.004. [DOI] [PubMed] [Google Scholar]
  • 220.World Health Organization. Ageing and life course. 2009 Available from: http://www.who.int/ageing/en/.
  • 221.Guralnik JM, Ferrucci L, Pieper CF, et al. Lower extremity function and subsequent disability: consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery. J Gerontol A Biol Sci Med Sci. 2000;55:M221–M231. doi: 10.1093/gerona/55.4.m221. [DOI] [PubMed] [Google Scholar]
  • 222.Tinetti ME, Baker DI, McAvay G, et al. A multifactorial intervention to reduce the risk of falling among elderly people living in the community. N Engl J Med. 1994;33:821–827. doi: 10.1056/NEJM199409293311301. [DOI] [PubMed] [Google Scholar]
  • 223.Inouye SK, Studenski S, Tinetti ME, Kuchel GA. Geriatric syndromes: clinical, research, and policy implications of a core geriatric concept. J Am Geriatr Soc. 2007;55:780–791. doi: 10.1111/j.1532-5415.2007.01156.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 224.Janssen I. Influence of sarcopenia on the development of physical disability: the Cardiovascular Health Study. J Am Geriatr Soc. 2006;54:56–62. doi: 10.1111/j.1532-5415.2005.00540.x. [DOI] [PubMed] [Google Scholar]
  • 225.Janssen I, Heymsfield SB, Ross R. Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc. 2002;50:889–896. doi: 10.1046/j.1532-5415.2002.50216.x. [DOI] [PubMed] [Google Scholar]
  • 226.Rolland Y, Lauwers-Cances V, Cristini C, et al. Difficulties with physical function associated with obesity, sarcopenia, and sarcopenic-obesity in community-dwelling elderly women: the EPIDOS (EPIDemiologie de l'OSteoporose) Study. Am J Clin Nutr. 2009;89:1895–1900. doi: 10.3945/ajcn.2008.26950. [DOI] [PubMed] [Google Scholar]
  • 227.Baumgartner RN, Koehler KM, Gallagher D, et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol. 1998;147:755–763. doi: 10.1093/oxfordjournals.aje.a009520. [DOI] [PubMed] [Google Scholar]
  • 228.Newman AB, Kupelian V, Visser M, et al. Sarcopenia: alternative definitions and associations with lower extremity function. J Am Geriatr Soc. 2003;51:1602–1609. doi: 10.1046/j.1532-5415.2003.51534.x. [DOI] [PubMed] [Google Scholar]
  • 229.Janssen I, Baumgartner RN, Ross R, Rosenberg IH, Roubenoff R. Skeletal muscle outpoints associated with elevated physical disability risk in older men and women. Am J Epidemiol. 2004;159:413–421. doi: 10.1093/aje/kwh058. [DOI] [PubMed] [Google Scholar]
  • 230.Visser M, Newman AB, Nevitt MC, et al. Reexamining the sarcopenia hypothesis. Muscle mass versus muscle strength. Health, Aging, and Body Composition Study Research Group. Ann N Y Acad Sci. 2000;904:456–461. [PubMed] [Google Scholar]
  • 231.Moreland JD, Richardson JA, Goldsmith CH, Clase CM. Muscle Weakness and Falls in Older Adults: A Systematic Review and Meta-Analysis. J Am Geriatr Soc. 2004;52:1121–1129. doi: 10.1111/j.1532-5415.2004.52310.x. [DOI] [PubMed] [Google Scholar]
  • 232.Szulc P, Beck TJ, Marchand F, Delmas PD. Low skeletal muscle mass is associated with poor structural parameters of bone and impaired balance in elderly men–the MINOS study. J Bone Miner Res. 2005;20:721–729. doi: 10.1359/JBMR.041230. [DOI] [PubMed] [Google Scholar]
  • 233.Lynch GS. Tackling Australia’s future health problems: developing strategies to combat sarcopenia-age-related muscle wasting and weakness. Internal Medicine Journal. 2004a;34:294–296. doi: 10.1111/j.1444-0903.2004.00568.x. [DOI] [PubMed] [Google Scholar]
  • 234.Janssen I, Shepard DS, Katzmarzyk PT, Roubenoff R. The healthcare costs of sarcopenia in the United States. Journal of the American Geriatrics Society. 2004;52:80–85. doi: 10.1111/j.1532-5415.2004.52014.x. [DOI] [PubMed] [Google Scholar]
  • 235.Rizzoli R. Nutrition: its role in bone health. Best Pract Res Clin Endocrinol Metab. 2008;22:813–829. doi: 10.1016/j.beem.2008.08.005. [DOI] [PubMed] [Google Scholar]
  • 236.Robinson S, Cooper C, Aihie Sayer A. Nutrition and sarcopenia: a review of the evidence and implications for preventive strategies. J Aging Res. 2012;2012:510801. doi: 10.1155/2012/510801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 237.Janssen HC, Samson MM, Verhaar HJ. Vitamin D deficiency, muscle function, and falls in elderly people. Am J Clin Nutr. 2002;75:611–615. doi: 10.1093/ajcn/75.4.611. [DOI] [PubMed] [Google Scholar]
  • 238.Body JJ, Bergmann P, Boonen S, et al. Non-pharmacological management of osteoporosis: a consensus of the Belgian Bone Club. Osteoporos Int. 2011;22:2769–2788. doi: 10.1007/s00198-011-1545-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 239.Gocek E, Marchwicka A, Baurska H, Chrobak A, Marcinkowska E. Opposite regulation of vitamin D receptor by ATRA in AML cells susceptible and resistant to vitamin D-induced differentiation. J Steroid Biochem Mol Biol. 2012 doi: 10.1016/j.jsbmb.2012.07.001. [Epub ahead of print]. [DOI] [PubMed] [Google Scholar]
  • 240.Annweiler C, Montero-Odasso M, Schott AM, Berrut G, Fantino B, Beauchet O. Fall prevention and vitamin D in the elderly: an overview of the key role of the non-bone effects. J Neuroeng Rehabil. 2010;7:50. doi: 10.1186/1743-0003-7-50. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 241.Gielen E, Boonen S, Vanderschueren D, et al. Calcium and vitamin d supplementation in men. J Osteoporos. 2011;2011:875249. doi: 10.4061/2011/875249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 242.Hamilton B. Vitamin D and human skeletal muscle. Scand J Med Sci Sports. 2010;20:182–190. doi: 10.1111/j.1600-0838.2009.01016.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 243.Annweiler C, Schott AM, Berrut G, Fantino B, Beauchet O. Vitamin D-related changes in physical performance: a systematic review. Journal of Nutrition, Health and Aging. 2009;13:893–898. doi: 10.1007/s12603-009-0248-x. [DOI] [PubMed] [Google Scholar]
  • 244.Cesari M, Incalzi RA, Zamboni V, Pahor M. Vitamin D hormone: a multitude of actions potentially influencing the physical function decline in older persons. Geriatr Gerontol Int. 2011;11:133–142. doi: 10.1111/j.1447-0594.2010.00668.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 245.Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. British Medical Journal. 2009;339:b3692. doi: 10.1136/bmj.b3692. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 246.Dawson-Hughes B. Serum 25-hydroxyvitamin D and functional outcomes in the elderly. American Journal of Clinical Nutrition. 2008;88:537S–540S. doi: 10.1093/ajcn/88.2.537S. [DOI] [PubMed] [Google Scholar]
  • 247.Dawson-Hughes B. Primer on the Metabolic Bone Diseases and Disorders of Bone Metabolism. American Society for Bone and Mineral Research, Calcium and vitamin D. 2008:231–233. [Google Scholar]
  • 248.Adams JS, Kantorovich V, Wu C, Javanbakht M, Hollis BW. Resolution of vitamin D insufficiency in osteopenic patients results in rapid recovery of bone mineral density. Journal of Clinical Endocrinology and Metabolism. 1999;84:2729–2730. doi: 10.1210/jcem.84.8.5899. [DOI] [PubMed] [Google Scholar]
  • 249.Freyschuss B, Ljunggren O, Saaf M, Mellstrom D, Avenell A. Calcium and vitamin D for prevention of osteoporotic fractures. Lancet. 2007;370:2098–2099. doi: 10.1016/S0140-6736(07)61896-0. [DOI] [PubMed] [Google Scholar]
  • 250.Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet. 2007;370:657–666. doi: 10.1016/S0140-6736(07)61342-7. [DOI] [PubMed] [Google Scholar]
  • 251.Avenell A, Gillespie WJ, Gillespie LD, O’Connell D. Vitamin D vitamin D analogues for preventing fractures associated with involutionala and postmenopausal osteoporosis. Cochrane Database Syst Rev. 2009;2 doi: 10.1002/14651858.CD000227.pub3. [DOI] [PubMed] [Google Scholar]
  • 252.Ott SM. Review: Vitamin D with calcium reduces fractures in adults. Ann Intern Med. 2012;156:JC6–JC7. doi: 10.7326/0003-4819-156-12-201206190-02007. [DOI] [PubMed] [Google Scholar]
  • 253.Garnero P, Munoz F, Sornay-Rendu E, Delmas PD. Associations of vitamin D status with bone mineral density, bone turnover bone loss fracture risk in healthy postmenopausal women. The OFELY study. Bone. 2007;40:716–722. doi: 10.1016/j.bone.2006.09.026. [DOI] [PubMed] [Google Scholar]
  • 254.Cooper L, Clifton-Bligh PB, Nery ML, et al. Vitamin D supplementation and bone mineral density in early postmenopausal women. American Journal of Clinical Nutrition. 2003;77:1324–1329. doi: 10.1093/ajcn/77.5.1324. [DOI] [PubMed] [Google Scholar]
  • 255.Paddon-Jones D, Sheffield-Moore M, Zhang XJ, et al. Amino acid ingestion improves muscle protein synthesis in the young and elderly. Am J Physiol Endocrinol Metab. 2004;286:E321–E328. doi: 10.1152/ajpendo.00368.2003. [DOI] [PubMed] [Google Scholar]
  • 256.Paddon-Jones D, Sheffield-Moore M, Katsanos CS, Zhang XJ, Wolfe RR. Differential stimulation of muscle protein synthesis in elderly humans following isocaloric ingestion of amino acids or whey protein. Exp Gerontol. 2006;41:215–219. doi: 10.1016/j.exger.2005.10.006. [DOI] [PubMed] [Google Scholar]
  • 257.Volpi E, Kobayashi H, Sheffield-Moore M, Mittendorfer B, Wolfe RR. Essential amino acids are primarily responsible for the amino acid stimulation of muscle protein anabolism in healthy elderly adults. Am J Clin Nutr. 2003;78:250–258. doi: 10.1093/ajcn/78.2.250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 258.Rennie MJ, Wilkes EA. Maintenance of the musculoskeletal mass by control of protein turnover: the concept of anabolic resistance and its relevance to the transplant recipient. Ann Transplant. 2005;10:31–34. [PubMed] [Google Scholar]
  • 259.Paddon-Jones D, Short KR, Campbell WW, Volpi E, Wolfe RR. Role of dietary protein in the sarcopenia of aging. Am J Clin Nutr. 2008;87:1562S–1566S. doi: 10.1093/ajcn/87.5.1562S. [DOI] [PubMed] [Google Scholar]
  • 260.Cuthbertson D, Smith K, Babraj J, et al. Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. Faseb J. 2005;19:422–424. doi: 10.1096/fj.04-2640fje. [DOI] [PubMed] [Google Scholar]
  • 261.Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A, Wolfe RR. Aging is associated with diminished accretion of muscle proteins after the ingestion of a small bolus of essential amino acids. Am J Clin Nutr. 2005;82:1065–1073. doi: 10.1093/ajcn/82.5.1065. [DOI] [PubMed] [Google Scholar]
  • 262.Houston DK, Nicklas BJ, Ding J, et al. Dietary protein intake is associated with lean mass change in older, community-dwelling adults: the Health, Aging, and Body Composition (Health ABC) study. American Journal of Clinical Nutrition. 2008;87:150–155. doi: 10.1093/ajcn/87.1.150. [DOI] [PubMed] [Google Scholar]
  • 263.Børsheim E, Bui QT, Tissier S, Kobayashi H, Ferrando AA, Wolfe RR. Effect of amino acid supplementation on muscle mass, strength and physical function in elderly. Clinical Nutrition. 2008;27:189–195. doi: 10.1016/j.clnu.2008.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 264.Paddon-Jones D, Rasmussen BB. Dietary protein recommendations and the prevention of sarcopenia. Current Opinion in Clinical Nutrition and Metabolic Care. 2009;12:86–90. doi: 10.1097/MCO.0b013e32831cef8b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 265.Milne AC, Potter J, Vivanti A, Avenell A. Protein and energy supplementation in elderly people at risk from malnutrition. Cochrane Database of Systematic Reviews. 2009 doi: 10.1002/14651858.CD003288.pub3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 266.Waters DL, Baumgartner RN, Garry PJ, Vellas B. Advantages of dietary, exercise-related, and therapeutic interventions to prevent and treat sarcopenia in adult patients: an update. Clin Interv Aging. 2010;5:259–270. doi: 10.2147/cia.s6920. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 267.Kim JS, Wilson JM, Lee SR. Dietary implications on mechanisms of sarcopenia: roles of protein, amino acids and antioxidants. J Nutr Biochem. 2010;21:1–13. doi: 10.1016/j.jnutbio.2009.06.014. [DOI] [PubMed] [Google Scholar]
  • 268.Rieu I, Balage M, Sornet C, et al. Increased availability of leucine with leucine-rich whey proteins improves postprandial muscle protein synthesis in aging rats. Nutrition. 2007;23:323–331. doi: 10.1016/j.nut.2006.12.013. [DOI] [PubMed] [Google Scholar]
  • 269.Hayes A, Cribb PJ. Effect of whey protein isolate on strength, body composition and muscle hypertrophy during resistance training. Curr Opin Clin Nutr Metab Care. 2008;11:40–44. doi: 10.1097/MCO.0b013e3282f2a57d. [DOI] [PubMed] [Google Scholar]
  • 270.Symons TB, Sheffield-Moore M, Wolfe RR, Paddon-Jones D. A moderate serving of high-quality protein maximally stimulates skeletal muscle protein synthesis in young and elderly subjects. J Am Diet Assoc. 2009;109:1582–1586. doi: 10.1016/j.jada.2009.06.369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 271.Blomstrand E, Eliasson J, Karlsson HK, Kohnke R. Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise. J Nutr. 2006;136:269S–273S. doi: 10.1093/jn/136.1.269S. [DOI] [PubMed] [Google Scholar]
  • 272.Feskanich D, Willett WC, Stampfer MJ, Colditz GA. Protein consumption and bone fractures in women. Am J Epidemiol. 1996;143:472–479. doi: 10.1093/oxfordjournals.aje.a008767. [DOI] [PubMed] [Google Scholar]
  • 273.Surdykowski AK, Kenny AM, Insogna KL, Kerstetter JE. Optimizing bone health in older adults: the importance of dietary protein. Aging health. 2010;6:345–357. doi: 10.2217/ahe.10.16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 274.Munger RG, Cerhan JR, Chiu BC. Prospective study of dietary protein intake and risk of hip fracture in postmenopausal women. Am J Clin Nutr. 1999;69:147–152. doi: 10.1093/ajcn/69.1.147. [DOI] [PubMed] [Google Scholar]
  • 275.Zhong Y, Okoro CA, Balluz LS. Association of total calcium and dietary protein intakes with fracture risk in postmenopausal women: the 1999–2002 National Health and Nutrition Examination Survey (NHANES) Nutrition. 2009;25:647–654. doi: 10.1016/j.nut.2008.12.002. [DOI] [PubMed] [Google Scholar]
  • 276.Hannan MT, Felson DT, Dawson-Hughes B, et al. Risk factors for longitudinal bone loss in elderly men and women: the Framingham Osteoporosis Study. J Bone Miner Res. 2000;15:710–720. doi: 10.1359/jbmr.2000.15.4.710. [DOI] [PubMed] [Google Scholar]
  • 277.Dawson-Hughes B, Harris SS. Calcium intake influences the association of protein intake with rates of bone loss in elderly men and women. Am J Clin Nutr. 2002;75:773–779. doi: 10.1093/ajcn/75.4.773. [DOI] [PubMed] [Google Scholar]
  • 278.Devine A, Dick IM, Islam AF, Dhaliwal SS, Prince RL. Protein consumption is an important predictor of lower limb bone mass in elderly women. Am J Clin Nutr. 2005;81:1423–1428. doi: 10.1093/ajcn/81.6.1423. [DOI] [PubMed] [Google Scholar]
  • 279.Darling AL, Millward DJ, Torgerson DJ, Hewitt CE, Lanham-New SA. Dietary protein and bone health: a systematic review and meta-analysis. Am J Clin Nutr. 2009;90:1674–1692. doi: 10.3945/ajcn.2009.27799. [DOI] [PubMed] [Google Scholar]
  • 280.Sellmeyer DE, Stone KL, Sebastian A, Cummings SR. A high ratio of dietary animal to vegetable protein increases the rate of bone loss, the risk of fracture in postmenopausal women Study of Osteoporotic Fractures Research Group. Am J Clin Nutr. 2001;73:118–122. doi: 10.1093/ajcn/73.1.118. [DOI] [PubMed] [Google Scholar]
  • 281.Arnett T. Regulation of bone cell function by acid-base balance. Proc Nutr Soc. 2003;62:511–520. doi: 10.1079/pns2003268. [DOI] [PubMed] [Google Scholar]
  • 282.McKenzie D, Bua E, McKiernan S, Cao Z, Aiken JM, Jonathan Wanagat. Mitochondrial DNA deletion mutations: a causal role in sarcopenia. Eur J Biochem. 2002;269:2010–2015. doi: 10.1046/j.1432-1033.2002.02867.x. [DOI] [PubMed] [Google Scholar]
  • 283.Wauquier F, Leotoing L, Coxam V, Guicheux J, Wittrant Y. Oxidative stress in bone remodelling and disease. Trends Mol Med. 2009;15:468–477. doi: 10.1016/j.molmed.2009.08.004. [DOI] [PubMed] [Google Scholar]
  • 284.Sahni S, Hannan MT, Gagnon D, et al. Protective effect of total and supplemental vitamin C intake on the risk of hip fracture–a 17-year follow-up from the Framingham Osteoporosis Study. Osteoporos Int. 2009;20:1853–1861. doi: 10.1007/s00198-009-0897-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 285.Semba DR, Ferrucci L, Sun K, et al. Oxidative stress and severe walking disability among older women. The American Journal of Medicine. 2007;120:1084–1089. doi: 10.1016/j.amjmed.2007.07.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 286.Mackinnon ES, Rao AV, Josse RG, Rao LG. Supplementation with the antioxidant lycopene significantly decreases oxidative stress parameters and the bone resorption marker N-telopeptide of type I collagen in postmenopausal women. Osteoporos Int. 2011;22:1091–1101. doi: 10.1007/s00198-010-1308-0. [DOI] [PubMed] [Google Scholar]
  • 287.Ruiz-Ramos M, Vargas LA, Fortoul Van der Goes TI, Cervantes-Sandoval A, Mendoza-Nunez VM. Supplementation of ascorbic acid and alpha-tocopherol is useful to preventing bone loss linked to oxidative stress in elderly. J Nutr Health Aging. 2010;14:467–472. doi: 10.1007/s12603-010-0099-5. [DOI] [PubMed] [Google Scholar]
  • 288.Chuin A, Labonte M, Tessier D, et al. Effect of antioxidants combined to resistance training on BMD in elderly women: a pilot study. Osteoporos Int. 2009;20:1253–1258. doi: 10.1007/s00198-008-0798-5. [DOI] [PubMed] [Google Scholar]
  • 289.Fusco D, Colloca G, Lo Monaco MR, Cesari M. Effects of antioxidant supplementation on the aging process. Clin Interv Aging. 2007;2:377–387. [PMC free article] [PubMed] [Google Scholar]
  • 290.Kaptoge S, Dalzell N, Jakes RW, Wareham N, Day NE, Khaw KT, Beck TJ, Loveridge N, Reeve J. Hip section modulus, a measure of bending resistance, is more strongly related to reported physical activity than BMD. Osteoporos Int. 2003;14:941–949. doi: 10.1007/s00198-003-1484-2. [DOI] [PubMed] [Google Scholar]
  • 291.Rittweger J, Simunic B, Bilancio G, et al. Bone loss in the lower leg during 35 days of bed rest is predominantly from the cortical compartment. Bone. 2009;44:612–618. doi: 10.1016/j.bone.2009.01.001. [DOI] [PubMed] [Google Scholar]
  • 292.Rolland Y, Czerwinski S, Abellan Van Kan G, et al. Sarcopenia: its assessment, etiology, pathogenesis, consequences and future perspectives. J Nutr Health Aging. 2008;12:433–450. doi: 10.1007/BF02982704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 293.Lee JS, Auyeung TW, Kwok T, Lau EM, Leung PC, Woo J. Associated factors and health impact of sarcopenia in older Chinese men and women: a cross-sectional study. Gerontology. 2007;53:404–410. doi: 10.1159/000107355. [DOI] [PubMed] [Google Scholar]
  • 294.Kortebein P, Ferrando A, Lombeida J, Wolfe R, Evans WJ. Effect of 10 days of bed rest on skeletal muscle in healthy older adults. JAMA. 2007;297:1772–1774. doi: 10.1001/jama.297.16.1772-b. [DOI] [PubMed] [Google Scholar]
  • 295.Hasten DL, Pak-Loduca J, Obert KA, Yarasheski KE. Resistance exercise acuteky increases MHC and mioxed muscle protein synthesis rates in 78–84 and 23–32 yr olds. American Journal of hysiology. 1993;265:E620–E626. doi: 10.1152/ajpendo.2000.278.4.E620. [DOI] [PubMed] [Google Scholar]
  • 296.Cress ME, Buchner DM, Questad KA, Esselman PC, deLateur BJ, Schwartz RS. Exercise: effects of physical functional performance in independent older adults. J Gerontol A Biol Sci Med Sci. 1999;54:242–248. doi: 10.1093/gerona/54.5.m242. [DOI] [PubMed] [Google Scholar]
  • 297.Sheffield-Moore M, Yeckel CW, Volpi E, et al. Postexercise protein metabolism in older and younger men following moderate-intensity aerobic exercise. Am J Physiol Endocrinol Metab. 2004;287:E513–E522. doi: 10.1152/ajpendo.00334.2003. [DOI] [PubMed] [Google Scholar]
  • 298.Charifi N, Kadi F, Feasson L, Denis C. Effects of endurance training on satellite cell frequency in skeletal muscle of old men. Muscle Nerve. 2003;28:87–92. doi: 10.1002/mus.10394. [DOI] [PubMed] [Google Scholar]
  • 299.Raguso CA, Kyle U, Kossovsky MP, et al. A 3-year longitudinal study on body composition changes in the elderly: role of physical exercise. Clin Nutr. 2006;25:573–580. doi: 10.1016/j.clnu.2005.10.013. [DOI] [PubMed] [Google Scholar]
  • 300.Latham NK, Anderson CS, Lee A, Bennett DA, Moseley A, Cameron ID. Fitness Collaborative. Group A randomized, controlled trial of quadriceps resistance exercise and vitamin D in frail older people: the Frailty Interventions Trial in Elderly Subjects (FITNESS) J Am Geriatr Soc. 2003;51:291–299. doi: 10.1046/j.1532-5415.2003.51101.x. [DOI] [PubMed] [Google Scholar]
  • 301.Blain H, Vuillemin A, Teissier A, Hanesse B, Guillemin F, Jeandel C. Influence of muscle strength and body weight and composition on regional bone mineral density in healthy women aged 60 years and over. Gerontology. 2001;47:207–212. doi: 10.1159/000052800. [DOI] [PubMed] [Google Scholar]
  • 302.Nguyen TV, Sambrook PN, Eisman JA. Bone loss, physical activity, and weight change in elderly women: the Dubbo Osteoporosis Epidemiology Study. J Bone Miner Res. 1998;13:1458–1467. doi: 10.1359/jbmr.1998.13.9.1458. [DOI] [PubMed] [Google Scholar]
  • 303.Sirola J, Tuppurainen M, Honkanen R, Jurvelin JS, Kroger H. Associations between grip strength change and axial postmenopausal bone loss--a 10-year population-based follow-up study. Osteoporos Int. 2005;16:1841–1848. doi: 10.1007/s00198-005-1944-y. [DOI] [PubMed] [Google Scholar]
  • 304.Howe TE, Shea B, Dawson LJ, et al. Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev. 2011 doi: 10.1002/14651858.CD000333.pub2. [DOI] [PubMed] [Google Scholar]
  • 305.Bonaiuti D, Shea B, Iovine R, et al. Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Reviews. 2009 doi: 10.1002/14651858.CD000333. [DOI] [PubMed] [Google Scholar]
  • 306.Russo CR. The effects of exercise on bone. Basic concepts and implications for the prevention of fractures. Clin Cases Miner Bone Metab. 2009;6:223–228. [PMC free article] [PubMed] [Google Scholar]
  • 307.Sayer AA, Syddall HE, Martin HJ, Dennison EM, Anderson FH, Cooper C. Falls, sarcopenia, and growth in early life: findings from the Hertfordshire cohort study. Am J Epidemiol. 2006;164:665–671. doi: 10.1093/aje/kwj255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 308.Inderjeeth CA, Foo AC, Lai MM, Glendenning P. Efficacy and safety of pharmacological agents in managing osteoporosis in the old: review of the evidence. Bone. 2009;44:744–751. doi: 10.1016/j.bone.2008.12.003. [DOI] [PubMed] [Google Scholar]
  • 309.Boonen S, Dejaeger E, Vanderschueren D, et al. Osteoporosis and osteoporotic fracture occurrence and prevention in the elderly: a geriatric perspective. Best Pract Res Clin Endocrinol Metab. 2008;22:765–785. doi: 10.1016/j.beem.2008.07.002. [DOI] [PubMed] [Google Scholar]
  • 310.Reginster JY. Antifracture efficacy of currently available therapies for postmenopausal osteoporosis. Drugs. 2011;71:65–78. doi: 10.2165/11587570-000000000-00000. [DOI] [PubMed] [Google Scholar]
  • 311.Rizzoli R. Management of the oldest old with osteoporosis European Geriatric Medicine. 2010;1:15–21. [Google Scholar]
  • 312.Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and non-vertebral fractures in women with post-menopausal osteoporosis: a randomised controlled trial. JAMA. 1999;28:1344–1352. doi: 10.1001/jama.282.14.1344. [DOI] [PubMed] [Google Scholar]
  • 313.Reginster JY, Minne HW, Sorenson OH, et al. Randomised trial of the effects of risedronate on vertebral fracture in women with established postmenopausal osteoporosis. Osteoporos Int. 2000;11:83–91. doi: 10.1007/s001980050010. [DOI] [PubMed] [Google Scholar]
  • 314.Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1–34) on fractures and bone density in post-menopausal women with osteoporosis. N Eng J Med. 2001;344:1434–1441. doi: 10.1056/NEJM200105103441904. [DOI] [PubMed] [Google Scholar]
  • 315.Walsh JB, Lems WF, Karras D, et al. Effectiveness of Teriparatide in women over 75 years of age with severe osteoporosis: 36-month results from the European Forsteo Observational Study (EFOS) Calcif Tissue Int. 2012;90:373–383. doi: 10.1007/s00223-012-9590-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 316.Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Eng J Med. 2004;350:459–468. doi: 10.1056/NEJMoa022436. [DOI] [PubMed] [Google Scholar]
  • 317.Ensrud KE, Black DM, Palermo L, et al. Treatment with alendronate prevents fractures in women at highest risk: results from the fracture intervention trial. Arch Int Med. 1997;157:2617–2624. [PubMed] [Google Scholar]
  • 318.Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756–765. doi: 10.1056/NEJMoa0809493. [DOI] [PubMed] [Google Scholar]
  • 319.Boonen S, Adachi JD, Man Z, et al. Treatment with denosumab reduces the incidence of new vertebral and hip fractures in post-menopausal women at high risk. J Clin Endocrinol Metab. 2011;96:1727–1736. doi: 10.1210/jc.2010-2784. [DOI] [PubMed] [Google Scholar]
  • 320.Papapoulos S, Chapurlat R, Libanati C, et al. Five years of denosumab exposure in women with ostmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res. 2012;27:694–701. doi: 10.1002/jbmr.1479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 321.Inderjeeth CA, Chan K, Kwan K, Lai M. Time to onset of efficacy in fracture reduction with current anti-osteoporosis treatments. J Bone Miner Metab. 2012 doi: 10.1007/s00774-012-0349-1. [Epub ahead of print] [DOI] [PubMed] [Google Scholar]
  • 322.Boonen S, Black DM, Colon-Emeric CS, et al. Efficacy and safety of a once-yearly intravenous zoledronic acid 5 mg for fracture prevention in elderly postmenopausal women with osteoporosis aged 75 and older. J Am Geriatr Soc. 2010;58:292–299. doi: 10.1111/j.1532-5415.2009.02673.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 323.McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Eng J Med. 2001;344:333–340. doi: 10.1056/NEJM200102013440503. [DOI] [PubMed] [Google Scholar]
  • 324.McCloskey EV, Beneton M, Charlesworth D, et al. Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled study. J BoneMiner Res. 2007;22:135–134. doi: 10.1359/jbmr.061008. [DOI] [PubMed] [Google Scholar]
  • 325.McCloskey EV, Johansson H, Oden A, et al. Denosumab reduces the risk of osteoporotic fractures in postmenopausal women, particularly in those with moderate to high fracture risk as assessed with FRAX. J Bone Miner Res. 2012;27:1480–1486. doi: 10.1002/jbmr.1606. [DOI] [PubMed] [Google Scholar]
  • 326.Seeman E, Vellas B, Benhamou C, et al. Strontium ranelate reduces the risk of vertebral and non-vertebral fractures in women 80 years of age and older. J Bone Miner Res. 2006;21:1113–1120. doi: 10.1359/jbmr.060404. [DOI] [PubMed] [Google Scholar]
  • 327.Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium ranelate reduces the risk of non-vertebral fracture in post-menopausal women with osteoporosis: treatment of peripheral osteoporosis: TROPOS Study. J Clin Endocrinol Metab. 2005;90:2816–2822. doi: 10.1210/jc.2004-1774. [DOI] [PubMed] [Google Scholar]
  • 328.Boonen S, Dejaeger E, Vanderschueren D, et al. Osteoporosis and osteoporotic fracture occurrence and prevention in the elderly: a geriatric perspective. Best Pract Res Clin Endocrinol Metab. 2008;22:765–785. doi: 10.1016/j.beem.2008.07.002. [DOI] [PubMed] [Google Scholar]
  • 329.Rajzbaum G, Jakob F, Karras D, et al. Characterization of patients in the European Forsteo Observational Study (EFOS): postmenopausal women entering teriparatide treatment in a community setting. Curr Med Res Opin. 2008;24:377–384. doi: 10.1185/030079908x261087. [DOI] [PubMed] [Google Scholar]
  • 330.Eisman J, Clapham S, Kehoe L. Australian BoneCare Study. Osteoporosis prevalence and levels of treatment in primary care: the Australian BoneCare Study. J Bone Miner Res. 2004;19:1969–1975. doi: 10.1359/JBMR.040905. [DOI] [PubMed] [Google Scholar]
  • 331.Klotzbuecher CM, Ross PD, Landsman PB, Abbott TA, 3rd, Berger M. Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res. 2000;15:721–739. doi: 10.1359/jbmr.2000.15.4.721. [DOI] [PubMed] [Google Scholar]
  • 332.Seeman E, Vellas B, Benhamou C, et al. Strontium ranelate reduces the risk of vertebral and nonvertebral fractures in women eighty years of age and older. J Bone Miner Res. 2006;21:1113–1120. doi: 10.1359/jbmr.060404. [DOI] [PubMed] [Google Scholar]
  • 333.Jansen JP, Bergman GJ, Huels J, Olson M. Prevention of vertebral fractures in osteoporosis: mixed treatment comparison of bisphosphonate therapies. Curr Med Res Opin. 2009;25:1861–1868. doi: 10.1185/03007990903035281. [DOI] [PubMed] [Google Scholar]
  • 334.Jansen JP, Bergman GJ, Huels J, Olson M. The efficacy of bisphosphonates in the prevention of vertebral, hip, and nonvertebral-nonhip fractures in osteoporosis: a network meta-analysis. Semin Arthritis Rheum. 2011;40:275.e1-2–284.e1-2. doi: 10.1016/j.semarthrit.2010.06.001. [DOI] [PubMed] [Google Scholar]
  • 335.Hopkins RB, Goeree R, Pullenayegum E, et al. The relative efficacy of nine osteoporosis medications for reducing the rate of fractures in post-menopausal women. BMC Musculoskelet Disord. 2011;12:209. doi: 10.1186/1471-2474-12-209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 336.Gruenewald DA, Matsumoto AM. Testosterone supplementation therapy for older men: potential benefits and risks. J Am Geriatr Soc. 2003;51:101–115. doi: 10.1034/j.1601-5215.2002.51018.x. [DOI] [PubMed] [Google Scholar]
  • 337.Sinha-Hikim I, Taylor WE, Gonzalez-Cadavid NF, Zheng W, Bhasin S. Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment. J Clin Endocrinol Metab. 2004;89:5245–5255. doi: 10.1210/jc.2004-0084. [DOI] [PubMed] [Google Scholar]
  • 338.Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 2004;350:482–492. doi: 10.1056/NEJMra022251. [DOI] [PubMed] [Google Scholar]
  • 339.Clarke BL, Khosla S. New selective estrogen and androgen receptor modulators. Curr Opin Rheumatol. 2009;21:374–379. doi: 10.1097/BOR.0b013e32832ca447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 340.Senechal M, Arguin H, Bouchard DR, et al. Weight gain since menopause and its associations with weight loss maintenance in obese postmenopausal women. Clin Interv Aging. 2011;6:221–225. doi: 10.2147/CIA.S23574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 341.Taaffe DR, Newman AB, Haggerty CL, et al. Estrogen replacement, muscle composition, and physical function: The Health ABC Study. Med Sci Sports Exerc. 2005;37:1741–1747. doi: 10.1249/01.mss.0000181678.28092.31. [DOI] [PubMed] [Google Scholar]
  • 342.Chlebowski RT, Hendrix SL, Langer RD, et al. WHI Investigators Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA. 2003;289:3243–3253. doi: 10.1001/jama.289.24.3243. [DOI] [PubMed] [Google Scholar]
  • 343.Sattler FR, Castaneda-Sceppa C, Binder EF, et al. Testosterone and growth hormone improve body composition and muscle performance in older men. J Clin Endocrinol Metab. 2009;94:1991–2001. doi: 10.1210/jc.2008-2338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 344.Blackman MR, Sorkin JD, Münzer T, et al. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA. 2002;288:2282–2292. doi: 10.1001/jama.288.18.2282. [DOI] [PubMed] [Google Scholar]
  • 345.Sherlock M, Toogood AA. Aging and the growth hormone/insulin like growth factor-I axis. Pituitary. 2007;10:189–203. doi: 10.1007/s11102-007-0039-5. [DOI] [PubMed] [Google Scholar]
  • 346.Sakuma K, Yamaguchi A. Sarcopenia and age-related endocrine function. Int J Endocrinol. 2012;2012:127362. doi: 10.1155/2012/127362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 347.Papadakis MA, Hamon G, Stotts N, et al. Effect of growth hormone replacement on wound healing in healthy older men. Wound Repair Regen. 1996;4:421–425. doi: 10.1046/j.1524-475X.1996.40405.x. [DOI] [PubMed] [Google Scholar]
  • 348.Welle S, Thornton C, Start M, McHenry B. Growth hormone increases muscle mass and strength but does not rejuvenate myofibrillar protein synthesis in healthy subjects over 60 years old. J Clin Endocrinol Metab. 1996;81:3239–3243. doi: 10.1210/jcem.81.9.8784075. [DOI] [PubMed] [Google Scholar]
  • 349.Lange KH, Andersen JL, Beyer N, et al. GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men. J Clin Endocrinol Metab. 2002;87:513–523. doi: 10.1210/jcem.87.2.8206. [DOI] [PubMed] [Google Scholar]
  • 350.Papadakis MA, Grady D, Black D, et al. Growth hormone replacement in healthy older men improves body composition but not functional ability. Ann Intern Med. 1996;124:708–716. doi: 10.7326/0003-4819-124-8-199604150-00002. [DOI] [PubMed] [Google Scholar]
  • 351.McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA. 1997;94:12457–12461. doi: 10.1073/pnas.94.23.12457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 352.Mendias CL, Bakhurin KI, Faulkner JA. Tendons of myostatin-deficient mice are small, brittle, and hypocellular. Proc Natl Acad Sci U S A. 2008;105:388–393. doi: 10.1073/pnas.0707069105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 353.Kjaer M, Jespersen JG. The battle to keep or lose skeletal muscle with ageing. J Physiol. 2009;587:1–2. doi: 10.1113/jphysiol.2008.167049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 354.Wagner KR, Fleckenstein JL, Amato AA, et al. A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol. 2008;63:561–571. doi: 10.1002/ana.21338. [DOI] [PubMed] [Google Scholar]
  • 355.Lee SJ, Reed LA, Davies MV, et al. Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc Natl Acad Sci USA. 2005;102:18117–18122. doi: 10.1073/pnas.0505996102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 356.Sumukadas D, Witham MD, Struthers AD, McMurdo ME. Effect of perindopril on physical function in elderly people with functional impairment: a randomized controlled trial. CMAJ. 2007;177:867–874. doi: 10.1503/cmaj.061339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 357.Bunout D, Barrera G, de la Maza MP, Leiva L, Backhouse C, Hirsch S. Effects of enalapril or nifedipine on muscle strength or functional capacity in elderly subjects. A double blind trial. J Renin Angiotensin Aldosterone Syst. 2009;10:77–84. doi: 10.1177/1470320309105338. [DOI] [PubMed] [Google Scholar]

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