Skip to main content
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2019 Jul 1.
Published in final edited form as: Metabolism. 2017 Dec 9;84:28–43. doi: 10.1016/j.metabol.2017.12.002

The Importance of the Circadian System & Sleep for Bone Health

Christine M Swanson 1, Wendy M Kohrt 2, Orfeu M Buxton 3,4,5,6, Carol A Everson 7, Kenneth P Wright Jr 1,8, Eric S Orwoll 9, Steven A Shea 10,11
PMCID: PMC5994176  NIHMSID: NIHMS934009  PMID: 29229227

Summary

Adequate sleep timed appropriately during the circadian night is important for numerous biological processes and systems. New evidence suggests that both sleep timing and duration may be important for optimal bone health as well. This review examines the diurnal variation of bone turnover markers (BTMs) and the importance of circadian clock genes in regulating bone mass. In addition, this review explores the evidence for a link between shift work (and its associated disturbances in sleep duration/quality and circadian alignment) and alterations in bone metabolism and bone health. Finally, we review how commonly used medications and over-the-counter substances (e.g. caffeine, melatonin) complicate the relationship between sleep and circadian disorders and bone health.

Keywords: sleep, circadian, bone, fracture, bone turnover

1.0 Introduction

Adequate amounts of appropriately timed sleep are necessary for optimal health and safety [1] while alterations in the timing and duration of sleep are associated with numerous metabolic, cardiovascular, endocrine, and neurological disorders [25]. Consistent with reports of increased fracture risk with shift work [6], sleep and circadian disruption can increase sleepiness and reduce vigilance to environmental hazards [79], and possibly adversely affect balance [10, 11] which all can lead to an increased risk of falls and bone fracture [12, 13]. Furthermore, the daily rhythm in bone turnover markers (BTMs) [14, 15], the existence of clock genes in bone cells, the identification of altered skeletal phenotypes in clock gene knockout (KO) models [1620], and the discovery that repeated sleep restriction arrests bone remodeling in laboratory rats [21], all indicate that disruptions in the physiology of sleep and circadian rhythmicity may also affect bone health.

Bone remodeling occurs throughout life as a tightly regulated process that balances bone resorption (performed by osteoclasts) and bone formation (performed by osteoblasts) (Figure 1). Bone turnover, directed in part by the osteocyte, serves to regulate calcium balance, repair microscopic cracks sustained during normal activity, and heal fractures. An imbalance between bone resorption and formation, as occurs with aging, sex hormone deficiency, or use of medications that alter bone metabolism (e.g., glucocorticoids), results in fragile bones (osteoporosis), and an increased risk of fracture. Biochemical markers of bone resorption and to a lesser degree, bone formation peak overnight [14, 22]. Conversely, some factors used for bone cell communication (e.g., nuclear factor kappa B (NF-kB) ligand [RANKL], osteoprotegerin [OPG], sclerostin) have not demonstrated consistent rhythmicity [2225]. The increase in BTMs overnight suggests bone remodeling may be affected in the millions of individuals who experience sleep and circadian disturbances.

Figure 1. Bone matrix and cells with representative 24h profiles of bone cell markers.

Figure 1

Osteoclasts (bone resorption) attach to the bone surface and secrete factors that degrade bone collagen, releasing CTX (and other breakdown products). Osteoblasts form bone matrix to fill in the resorption cavity. An important element in bone formation involves procollagen synthesis and its cleavage to form collagen, the main scaffolding for the bone matrix. When procollagen is cleaved, its terminal ends are released (P1NP, P1CP). Osteoclast and osteoblast activity are coupled, and regulated, in part, by the osteocyte. The osteocyte is a terminally differentiated osteoblast imbedded in the bone matrix that secretes proteins (such as FGF-23). Osteocytes use dendritic processes to sense mechanical loading and transmit signals to regulate the activity of other bone cells. Markers of bone turnover, such as CTX and P1NP, and the osteocyte-derived protein FGF-23 display a 24h diurnal variation (representative curves generated using data from Swanson et al [22]).

The timing and duration of sleep are influenced by environmental (light/dark cycles, work schedules, duration of prior wakefulness) and circadian (internal biological timing) factors. Circadian rhythmicity is maintained through a well-described molecular clock involving the transcription of circadian-related genes such as Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) which are activated by the dimerization of brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK). PER and CRY proteins then inhibit the BMAL1-CLOCK complex, until they are degraded, a cycle that takes approximately 24 hours (h), at which time the cycle starts again [18, 19]. Such clock genes have been identified in the central clock located in the hypothalamic suprachiasmatic nucleus (SCN), and in peripheral cells [26], including osteoclasts [16, 27], osteoblasts [19, 28], and osteocytes [19]. The central clock communicates with peripheral clocks through a variety of mechanisms including direct neural connections, hormonal signals (e.g. melatonin, cortisol), the sympathetic nervous system (SNS), and body temperature regulation to ensure synchronization across the organism [29]. In human osteoblast cell cultures, 2 hours of exposure to dexamethasone or isoprenaline (a β–adrenergic agonist) induced expression of clock genes but variable expression of osteoblast markers (e.g. osteocalcin) [28]. Data from the same group suggests dexamethasone may also stimulate clock gene expression in murine osteoclast cultures [27]. These studies suggest that the SNS and glucocorticoids may play a role in synchronizing the SCN with peripheral bone clock genes. During entrainment to the light-dark cycle, the central clock and peripheral clocks located in cells outside of the SCN are synchronized. However, circadian disruption as can occur acutely with jet lag, or chronically with night shift work and “social jet lag” [30], can cause external/internal desynchrony resulting in numerous health consequences [2, 31]. A 24h rhythm can be driven by this endogenous circadian system that coordinates cellular processes in anticipation of expected daily behaviors. Physiological variability across the day and night can also occur acutely in response to (rather than in anticipation of) daily behavioral patterns (e.g. wake-sleep, fasting-feeding, light-dark). The anticipatory (endogenous) vs. reactive (behavioral) control of the daily patterns in biological processes has important implications for both how rhythms are affected by circadian disruption and for designing appropriate therapies. Disturbances in the timing and duration of sleep or in the biological processes normally served by sleep could potentially disrupt the rhythmicity of BTMs, the balance between bone resorption and formation, and consequently bone mass/quality and fracture risk.

Night shift work inherently alters sleep timing and duration and has been associated with low bone mineral density (BMD) [32] and an increased risk of fracture [6]. Night-shift work is unavoidable in today’s society, and almost one in five of the American work-force performs some kind of shift work [33]. Therefore, it is important to understand how sleep and circadian disruption affect different biological systems, such as bone metabolism. That information may help identify and implement appropriate therapy to mitigate the risks associated with shift work. Here we review the physiology underlying the relationships between bone metabolism/health, the circadian system and sleep; examine the relationship between night-shift work (and its associated sleep/circadian disruptions) and bone health; and consider how medications and over-the-counter substances (e.g. caffeine, melatonin) commonly used to treat various sleep/circadian disturbances may influence the risk of osteoporosis and fracture.

2.0 Methods

PubMed was searched for the following terms: bone AND sleep; sleep AND fracture; (osteoblast OR osteoclast OR osteocyte) AND (circadian OR rhythm OR sleep); (shift work OR circadian misalignment OR sleep duration) AND (low BMD OR fracture OR osteoporosis); (sleep medication OR benzodiazepine OR Ambien OR Z-drugs) AND (bone OR fracture OR osteoporosis); (caffeine OR melatonin use) AND bone; and Suvorexant AND (falls OR fracture OR bone OR osteoporosis). Search results were reviewed for relevance based on title and abstract. Relevant articles were also identified from the authors’ catalogs, if not already found in the above searches. Relevant articles in English were reviewed.

3.0 The physiologic link between the endogenous circadian system and bone metabolism

Daily variations in normal bone physiology suggest there is a time-dependent component of bone turnover that is important for optimal bone health and that sleep or circadian disruptions could negatively affect the skeleton. Disturbances in circadian clock genes alter skeletal phenotype [1620]. In addition, data suggest that circadian timing may play a role in fracture healing [34] and the optimal response to osteoporosis pharmacotherapy [35, 36].

BTMs Display a 24h Rhythm

BTMs display a diurnal rhythm in humans [14, 15]. In vitro studies demonstrate clock gene expression in bone and suggest this peripheral tissue has endogenous circadian rhythmicity [37, 38]. BTM levels increase overnight, with a peak in the early morning hours, and decrease across the day with a nadir in the late afternoon [14]. This rhythm is more robust in markers of bone resorption (such as C-terminal cross-linked telopeptide of type I collagen - CTX), than in markers of bone formation (such as N-terminal propeptide of type I procollagen - P1NP).

Bone resorption markers, including serum and urinary CTX [14], serum and urinary N-terminal cross-linked telopeptide of type I collagen (NTX) [39], and urinary pyridinium crosslinks [40], have a clear sinusoidal rhythm across the 24h day (Figure 1). The amplitude of the rhythms is diminished with fasting [14, 41, 42] and with anti-resorptive therapy [39], however, the general 24h sinusoidal curve persists. The 24h profile of bone resorption markers is unrelated to sex [14, 43], age [14], menopausal status [14], posture/bedrest [14], or parathyroid hormone (PTH) [44]. Two human studies have shown that the 24h profile of bone resorption markers are not associated with serum cortisol [45, 46]. These data conflict with two earlier reports [43, 47]. There are challenges in studying the relationship between cortisol and the rhythmicity of bone resorption markers, including the inability to pharmacologically mimic the physiologic concentrations and pulsatility of cortisol. Although murine cell culture data suggest glucocorticoids may be important in central-peripheral osteoclast clock synchronization, human data (including the large, rigorous study designs employed by Heshmati et al [46] and Schlemmer et al [45]) suggest cortisol does not have a dominant role in bone resorption marker rhythmicity. The persistence of CTX rhythmicity in blind individuals suggests independence from the light/dark cycle [14]. Oral intake of food and calcium can decrease levels of bone resorption markers, depending on the time of intake [48], with postprandial decreases likely mediated by glucagon-like-peptide-2 (GLP-2) [42, 49]. Although circadian protocols in humans that are capable of separating endogenous (circadian) rhythms from exogenous (behavioral/environmental) diurnal profiles are lacking, the daily variation of bone resorption markers likely reflects an endogenous circadian rhythm that is important for normal bone metabolism but that can be influenced by exogenous effects (e.g. behavior or environmental changes).

The general shape and timing of bone formation marker rhythmicity is similar to that of bone resorption markers, however, the amplitudes and regulatory pathways differ. Osteocalcin, a protein produced by the osteoblast primarily during mineralization, is used to reflect osteoblast activity [50, 51]. Osteocalcin displays a consistent rhythmicity, similar to that of bone resorption markers, peaking overnight in the early morning hours [14]. Its 24h pattern is not related to that of growth hormone (GH) [50], but is related to serum cortisol [46]. Conversely, P1NP, the N-terminal portion of procollagen that is cleaved to form collagen for the bone matrix, has a smaller amplitude rhythm appreciated only in large studies (Figure 1) [15, 22, 35]. It is possible that the rhythm robustness of bone cells is reflective of their respective functions or cell lineage – osteoclasts are derived from hematopoietic stem cells and osteoblasts are derived from mesenchymal stem cells. The clinical implications of the relatively larger overnight increase in bone resorption compared to bone formation markers are not yet understood. This balance may be important for normal bone metabolism and perturbations in circadian rhythmicity and timing of food intake (e.g., night-shift work) could alter bone metabolism and health.

The osteocyte is a terminally differentiated osteoblast that is imbedded in the bone matrix, represents over 95% of bone cells in the adult skeleton [52], and is responsible for sensing mechanical loading and transmitting that signal to regulate the activity of other bone cells [52]. Bmal1 was identified in osteocytes [19] and some markers of osteocyte function display a similar 24h profile to other BTMs. Fibroblast growth factor-23 (FGF-23) is a protein secreted by the osteocyte to regulate phosphate metabolism. FGF-23 levels also display a diurnal rhythm, peaking in the morning (Figure 1) [22, 53, 54]. FGF-23 rhythmicity displays more inter-individual variability compared to the robust CTX rhythm [22]. This could be related to differences in sympathetic tone as FGF-23 rhythmicity appears to be regulated, at least in part, by β–adrenergic tone via Bmal1 [54]. Sclerostin is an osteocyte-derived protein that suppresses bone formation and stimulates bone resorption during mechanical unloading. There have been conflicting reports regarding 24h variation in levels of serum sclerostin [22, 55]. It is possible that sclerostin levels are more heavily regulated by environmental/postural changes rather than inherent circadian rhythmicity. More research in this area is needed because it may impact the efficacy and recommended administration time of investigational pharmacological agents directed against sclerostin.

Clock Genes Alter Bone Health and Phenotype

In vitro data support the existence of endogenous circadian rhythmicity in BTMs [37, 38]. Clock gene KO models demonstrate how alterations in clock gene and circadian physiology have the potential to alter bone turnover and skeletal phenotype [1620]. Global and osteoblast-specific Bmal1 KO mice have a low BMD phenotype due to higher levels of bone resorption (and formation) and decreased osteoblast differentiation [19, 20]. Conversely, osteoclast-specific Bmal1 KO mice have a high BMD phenotype due to decreased bone resorption [18]. Peripheral (not central) clock genes, specifically osteoblast Bmal1, are the proposed regulators of bone resorption by inhibition of osteoclastogenesis [18]. In the absence of Bmal1 (globally or in the osteoblast), osteoclastogenesis is upregulated, in part, through osteoblastic RANKL expression [19]. Similarly, female mice lacking Cry/Per genes have a high bone volume phenotype [16, 17]. Cry2-deficient female mice achieve high bone volume through reduced osteoclast activity and bone resorption. Conversely, the high bone volume phenotype in Per2-deficient female mice results from an increased bone formation rate in the absence of leptin [16, 17]. These animal studies highlight the importance and complexity of the regulation of bone mass by peripheral clock genes in bone cells.

Circadian Medicine in Bone Health: Chronotherapy and the Role of the 24h Clock in Fracture Healing

Chronotherapy utilizes time of medication administration to affect its pharmacokinetics, efficacy, and safety profile [56, 57]. Classic examples of successful chronotherapy include treatment of hypertension and cancer. For example, evening administration of anti-hypertensive medications leads to better blood pressure control and a significantly decreased risk of cardiovascular events (RR 0.39, 95% CI 0.29, 0.51) compared to morning administration [58]. Similarly, the timing of chemotherapy drug administration affects the efficacy and patient tolerability of these agents [59]. There is likely a similar role for chronotherapy in osteoporosis.

Kunimoto et al identified an endogenous 24h interval of Per2 expression at femur fracture healing sites using bioluminescence in mice [34]. The addition of PTH resets this rhythmicity and shortens the time to the next peak. These findings highlight the role of clocks in fracture repair and may have additional relevance for the optimal administration time of PTH-related medications (e.g. teriparatide, abaloparatide) used to treat osteoporosis. Luchavova et al found that mean [CTX] was higher in women who received evening compared to morning teriparatide [35]. Furthermore, after 12 months of teriparatide treatment, lumbar spine BMD increased more in women who received morning teriparatide injections (9.1%) compared to evening injections (4.8%) [36]. Administration time is likely less important for bisphosphonates or denosumab, which have longer half-lives. However, timing of administration may augment the therapeutic effect for shorter-acting agents, particularly PTH and PTH-rp analogs.

4.0 Associations among shift work, the associated sleep/circadian disturbances, and the risk of osteoporosis, falls, and fractures

Circadian rhythmicity of BTMs are likely important for maintaining optimal bone health across the lifetime. Sleep and circadian disturbances, as occur in night-shift work, could potentially disrupt bone physiology and impair bone health. Night-shift work inherently alters the sleep/wake cycle and often results in less restful and shortened sleep duration, thereby disrupting circadian rhythmicity and/or functions served by sleep [6062]. Human and other animal studies suggest that shift work and its associated sleep and circadian disruptions may be detrimental to bone health and increase fall risk.

Night-Shift Work is Associated with Low BMD and Increased Fracture Risk

Quevedo et al identified lower BMD at the lumbar spine and femoral neck in Chilean postmenopausal female nurses who reported working a rotating shift (N = 39) compared to those who worked daytime shifts (N = 31) [32]. However, this study did not adjust for the higher prevalence of smoking and coffee intake in the women working rotating shifts [32]. A subsequent larger (N = 3,005) study of young (average age 36.4 years) Korean men and women also found lower BMD at the lumbar spine and total hip in people who worked shifts outside daytime hours, particularly in those who worked the night shift [63]. Conversely, there was no difference in BMD in middle-aged male and female shift workers (N = 225) in the NHANES cohort compared to regular workers (N = 738) [64].

Two studies observed an increased fracture risk in shift workers. The Nurses Health Study identified a higher risk of hip and wrist fractures after 8 years of follow-up in women who reported 20+ years of night-shift work compared to women who had never worked night shifts [6]. In addition, Kim et al reported a nearly 2-fold increase in the percentage of individuals who experienced self-reported fractures (femur, wrist, or spine) in non-daytime workers compared to daytime workers in the Korea National Health and Nutrition Examination Survey (2.1% vs. 1.2%) [63]. Although this difference was not statistically significant at the traditional statistical cutoff (p = 0.06), the magnitude of the difference may be clinically significant [63].

These investigators speculated that increases in cortisol and/or inflammation or differences in light exposure, vitamin D status, and/or physical activity could explain the increased risk of low BMD and fracture in night-shift workers. However, cross-sectional and epidemiological designs preclude identification of cause and effect relationships and mechanisms. An interventional study that exposed 10 healthy men to a forced desynchrony protocol (cumulative sleep restriction with concurrent circadian misalignment), akin to the stresses endured during rotating shift work, identified significantly lower levels of a bone formation marker (P1NP) with no change in a bone resorption marker (CTX) [65]. These changes were more pronounced in the younger men who had higher BTM concentrations at baseline [65]. It is unclear if sleep restriction or the history of circadian misalignment caused the changes in bone formation, however, these findings are consistent with those from a prior chronic sleep restriction study in rats [21]. Taken together, these studies indicate that night-shift work is likely detrimental to bone health, potentially by altering the balance between bone resorption and formation.

Animal data support the link among sleep and circadian disturbances and altered bone health. In a study by Everson et al [21], repeated 10-day periods of sleep restriction during 10–15% of the expected rat lifespan resulted in decreased osteoblast number and activity and an increased marker of osteoclast activity (TRACP 5b). These cellular changes were thought to be the result of the sleep restriction itself rather than an independent effect of alterations in circadian rhythm, and were reflected in BMDs averaging nearly three standard deviations below control values. Similar findings were subsequently found by Xu et al, using different methodologies [66]. Furthermore, mice exposed to continuous light exposure for 24 weeks had decreased trabecular bone volume compared to mice that experienced normal light-dark cycles associated with decreased behavioral and SCN rhythmicity, and an increase in inflammatory markers (TNF-α) [67]. No changes were appreciated in cortical bone but trabeculae in the mice exposed to continuous light were fewer in number, thinner, and had more porosity compared with control mice. These changes reversed rapidly after restoration of normal light-dark cycles [67]. These animal data are consistent with negative molecular and structural skeletal effects of sleep and circadian disruption that could predispose individuals to lower bone strength and increased fracture risk.

Long and Short Sleep Duration Have Been Associated with Low BMD

Disrupted and insufficient sleep are major complaints of shift workers. Both long [13, 6875] and short [70, 71, 7480] self-reported sleep duration have been associated with low BMD/osteoporosis or fracture in previous, mostly cross-sectional, studies (Table 1). In addition, one study found that long (≥8 h) compared to short (<6 h) sleep duration was associated with an increased risk of osteoporosis [81] and two studies reported no association between sleep duration and BMD [82, 83]. A recent meta-analysis [84] determined that long sleep duration (defined as ≥8 h/day) was associated with a 22% higher risk of osteoporosis in middle-aged and elderly women (OR 1.22, 95% CI 1.06–1.38), while no association was identified for women with short sleep duration (defined as ≤7 h/day). Although this analysis highlighted the significant heterogeneity in past studies, it did not include two studies that found a significant association between short sleep duration and BMD, including one that was published after the meta-analysis was performed [76, 77].

Table 1.

Summary of epidemiological studies examining associations between self-reported sleep duration and bone outcomes in humans.

Study Study Population Definition of Short Sleep Duration Definition of Normal Sleep Duration Definition of Long Sleep Duration Outcome Measure Findings
Sleep Duration and Bone Mineral Density (BMD) or Osteoporosis
Kobayashi et al 2012 [81] N = 19,321 (only 12,589 included in analyses)
Age: ≥50 years (avg 60.9 years)
48% female (Japan)
<6 h/day N/A (comparator group: <6h/day) ≥8 h/day Radial BMD by DXA
  • Long sleep (≥8 h) associated with increased risk of osteoporosis vs. short sleep (<6 h)

    OR 1.35; CI 1.06–1.73

Niu et al 2015 [68] N = 750
Age: 47–79 years
72% female (Puerto Ricans in Boston)
≤5, 6 and 7 h/day 8 h/day ≥9 h/day L-spine, total hip, femoral neck BMD by DXA
  • In men, long sleep (≥ 9 h/day) associated with lower femoral neck BMD vs. 8 h/day

  • No associations seen at other skeletal sites, in women, or for shorter sleep durations vs. 8 h/day

Tian et al 2015 [69] N = 31,769
Age: 45–86 years
53% female (China)
<7 h/day 7–8 h/day 8–9 h/day
≥9 h/day
BMD by Calcaneal quantitative ultrasonography (QUS)
  • Long sleep (≥9 h/day) associated with increased risk of osteoporosis in men (OR 1.40; CI 1.22–1.62) and women (OR 1.20; CI 1.07–1.33) vs. 7–8 h/day

  • 8–9 h/day sleep associated with increased risk of osteoporosis in men only (vs. 7–8 h/day)

  • Increased risk of osteoporosis with early sleep timing (before 21:00h) vs. normal sleep timing (21:00–23:00h) in men (OR 1.43; CI 1.16–1.78)

  • Potentially underpowered for short sleep duration due to small numbers

Chen et al 2014 [70] N = 8,688
Age: ≥40 years (avg 54 years)
55% female (China)
<7 h/day
7–8 h/day
8–9 h/day 9–10 h/day
≥10 h/day
BMD by Calcaneal QUS
  • Short sleep (7–8 h/day) and long sleep (9–10 h/day and ≥10 h/day) associated with increased risk of osteoporosis in postmenopausal women only (not in men or premenopausal women)

Wang et al 2015 [71] N = 6,510
Age: ≥40 years (avg 58 years)
100% female (China)
≤ 7 h/day
>7 to ≤ 8 h/day
>8 to ≤ 9 h/day >9 to ≤ 10 h/day
>10 h/day
BMD by Calcaneal QUS
  • Short sleep (≤ 7 h/day) and long sleep (>10 h/day) associated with increased risk of osteopenia and osteoporosis vs. normal sleep (>8 to ≤ 9 h/day) in postmenopausal women only

Cunningham et al 2015 [74] N = 5,288
Age: ≥50 years (avg 66 years)
50% female (NHANES – U.S.)
<6 h/day 6–8 h/day ≥9 h/day Self-report or femoral neck BMD by DXA
  • Short sleep (OR 1.59; CI 1.07–2.37) and long sleep (OR 1.51; CI 1.01–2.24) associated with increased risk of osteoporosis

Moradi et al 2017 (Systematic Review & Meta-Analysis)*[84] N = 31,625
Age: 40–86 years (China, USA, Japan)
≤ 7 h/day 7–8 h/day ≥8 h/day N/A
  • Inverse relationship between sleep duration and osteoporosis (OR 1.07; CI 1.00–1.15)

  • In middle aged and elderly women long sleep duration associated with osteoporosis (OR 1.22; CI 1.06–1.38) but not short sleep duration (OR 0.98; CI 0.90–1.05)

Specker et al 2007 [79] N = 1,146
Age: 20–66 years
57% female (South Dakota)
<6.5 h of sleep on average on weekdays 6.5–10 h of sleep on average on weekdays N/A Distal radius by pQCT Spine & hip BMD by DXA
  • Lower cortical vBMD in women with short vs. adequate sleep at 20% distal radius

  • Higher vBMD in men with short vs. adequate sleep at 20% distal radius

  • Lower estimate of torsional bending strength in men with short vs. adequate sleep

Fu et al 2011 [76] N = 602
Age: 18–80 years
100% female (China)
≤ 5 h/day
6 h/day
7 h/day
8 h/day ≥9 h/day BMD by DXA
  • Short sleep (≤ 5 h/day and 6 h/day) associated with increased risk of lower BMD at the spine, particularly in the ≥45 years group

Lima et al 2012 [75] N = 2,637
Age: ≥18 years (avg 42 years)
52% female (Brazil)
≤ 6 h/day 7–8 h/day ≥9 h/day Self-reported osteoporosis
  • Short sleep (OR 1.66; CI 1.01–2.73) and long sleep (OR 1.90; CI 1.05–3.44) duration associated with an increased risk of osteoporosis

Kim et al 2014 [73] N = 2,679
Age: ≥60 years
48% female (Korea)
≤ 5 h/day
<6 h/day
7 h/day ≥8 h/day L-spine, total hip and femoral neck BMD by DXA
  • Longer sleep associated with lower BMD at the total hip and femoral neck in women

Saint Martin et al 2016 [72] N = 500 (avg 66 years)
58% female (France)
<6 h/day 6–8 h/day ≥8 h/day L-spine and femur BMD by DXA
  • Long sleep associated with increased risk of osteopenia and osteoporosis vs. 6–8 h/day

Kuriyama et al 2017 [77] N = 221 (avg 55 years)
51% female (Japan)
<6 h/day ≥6 h/day N/A BMD by ultrasonic bone densitometer at distal radius
  • Short sleep associated with decreased cortical bone thickness and increased marker of bone resorption (TRACP-5b)

Marques et al 2017 [82] N = 5,764
Age: 66–96 years (avg 77 years)
58% female (Reykjavik, Iceland)
<6 h/day 6–8 h/day >8 h/day Proximal femur integral vBMD by CT
  • No association between short or long sleep duration and vBMD in men or women in fully adjusted models

Lucassen et al 2017 [83] N = 915
Age 45–65 years (avg 59 years)
56% female (Netherlands)
N/A N/A N/A L-spine and hip BMD by DXA
  • No overall association between sleep duration (analyzed as a continuous variable) and BMD or osteopenia at the spine or hip.

    • Men with shorter sleep duration had lower L-spine BMD

  • Pittsburgh Sleep Quality Index (PSQI) score, self-rated poor sleep quality, sleep latency and later sleep timing associated with increased risk of osteopenia.

Sleep Duration and Fracture
Stone et al 2006 [13] N = 8,101
Age: ≥69 years (avg 77 years)
100% female (USA)
<6 h/day
6 to <8 h/day
8 to <9 h/day 9 to <10 h/day
≥10 h/day
Self-reported falls and adjudicated fractures
  • Increased risk of falls and non-spine fractures with long sleep (≥10 h/day) vs. 8 to <9 h sleep in age-adjusted but not multivariate analyses

  • Included naps

Chen et al 2017 [80] N = 512,187 (avg 48 years)
49% female (China)
<7 h/day (average sleep time per day) ≥ 7 h/day (average sleep time per day) Self-reported fractures, verified by research team
  • < 7 h sleep/day identified as a risk for traumatic fractures (OR 2.70; CI 1.28–5.70)

Osteoporosis and Sleep Problems
Foley et al 2004 [78] N = 1,506
Age: 55–84 years
58% female (National Sleep Foundation - USA)
<6 h/night N/A N/A Self-reported osteoporosis diagnosis
  • Those with osteoporosis more likely to report sleeping <6 h/night (OR 1.67; CI 1.04–2.68)

*

Studies listed under “Sleep Duration and Bone Mineral Density (BMD) or Osteoporosis” below Moradi et al 2017 were not included in that meta-analysis.

Abbreviations: average (avg); bone mineral density (BMD), volumetric BMD (vBMD), quantitative ultrasonography (QUS), dual-energy x-ray absorptiometry (DXA); hours (h); Sample size (N); Not applicable (N/A); United States of America (USA); peripheral quantitative computed tomography (pQCT); computed tomography (CT); Tartrate-resistant acid phosphatase 5b (TRACP-5b); 95% confidence interval (CI); odds ratio (OR), Pittsburgh Sleep Quality Index (PSQI)

Studies investigating the association between sleep duration and BMD differed significantly from each other in the following ways: (i) study population including age, race, gender, sex-hormone status, and the presence/absence of sleep comorbidities; (ii) the method/anatomical site used for BMD assessment thereby diminishing the ability to consistently detect a difference in effect on cortical vs. trabecular bone; (iii) the cutoffs used to define short/normal/long sleep durations; and (iv) whether or not naps were included (Table 1). In addition, the small sample sizes for the osteoporosis/very low BMD groups [83] and analyses using categorical designations for sleep duration and BMD (e.g. “6–7 hours” or “osteoporosis” instead of continuous BMD variables) may limit the ability to accurately detect the relationship between sleep duration and BMD. Arguably the most important limitation of these studies is utilization of subjectively measured sleep duration, often assessed at one time point and without regard to the amount of sleep needed by an individual to feel rested. Future research should determine whether subjective or objective sleep parameters are more strongly and consistently correlated with skeletal outcomes. Furthermore, prospective studies with sleep duration monitored periodically over months or years may give more insight into the stability of sleep duration over time and how that correlates with bone parameters (BTMs, BMD), which change slowly over time.

The mechanisms by which sleep duration affects bone metabolism and bone density are unknown. Possible mechanisms include alterations in the normal rhythmicity of bone cells, hormone levels (e.g. sex steroids, cortisol), increases in sympathetic tone [29, 77], inflammation [85, 86], metabolic derangements, or fatigue/physical inactivity (Figure 2). The role of the central nervous system in regulating bone metabolism may be particularly important in the skeletal effects of disrupted sleep because of the SNS activation associated with sleep and circadian disruption. The SNS can influence bone cell clock genes and negatively impact bone metabolism through a complex network involving leptin, serotonin, neuropeptide Y, balance with the parasympathetic nervous system, and direct stimulation of bone cells via β–adrenergic receptors on osteoblasts (readers are referred to Figure 1 in a recent review by Dimitri et al [87]. Although the relationship between sleep stages and bone metabolism has not been evaluated, rapid eye movement (REM) sleep, which is associated with higher levels of sympathetic tone [88], predominates in the latter half of the night when BTMs peak [14], whereas non-REM (NREM) sleep predominates in the early part of the night. The individual effects of sleep duration and circadian alignment on bone health need further investigation to determine if these disturbances produce similar, additive, or synergistic impairments in bone health [71, 83].

Figure 2. Conceptual framework of how circadian rhythm and sleep disturbances alter bone health.

Figure 2

Sleep and circadian disturbances, in the form of night-shift work and/or altered sleep duration, impair bone formation, microarchitecture and strength and are associated with lower BMD through several potential mediators (ovals). Together, these changes in bone density and quality lead to an increased fracture risk. Circadian rhythm and sleep disturbances can also increase fracture risk by increasing the risk for falls, with or without sleep medications used to treat these disorders (e.g. benzodiazepines, Z-drugs like zolpidem). Age and/or sex differences may influence the circadian rhythm and sleep disturbances, mediators, and fracture risk.

Obstructive Sleep Apnea (OSA) and Bone Health

Data are mixed regarding the association between OSA and bone density [29], however, it is likely that OSA with its associated co-morbidities and underlying physiologic/metabolic derangements (increased sympathetic drive, inflammation, insulin resistance, nocturnal hypoxia etc.) are associated with increased bone resorption [89] and subsequently lower BMD [90].

Sleep and Circadian Disturbances Increase Fall Risk

Sleep and circadian disturbances cause sleepiness and decreased vigilance to environmental hazards [79], which may result in an increased risk of falls and fractures. In addition, the acute impairment in performance sometimes seen upon wakening (“sleep inertia”) and prolonged wakefulness both decrease postural stability and balance, increasing the risk for falls [10, 11, 91]. Moreover, insomnia has been associated with an increased risk of falls [12] and the greater the burden of insomnia symptoms predicts 2-year fall risk in older adults [92]. Circadian regulation of the cardiovascular response to postural stress in humans increases the risk of pre-syncope during the biological night, potentially increasing the risk for syncope and falls in night-shift workers [93].

5.0 The risk of falls/fractures with caffeine and medications used for sleep/circadian disruption

Medications taken for sleep and circadian disturbances can alter sleep architecture [94], sleep inertia [95, 96], and fall risk. Individuals with sleep/circadian disorders, including night-shift workers, frequently use over-the-counter (OTC) substances (e.g. caffeine) to compensate for daytime fatigue due, in part, to inadequate sleep duration [97, 98]. They also use OTC and prescription medications (e.g., melatonin, benzodiazepines, zolpidem) to induce, prolong, and re-entrain their sleep [97100]. Of rehabilitation patients who sustained a femoral neck fracture after a fall, 51% reported using a hypnotic or other tranquilizing medication for sleep [101]. These OTC and prescription agents likely influence the sleep-bone relationship either by mechanistically altering bone metabolism and/or calcium balance (caffeine), or by increasing the risk of falls and fracture through impairments in muscle tone, balance, and cognition.

Benzodiazepines and Z-drugs Are Associated with an Increased Risk of Falls and Fractures

Untreated insomnia and other sleep disturbances are associated with falls [12, 102104], but physician-prescribed sleep medications increase fall risk further [92]. Epidemiological studies have consistently shown an increased risk of falls and fractures with use of hypnotics such as benzodiazepines [105, 106]. More recent systematic reviews and meta-analyses have confirmed these findings with a reported Relative Risk (RR) of hip fracture of 1.52 (95% CI 1.37–1.68 p < 0.001) [103] with the highest risk seen at time of initiation (RR 2.40, 95% CI 1.88–3.05 p < 0.001 with short term use vs. RR 1.20, 95% CI 1.08–1.34 p < 0.001 with long term use) [103]. The risk of fracture increases with the duration of action of the specific benzodiazepine. The highest risk is seen with diazepam (long half-life), followed by lorazepam [107]. Like benzodiazepines, newer agents such as zolpidem and zaleplon (often called “Z-drugs”) induce central nervous system sedation by binding to the GABA-benzodiazepine receptor complex to enhance the effects of GABA [103]. Although Z-drugs were initially thought to be safer than traditional benzodiazepines because of their shorter half-life and lower risk of subsequent daytime sedation and dependency [103, 106], zolpidem appears to have a similarly increased risk of hip fracture (RR 1.90, 95% CI 1.68–2.13 p < 0.001) [103]. A recent meta-analysis found that zolpidem was associated with a 92% higher risk of fracture (RR 1.92, 95% CI 1.65–2.24; I2 = 50.9%) and that this risk was highest for hip fractures compared to any other site [108]. The limited evidence on Z-drugs suggests that the risk of falls and fractures are greatest with higher doses [108] and in the initial weeks of use [103, 108]. Tom et al confirmed the increased risk of hip fracture with zolpidem, however, no relationship was identified for a different Z-drug, eszopiclone [109]. Therefore, the association between zolpidem and increased fracture risk may not indicate a drug class effect for Z-drugs. It is presumed that these medications increase fracture risk through sedation, subsequent impairments in balance, cognition, and reaction times, and an increased risk of falls [10, 103, 110].

Studies investigating the association between benzodiazepines and Z-drugs with falls and fractures have limitations that potentially underestimate fracture risk. Prescription records were often used to ascertain exposure status rather than an actual account of medication administration. In addition, many of the studies of Z-drugs used prescription databases to ascertain medication exposure after identifying cases that had a fracture requiring hospitalization. These surveys ignore fractures that do not require hospitalization/surgery, making it difficult to ascertain how drug dose and timing truly affect the medication risks [111]. Therefore, both the indication (e.g., insomnia, short sleep duration) and medication increase the risk of falls and fractures [104].

Caffeine and Bone Health

There are several mechanisms by which caffeine is potentially deleterious to bone. Caffeine has been shown to negatively alter calcium homeostasis through hypercalciuria [112] and decreased gastrointestinal calcium absorption [112]. Caffeine could induce bone loss through direct effects on bone cells that favor osteoclast differentiation and osteoblast apoptosis, as indicated by rat models [113, 114]. It is possible that consumption of caffeine-containing drinks limit intake of other calcium-rich (e.g. milk) or more bone-neutral (e.g. water) beverages or because it contains other substances that might impact bone health (e.g. phosphorous, polyphenols, acid, sugar) [115, 116]. There have been some epidemiological studies of the role caffeine has in bone health, with mixed results [105, 116118]. The conflicting data may be due, in part, to differences in study population (age, sex, menopausal status) [117], follow-up time [112, 119], fracture definition/ascertainment [116], availability of information on confounders (such as calcium intake) [112] and subsequent appropriate statistical adjustments, and/or several aspects of caffeine intake that are difficult to capture accurately [112]. These include the source of caffeine (coffee, soda, tea), geographic variation in coffee strength and preparation that can affect caffeine levels, and assumptions regarding average serving size [112, 116]. For example, differing results for caffeine-associated fracture risk were found in the Swedish Mammography Cohort study in 2006 compared with 2013 [112, 119], possibly reflecting longer follow-up time and refinements in questionnaires. In addition, two recent meta-analyses that used slightly different inclusion/exclusion criteria concluded that coffee intake was associated with an increased fracture risk in women but not men [116, 117]. The increased fracture risk in women was seen with as little as 2 cups of coffee per day (RR 1.02, 95% CI: 1.01–1.04) and increased with greater intake (RR of 8 cups/day 1.54, 95% CI: 1.19–1.99) [116]. Since the protective effect in men was of greater magnitude (RR 0.76, 95% CI 0.62–0.94) for all but the highest levels of female coffee consumption, the overall effect of caffeine is unclear. A long-term, prospective intervention trial is needed to clarify if these associations translate into a clinically significant cause-and-effect relationship at typical levels of coffee/caffeine consumption.

Melatonin and Bone Health

Melatonin is low in night-shift workers [120] and is commonly used as an OTC supplement for jet lag and insomnia and therefore bears special mention. Melatonin is thought to be beneficial to bone by promoting osteoblast formation and decreasing bone resorption through decreased synthesis of RANKL and increased OPG synthesis [121, 122]. In addition, animals lacking melatonin have lower BMD compared to controls [121, 123, 124]. A small, randomized controlled trial in humans identified an increase in femoral neck BMD (an anatomical site with a larger precision error than other anatomical sites) with daily melatonin (1 mg/day or 3 mg/day) for a year and an increase in lumbar spine volumetric BMD (vBMD) by QCT with high dose melatonin only (3 mg/day) [125]. However, no significant change was identified in BTMs or in areal BMD at other skeletal sites [125], or in other studies [126]. Larger human studies of longer duration are needed to determine the pharmacological role (and dose) for melatonin in the treatment of postmenopausal osteoporosis.

6.0 Summary & Future Directions

The diurnal variation in BTMs and animal clock gene KO models suggest that circadian rhythmicity is important for bone health [14, 15, 17, 20]. Some epidemiological studies support this inference as night-shift work, which causes both sleep disruption and circadian misalignment, has been associated with lower BMD and increased fracture risk [6, 32]. Experimental studies of rats and healthy men reveal that sleep and circadian disruption impair bone formation [21, 65]. Use of OTC and prescription medications for sleep/circadian disorders further increase the risk of falls and fractures [103, 116, 117]. Moreover, it seems plausible that these factors interact, such that sleep deficiency and/or circadian disruption may increase the risk of falls due to reduced vigilance/balance, and may make a fracture more likely to occur due to suboptimal bone health. Further investigations are needed to clarify:

  1. If and how communication among bone cells is affected by disturbances in sleep and circadian rhythms.

  2. Cause and effect relationships between sleep duration and sleep stages with bone health using objective sleep measures over time with standardized bone mass and quality assessments.

  3. If BTM rhythmicity uses the anticipated rest/activity cycle (via endogenous circadian control) to regulate bone metabolism or if this rhythm is a response to behavioral changes.

  4. The specific effects of sleep disorders and circadian disruption on bone modeling, and remodeling and if these disturbances differentially affect trabecular and cortical bone.

  5. The mechanisms by which sleep and circadian disorders affect BMD and fall/fracture risk.

  6. The effects of age, sex, and body composition on the sleep/circadian-bone relationship.

Acknowledgments

This work supported by

This manuscript did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Manuscript Concept: SAS, CMS

Manuscript Draft: CMS

Manuscript Revisions: CMS, WMK, OMB, CAE, KPW, ESO, SAS

Approval of Final Draft: CMS, WMK, OMB, CAE, KPW, ESO, SAS

Outside of the current work, CMS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number K23 AR070275.

Outside of the current work, CAE is the PI on a grant awarded by the U.S. Army Medical Research and Materiel Command (W81XWH-16-1-0225)

Outside of the current work, KPW has current support from the National Institutes of Health funding via the following institutes: National Heart, Lung and Blood Institute (NHLBI), National Institute of Child Health and Human Development (NICHD), under the following grant numbers: R01HL132150, R01 HL135598, R01 HL131458, U01 NIH HL111478, R01 HD087707; and from the Office of Naval Research MURI N00014-15-1-2809 and CurAegis Inc., PAC-12 and Philips Inc.

Outside of the current work, ESO as PI for the The Osteoporotic Fractures in Men (MrOS) Study, is supported by National Institutes of Health funding via the following institutes: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research, under the following grant numbers: U01AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01AR066160, and UL1 TR000128.

SAS was supported by the Oregon Institute of Occupational Health Sciences at Oregon Health & Science University via funds from the Division of Consumer and Business Services of the State of Oregon. Outside of the current work, SAS receives support from NIH grants R01 HL125893, HL125893-03S1 and R01 HL140577 (to SA Shea), NIH grant R01 HL118601 (to FA Scheer), DoD grant PT150133 (to L Hammer), and CDC grant U19 OH010154 (to WK Anger).

The content is solely the responsibility of the authors and does not necessarily represent the views of the National Institutes of Health.

Abbreviations

BTMs

Bone turnover markers

CTX

C-terminal cross-linked telopeptide of type I collagen

P1NP

N-terminal propeptide of type I procollagen

FGF-23

Fibroblast growth factor-23

PTH

Parathyroid hormone

BMD

Bone mineral density

vBMD

Volumetric bone mineral density

PER

Period

CRY

Cryptochrome

BMAL1

Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1

CLOCK

circadian locomotor output cycles kaput

OTC

Over-the-counter

KO

knockout

NF-kB

nuclear factor kappa B

RANKL

ligand

OPG

osteoprotegerin

h

hour

SNS

sympathetic nervous system

RR

Relative Risk

OR

Odds Ratio

Footnotes

Disclosure Summary:

WMK, CAE, SAS have nothing to disclose

CMS has consulted for Radius (outside of the current work).

OMB Previously served as consultant to Takeda Pharmaceuticals North America (speaker’s bureau), Dinsmore LLC (expert witness testimony), Matsutani America (scientific advisory board), and Chevron (speaking fees). Outside of the submitted work, prior investigator-initiated research grant support from Sepracor (now Sunovion) and Cephalon (now Teva). Outside of the current work, OMB received two subcontract grants to Penn State from Mobile Sleep Technologies (NSF/STTR #1622766, NIH/NIA SBIR R43AG056250).

KPW has received grants/research support from CurAegis Technologies (formerly known as Torvec Inc.), Philips Inc. and Somalogics, Inc.; consulting fees or served as a paid member of scientific advisory boards for CurAegis Technologies, NIH, Circadian Therapeutics; speaker honorarium from American Academy of Sleep Medicine, American College of Chest Physicians, American Diabetes Association, The Obesity Society, Philips Inc.; Stock Options: CurAegis Technologies.

ESO has received research support from or consulting for Radius, Lilly, and Merck

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.Luyster FS, Strollo PJ, Jr, Zee PC, Walsh JK Boards of Directors of the American Academy of Sleep M, the Sleep Research S. Sleep: a health imperative. Sleep. 2012;35:727–34. doi: 10.5665/sleep.1846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Buxton OM, Cain SW, O’Connor SP, Porter JH, Duffy JF, Wang W, et al. Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. Science translational medicine. 2012;4:129ra43. doi: 10.1126/scitranslmed.3003200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Scheer FA, Hilton MF, Mantzoros CS, Shea SA. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proceedings of the National Academy of Sciences of the United States of America. 2009;106:4453–8. doi: 10.1073/pnas.0808180106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Wittert G. The relationship between sleep disorders and testosterone. Current opinion in endocrinology, diabetes, and obesity. 2014;21:239–43. doi: 10.1097/MED.0000000000000069. [DOI] [PubMed] [Google Scholar]
  • 5.Goel N, Rao H, Durmer JS, Dinges DF. Neurocognitive consequences of sleep deprivation. Semin Neurol. 2009;29:320–39. doi: 10.1055/s-0029-1237117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Feskanich D, Hankinson SE, Schernhammer ES. Nightshift work and fracture risk: the Nurses’ Health Study. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2009;20:537–42. doi: 10.1007/s00198-008-0729-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Akerstedt T. Sleepiness as a consequence of shift work. Sleep. 1988;11:17–34. doi: 10.1093/sleep/11.1.17. [DOI] [PubMed] [Google Scholar]
  • 8.Haraldsson PO, Akerstedt T. Drowsiness--greater traffic hazard than alcohol. Causes, risks and treatment. Lakartidningen. 2001;98:3018–23. [PubMed] [Google Scholar]
  • 9.Garbarino S, Mascialino B, Penco MA, Squarcia S, De Carli F, Nobili L, et al. Professional shift-work drivers who adopt prophylactic naps can reduce the risk of car accidents during night work. Sleep. 2004;27:1295–302. doi: 10.1093/sleep/27.7.1295. [DOI] [PubMed] [Google Scholar]
  • 10.Frey DJ, Ortega JD, Wiseman C, Farley CT, Wright KP., Jr Influence of zolpidem and sleep inertia on balance and cognition during nighttime awakening: a randomized placebo-controlled trial. Journal of the American Geriatrics Society. 2011;59:73–81. doi: 10.1111/j.1532-5415.2010.03229.x. [DOI] [PubMed] [Google Scholar]
  • 11.Robillard R, Prince F, Boissonneault M, Filipini D, Carrier J. Effects of increased homeostatic sleep pressure on postural control and their modulation by attentional resources. Clin Neurophysiol. 2011;122:1771–8. doi: 10.1016/j.clinph.2011.02.010. [DOI] [PubMed] [Google Scholar]
  • 12.Stone KL, Blackwell TL, Ancoli-Israel S, Cauley JA, Redline S, Marshall LM, et al. Sleep disturbances and risk of falls in older community-dwelling men: the outcomes of Sleep Disorders in Older Men (MrOS Sleep) Study. Journal of the American Geriatrics Society. 2014;62:299–305. doi: 10.1111/jgs.12649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Stone KL, Ewing SK, Lui LY, Ensrud KE, Ancoli-Israel S, Bauer DC, et al. Self-reported sleep and nap habits and risk of falls and fractures in older women: the study of osteoporotic fractures. Journal of the American Geriatrics Society. 2006;54:1177–83. doi: 10.1111/j.1532-5415.2006.00818.x. [DOI] [PubMed] [Google Scholar]
  • 14.Qvist P, Christgau S, Pedersen BJ, Schlemmer A, Christiansen C. Circadian variation in the serum concentration of C-terminal telopeptide of type I collagen (serum CTx): effects of gender, age, menopausal status, posture, daylight, serum cortisol, and fasting. Bone. 2002;31:57–61. doi: 10.1016/s8756-3282(02)00791-3. [DOI] [PubMed] [Google Scholar]
  • 15.Redmond J, Fulford AJ, Jarjou L, Zhou B, Prentice A, Schoenmakers I. Diurnal Rhythms of Bone Turnover Markers in Three Ethnic Groups. The Journal of clinical endocrinology and metabolism. 2016:jc20161183. doi: 10.1210/jc.2016-1183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Fu L, Patel MS, Bradley A, Wagner EF, Karsenty G. The molecular clock mediates leptin-regulated bone formation. Cell. 2005;122:803–15. doi: 10.1016/j.cell.2005.06.028. [DOI] [PubMed] [Google Scholar]
  • 17.Maronde E, Schilling AF, Seitz S, Schinke T, Schmutz I, van der Horst G, et al. The clock genes Period 2 and Cryptochrome 2 differentially balance bone formation. PloS one. 2010;5:e11527. doi: 10.1371/journal.pone.0011527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Xu C, Ochi H, Fukuda T, Sato S, Sunamura S, Takarada T, et al. Circadian Clock Regulates Bone Resorption in Mice. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research. 2016;31:1344–55. doi: 10.1002/jbmr.2803. [DOI] [PubMed] [Google Scholar]
  • 19.Takarada T, Xu C, Ochi H, Nakazato R, Yamada D, Nakamura S, et al. Bone Resorption Is Regulated by Circadian Clock in Osteoblasts. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research. 2017;32:872–81. doi: 10.1002/jbmr.3053. [DOI] [PubMed] [Google Scholar]
  • 20.Samsa WE, Vasanji A, Midura RJ, Kondratov RV. Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype. Bone. 2016;84:194–203. doi: 10.1016/j.bone.2016.01.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Everson CA, Folley AE, Toth JM. Chronically inadequate sleep results in abnormal bone formation and abnormal bone marrow in rats. Experimental biology and medicine. 2012;237:1101–9. doi: 10.1258/ebm.2012.012043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Swanson C, Shea SA, Wolfe P, Markwardt S, Cain SW, Munch M, et al. 24-hour profile of serum sclerostin and its association with bone biomarkers in men. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2017;28:3205–13. doi: 10.1007/s00198-017-4162-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Dovio A, Generali D, Tampellini M, Berruti A, Tedoldi S, Torta M, et al. Variations along the 24-hour cycle of circulating osteoprotegerin and soluble RANKL: a rhythmometric analysis. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2008;19:113–7. doi: 10.1007/s00198-007-0423-z. [DOI] [PubMed] [Google Scholar]
  • 24.Shimizu M, Onoe Y, Mikumo M, Miyabara Y, Kuroda T, Yoshikata R, et al. Variations in circulating osteoprotegerin and soluble RANKL during diurnal and menstrual cycles in young women. Horm Res. 2009;71:285–9. doi: 10.1159/000208802. [DOI] [PubMed] [Google Scholar]
  • 25.Tarquini R, Mazzoccoli G, Dolenti S, Gaudiano P, Comuni C, Laffi G, et al. Circasemidian rather than circadian variation of circulating osteoprotegerin in clinical health. Biomed Pharmacother. 2005;59(Suppl 1):S225–8. doi: 10.1016/s0753-3322(05)80036-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Mavroudis PD, Scheff JD, Calvano SE, Lowry SF, Androulakis IP. Entrainment of peripheral clock genes by cortisol. Physiological genomics. 2012;44:607–21. doi: 10.1152/physiolgenomics.00001.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Fujihara Y, Kondo H, Noguchi T, Togari A. Glucocorticoids mediate circadian timing in peripheral osteoclasts resulting in the circadian expression rhythm of osteoclast-related genes. Bone. 2014;61:1–9. doi: 10.1016/j.bone.2013.12.026. [DOI] [PubMed] [Google Scholar]
  • 28.Komoto S, Kondo H, Fukuta O, Togari A. Comparison of beta-adrenergic and glucocorticoid signaling on clock gene and osteoblast-related gene expressions in human osteoblast. Chronobiology international. 2012;29:66–74. doi: 10.3109/07420528.2011.636496. [DOI] [PubMed] [Google Scholar]
  • 29.Swanson CM, Shea SA, Stone KL, Cauley JA, Rosen CJ, Redline S, et al. Obstructive sleep apnea and metabolic bone disease: insights into the relationship between bone and sleep. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research. 2015;30:199–211. doi: 10.1002/jbmr.2446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Roenneberg T, Allebrandt KV, Merrow M, Vetter C. Social jetlag and obesity. Curr Biol. 2012;22:939–43. doi: 10.1016/j.cub.2012.03.038. [DOI] [PubMed] [Google Scholar]
  • 31.(NIOSH) NIfOSaH. Work Schedules: Shift Work and Long Hours. [Google Scholar]
  • 32.Quevedo I, Zuniga AM. Low bone mineral density in rotating-shift workers. J Clin Densitom. 2010;13:467–9. doi: 10.1016/j.jocd.2010.07.004. [DOI] [PubMed] [Google Scholar]
  • 33.McMenamin TM. A time to work: recent trends in shift work and flexible schedules. Monthly Labor Review. 2007 Dec; [Google Scholar]
  • 34.Kunimoto T, Okubo N, Minami Y, Fujiwara H, Hosokawa T, Asada M, et al. A PTH-responsive circadian clock operates in ex vivo mouse femur fracture healing site. Sci Rep. 2016;6:22409. doi: 10.1038/srep22409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Luchavova M, Zikan V, Michalska D, Raska I, Jr, Kubena AA, Stepan JJ. The effect of timing of teriparatide treatment on the circadian rhythm of bone turnover in postmenopausal osteoporosis. European journal of endocrinology/European Federation of Endocrine Societies. 2011;164:643–8. doi: 10.1530/EJE-10-1108. [DOI] [PubMed] [Google Scholar]
  • 36.Michalska D, Luchavova M, Zikan V, Raska I, Jr, Kubena AA, Stepan JJ. Effects of morning vs. evening teriparatide injection on bone mineral density and bone turnover markers in postmenopausal osteoporosis. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2012;23:2885–91. doi: 10.1007/s00198-012-1955-4. [DOI] [PubMed] [Google Scholar]
  • 37.McElderry JD, Zhao G, Khmaladze A, Wilson CG, Franceschi RT, Morris MD. Tracking circadian rhythms of bone mineral deposition in murine calvarial organ cultures. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research. 2013;28:1846–54. doi: 10.1002/jbmr.1924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Okubo N, Minami Y, Fujiwara H, Umemura Y, Tsuchiya Y, Shirai T, et al. Prolonged bioluminescence monitoring in mouse ex vivo bone culture revealed persistent circadian rhythms in articular cartilages and growth plates. PloS one. 2013;8:e78306. doi: 10.1371/journal.pone.0078306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Gertz BJ, Clemens JD, Holland SD, Yuan W, Greenspan S. Application of a new serum assay for type I collagen cross-linked N-telopeptides: assessment of diurnal changes in bone turnover with and without alendronate treatment. Calcified tissue international. 1998;63:102–6. doi: 10.1007/s002239900497. [DOI] [PubMed] [Google Scholar]
  • 40.Schlemmer A, Hassager C, Jensen SB, Christiansen C. Marked diurnal variation in urinary excretion of pyridinium cross-links in premenopausal women. The Journal of clinical endocrinology and metabolism. 1992;74:476–80. doi: 10.1210/jcem.74.3.1740479. [DOI] [PubMed] [Google Scholar]
  • 41.Aerssens J, Declerck K, Maeyaert B, Boonen S, Dequeker J. The effect of modifying dietary calcium intake pattern on the circadian rhythm of bone resorption. Calcified tissue international. 1999;65:34–40. doi: 10.1007/s002239900654. [DOI] [PubMed] [Google Scholar]
  • 42.Szulc P, Delmas PD. Biochemical markers of bone turnover: potential use in the investigation and management of postmenopausal osteoporosis. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2008;19:1683–704. doi: 10.1007/s00198-008-0660-9. [DOI] [PubMed] [Google Scholar]
  • 43.Lakatos P, Blumsohn A, Eastell R, Tarjan G, Shinoda H, Stern PH. Circadian rhythm of in vitro bone-resorbing activity in human serum. The Journal of clinical endocrinology and metabolism. 1995;80:3185–90. doi: 10.1210/jcem.80.11.7593424. [DOI] [PubMed] [Google Scholar]
  • 44.Ledger GA, Burritt MF, Kao PC, O’Fallon WM, Riggs BL, Khosla S. Role of parathyroid hormone in mediating nocturnal and age-related increases in bone resorption. The Journal of clinical endocrinology and metabolism. 1995;80:3304–10. doi: 10.1210/jcem.80.11.7593443. [DOI] [PubMed] [Google Scholar]
  • 45.Schlemmer A, Hassager C, Alexandersen P, Fledelius C, Pedersen BJ, Kristensen IO, et al. Circadian variation in bone resorption is not related to serum cortisol. Bone. 1997;21:83–8. doi: 10.1016/s8756-3282(97)00039-2. [DOI] [PubMed] [Google Scholar]
  • 46.Heshmati HM, Riggs BL, Burritt MF, McAlister CA, Wollan PC, Khosla S. Effects of the circadian variation in serum cortisol on markers of bone turnover and calcium homeostasis in normal postmenopausal women. The Journal of clinical endocrinology and metabolism. 1998;83:751–6. doi: 10.1210/jcem.83.3.4627. [DOI] [PubMed] [Google Scholar]
  • 47.Kendler FL, Priestman A, Cameron EC. Acute effects of dexamethasone on serum osteocalcin, urine pyridinoline and urine deoxypyridinoline in normals. Journal of Bone and Mineral Research. 1994;9(Suppl 1):S262. [Google Scholar]
  • 48.Blumsohn A, Herrington K, Hannon RA, Shao P, Eyre DR, Eastell R. The effect of calcium supplementation on the circadian rhythm of bone resorption. The Journal of clinical endocrinology and metabolism. 1994;79:730–5. doi: 10.1210/jcem.79.3.8077353. [DOI] [PubMed] [Google Scholar]
  • 49.Henriksen DB, Alexandersen P, Bjarnason NH, Vilsboll T, Hartmann B, Henriksen EE, et al. Role of gastrointestinal hormones in postprandial reduction of bone resorption. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research. 2003;18:2180–9. doi: 10.1359/jbmr.2003.18.12.2180. [DOI] [PubMed] [Google Scholar]
  • 50.Ebeling PR, Butler PC, Eastell R, Rizza RA, Riggs BL. The nocturnal increase in growth hormone is not the cause of the nocturnal increase in serum osteocalcin. The Journal of clinical endocrinology and metabolism. 1991;73:368–72. doi: 10.1210/jcem-73-2-368. [DOI] [PubMed] [Google Scholar]
  • 51.Eastell R, Szulc P. Use of bone turnover markers in postmenopausal osteoporosis. Lancet Diabetes Endocrinol. 2017 doi: 10.1016/S2213-8587(17)30184-5. [DOI] [PubMed] [Google Scholar]
  • 52.Dallas SL, Prideaux M, Bonewald LF. The osteocyte: an endocrine cell … and more. Endocrine reviews. 2013;34:658–90. doi: 10.1210/er.2012-1026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Smith ER, Cai MM, McMahon LP, Holt SG. Biological variability of plasma intact and C-terminal FGF23 measurements. The Journal of clinical endocrinology and metabolism. 2012;97:3357–65. doi: 10.1210/jc.2012-1811. [DOI] [PubMed] [Google Scholar]
  • 54.Kawai M, Kinoshita S, Shimba S, Ozono K, Michigami T. Sympathetic activation induces skeletal Fgf23 expression in a circadian rhythm-dependent manner. The Journal of biological chemistry. 2014;289:1457–66. doi: 10.1074/jbc.M113.500850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Santosh HS, Ahluwalia R, Hamilton A, Barraclough DL, Fraser WD, Vora JP. Circadian Rhythm of Circulating Sclerostin in Healthy Young Men. 15th European Congress of Endocrinology; Copenhagen, Denmark. 2013; p. P72. [Google Scholar]
  • 56.Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB. A circadian gene expression atlas in mammals: Implications for biology and medicine. Proceedings of the National Academy of Sciences of the United States of America. 2014;111:16219–24. doi: 10.1073/pnas.1408886111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Levi F, Schibler U. Circadian rhythms: mechanisms and therapeutic implications. Annu Rev Pharmacol Toxicol. 2007;47:593–628. doi: 10.1146/annurev.pharmtox.47.120505.105208. [DOI] [PubMed] [Google Scholar]
  • 58.Hermida RC, Ayala DE, Mojon A, Fernandez JR. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiology international. 2010;27:1629–51. doi: 10.3109/07420528.2010.510230. [DOI] [PubMed] [Google Scholar]
  • 59.Levi F, Focan C, Karaboue A, de la Valette V, Focan-Henrard D, Baron B, et al. Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Advanced drug delivery reviews. 2007;59:1015–35. doi: 10.1016/j.addr.2006.11.001. [DOI] [PubMed] [Google Scholar]
  • 60.Liira J, Verbeek JH, Costa G, Driscoll TR, Sallinen M, Isotalo LK, et al. Pharmacological interventions for sleepiness and sleep disturbances caused by shift work. Cochrane Database Syst Rev. 2014:CD009776. doi: 10.1002/14651858.CD009776.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Akerstedt T, Ingre M, Broman JE, Kecklund G. Disturbed sleep in shift workers, day workers, and insomniacs. Chronobiology international. 2008;25:333–48. doi: 10.1080/07420520802113922. [DOI] [PubMed] [Google Scholar]
  • 62.Sallinen M, Harma M, Mutanen P, Ranta R, Virkkala J, Muller K. Sleep-wake rhythm in an irregular shift system. Journal of sleep research. 2003;12:103–12. doi: 10.1046/j.1365-2869.2003.00346.x. [DOI] [PubMed] [Google Scholar]
  • 63.Kim BK, Choi YJ, Chung YS. Other than daytime working is associated with lower bone mineral density: the Korea National Health and Nutrition Examination Survey 2009. Calcified tissue international. 2013;93:495–501. doi: 10.1007/s00223-013-9779-6. [DOI] [PubMed] [Google Scholar]
  • 64.Santhanam P, Khthir R, Dial L, Driscoll HK, Gress TW. Femoral Neck Bone Mineral Density in Persons Over 50 Years Performing Shiftwork: An Epidemiological Study. J Occup Environ Med. 2016;58:e63–5. doi: 10.1097/JOM.0000000000000662. [DOI] [PubMed] [Google Scholar]
  • 65.Swanson C, Shea SA, Wolfe P, Cain SW, Munch M, Vujovic N, et al. Bone Turnover Markers After Sleep Restriction and Circadian Disruption: A Mechanism for Sleep-Related Bone Loss in Humans. The Journal of clinical endocrinology and metabolism. 2017;102:3722–30. doi: 10.1210/jc.2017-01147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Xu X, Wang L, Chen L, Su T, Zhang Y, Wang T, et al. Effects of chronic sleep deprivation on bone mass and bone metabolism in rats. J Orthop Surg Res. 2016;11:87. doi: 10.1186/s13018-016-0418-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Lucassen EA, Coomans CP, van Putten M, de Kreij SR, van Genugten JH, Sutorius RP, et al. Environmental 24-hr Cycles Are Essential for Health. Curr Biol. 2016;26:1843–53. doi: 10.1016/j.cub.2016.05.038. [DOI] [PubMed] [Google Scholar]
  • 68.Niu J, Sahni S, Liao S, Tucker KL, Dawson-Hughes B, Gao X. Association between Sleep Duration, Insomnia Symptoms and Bone Mineral Density in Older Boston Puerto Rican Adults. PloS one. 2015;10:e0132342. doi: 10.1371/journal.pone.0132342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Tian Y, Shen L, Wu J, Xu G, Yang S, Song L, et al. Sleep duration and timing in relation to osteoporosis in an elderly Chinese population: a cross-sectional analysis in the Dongfeng-Tongji cohort study. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2015;26:2641–8. doi: 10.1007/s00198-015-3172-4. [DOI] [PubMed] [Google Scholar]
  • 70.Chen G, Chen L, Wen J, Yao J, Li L, Lin L, et al. Associations between sleep duration, daytime nap duration, and osteoporosis vary by sex, menopause, and sleep quality. The Journal of clinical endocrinology and metabolism. 2014;99:2869–77. doi: 10.1210/jc.2013-3629. [DOI] [PubMed] [Google Scholar]
  • 71.Wang K, Wu Y, Yang Y, Chen J, Zhang D, Hu Y, et al. The associations of bedtime, nocturnal, and daytime sleep duration with bone mineral density in pre- and post-menopausal women. Endocrine. 2015;49:538–48. doi: 10.1007/s12020-014-0493-6. [DOI] [PubMed] [Google Scholar]
  • 72.Saint Martin M, Labeix P, Garet M, Thomas T, Barthelemy JC, Collet P, et al. Does Subjective Sleep Affect Bone Mineral Density in Older People with Minimal Health Disorders? The PROOF Cohort. Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine. 2016;12:1461–9. doi: 10.5664/jcsm.6266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Kim N, Choi HR, Kim SW, Kim BS, Won CW, Kim SY. Association between Bone Mineral Density and Sleep Duration in the Korean Elderly Population. Korean J Fam Med. 2014;35:90–7. doi: 10.4082/kjfm.2014.35.2.90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Cunningham TD, Di Pace BS. Is Self-Reported Sleep Duration Associated with Osteoporosis? Data from a 4-Year Aggregated Analysis from the National Health and Nutrition Examination Survey. Journal of the American Geriatrics Society. 2015;63:1401–6. doi: 10.1111/jgs.13477. [DOI] [PubMed] [Google Scholar]
  • 75.Lima MG, Bergamo Francisco PM, de Azevedo Barros MB. Sleep duration pattern and chronic diseases in Brazilian adults (ISACAMP, 2008/09) Sleep medicine. 2012;13:139–44. doi: 10.1016/j.sleep.2011.07.011. [DOI] [PubMed] [Google Scholar]
  • 76.Fu X, Zhao X, Lu H, Jiang F, Ma X, Zhu S. Association between sleep duration and bone mineral density in Chinese women. Bone. 2011;49:1062–6. doi: 10.1016/j.bone.2011.08.008. [DOI] [PubMed] [Google Scholar]
  • 77.Kuriyama N, Inaba M, Ozaki E, Yoneda Y, Matsui D, Hashiguchi K, et al. Association between loss of bone mass due to short sleep and leptin-sympathetic nervous system activity. Arch Gerontol Geriatr. 2017;70:201–8. doi: 10.1016/j.archger.2017.02.005. [DOI] [PubMed] [Google Scholar]
  • 78.Foley D, Ancoli-Israel S, Britz P, Walsh J. Sleep disturbances and chronic disease in older adults: results of the 2003 National Sleep Foundation Sleep in America Survey. Journal of psychosomatic research. 2004;56:497–502. doi: 10.1016/j.jpsychores.2004.02.010. [DOI] [PubMed] [Google Scholar]
  • 79.Specker BL, Binkley T, Vukovich M, Beare T. Volumetric bone mineral density and bone size in sleep-deprived individuals. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2007;18:93–9. doi: 10.1007/s00198-006-0207-x. [DOI] [PubMed] [Google Scholar]
  • 80.Chen W, Lv H, Liu S, Liu B, Zhu Y, Chen X, et al. National incidence of traumatic fractures in China: a retrospective survey of 512 187 individuals. Lancet Glob Health. 2017;5:e807–e17. doi: 10.1016/S2214-109X(17)30222-X. [DOI] [PubMed] [Google Scholar]
  • 81.Kobayashi D, Takahashi O, Deshpande GA, Shimbo T, Fukui T. Association between osteoporosis and sleep duration in healthy middle-aged and elderly adults: a large-scale, cross-sectional study in Japan. Sleep & breathing = Schlaf & Atmung. 2012;16:579–83. doi: 10.1007/s11325-011-0545-6. [DOI] [PubMed] [Google Scholar]
  • 82.Marques EA, Figueiredo P, Gudnason V, Lang T, Sigurdsson G, Sigurdsson S, et al. Associations of 24-hour sleep duration and CT-derived measurements of muscle and bone: The AGES-Reykjavik Study. Exp Gerontol. 2017;93:1–6. doi: 10.1016/j.exger.2017.04.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Lucassen EA, de Mutsert R, le Cessie S, Appelman-Dijkstra NM, Rosendaal FR, van Heemst D, et al. Poor sleep quality and later sleep timing are risk factors for osteopenia and sarcopenia in middle-aged men and women: The NEO study. PloS one. 2017;12:e0176685. doi: 10.1371/journal.pone.0176685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Moradi S, Shab-Bidar S, Alizadeh S, Djafarian K. Association between sleep duration and osteoporosis risk in middle-aged and elderly women: A systematic review and meta-analysis of observational studies. Metabolism. 2017;69:199–206. doi: 10.1016/j.metabol.2017.01.027. [DOI] [PubMed] [Google Scholar]
  • 85.Meier-Ewert HK, Ridker PM, Rifai N, Regan MM, Price NJ, Dinges DF, et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol. 2004;43:678–83. doi: 10.1016/j.jacc.2003.07.050. [DOI] [PubMed] [Google Scholar]
  • 86.Cauley JA, Danielson ME, Boudreau RM, Forrest KY, Zmuda JM, Pahor M, et al. Inflammatory markers and incident fracture risk in older men and women: the Health Aging and Body Composition Study. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research. 2007;22:1088–95. doi: 10.1359/jbmr.070409. [DOI] [PubMed] [Google Scholar]
  • 87.Dimitri P, Rosen C. The Central Nervous System and Bone Metabolism: An Evolving Story. Calcified tissue international. 2017;100:476–85. doi: 10.1007/s00223-016-0179-6. [DOI] [PubMed] [Google Scholar]
  • 88.Somers VK, Dyken ME, Mark AL, Abboud FM. Sympathetic-nerve activity during sleep in normal subjects. The New England journal of medicine. 1993;328:303–7. doi: 10.1056/NEJM199302043280502. [DOI] [PubMed] [Google Scholar]
  • 89.Tomiyama H, Okazaki R, Inoue D, Ochiai H, Shiina K, Takata Y, et al. Link between obstructive sleep apnea and increased bone resorption in men. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2008;19:1185–92. doi: 10.1007/s00198-007-0556-0. [DOI] [PubMed] [Google Scholar]
  • 90.Chen YL, Weng SF, Shen YC, Chou CW, Yang CY, Wang JJ, et al. Obstructive Sleep Apnea and Risk of Osteoporosis: A Population-Based Cohort Study in Taiwan. The Journal of clinical endocrinology and metabolism. 2014:jc20141718. doi: 10.1210/jc.2014-1718. [DOI] [PubMed] [Google Scholar]
  • 91.Sobeih TM, Davis KG, Succop PA, Jetter WA, Bhattacharya A. Postural balance changes in on-duty firefighters: effect of gear and long work shifts. J Occup Environ Med. 2006;48:68–75. doi: 10.1097/01.jom.0000181756.38010.d2. [DOI] [PubMed] [Google Scholar]
  • 92.Chen TY, Lee S, Buxton OM. A Greater Extent of Insomnia Symptoms and Physician-Recommended Sleep Medication Use Predict Fall Risk in Community-Dwelling Older Adults. Sleep. 2017 doi: 10.1093/sleep/zsx142. [DOI] [PubMed] [Google Scholar]
  • 93.Hu K, Scheer FA, Laker M, Smales C, Shea SA. Endogenous circadian rhythm in vasovagal response to head-up tilt. Circulation. 2011;123:961–70. doi: 10.1161/CIRCULATIONAHA.110.943019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Balkin TJ, O’Donnell VM, Kamimori GH, Redmond DP, Belenky G. Administration of triazolam prior to recovery sleep: effects on sleep architecture, subsequent alertness and performance. Psychopharmacology (Berl) 1989;99:526–31. doi: 10.1007/BF00589903. [DOI] [PubMed] [Google Scholar]
  • 95.Van Dongen HP, Price NJ, Mullington JM, Szuba MP, Kapoor SC, Dinges DF. Caffeine eliminates psychomotor vigilance deficits from sleep inertia. Sleep. 2001;24:813–9. doi: 10.1093/sleep/24.7.813. [DOI] [PubMed] [Google Scholar]
  • 96.Balkin TJ, O’Donnell VM, Kamimori GH, Redmond DP, Belenky G. Sleep inertia following triazolam-induced recovery sleep. Human Psychopharmacology: Clinical & Experimental. 1989;4:291–6. doi: 10.1007/BF00589903. [DOI] [PubMed] [Google Scholar]
  • 97.Niedhammer I, Lert F, Marne MJ. Psychotropic drug use and shift work among French nurses (1980–1990) Psychol Med. 1995;25:329–38. doi: 10.1017/s0033291700036230. [DOI] [PubMed] [Google Scholar]
  • 98.Morgenthaler TI, Lee-Chiong T, Alessi C, Friedman L, Aurora RN, Boehlecke B, et al. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 2007;30:1445–59. doi: 10.1093/sleep/30.11.1445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Futenma K, Asaoka S, Takaesu Y, Komada Y, Ishikawa J, Murakoshi A, et al. Impact of hypnotics use on daytime function and factors associated with usage by female shift work nurses. Sleep medicine. 2015;16:604–11. doi: 10.1016/j.sleep.2014.11.018. [DOI] [PubMed] [Google Scholar]
  • 100.Bertisch SM, Herzig SJ, Winkelman JW, Buettner C. National use of prescription medications for insomnia: NHANES 1999–2010. Sleep. 2014;37:343–9. doi: 10.5665/sleep.3410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101.Tsur A, Eluz D, Itah D, Segal Z, Shakeer N, Galin A. Clinical profile of fallers with femoral neck fractures. PM R. 2014;6:390–4. doi: 10.1016/j.pmrj.2013.10.013. [DOI] [PubMed] [Google Scholar]
  • 102.Avidan AY, Fries BE, James ML, Szafara KL, Wright GT, Chervin RD. Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. Journal of the American Geriatrics Society. 2005;53:955–62. doi: 10.1111/j.1532-5415.2005.53304.x. [DOI] [PubMed] [Google Scholar]
  • 103.Donnelly K, Bracchi R, Hewitt J, Routledge PA, Carter B. Benzodiazepines, Z-drugs and the risk of hip fracture: A systematic review and meta-analysis. PloS one. 2017;12:e0174730. doi: 10.1371/journal.pone.0174730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104.Widera E. What’s to blame for falls and fractures? Poor sleep or the sleeping medication?: Comment on “Nonbenzodiazepine sleep medication use and hip fractures in nursing home residents”. JAMA internal medicine. 2013;173:761–2. doi: 10.1001/jamainternmed.2013.3801. [DOI] [PubMed] [Google Scholar]
  • 105.Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. The New England journal of medicine. 1995;332:767–73. doi: 10.1056/NEJM199503233321202. [DOI] [PubMed] [Google Scholar]
  • 106.Wang PS, Bohn RL, Glynn RJ, Mogun H, Avorn J. Zolpidem use and hip fractures in older people. Journal of the American Geriatrics Society. 2001;49:1685–90. doi: 10.1111/j.1532-5415.2001.49280.x. [DOI] [PubMed] [Google Scholar]
  • 107.Finkle WD, Der JS, Greenland S, Adams JL, Ridgeway G, Blaschke T, et al. Risk of fractures requiring hospitalization after an initial prescription for zolpidem, alprazolam, lorazepam, or diazepam in older adults. Journal of the American Geriatrics Society. 2011;59:1883–90. doi: 10.1111/j.1532-5415.2011.03591.x. [DOI] [PubMed] [Google Scholar]
  • 108.Park SM, Ryu J, Lee DR, Shin D, Yun JM, Lee J. Zolpidem use and risk of fractures: a systematic review and meta-analysis. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2016;27:2935–44. doi: 10.1007/s00198-016-3605-8. [DOI] [PubMed] [Google Scholar]
  • 109.Tom SE, Wickwire EM, Park Y, Albrecht JS. Nonbenzodiazepine Sedative Hypnotics and Risk of Fall-Related Injury. Sleep. 2016;39:1009–14. doi: 10.5665/sleep.5742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.Drake CL, Durrence H, Cheng P, Roth T, Pillai V, Peterson EL, et al. Arousability and fall risk during forced awakenings from nocturnal sleep among healthy males following administration of zolpidem 10 mg and doxepin 6 mg: A randomized, placebo-controlled, four-way crossover trial. Sleep. 2017 doi: 10.1093/sleep/zsx086. [DOI] [PubMed] [Google Scholar]
  • 111.Lai MM, Lin CC, Lin CC, Liu CS, Li TC, Kao CH. Long-term use of zolpidem increases the risk of major injury: a population-based cohort study. Mayo Clin Proc. 2014;89:589–94. doi: 10.1016/j.mayocp.2014.01.021. [DOI] [PubMed] [Google Scholar]
  • 112.Hallstrom H, Wolk A, Glynn A, Michaelsson K. Coffee, tea and caffeine consumption in relation to osteoporotic fracture risk in a cohort of Swedish women. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2006;17:1055–64. doi: 10.1007/s00198-006-0109-y. [DOI] [PubMed] [Google Scholar]
  • 113.Tsuang YH, Sun JS, Chen LT, Sun SC, Chen SC. Direct effects of caffeine on osteoblastic cells metabolism: the possible causal effect of caffeine on the formation of osteoporosis. J Orthop Surg Res. 2006;1:7. doi: 10.1186/1749-799X-1-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114.Liu SH, Chen C, Yang RS, Yen YP, Yang YT, Tsai C. Caffeine enhances osteoclast differentiation from bone marrow hematopoietic cells and reduces bone mineral density in growing rats. J Orthop Res. 2011;29:954–60. doi: 10.1002/jor.21326. [DOI] [PubMed] [Google Scholar]
  • 115.Fung TT, Arasaratnam MH, Grodstein F, Katz JN, Rosner B, Willett WC, et al. Soda consumption and risk of hip fractures in postmenopausal women in the Nurses’ Health Study. Am J Clin Nutr. 2014;100:953–8. doi: 10.3945/ajcn.114.083352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116.Lee DR, Lee J, Rota M, Lee J, Ahn HS, Park SM, et al. Coffee consumption and risk of fractures: a systematic review and dose-response meta-analysis. Bone. 2014;63:20–8. doi: 10.1016/j.bone.2014.02.007. [DOI] [PubMed] [Google Scholar]
  • 117.Liu H, Yao K, Zhang W, Zhou J, Wu T, He C. Coffee consumption and risk of fractures: a meta-analysis. Arch Med Sci. 2012;8:776–83. doi: 10.5114/aoms.2012.31612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118.Hannan MT, Felson DT, Dawson-Hughes B, Tucker KL, Cupples LA, Wilson PW, et al. Risk factors for longitudinal bone loss in elderly men and women: the Framingham Osteoporosis Study. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research. 2000;15:710–20. doi: 10.1359/jbmr.2000.15.4.710. [DOI] [PubMed] [Google Scholar]
  • 119.Hallstrom H, Byberg L, Glynn A, Lemming EW, Wolk A, Michaelsson K. Long-term coffee consumption in relation to fracture risk and bone mineral density in women. American journal of epidemiology. 2013;178:898–909. doi: 10.1093/aje/kwt062. [DOI] [PubMed] [Google Scholar]
  • 120.Dumont M, Paquet J. Progressive decrease of melatonin production over consecutive days of simulated night work. Chronobiology international. 2014;31:1231–8. doi: 10.3109/07420528.2014.957304. [DOI] [PubMed] [Google Scholar]
  • 121.Amstrup AK, Sikjaer T, Mosekilde L, Rejnmark L. Melatonin and the skeleton. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2013;24:2919–27. doi: 10.1007/s00198-013-2404-8. [DOI] [PubMed] [Google Scholar]
  • 122.Maria S, Witt-Enderby PA. Melatonin effects on bone: potential use for the prevention and treatment for osteopenia, osteoporosis, and periodontal disease and for use in bone-grafting procedures. Journal of pineal research. 2013 doi: 10.1111/jpi.12116. [DOI] [PubMed] [Google Scholar]
  • 123.Egermann M, Gerhardt C, Barth A, Maestroni GJ, Schneider E, Alini M. Pinealectomy affects bone mineral density and structure--an experimental study in sheep. BMC Musculoskelet Disord. 2011;12:271. doi: 10.1186/1471-2474-12-271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 124.Turgut M, Kaplan S, Turgut AT, Aslan H, Guvenc T, Cullu E, et al. Morphological, stereological and radiological changes in pinealectomized chicken cervical vertebrae. Journal of pineal research. 2005;39:392–9. doi: 10.1111/j.1600-079X.2005.00263.x. [DOI] [PubMed] [Google Scholar]
  • 125.Amstrup AK, Sikjaer T, Heickendorff L, Mosekilde L, Rejnmark L. Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: a randomized controlled trial. Journal of pineal research. 2015;59:221–9. doi: 10.1111/jpi.12252. [DOI] [PubMed] [Google Scholar]
  • 126.Kotlarczyk MP, Lassila HC, O’Neil CK, D’Amico F, Enderby LT, Witt-Enderby PA, et al. Melatonin osteoporosis prevention study (MOPS): a randomized, double-blind, placebo-controlled study examining the effects of melatonin on bone health and quality of life in perimenopausal women. Journal of pineal research. 2012;52:414–26. doi: 10.1111/j.1600-079X.2011.00956.x. [DOI] [PubMed] [Google Scholar]

RESOURCES