Skip to main content
Innovative Surgical Sciences logoLink to Innovative Surgical Sciences
. 2016 Dec 3;1(2):57–63. doi: 10.1515/iss-2016-0021

Mechanobiology of bone remodeling and fracture healing in the aged organism

Melanie Haffner-Luntzer 1,, Astrid Liedert 1, Anita Ignatius 1
PMCID: PMC6753991  PMID: 31579720

Abstract

Bone can adapt to changing load demands by mechanically regulated bone remodeling. Osteocytes, osteoblasts, and mesenchymal stem cells are mechanosensitive and respond to mechanical signals through the activation of specific molecular signaling pathways. The process of bone regeneration after fracture is similarly and highly regulated by the biomechanical environment at the fracture site. Depending on the tissue strains, mesenchymal cells differentiate into fibroblasts, chondrocytes, or osteoblasts, determining the course and the success of healing. In the aged organism, mechanotransduction in both intact and fractured bones may be altered due to changed hormone levels and expression of growth factors and other signaling molecules. It is proposed that altered mechanotransduction may contribute to disturbed healing in aged patients. This review explains the basic principles of mechanotransduction in the bone and the fracture callus and summarizes the current knowledge on aging-induced changes in mechanobiology. Furthermore, the methods for external biomechanical stimulation of intact and fractured bones are discussed with respect to a possible application in the elderly patient.

Keywords: bone, mechanostimulation, regeneration, ultrasound, vibration

Abbreviations

BMP, bone morphogenetic protein; CSF, colony-stimulating factor; COX-2, cyclooxygenase-2; ER, estrogen receptor; IGF-I, insulin-like growth factor-I; LIPUS, low-intensity pulsed ultrasound; LMHFV, low-magnitude, high-frequency vibration; MSCs, mesenchymal stem cells; OPG, osteoprotegerin; PGE2, prostaglandin E2; RANKL, receptor activator of nuclear factor-κB (NF-κB) ligand; TGF-β, transforming growth factor-β; vitamin D3, 1,25-dihydroxycholecalciferol.

Mechanobiology of bone tissue

Bone mass is maintained during life via constant bone formation and resorption, a process termed as bone remodeling. Bone-forming osteoblasts synthesize collagen and regulate extracellular matrix mineralization, whereas bone-resorbing osteoclasts maintain bone degradation by acidifying and solubilizing the bone mineral. The most numerous cells in bone tissue, the osteocytes, form a close communication network with their neighbor osteocytes and the other bone cells through gap junctions. Osteocytes are involved in regulating osteoblast and osteoclast activity and survival.

At the endocrine and molecular levels, several factors can influence the bone remodeling process. Hormones, including estrogen, insulin, cortisol, epinephrine, parathyroid hormone, and 1,25-dihydroxycholecalciferol (vitamin D3), regulate the activity of bone cells and control the balance between resorption and formation. Many growth factors and signaling pathways can exert osteoanabolic or osteocatabolic functions. For example, the process of osteoclast formation is regulated by colony-stimulating factor (CSF), several interleukins, parathyroid hormone, calcitonin, and vitamin D3 as well as the ratio of receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) to osteoprotegerin (OPG), both factors secreted by osteoblasts. Signaling pathways involved in osteoblast recruitment and maturation include transforming growth factor-β (TGF-β), bone morphogenetic proteins (BMPs), insulin-like growth factor-I (IGF-I), and the Wnt/β-catenin signaling pathway [1].

In 1892, the anatomist and surgeon Julius Wolff postulated that bone remodeling is not only influenced by biological factors but is also under tight biomechanical control for a more efficient adaptation to changing load situations [2]. In 1987, Harold Frost extended Wolff’s theory and demonstrated the dependence of bone formation on the quality and frequency of the mechanical stimulus. Frost postulated that different biomechanical loading ranges provoked either bone formation or resorption (the “mechanostat theory”), which was also shown by others [3], [4], [5], [6]. The cellular and molecular mechanisms involved are not yet fully understood. One well-established theory suggests that osteocytes are the main mechanosensoric cells in the bone [7], [8], [9]. Osteocytes may act as a sensor of local bone stresses, which arise from bending and compressive forces during walking. Tissue deformation induces interstitial bone fluid flow and osteocytes are able to sense the flow-induced shear stress on the surface of their cell bodies. Ion channels and integrin receptors are critical for the transduction of the mechanical signals into biochemical signals inside the cells. The process of converting external mechanical forces into a biochemical response is termed as cellular mechanotransduction [10]. Experimental studies demonstrated the involvement of numerous molecular pathways and mediators in mechanotransduction [11], [12], [13]. One main osteocytic mediator for load-induced bone formation is prostaglandin E2 (PGE2), which is secreted after the mechanically induced expression of cyclooxygenase-2 (COX-2) [10], [14]. Furthermore, mechanically stimulated osteocytes react by increasing their OPG/RANKL ratio, thus interacting with osteoclasts. Additionally, the osteocytic expression of sclerostin can be influenced by mechanical load [15]. Sclerostin is a regulator of osteoblastic bone formation. When sclerostin binds to low-density lipoprotein receptor-related proteins 5 and 6 on the cell membrane of osteoblasts, it inhibits canonical Wnt/β-catenin signaling and reduces osteoblastic bone formation. Therefore, sclerostin acts as a coupling factor between osteocytes and osteoblasts.

In recent years, growing evidence has suggested that also other cells involved in bone metabolism, for example, bone-lining cells, osteoblasts, and mesenchymal stem cells (MSCs), may be mechanosensitive [16]. The in vitro mechanical stimulation of these cells led to increased osteogenic differentiation and matrix mineralization [17], [18], [19]. Therefore, the adaptation of bone to mechanical load involved several interacting cell types, signaling molecules, and pathways.

Disturbed mechanobiology in the aged organism

The process of mechanotransduction in the bone can be disturbed by several pathological conditions, such as during postmenopausal osteoporosis and in the aged organism. Postmenopausal osteoporosis is characterized by the loss of ovary-derived estrogen, leading to a high bone turnover, an imbalance of bone homeostasis toward increased bone resorption, and a subsequent bone loss. The estrogen receptor (ER) signaling pathway is also important for the transmission of mechanical signals. In his “mechanostat theory” [4], Frost postulated that estrogen might decrease the mechanical threshold for bone formation and can sensitize the bone to mechanical stimuli. This was confirmed in several experimental studies [20], and it was shown that mechanotransduction is altered in osteoblasts from estrogen-deficient, osteoporotic patients [21]. However, the influence of estrogen on mechanically regulated bone formation appears to be strongly dependent on the timing of estrogen administration [22]. Moreover, the expression ratio of the two ERs, ERα and ERβ, appears to be essential, with ERα probably increasing mechanosensitivity and ERβ decreasing it [23]. The expression of both receptors is largely regulated by estrogen [24].

Similarly, in the aged organism, bone mass is gradually lost. In contrast to postmenopausal osteoporosis, the mechanism is not a high bone turnover but rather a low bone turnover. The reasons might be the reduction of the proliferation and differentiation capacity of stem cells, decreased physical activity, increased inflammatory cytokine levels, and reduced expression of several osteoanabolic mediators, including sex hormones, IGF-I, and molecules of the Wnt/β-catenin signaling pathway [25], [26], [27], [28].

Because many such mediators are also involved in mechanotransduction, it has been recently proposed that the mechanosensitivity of bone cells per se may decrease during aging, which can contribute to senile bone loss. However, the influence of age on the mechanotransduction processes in the bone remains controversial. There are experimental studies showing increased [29], [30], decreased [31], [32], [33], and unaffected [34], [35], [36] mechanoresponsiveness of bone tissue during aging, which depends on the applied stimulus and the determined outcome parameters. In clinical studies, both an anabolic response to physical exercise and no change have been reported in older humans in comparison to young control groups [37], [38]. Nevertheless, clinical studies have reported the effectiveness of external mechanostimulation on bone formation in aged osteoporotic patients. In particular, the so-called “low-magnitude, high-frequency whole-body vibration” (LMHFV) was shown to improve bone mass in aged postmenopausal women [39], [40], [41], [42]. Therefore, even if the threshold value at which bone reacts to mechanical loading may be altered in the aged subject, mechanostimulation may still represent a therapeutic option to reduce aging-induced bone loss.

Mechanobiology of fracture healing

The biomechanical environment is not only critical for bone homeostasis but also during fracture healing. The rigid fixation of long-bone fractures resulting in minimal interfragmentary movements induces direct intramembranous bone healing, whereas flexible fixation with higher interfragmentary movements results in callus healing with endochondral bone formation [43], [44]. Too flexible fixation can result in nonunions with hypertrophic fibrous tissue near the fracture gap. Similarly, too low biomechanical stimulation is detrimental for bone healing. The underlying mechanism of biomechanical influence on fracture healing is described in Pauwels’ theory of “causal histogenesis” [45]. He postulated the profound influence of the mechanical environment on tissue differentiation. In more detail, Claes et al. demonstrated in 1998 that, if there are high stresses at the fracture area, mesenchymal cells are likely to form fibrous tissue, whereas osseous tissue is generated under low stress conditions. At intermediate stresses, mesenchymal cells will differentiate into chondrocytes and initiate cartilaginous callus formation, which initially bridges the fracture gap [46], [47], [48]. Several molecular factors are influenced by the mechanical environment during bone regeneration. In the inflammatory phase of fracture healing, cytokines, including chemokine C-X-C motif ligand 3, von Willebrand factor, macrophage-CSF, and tumor necrosis factor-α, are altered depending on the biomechanical environment at the fracture side [49], [50], [51]. During the endochondral ossification process, signaling pathways and molecules involved in chondrocyte maturation, including Indian hedgehog and collagen 2, are demonstrated to be decreased in the fracture calli of stabilized fractures compared to nonstabilized fractures [52]. Additionally, the expression of several components of the BMP signaling cascade, including BMP-2, Noggin, p-Smad, and BMP receptor-1A, is strongly influenced by the mechanical environment. Yu et al. [53] proposed that biomechanical stimuli might activate the osteoanabolic BMP signaling pathway, thereby influencing the cell-fate decision during the regeneration process. Lienau et al. [51] demonstrated that important osteoblastic mediators, including BMPs, IGF-I, OPG, and TGF-β, are reduced in animals with delayed fracture healing due to rotational instability. A serum analysis of fracture patients demonstrated increased levels of TGF-β and IGF-I in patients with flexible osteosynthesis [54]. Other experimental studies showed a differential expression of angiogenic factors, including vascular endothelial growth factor and cysteine-rich angiogenic inducer 61, depending on the biomechanical environment at the fracture site [49], [50]. Genome-wide expression arrays comparing activated or repressed genes during nonstimulated and biomechanically stimulated fracture healing showed a differential expression of more than 100 genes, mainly associated with chondrocytic/osteoblastic differentiation, cell adhesion, or cell signaling pathways [55]. Therefore, the biomechanical environment critically influences cell-fate decision and thus fracture healing.

Fracture healing and mechanostimulation in the aged organism

Both clinical and experimental studies indicated that fracture healing is disturbed in the aged organism [56], [57], [58], [59], [60], [61], [62]. Experimental studies demonstrated a reduced osteogenic capacity of MSCs [63], disturbed cartilaginous and bony callus maturation [61], [64], decreased callus vascularization [60], and lower expression of osteoanabolic signaling molecules [63], [65]. Additionally, aging-induced changes in the inflammatory and oxidative stress response may be one reason for disturbed bone healing [66]. Confirming this, Xing et al. [67] demonstrated that the rejuvenation of inflammatory cells increased bone and callus formation in aged mice. Therefore, cells from both hematopoietic and mesenchymal lineages appear to be involved in aging-induced delayed healing.

Because it was also shown that the expression of the mechanosensitive gene COX-2 is markedly reduced in the fracture callus of aged animals [68], the question arises as to whether aging can also disturb the mechanobiological control of fracture healing and whether the “optimal” biomechanical conditions for successful bone healing are the same in young and aged patients. There are only a few studies investigating the effect of aging on the mechanobiology of fracture healing. It was demonstrated in aged rats that mechanical optimization of fracture fixation failed to improve healing [69]. Young control animals displayed a significantly larger callus volume and stiffness after semirigid fixation compared to rigid fixation. However, in aged animals, there were no differences between the two fixation groups. Likewise, Mehta et al. [70] demonstrated that changing the biomechanical environment did not alter bony callus formation, callus microstructure, or mineralization in aged animals unlike in young animals. In another study, the authors showed a different mechanoresponsiveness of several genes, including TGF-β, MMP-9, and MMP-13, in aged compared to young rats and a reduced ability of aged MSCs to sense and adapt to mechanical stimuli [49]. Together, these studies suggested that reduced mechanotransduction in the aged organism may indeed contribute to disturbed bone regeneration. In contrast, a recent study demonstrated that changing the biomechanical environment at the fracture site did influence bone healing in aged rats [71]. High interfragmentary movements led to increased callus size with greater amounts of cartilaginous tissue. However, the late phase of fracture healing was not influenced by fracture fixation stability. In summary, the mechanobiology of fracture healing in the aged organism requires further investigation.

A further possibility, in addition to fracture fixation to influence bone healing mechanically, is the application of external biomechanical stimuli. In the literature, many different methods are described to influence the healing process [72], [73], [74]. One promising approach is the application of low-intensity pulsed ultrasound (LIPUS). Treatment with LIPUS during callus formation was generally demonstrated to accelerate the healing process in both clinical and experimental studies [73], [75], [76], [77], [78], [79], [80]. Importantly, LIPUS also augmented fracture repair in aged patients [77] and animals [81], [82]. Molecular analyses showed increased neovascularization and bone formation in the fracture callus of aged individuals [82]. Interestingly, LIPUS treatment reduced the healing time in aged wild-type mice but not in COX-2 knockout mice, indicating a critical role of this mechanoresponsive gene and its downstream mediator PGE2. Confirming this, injections with a PGE2 receptor agonist restored the positive effects of LIPUS on fracture healing [83]. Therefore, reduced COX-2 and PGE2 expression in the fracture callus of aged subjects may be critical for the healing process, whereas their expression can be increased by external mechanical stimulation to accelerate the regeneration. Another noninvasive biomechanical treatment to counteract delayed fracture healing is the application of whole-body LMHFV. In vitro experiments using preosteoblastic and MSCs demonstrated an increased osteogenic response after vibration therapy [17], [84], [85]. However, in vivo studies investigating the effects of LMHFV on fracture healing produced conflicting results, which appeared to be due to different animal models. Vibration therapy accelerated bone regeneration in estrogen-deficient, osteoporotic animals [86], [87], [88], [89], [90], whereas no or even negative effects were shown in estrogen-competent animals [90], [91]. Therefore, the success of LMHFV during fracture healing appears to be profoundly influenced by the estrogen level. Notably, aged estrogen-deficient mice also displayed improved fracture healing after LMHFV [92]. Therefore, this method could be suitable to accelerate fracture healing in aged and postmenopausal patients. However, further studies are required to evaluate the safety and efficacy of LMHFV during bone healing in clinical practice.

In conclusion, mechanotransduction on the tissue, cellular, and molecular levels is strongly influenced by aging. The mechanoresponsiveness of both intact and fractured bones may differ between young and aged subjects. Particularly during the process of fracture healing, which is under tight biomechanical control, external mechanostimulation is able to influence the healing process even in the aged organism. Therefore, therapies such as LIPUS and LMHFV might have the potential to counteract delayed bone regeneration in the elderly. However, further studies and randomized clinical trials are needed to prove the effects of biomechanical stimulation on fracture healing in the aged patient.

Supporting Information

Supplemental Material

The article (DOI: iss-2016-0021) offers reviewer assessments as supplementary material.

Author Statement

Research funding: Authors state no funding involved. Conflict of interest: Authors state no conflict of interest. Informed consent: Informed consent is not applicable. Ethical approval: The conducted research is not related to either human or animal use.

Author Contributions

Writing of the manuscript: Melanie Haffner-Luntzer; Anita Ignatius; Revision of the manuscript: Melanie Haffner-Luntzer, Astrid Liedert, Anita Ignatius; Approval of the manuscript: Melanie Haffner-Luntzer, Astrid Liedert, Anita Ignatius.

Publication Funding

The German Society of Surgery funded the article processing charges of this article.

References

  • [1].Harada S, Rodan GA. Control of osteoblast function and regulation of bone mass. Nature 2003;423:349–355. [DOI] [PubMed]; Harada S, Rodan GA. Control of osteoblast function and regulation of bone mass. Nature. 2003;423:349–355. doi: 10.1038/nature01660. [DOI] [PubMed] [Google Scholar]
  • [2].Wolff J. Das Gesetz der Transformation der Knochen. Berlin, Germany: A. Hirschwald, 1892.; Wolff J. Das Gesetz der Transformation der Knochen. Berlin, Germany: A. Hirschwald; 1892. [Google Scholar]
  • [3].Rubin CT, McLeod KJ. Promotion of bony ingrowth by frequency-specific, low-amplitude mechanical strain. Clin Orthopaed Relat Res 1994;298:165–174. [PubMed]; Rubin CT, McLeod KJ. Promotion of bony ingrowth by frequency-specific, low-amplitude mechanical strain. Clin Orthopaed Relat Res. 1994;298:165–174. [PubMed] [Google Scholar]
  • [4].Frost HM. Bone “mass” and the “mechanostat”: a proposal. Anat Rec 1987;219:1–9. [DOI] [PubMed]; Frost HM. Bone “mass” and the “mechanostat”: a proposal. Anat Rec. 1987;219:1–9. doi: 10.1002/ar.1092190104. [DOI] [PubMed] [Google Scholar]
  • [5].Frost HM. Skeletal structural adaptations to mechanical usage (SATMU): 1. Redefining Wolff’s law: the bone modeling problem. Anat Rec 1990;226:403–413. [DOI] [PubMed]; Frost HM. Skeletal structural adaptations to mechanical usage (SATMU): 1. Redefining Wolff’s law: the bone modeling problem. Anat Rec. 1990;226:403–413. doi: 10.1002/ar.1092260402. [DOI] [PubMed] [Google Scholar]
  • [6].Frost HM. Skeletal structural adaptations to mechanical usage (SATMU): 2. Redefining Wolff’s law: the remodeling problem. Anat Rec 1990;226:414–422. [DOI] [PubMed]; Frost HM. Skeletal structural adaptations to mechanical usage (SATMU): 2. Redefining Wolff’s law: the remodeling problem. Anat Rec. 1990;226:414–422. doi: 10.1002/ar.1092260403. [DOI] [PubMed] [Google Scholar]
  • [7].Burger EH, Klein-Nulen J. Responses of bone cells to biomechanical forces in vitro. Adv Dent Res 1999;13:93–98. [DOI] [PubMed]; Burger EH, Klein-Nulen J. Responses of bone cells to biomechanical forces in vitro. Adv Dent Res. 1999;13:93–98. doi: 10.1177/08959374990130012201. [DOI] [PubMed] [Google Scholar]
  • [8].Mullender MG, Huiskes R. Osteocytes and bone lining cells: which are the best candidates for mechano-sensors in cancellous bone? Bone 1997;20:527–532. [DOI] [PubMed]; Mullender MG, Huiskes R. Osteocytes and bone lining cells: which are the best candidates for mechano-sensors in cancellous bone? Bone. 1997;20:527–532. doi: 10.1016/s8756-3282(97)00036-7. [DOI] [PubMed] [Google Scholar]
  • [9].Weinbaum S, Cowin SC, Zeng Y. A model for the excitation of osteocytes by mechanical loading-induced bone fluid shear stresses. J Biomech 1994;27:339–360. [DOI] [PubMed]; Weinbaum S, Cowin SC, Zeng Y. A model for the excitation of osteocytes by mechanical loading-induced bone fluid shear stresses. J Biomech. 1994;27:339–360. doi: 10.1016/0021-9290(94)90010-8. [DOI] [PubMed] [Google Scholar]
  • [10].Duncan RL, Turner CH. Mechanotransduction and the functional response of bone to mechanical strain. Calcified Tissue Int 1995;57:344–358. [DOI] [PubMed]; Duncan RL, Turner CH. Mechanotransduction and the functional response of bone to mechanical strain. Calcified Tissue Int. 1995;57:344–358. doi: 10.1007/BF00302070. [DOI] [PubMed] [Google Scholar]
  • [11].Mikuni-Takagaki Y, Naruse K, Azuma Y, Miyauchi A. The role of calcium channels in osteocyte function. J Musculoskelet Neuronal Interact 2002;2:252–255. [PubMed]; Mikuni-Takagaki Y, Naruse K, Azuma Y, Miyauchi A. The role of calcium channels in osteocyte function. J Musculoskelet Neuronal Interact. 2002;2:252–255. [PubMed] [Google Scholar]
  • [12].Ross TD, Coon BG, Yun S, et al. Integrins in mechanotransduction. Curr Opin Cell Biol 2013;25:613–618. [DOI] [PMC free article] [PubMed]; Ross TD, Coon BG, Yun S. et al. Integrins in mechanotransduction. Curr Opin Cell Biol. 2013;25:613–618. doi: 10.1016/j.ceb.2013.05.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Liedert A, Kaspar D, Blakytny R, Claes L, Ignatius A. Signal transduction pathways involved in mechanotransduction in bone cells. Biochem Biophys Res Commun 2006;349:1–5. [DOI] [PubMed]; Liedert A, Kaspar D, Blakytny R, Claes L, Ignatius A. Signal transduction pathways involved in mechanotransduction in bone cells. Biochem Biophys Res Commun. 2006;349:1–5. doi: 10.1016/j.bbrc.2006.07.214. [DOI] [PubMed] [Google Scholar]
  • [14].Rosa N, Simoes R, Magalhaes FD, Marques AT. From mechanical stimulus to bone formation: a review. Med Eng Phys 2015;37:719–728. [DOI] [PubMed]; Rosa N, Simoes R, Magalhaes FD, Marques AT. From mechanical stimulus to bone formation: a review. Med Eng Phys. 2015;37:719–728. doi: 10.1016/j.medengphy.2015.05.015. [DOI] [PubMed] [Google Scholar]
  • [15].Robling AG, Niziolek PJ, Baldridge LA, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem 2008;283:5866–5875. [DOI] [PubMed]; Robling AG, Niziolek PJ, Baldridge LA. et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008;283:5866–5875. doi: 10.1074/jbc.M705092200. [DOI] [PubMed] [Google Scholar]
  • [16].Qin YX, Hu M. Mechanotransduction in musculoskeletal tissue regeneration: effects of fluid flow, loading, and cellular-molecular pathways. BioMed Res Int 2014;2014:863421. [DOI] [PMC free article] [PubMed]; Qin YX, Hu M. Mechanotransduction in musculoskeletal tissue regeneration: effects of fluid flow, loading, and cellular-molecular pathways. BioMed Res Int. 2014;2014:863421. doi: 10.1155/2014/863421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [17].Uzer G, Pongkitwitoon S, Ete Chan M, Judex S. Vibration induced osteogenic commitment of mesenchymal stem cells is enhanced by cytoskeletal remodeling but not fluid shear. J Biomech 2013;46:2296–2302. [DOI] [PMC free article] [PubMed]; Uzer G, Pongkitwitoon S, Ete Chan M, Judex S. Vibration induced osteogenic commitment of mesenchymal stem cells is enhanced by cytoskeletal remodeling but not fluid shear. J Biomech. 2013;46:2296–2302. doi: 10.1016/j.jbiomech.2013.06.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Kim IS, Song YM, Lee B, Hwang SJ. Human mesenchymal stromal cells are mechanosensitive to vibration stimuli. J Dent Res 2012;91:1135–1140. [DOI] [PubMed]; Kim IS, Song YM, Lee B, Hwang SJ. Human mesenchymal stromal cells are mechanosensitive to vibration stimuli. J Dent Res. 2012;91:1135–1140. doi: 10.1177/0022034512465291. [DOI] [PubMed] [Google Scholar]
  • [19].Tanaka SM, Li J, Duncan RL, Yokota H, Burr DB, Turner CH. Effects of broad frequency vibration on cultured osteoblasts. J Biomech 2003;36:73–80. [DOI] [PubMed]; Tanaka SM, Li J, Duncan RL, Yokota H, Burr DB, Turner CH. Effects of broad frequency vibration on cultured osteoblasts. J Biomech. 2003;36:73–80. doi: 10.1016/s0021-9290(02)00245-2. [DOI] [PubMed] [Google Scholar]
  • [20].Li CY, Jee WS, Chen JL, et al. Estrogen and “exercise” have a synergistic effect in preventing bone loss in the lumbar vertebra and femoral neck of the ovariectomized rat. Calcified Tissue Int 2003;72:42–49. [DOI] [PubMed]; Li CY, Jee WS, Chen JL. et al. Estrogen and “exercise” have a synergistic effect in preventing bone loss in the lumbar vertebra and femoral neck of the ovariectomized rat. Calcified Tissue Int. 2003;72:42–49. doi: 10.1007/s00223-001-1086-y. [DOI] [PubMed] [Google Scholar]
  • [21].Sterck JG, Klein-Nulend J, Lips P, Burger EH. Response of normal and osteoporotic human bone cells to mechanical stress in vitro. Am J Physiol 1998;274:E1113–E1120. [DOI] [PubMed]; Sterck JG, Klein-Nulend J, Lips P, Burger EH. Response of normal and osteoporotic human bone cells to mechanical stress in vitro. Am J Physiol. 1998;274:E1113–E1120. doi: 10.1152/ajpendo.1998.274.6.E1113. [DOI] [PubMed] [Google Scholar]
  • [22].Jagger CJ, Chow JW, Chambers TJ. Estrogen suppresses activation but enhances formation phase of osteogenic response to mechanical stimulation in rat bone. J Clin Invest 1996;98:2351–2357. [DOI] [PMC free article] [PubMed]; Jagger CJ, Chow JW, Chambers TJ. Estrogen suppresses activation but enhances formation phase of osteogenic response to mechanical stimulation in rat bone. J Clin Invest. 1996;98:2351–2357. doi: 10.1172/JCI119047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Saxon LK, Turner CH. Estrogen receptor β: the antimechanostat? Bone 2005;36:185–192. [DOI] [PubMed]; Saxon LK, Turner CH. Estrogen receptor β: the antimechanostat? Bone. 2005;36:185–192. doi: 10.1016/j.bone.2004.08.003. [DOI] [PubMed] [Google Scholar]
  • [24].Zaman G, Jessop HL, Muzylak M, et al. Osteocytes use estrogen receptor α to respond to strain but their ERα content is regulated by estrogen. J Bone Miner Res 2006;21:1297–1306. [DOI] [PubMed]; Zaman G, Jessop HL, Muzylak M. et al. Osteocytes use estrogen receptor α to respond to strain but their ERα content is regulated by estrogen. J Bone Miner Res. 2006;21:1297–1306. doi: 10.1359/jbmr.060504. [DOI] [PubMed] [Google Scholar]
  • [25].Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev 2008;29:535–559. [DOI] [PMC free article] [PubMed]; Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev. 2008;29:535–559. doi: 10.1210/er.2007-0036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Kaufman JM. Osteoporosis in the elderly man. Ann Endocrinol (Paris) 2003;64:141–147. [PubMed]; Kaufman JM. Osteoporosis in the elderly man. Ann Endocrinol (Paris) 2003;64:141–147. [PubMed] [Google Scholar]
  • [27].Rauner M, Sipos W, Pietschmann P. Age-dependent Wnt gene expression in bone and during the course of osteoblast differentiation. Age (Dordrecht, Netherlands) 2008;30:273–282. [DOI] [PMC free article] [PubMed]; Rauner M, Sipos W, Pietschmann P. Age-dependent Wnt gene expression in bone and during the course of osteoblast differentiation. Age (Dordrecht, Netherlands) 2008;30:273–282. doi: 10.1007/s11357-008-9069-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Kuang W, Xu X, Lin J, et al. Functional and molecular changes of MSCs in aging. Curr Stem Cell Res Ther 2015;10:384–391. [DOI] [PubMed]; Kuang W, Xu X, Lin J. et al. Functional and molecular changes of MSCs in aging. Curr Stem Cell Res Ther. 2015;10:384–391. doi: 10.2174/1574888x10666150211162933. [DOI] [PubMed] [Google Scholar]
  • [29].Buhl KM, Jacobs CR, Turner RT, Evans GL, Farrell PA, Donahue HJ. Aged bone displays an increased responsiveness to low-intensity resistance exercise. J Appl Physiol 2001;90:1359–1364. [DOI] [PubMed]; Buhl KM, Jacobs CR, Turner RT, Evans GL, Farrell PA, Donahue HJ. Aged bone displays an increased responsiveness to low-intensity resistance exercise. J Appl Physiol. 2001;90:1359–1364. doi: 10.1152/jappl.2001.90.4.1359. [DOI] [PubMed] [Google Scholar]
  • [30].Leppanen OV, Sievanen H, Jokihaara J, Pajamaki I, Kannus P, Jarvinen TL. Pathogenesis of age-related osteoporosis: impaired mechano-responsiveness of bone is not the culprit. PLoS ONE 2008;3:e2540. [DOI] [PMC free article] [PubMed]; Leppanen OV, Sievanen H, Jokihaara J, Pajamaki I, Kannus P, Jarvinen TL. Pathogenesis of age-related osteoporosis: impaired mechano-responsiveness of bone is not the culprit. PLoS ONE. 2008;3:e2540. doi: 10.1371/journal.pone.0002540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Rubin CT, Bain SD, McLeod KJ. Suppression of the osteogenic response in the aging skeleton. Calcified Tissue Int 1992;50:306–313. [DOI] [PubMed]; Rubin CT, Bain SD, McLeod KJ. Suppression of the osteogenic response in the aging skeleton. Calcified Tissue Int. 1992;50:306–313. doi: 10.1007/BF00301627. [DOI] [PubMed] [Google Scholar]
  • [32].Turner CH, Takano Y, Owan I. Aging changes mechanical loading thresholds for bone formation in rats. J Bone Miner Res 1995;10:1544–1549. [DOI] [PubMed]; Turner CH, Takano Y, Owan I. Aging changes mechanical loading thresholds for bone formation in rats. J Bone Miner Res. 1995;10:1544–1549. doi: 10.1002/jbmr.5650101016. [DOI] [PubMed] [Google Scholar]
  • [33].Joiner DM, Tayim RJ, McElderry JD, Morris MD, Goldstein SA. Aged male rats regenerate cortical bone with reduced osteocyte density and reduced secretion of nitric oxide after mechanical stimulation. Calcified Tissue Int 2014;94:484–494. [DOI] [PMC free article] [PubMed]; Joiner DM, Tayim RJ, McElderry JD, Morris MD, Goldstein SA. Aged male rats regenerate cortical bone with reduced osteocyte density and reduced secretion of nitric oxide after mechanical stimulation. Calcified Tissue Int. 2014;94:484–494. doi: 10.1007/s00223-013-9832-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [34].Raab DM, Smith EL, Crenshaw TD, Thomas DP. Bone mechanical properties after exercise training in young and old rats. J Appl Physiol 1990;68:130–134. [DOI] [PubMed]; Raab DM, Smith EL, Crenshaw TD, Thomas DP. Bone mechanical properties after exercise training in young and old rats. J Appl Physiol. 1990;68:130–134. doi: 10.1152/jappl.1990.68.1.130. [DOI] [PubMed] [Google Scholar]
  • [35].Jarvinen TL, Pajamaki I, Sievanen H, et al. Femoral neck response to exercise and subsequent deconditioning in young and adult rats. J Bone Miner Res 2003;18:1292–1299. [DOI] [PubMed]; Jarvinen TL, Pajamaki I, Sievanen H. et al. Femoral neck response to exercise and subsequent deconditioning in young and adult rats. J Bone Miner Res. 2003;18:1292–1299. doi: 10.1359/jbmr.2003.18.7.1292. [DOI] [PubMed] [Google Scholar]
  • [36].Hagino H, Raab DM, Kimmel DB, Akhter MP, Recker RR. Effect of ovariectomy on bone response to in vivo external loading. J Bone Miner Res 1993;8:347–357. [DOI] [PubMed]; Hagino H, Raab DM, Kimmel DB, Akhter MP, Recker RR. Effect of ovariectomy on bone response to in vivo external loading. J Bone Miner Res. 1993;8:347–357. doi: 10.1002/jbmr.5650080312. [DOI] [PubMed] [Google Scholar]
  • [37].Pruitt LA, Taaffe DR, Marcus R. Effects of a one-year high-intensity versus low-intensity resistance training program on bone mineral density in older women. J Bone Miner Res 1995;10:1788–1795. [DOI] [PubMed]; Pruitt LA, Taaffe DR, Marcus R. Effects of a one-year high-intensity versus low-intensity resistance training program on bone mineral density in older women. J Bone Miner Res. 1995;10:1788–1795. doi: 10.1002/jbmr.5650101123. [DOI] [PubMed] [Google Scholar]
  • [38].Allison SJ, Folland JP, Rennie WJ, Summers GD, Brooke-Wavell K. High impact exercise increased femoral neck bone mineral density in older men: a randomised unilateral intervention. Bone 2013;53:321–328. [DOI] [PubMed]; Allison SJ, Folland JP, Rennie WJ, Summers GD, Brooke-Wavell K. High impact exercise increased femoral neck bone mineral density in older men: a randomised unilateral intervention. Bone. 2013;53:321–328. doi: 10.1016/j.bone.2012.12.045. [DOI] [PubMed] [Google Scholar]
  • [39].Verschueren SM, Roelants M, Delecluse C, Swinnen S, Vanderschueren D, Boonen S. Effect of 6-month whole body vibration training on hip density, muscle strength, and postural control in postmenopausal women: a randomized controlled pilot study. J Bone Miner Res 2004;19:352–359. [DOI] [PubMed]; Verschueren SM, Roelants M, Delecluse C, Swinnen S, Vanderschueren D, Boonen S. Effect of 6-month whole body vibration training on hip density, muscle strength, and postural control in postmenopausal women: a randomized controlled pilot study. J Bone Miner Res. 2004;19:352–359. doi: 10.1359/JBMR.0301245. [DOI] [PubMed] [Google Scholar]
  • [40].Lai CL, Tseng SY, Chen CN, Liao WC, Wang CH, Lee MC, et al. Effect of 6 months of whole body vibration on lumbar spine bone density in postmenopausal women: a randomized controlled trial. Clin Interv Aging 2013;8:1603–1609. [DOI] [PMC free article] [PubMed]; Lai CL, Tseng SY, Chen CN, Liao WC, Wang CH, Lee MC. et al. Effect of 6 months of whole body vibration on lumbar spine bone density in postmenopausal women: a randomized controlled trial. Clin Interv Aging. 2013;8:1603–1609. doi: 10.2147/CIA.S53591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Rubin C, Recker R, Cullen D, Ryaby J, McCabe J, McLeod K. Prevention of postmenopausal bone loss by a low-magnitude, high-frequency mechanical stimuli: a clinical trial assessing compliance, efficacy, and safety. J Bone Miner Res 2004;19:343–351. [DOI] [PubMed]; Rubin C, Recker R, Cullen D, Ryaby J, McCabe J, McLeod K. Prevention of postmenopausal bone loss by a low-magnitude, high-frequency mechanical stimuli: a clinical trial assessing compliance, efficacy, and safety. J Bone Miner Res. 2004;19:343–351. doi: 10.1359/JBMR.0301251. [DOI] [PubMed] [Google Scholar]
  • [42].Ma C, Liu A, Sun M, Zhu H, Wu H. Effect of whole-body vibration on reduction of bone loss and fall prevention in postmenopausal women: a meta-analysis and systematic review. J Orthopaed Surg Res 2016;11:24. [DOI] [PMC free article] [PubMed]; Ma C, Liu A, Sun M, Zhu H, Wu H. Effect of whole-body vibration on reduction of bone loss and fall prevention in postmenopausal women: a meta-analysis and systematic review. J Orthopaed Surg Res. 2016;11:24. doi: 10.1186/s13018-016-0357-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [43].Augat P, Margevicius K, Simon J, Wolf S, Suger G, Claes L. Local tissue properties in bone healing: influence of size and stability of the osteotomy gap. J Orthop Res 1998;16:475–481. [DOI] [PubMed]; Augat P, Margevicius K, Simon J, Wolf S, Suger G, Claes L. Local tissue properties in bone healing: influence of size and stability of the osteotomy gap. J Orthop Res. 1998;16:475–481. doi: 10.1002/jor.1100160413. [DOI] [PubMed] [Google Scholar]
  • [44].Perren SM, Rahn BA. Biomechanics of fracture healing. Can J Surg 1980;23:228–232. [PubMed]; Perren SM, Rahn BA. Biomechanics of fracture healing. Can J Surg. 1980;23:228–232. [PubMed] [Google Scholar]
  • [45].Pauwels F. Eine neue Theorie über den Einfluß mechanischer Reize auf die Differenzierung der Stützgewebe. Z Anat Entwicklung 1960;121:478–515.; Pauwels F. Eine neue Theorie über den Einfluß mechanischer Reize auf die Differenzierung der Stützgewebe. Z Anat Entwicklung. 1960;121:478–515. [Google Scholar]
  • [46].Claes LE, Heigele CA. Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing. J Biomech 1999;32:255–266. [DOI] [PubMed]; Claes LE, Heigele CA. Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing. J Biomech. 1999;32:255–266. doi: 10.1016/s0021-9290(98)00153-5. [DOI] [PubMed] [Google Scholar]
  • [47].Claes L, Veeser A, Gockelmann M, Simon U, Ignatius A. A novel model to study metaphyseal bone healing under defined biomechanical conditions. Arch Orthopaed Trauma Surg 2009;129:923–928. [DOI] [PubMed]; Claes L, Veeser A, Gockelmann M, Simon U, Ignatius A. A novel model to study metaphyseal bone healing under defined biomechanical conditions. Arch Orthopaed Trauma Surg. 2009;129:923–928. doi: 10.1007/s00402-008-0692-9. [DOI] [PubMed] [Google Scholar]
  • [48].Claes LE, Heigele CA, Neidlinger-Wilke C, et al. Effects of mechanical factors on the fracture healing process. Clin Orthopaed Relat Res 1998;129:S132–S147. [DOI] [PubMed]; Claes LE, Heigele CA, Neidlinger-Wilke C. et al. Effects of mechanical factors on the fracture healing process. Clin Orthopaed Relat Res. 1998;129:S132–S147. doi: 10.1097/00003086-199810001-00015. [DOI] [PubMed] [Google Scholar]
  • [49].Ode A, Duda GN, Geissler S, et al. Interaction of age and mechanical stability on bone defect healing: an early transcriptional analysis of fracture hematoma in rat. PLoS ONE 2014;9:e106462. [DOI] [PMC free article] [PubMed]; Ode A, Duda GN, Geissler S. et al. Interaction of age and mechanical stability on bone defect healing: an early transcriptional analysis of fracture hematoma in rat. PLoS ONE. 2014;9:e106462. doi: 10.1371/journal.pone.0106462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [50].Lienau J, Schmidt-Bleek K, Peters A, et al. Differential regulation of blood vessel formation between standard and delayed bone healing. J Orthop Res 2009;27:1133–1140. [DOI] [PubMed]; Lienau J, Schmidt-Bleek K, Peters A. et al. Differential regulation of blood vessel formation between standard and delayed bone healing. J Orthop Res. 2009;27:1133–1140. doi: 10.1002/jor.20870. [DOI] [PubMed] [Google Scholar]
  • [51].Lienau J, Schmidt-Bleek K, Peters A, et al. Insight into the molecular pathophysiology of delayed bone healing in a sheep model. Tissue Eng Pt A 2010;16:191–199. [DOI] [PubMed]; Lienau J, Schmidt-Bleek K, Peters A. et al. Insight into the molecular pathophysiology of delayed bone healing in a sheep model. Tissue Eng Pt A. 2010;16:191–199. doi: 10.1089/ten.TEA.2009.0187. [DOI] [PubMed] [Google Scholar]
  • [52].Le AX, Miclau T, Hu D, Helms JA. Molecular aspects of healing in stabilized and non-stabilized fractures. J Orthop Res 2001;19:78–84. [DOI] [PubMed]; Le AX, Miclau T, Hu D, Helms JA. Molecular aspects of healing in stabilized and non-stabilized fractures. J Orthop Res. 2001;19:78–84. doi: 10.1016/S0736-0266(00)00006-1. [DOI] [PubMed] [Google Scholar]
  • [53].Yu YY, Lieu S, Lu C, Miclau T, Marcucio RS, Colnot C. Immunolocalization of BMPs, BMP antagonists, receptors, and effectors during fracture repair. Bone 2010;46:841–851. [DOI] [PubMed]; Yu YY, Lieu S, Lu C, Miclau T, Marcucio RS, Colnot C. Immunolocalization of BMPs, BMP antagonists, receptors, and effectors during fracture repair. Bone. 2010;46:841–851. doi: 10.1016/j.bone.2009.11.005. [DOI] [PubMed] [Google Scholar]
  • [54].Kaspar D, Neidlinger-Wilke C, Holbein O, Claes L, Ignatius A. Mitogens are increased in the systemic circulation during bone callus healing. J Orthop Res 2003;21:320–325. [DOI] [PubMed]; Kaspar D, Neidlinger-Wilke C, Holbein O, Claes L, Ignatius A. Mitogens are increased in the systemic circulation during bone callus healing. J Orthop Res. 2003;21:320–325. doi: 10.1016/S0736-0266(02)00134-1. [DOI] [PubMed] [Google Scholar]
  • [55].Salisbury Palomares KT, Gerstenfeld LC, Wigner NA, Lenburg ME, Einhorn TA, Morgan EF. Transcriptional profiling and biochemical analysis of mechanically induced cartilaginous tissues in a rat model. Arthritis Rheum 2010;62:1108–1118. [DOI] [PMC free article] [PubMed]; Salisbury Palomares KT, Gerstenfeld LC, Wigner NA, Lenburg ME, Einhorn TA, Morgan EF. Transcriptional profiling and biochemical analysis of mechanically induced cartilaginous tissues in a rat model. Arthritis Rheum. 2010;62:1108–1118. doi: 10.1002/art.27343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [56].Robinson CM, Court-Brown CM, McQueen MM, Wakefield AE. Estimating the risk of nonunion following nonoperative treatment of a clavicular fracture. J Bone Joint Surg 2004;86-A:1359–1365. [DOI] [PubMed]; Robinson CM, Court-Brown CM, McQueen MM, Wakefield AE. Estimating the risk of nonunion following nonoperative treatment of a clavicular fracture. J Bone Joint Surg. 2004;86-A:1359–1365. doi: 10.2106/00004623-200407000-00002. [DOI] [PubMed] [Google Scholar]
  • [57].Histing T, Stenger D, Kuntz S, et al. Increased osteoblast and osteoclast activity in female senescence-accelerated, osteoporotic SAMP6 mice during fracture healing. J Surg Res 2012;175:271–277. [DOI] [PubMed]; Histing T, Stenger D, Kuntz S. et al. Increased osteoblast and osteoclast activity in female senescence-accelerated, osteoporotic SAMP6 mice during fracture healing. J Surg Res. 2012;175:271–277. doi: 10.1016/j.jss.2011.03.052. [DOI] [PubMed] [Google Scholar]
  • [58].Histing T, Kuntz S, Stenger D, et al. Delayed fracture healing in aged senescence-accelerated P6 mice. J Invest Surg 2013;26:30–35. [DOI] [PubMed]; Histing T, Kuntz S, Stenger D. et al. Delayed fracture healing in aged senescence-accelerated P6 mice. J Invest Surg. 2013;26:30–35. doi: 10.3109/08941939.2012.687435. [DOI] [PubMed] [Google Scholar]
  • [59].Haffner-Luntzer M, Kovtun A, Rapp AE, Ignatius A. Mouse models in bone fracture healing research. Curr Mol Biol Rep 2016;2:101–111.; Haffner-Luntzer M, Kovtun A, Rapp AE, Ignatius A. Mouse models in bone fracture healing research. Curr Mol Biol Rep. 2016;2:101–111. [Google Scholar]
  • [60].Lu C, Hansen E, Sapozhnikova A, Hu D, Miclau T, Marcucio RS. Effect of age on vascularization during fracture repair. J Orthop Res 2008;26:1384–1389. [DOI] [PMC free article] [PubMed]; Lu C, Hansen E, Sapozhnikova A, Hu D, Miclau T, Marcucio RS. Effect of age on vascularization during fracture repair. J Orthop Res. 2008;26:1384–1389. doi: 10.1002/jor.20667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [61].Meyer RA Jr, Tsahakis PJ, Martin DF, Banks DM, Harrow ME, Kiebzak GM. Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J Orthop Res 2001;19:428–435. [DOI] [PubMed]; Meyer RA Jr, Tsahakis PJ, Martin DF, Banks DM, Harrow ME, Kiebzak GM. Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J Orthop Res. 2001;19:428–435. doi: 10.1016/S0736-0266(00)90034-2. [DOI] [PubMed] [Google Scholar]
  • [62].Ekeland A, Engesoeter LB, Langeland N. Influence of age on mechanical properties of healing fractures and intact bones in rats. Acta Orthop Scand 1982;53:527–534. [DOI] [PubMed]; Ekeland A, Engesoeter LB, Langeland N. Influence of age on mechanical properties of healing fractures and intact bones in rats. Acta Orthop Scand. 1982;53:527–534. doi: 10.3109/17453678208992252. [DOI] [PubMed] [Google Scholar]
  • [63].Yukata K, Xie C, Li TF, et al. Aging periosteal progenitor cells have reduced regenerative responsiveness to bone injury and to the anabolic actions of PTH 1-34 treatment. Bone 2014;62:79–89. [DOI] [PMC free article] [PubMed]; Yukata K, Xie C, Li TF. et al. Aging periosteal progenitor cells have reduced regenerative responsiveness to bone injury and to the anabolic actions of PTH 1-34 treatment. Bone. 2014;62:79–89. doi: 10.1016/j.bone.2014.02.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [64].Lu C, Miclau T, Hu D, et al. Cellular basis for age-related changes in fracture repair. J Orthop Res 2005;23:1300–1307. [DOI] [PMC free article] [PubMed]; Lu C, Miclau T, Hu D. et al. Cellular basis for age-related changes in fracture repair. J Orthop Res. 2005;23:1300–1307. doi: 10.1016/j.orthres.2005.04.003.1100230610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [65].Matsumoto K, Shimo T, Kurio N, et al. Expression and role of sonic hedgehog in the process of fracture healing with aging. In Vivo 2016;30:99–105. [PubMed]; Matsumoto K, Shimo T, Kurio N. et al. Expression and role of sonic hedgehog in the process of fracture healing with aging. In Vivo. 2016;30:99–105. [PubMed] [Google Scholar]
  • [66].Wang Z, Ehnert S, Ihle C, et al. Increased oxidative stress response in granulocytes from older patients with a hip fracture may account for slow regeneration. Oxid Med Cell Longev 2014;2014:819847. [DOI] [PMC free article] [PubMed]; Wang Z, Ehnert S, Ihle C. et al. Increased oxidative stress response in granulocytes from older patients with a hip fracture may account for slow regeneration. Oxid Med Cell Longev. 2014;2014:819847. doi: 10.1155/2014/819847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [67].Xing Z, Lu C, Hu D, Miclau T, 3rd, Marcucio RS. Rejuvenation of the inflammatory system stimulates fracture repair in aged mice. J Orthop Res 2010;28:1000–1006. [DOI] [PMC free article] [PubMed]; Xing Z, Lu C, Hu D, Miclau T 3rd, Marcucio RS. Rejuvenation of the inflammatory system stimulates fracture repair in aged mice. J Orthop Res. 2010;28:1000–1006. doi: 10.1002/jor.21087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [68].Naik AA, Xie C, Zuscik MJ, et al. Reduced COX-2 expression in aged mice is associated with impaired fracture healing. J Bone Miner Res 2009;24:251–264. [DOI] [PMC free article] [PubMed]; Naik AA, Xie C, Zuscik MJ. et al. Reduced COX-2 expression in aged mice is associated with impaired fracture healing. J Bone Miner Res. 2009;24:251–264. doi: 10.1359/jbmr.081002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [69].Strube P, Sentuerk U, Riha T, et al. Influence of age and mechanical stability on bone defect healing: age reverses mechanical effects. Bone 2008;42:758–764. [DOI] [PubMed]; Strube P, Sentuerk U, Riha T. et al. Influence of age and mechanical stability on bone defect healing: age reverses mechanical effects. Bone. 2008;42:758–764. doi: 10.1016/j.bone.2007.12.223. [DOI] [PubMed] [Google Scholar]
  • [70].Mehta M, Strube P, Peters A, et al. Influences of age and mechanical stability on volume, microstructure, and mineralization of the fracture callus during bone healing: is osteoclast activity the key to age-related impaired healing? Bone 2010;47:219–228. [DOI] [PubMed]; Mehta M, Strube P, Peters A. et al. Influences of age and mechanical stability on volume, microstructure, and mineralization of the fracture callus during bone healing: is osteoclast activity the key to age-related impaired healing? Bone. 2010;47:219–228. doi: 10.1016/j.bone.2010.05.029. [DOI] [PubMed] [Google Scholar]
  • [71].Histing T, Heerschop K, Klein M, et al. Effect of stabilization on the healing process of femur fractures in aged mice. J Invest Surg 2016;29:202–208. [DOI] [PubMed]; Histing T, Heerschop K, Klein M. et al. Effect of stabilization on the healing process of femur fractures in aged mice. J Invest Surg. 2016;29:202–208. doi: 10.3109/08941939.2015.1127448. [DOI] [PubMed] [Google Scholar]
  • [72].Schaden W, Mittermayr R, Haffner N, Smolen D, Gerdesmeyer L, Wang CJ. Extracorporeal shockwave therapy (ESWT) – first choice treatment of fracture non-unions? Int J Surg 2015;24:179–183. [DOI] [PubMed]; Schaden W, Mittermayr R, Haffner N, Smolen D, Gerdesmeyer L, Wang CJ. Extracorporeal shockwave therapy (ESWT) – first choice treatment of fracture non-unions? Int J Surg. 2015;24:179–183. doi: 10.1016/j.ijsu.2015.10.003. [DOI] [PubMed] [Google Scholar]
  • [73].Claes L, Willie B. The enhancement of bone regeneration by ultrasound. Prog Biophys Mol Biol 2007;93:384–398. [DOI] [PubMed]; Claes L, Willie B. The enhancement of bone regeneration by ultrasound. Prog Biophys Mol Biol. 2007;93:384–398. doi: 10.1016/j.pbiomolbio.2006.07.021. [DOI] [PubMed] [Google Scholar]
  • [74].Rajaei Jafarabadi M, Rouhi G, Kaka G, Sadraie SH, Arum J. The effects of photobiomodulation and low-amplitude high-frequency vibration on bone healing process: a comparative study. Lasers Med Sci 2016;31:1827–1836. [DOI] [PubMed]; Rajaei Jafarabadi M, Rouhi G, Kaka G, Sadraie SH, Arum J. The effects of photobiomodulation and low-amplitude high-frequency vibration on bone healing process: a comparative study. Lasers Med Sci. 2016;31:1827–1836. doi: 10.1007/s10103-016-2058-9. [DOI] [PubMed] [Google Scholar]
  • [75].Farkash U, Bain O, Gam A, Nyska M, Sagiv P. Low-intensity pulsed ultrasound for treating delayed union scaphoid fractures: case series. J Orthopaed Surg Res 2015;10:72. [DOI] [PMC free article] [PubMed]; Farkash U, Bain O, Gam A, Nyska M, Sagiv P. Low-intensity pulsed ultrasound for treating delayed union scaphoid fractures: case series. J Orthopaed Surg Res. 2015;10:72. doi: 10.1186/s13018-015-0221-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [76].Liu Y, Wei X, Kuang Y, et al. Ultrasound treatment for accelerating fracture healing of the distal radius. A control study. Acta Cir Bras 2014;29:765–770. [DOI] [PubMed]; Liu Y, Wei X, Kuang Y. et al. Ultrasound treatment for accelerating fracture healing of the distal radius. A control study. Acta Cir Bras. 2014;29:765–770. doi: 10.1590/s0102-86502014001800012. [DOI] [PubMed] [Google Scholar]
  • [77].Zura R, Della Rocca GJ, Mehta S, et al. Treatment of chronic (>1 year) fracture nonunion: Heal rate in a cohort of 767 patients treated with low-intensity pulsed ultrasound (LIPUS). Injury 2015;46:2036–2041. [DOI] [PubMed]; Zura R, Della Rocca GJ, Mehta S. et al. Treatment of chronic (>1 year) fracture nonunion: Heal rate in a cohort of 767 patients treated with low-intensity pulsed ultrasound (LIPUS) Injury. 2015;46:2036–2041. doi: 10.1016/j.injury.2015.05.042. [DOI] [PubMed] [Google Scholar]
  • [78].Cheung WH, Chin WC, Qin L, Leung KS. Low intensity pulsed ultrasound enhances fracture healing in both ovariectomy-induced osteoporotic and age-matched normal bones. J Orthop Res 2012;30:129–136. [DOI] [PubMed]; Cheung WH, Chin WC, Qin L, Leung KS. Low intensity pulsed ultrasound enhances fracture healing in both ovariectomy-induced osteoporotic and age-matched normal bones. J Orthop Res. 2012;30:129–136. doi: 10.1002/jor.21487. [DOI] [PubMed] [Google Scholar]
  • [79].Rutten S, van den Bekerom MP, Sierevelt IN, Nolte PA. Enhancement of bone-healing by low-intensity pulsed ultrasound: a systematic review. JBJS Rev 2016;4. [DOI] [PubMed]; Rutten S, van den Bekerom MP, Sierevelt IN, Nolte PA. Enhancement of bone-healing by low-intensity pulsed ultrasound: a systematic review. JBJS Rev. 2016:4. doi: 10.2106/JBJS.RVW.O.00027. [DOI] [PubMed] [Google Scholar]
  • [80].Nolte P, Anderson R, Strauss E, et al. Heal rate of metatarsal fractures: A propensity-matching study of patients treated with low-intensity pulsed ultrasound (LIPUS) vs. surgical and other treatments. Injury 2016;47:2584–2590. [DOI] [PubMed]; Nolte P, Anderson R, Strauss E. et al. Heal rate of metatarsal fractures: A propensity-matching study of patients treated with low-intensity pulsed ultrasound (LIPUS) vs. surgical and other treatments. Injury. 2016;47:2584–2590. doi: 10.1016/j.injury.2016.09.023. [DOI] [PubMed] [Google Scholar]
  • [81].Aonuma H, Miyakoshi N, Kasukawa Y, et al. Effects of combined therapy of alendronate and low-intensity pulsed ultrasound on metaphyseal bone repair after osteotomy in the proximal tibia of aged rats. J Bone Miner Metab 2014;32:232–239. [DOI] [PubMed]; Aonuma H, Miyakoshi N, Kasukawa Y. et al. Effects of combined therapy of alendronate and low-intensity pulsed ultrasound on metaphyseal bone repair after osteotomy in the proximal tibia of aged rats. J Bone Miner Metab. 2014;32:232–239. doi: 10.1007/s00774-013-0492-3. [DOI] [PubMed] [Google Scholar]
  • [82].Katano M, Naruse K, Uchida K, et al. Low intensity pulsed ultrasound accelerates delayed healing process by reducing the time required for the completion of endochondral ossification in the aged mouse femur fracture model. Exp Anim 2011;60:385–395. [DOI] [PubMed]; Katano M, Naruse K, Uchida K. et al. Low intensity pulsed ultrasound accelerates delayed healing process by reducing the time required for the completion of endochondral ossification in the aged mouse femur fracture model. Exp Anim. 2011;60:385–395. doi: 10.1538/expanim.60.385. [DOI] [PubMed] [Google Scholar]
  • [83].Naruse K, Sekiya H, Harada Y, et al. Prolonged endochondral bone healing in senescence is shortened by low-intensity pulsed ultrasound in a manner dependent on COX-2. Ultrasound Med Biol 2010;36:1098–1108. [DOI] [PubMed]; Naruse K, Sekiya H, Harada Y. et al. Prolonged endochondral bone healing in senescence is shortened by low-intensity pulsed ultrasound in a manner dependent on COX-2. Ultrasound Med Biol. 2010;36:1098–1108. doi: 10.1016/j.ultrasmedbio.2010.04.011. [DOI] [PubMed] [Google Scholar]
  • [84].Uzer G, Thompson WR, Sen B, et al. Cell mechanosensitivity to extremely low-magnitude signals is enabled by a LINCed nucleus. Stem Cells (Dayton, OH) 2015;33:2063–2076. [DOI] [PMC free article] [PubMed]; Uzer G, Thompson WR, Sen B. et al. Cell mechanosensitivity to extremely low-magnitude signals is enabled by a LINCed nucleus. Stem Cells (Dayton, OH) 2015;33:2063–2076. doi: 10.1002/stem.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [85].Bacabac RG, Smit TH, Van Loon JJ, Doulabi BZ, Helder M, Klein-Nulend J. Bone cell responses to high-frequency vibration stress: does the nucleus oscillate within the cytoplasm? FASEB J 2006;20:858–864. [DOI] [PubMed]; Bacabac RG, Smit TH, Van Loon JJ, Doulabi BZ, Helder M, Klein-Nulend J. Bone cell responses to high-frequency vibration stress: does the nucleus oscillate within the cytoplasm? FASEB J. 2006;20:858–864. doi: 10.1096/fj.05-4966.com. [DOI] [PubMed] [Google Scholar]
  • [86].Chung SL, Leung KS, Cheung WH. Low-magnitude high-frequency vibration enhances gene expression related to callus formation, mineralization and remodeling during osteoporotic fracture healing in rats. J Orthop Res 2014;32:1572–1579. [DOI] [PubMed]; Chung SL, Leung KS, Cheung WH. Low-magnitude high-frequency vibration enhances gene expression related to callus formation, mineralization and remodeling during osteoporotic fracture healing in rats. J Orthop Res. 2014;32:1572–1579. doi: 10.1002/jor.22715. [DOI] [PubMed] [Google Scholar]
  • [87].Wei FY, Chow SK, Leung KS, et al. Low-magnitude high-frequency vibration enhanced mesenchymal stem cell recruitment in osteoporotic fracture healing through the SDF-1/CXCR4 pathway. Eur Cell Mater 2016;31:341–354. [DOI] [PubMed]; Wei FY, Chow SK, Leung KS. et al. Low-magnitude high-frequency vibration enhanced mesenchymal stem cell recruitment in osteoporotic fracture healing through the SDF-1/CXCR4 pathway. Eur Cell Mater. 2016;31:341–354. doi: 10.22203/ecm.v031a22. [DOI] [PubMed] [Google Scholar]
  • [88].Komrakova M, Sehmisch S, Tezval M, et al. Identification of a vibration regime favorable for bone healing and muscle in estrogen-deficient rats. Calcified Tissue Int 2013;92:509–520. [DOI] [PMC free article] [PubMed]; Komrakova M, Sehmisch S, Tezval M. et al. Identification of a vibration regime favorable for bone healing and muscle in estrogen-deficient rats. Calcified Tissue Int. 2013;92:509–520. doi: 10.1007/s00223-013-9706-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [89].Chow DH, Leung KS, Qin L, Leung AH, Cheung WH. Low-magnitude high-frequency vibration (LMHFV) enhances bone remodeling in osteoporotic rat femoral fracture healing. J Orthop Res 2011;29:746–752. [DOI] [PubMed]; Chow DH, Leung KS, Qin L, Leung AH, Cheung WH. Low-magnitude high-frequency vibration (LMHFV) enhances bone remodeling in osteoporotic rat femoral fracture healing. J Orthop Res. 2011;29:746–752. doi: 10.1002/jor.21303. [DOI] [PubMed] [Google Scholar]
  • [90].Stuermer EK, Komrakova M, Werner C, et al. Musculoskeletal response to whole-body vibration during fracture healing in intact and ovariectomized rats. Calcified Tissue Int 2010;87:168–180. [DOI] [PMC free article] [PubMed]; Stuermer EK, Komrakova M, Werner C. et al. Musculoskeletal response to whole-body vibration during fracture healing in intact and ovariectomized rats. Calcified Tissue Int. 2010;87:168–180. doi: 10.1007/s00223-010-9381-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [91].Wehrle E, Wehner T, Heilmann A, et al. Distinct frequency dependent effects of whole-body vibration on non-fractured bone and fracture healing in mice. J Orthop Res 2014;32:1006–1013. [DOI] [PubMed]; Wehrle E, Wehner T, Heilmann A. et al. Distinct frequency dependent effects of whole-body vibration on non-fractured bone and fracture healing in mice. J Orthop Res. 2014;32:1006–1013. doi: 10.1002/jor.22629. [DOI] [PubMed] [Google Scholar]
  • [92].Wehrle E, Liedert A, Heilmann A, et al. The impact of low-magnitude high-frequency vibration on fracture healing is profoundly influenced by the oestrogen status in mice. Dis Models Mech 2015;8:93–104. [DOI] [PMC free article] [PubMed]; Wehrle E, Liedert A, Heilmann A. et al. The impact of low-magnitude high-frequency vibration on fracture healing is profoundly influenced by the oestrogen status in mice. Dis Models Mech. 2015;8:93–104. doi: 10.1242/dmm.018622. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials


Articles from Innovative Surgical Sciences are provided here courtesy of De Gruyter

RESOURCES