The prevention of fragility fractures in bone—pathologic fractures resulting from daily activity and mostly occurring in the elderly population—has been a long-term clinical quest. Recent research indicating that falls in the elderly might be the consequence of fracture rather than its cause has raised fundamental questions about the origin of fragility fractures. Is day-to-day cyclic loading, instead of a single-load event such as a fall, the main cause of progressively growing fractures? Are fragility fractures predominantly affected by bone quality rather than bone mass, which is the clinical indicator of fracture risk? Do osteocytes actively participate in the bone repair process? In this Perspective, we discuss the central role of cyclic fatigue in bone fragility fracture.
This is a preview of subscription content, access via your institution
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 digital issues and online access to articles
$79.00 per year
only $6.58 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Cole, J. H. & van der Meulen, M. C. Whole bone mechanics and bone quality. Clin. Orthopaed. Rel. Res. 469, 2139–2149 (2011).
Breithaupt, J. Zur pathologie des menschlichen fusses. Med. Zeitung 24, 169–171 (1855).
Pirker, H. Bruch der oberschenkeldiaphyse durch muskelzug. Arch. Klin. Chir. 175, 155–168 (1934).
Burrows, H. J. Spontaneous fracture of the apparently normal fibula in its lowest third. British J. Surg. 28, 82–87 (1940).
Fredericson, M., Jennings, F., Beaulieu, C. & Matheson, G. O. Stress fractures in athletes. Topics in Magnetic Resonance Imaging 17, 309–325 (2006).
Brukner, P., Bradshaw, C. & Bennell, K. Managing common stress fractures: let risk level guide treatment. Phys. Sports Med. 26, 39–47 (1998).
Iwamoto, J. & Takeda, T. Stress fractures in athletes: review of 196 cases. J. Orthopaed. Sci. 8, 273–278 (2003).
Meurman, K. & Elfving, S. Stress fracture in soldiers: a multifocal bone disorder. A comparative radiological and scintigraphic study. Radiology. 134, 483–487 (1980).
Schaffler, M., Radin, E. & Burr, D. Long-term fatigue behavior of compact bone at low strain magnitude and rate. Bone. 11, 321–326 (1990).
Schaffler, M., Radin, E. & Burr, D. Mechanical and morphological effects of strain rate on fatigue of compact bone. Bone. 10, 207–214 (1989).
Schaffler, M. B. in Musculoskeletal Fatigue and Stress Fractures 161–182 (CRC, Boca Raton, 2000).
Pentecost, R. L., Murray, R. A. & Brindley, H. H. Fatigue, insufficiency, and pathologic fractures. JAMA 187, 1001–1004 (1964).
Breer, S. et al. Stress fractures in elderly patients. Int. Orthopaed. 36, 2581–2587 (2012).
Carpintero, P., Berral, F. J., Baena, P., Garcia-Frasquet, A. & Lancho, J. L. Delayed diagnosis of fatigue fractures in the elderly. Am. J. Sports Med. 25, 659–662 (1997).
Miller, K. E. Diagnosis of insufficiency fracture in the elderly. Am. Fam. Phys. 57, 1968–1968 (1998).
Kaye, R. A. Insufficiency stress fractures of the foot and ankle in postmenopausal women. Foot Ankle Int. 19, 221–224 (1998).
Bentolila, V. et al. Intracortical remodeling in adult rat long bones after fatigue loading. Bone 23, 275–281 (1998).
Colopy, S. et al. Response of the osteocyte syncytium adjacent to and distant from linear microcracks during adaptation to cyclic fatigue loading. Bone 35, 881–891 (2004).
Frost, H. Presence of microscopic cracks in vivo in bone. Henry Ford Hosp. Med. Bull. 8, 35 (1960).
Burr, D. B. et al. Bone microdamage and skeletal fragility in osteoporotic and stress fractures. J. Bone Miner. Res. 12, 6–15 (1997).
Nyman, J. S. & Makowski, A. J. The contribution of the extracellular matrix to the fracture resistance of bone. Curr. Osteopor. Rep. 10, 169–177 (2012).
Jepsen, K. J. The aging cortex: to crack or not to crack. Osteopor. Int. 14, 57–66 (2003).
Seref-Ferlengez, Z., Kennedy, O. D. & Schaffler, M. B. Bone microdamage, remodeling and bone fragility: how much damage is too much damage? BoneKEy Rep. 4, 644 (2015).
Hernandez, C. J. Bone fatigue, stress fractures and bone repair (Sun Valley 2013). BoneKEy Rep. 10, 448 (2013).
Krestan, C. & Hojreh, A. Imaging of insufficiency fractures. Eur. J. Radiol. 71, 398–405 (2009).
Lenart, B. et al. Association of low-energy femoral fractures with pro- longed bisphosphonate use: a case control study. Osteopor. Int. 20, 1353–1362 (2009).
Ettinger, B., Burr, D. B. & Ritchie, R. O. Proposed pathogenesis for atypical femoral fractures: lessons from materials research. Bone 55, 495–500 (2013).
Shane, E. et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the american society for bone and mineral research. J. Bone Miner. Res. 25, 2267–2294 (2010).
Acevedo, C. et al. Alendronate treatment alters bone tissues at multiple structural levels in healthy canine cortical bone. Bone 81, 352–363 (2015).
Aspenberg, P. Atypical fractures, a biased perspective. Injury. 47, S28–S30 (2016).
Mann, G. et al. in Sports Injuries 787–813 (Springer, Berlin, 2012).
Soubrier, M. et al. Insufficiency fracture: a survey of 60 cases and review of the literature. Joint Bone Spine 70, 209–218 (2003).
Frey, M. E. et al. Percutaneous sacroplasty for osteoporotic sacral insufficiency fractures: a prospective, multicenter, observational pilot study. Spine J. 8, 367–373 (2008).
Moran, D. S., Evans, R. K. & Hadad, E. Imaging of lower extremity stress fracture injuries. Sports Med. 38, 345–356 (2008).
Idiyatullin, D., Garwood, M., Gaalaas, L. & Nixdorf, D. R. Role of MRI for detecting micro cracks in teeth. Dentomaxillofac. Radiol. 45, 20160150 (2016).
Zimmermann, E. A., Busse, B. & Ritchie, R. O. The fracture mechanics of human bone: influence of disease and treatment. BoneKEy Rep. 4, 743 (2015).
Hernandez, C. J. & van der Meulen, M. C. Understanding bone strength is not enough. J. Bone Miner. Res. 32, 1157–1162 (2017).
Fujiwara, S. Importance of raising awareness about spontaneous insufficiency fractures in the bedridden elderly. Int. J. Clin. Rheumatol. 5, 395–397 (2010).
Takamoto, S. et al. Spontaneous fractures of long bones associated with joint contractures in bedridden elderly inpatients: clinical features and outcome. J. Am. Geriatr. Soc. 53, 1439–1441 (2005).
Taillandier, J., Langue, F., Alemanni, M. & Taillandier-Heriche, E. Mortality and functional outcomes of pelvic insufficiency fractures in older patients. Joint Bone Spine. 70, 287–289 (2003).
Schwendner, K. I., Mikesky, A. E., Holt, W. S. Jr, Peacock, M. & Burr, D. B. Differences in muscle endurance and recovery between fallers and nonfallers, and between young and older women. J. Gerontol. Ser. A Biol. Sci. Med. Sci 52, M155–M160 (1997).
Burr, D. B. Muscle strength, bone mass, and age-related bone loss. J. Bone Miner. Res. 12, 1547–1551 (1997).
Sloan, J. & Holloway, G. Fractured neck of the femur: the cause of the fall? Injury 13, 230–232 (1981).
Dorne, H. & Lander, P. H. Spontaneous stress fractures of the femoral neck. Am. J. Roentgenol. 144, 343–347 (1985).
Tountas, A. A. Insufficiency stress fractures of the femoral neck in elderly women. Clin. Orthopaed. Rel. Res. 292, 202–209 (1993).
Lyders, E., Whitlow, C., Baker, M. & Morris, P. Imaging and treatment of sacral insufficiency fractures. Am. J. Neuroradiol. 31, 201–210 (2010).
Weber, M., Hasler, P. & Gerber, H. Insufficiency fractures of the sacrum: twenty cases and review of the literature. Spine 18, 2507–2512 (1993).
West, S. G., Troutner, J. L., Baker, M. R. & Place, H. M. Sacral insufficiency fractures in rheumatoid arthritis. Spine 19, 2117–2121 (1994).
Featherstone, T. Magnetic resonance imaging in the diagnosis of sacral stress fracture. British J. Sports Med. 33, 276–277 (1999).
Kane, R. S., Burns, E. A. & Goodwin, J. S. Minimal trauma fractures in older nursing home residents: the interaction of functional status, trauma, and site of fracture. J. Am. Geriatr. Soc. 43, 156–159 (1995).
Lapina, O. & Tiskevicius, S. Sacral insufficiency fracture after pelvic radiotherapy: a diagnostic challenge for a radiologist. Medicina 50, 249–254 (2014).
Haentjens, P. et al. Meta-analysis: excess mortality after hip fracture among older women and men. Ann. Intern. Med. 152, 380–390 (2010).
LeBlanc, E. S. et al. Hip fracture and increased short-term but not long-term mortality in healthy older women. Arch. Intern. Med. 171, 1831–1837 (2011).
Taylor, D., Hazenberg, J. G. & Lee, T. C. Living with cracks: damage and repair in human bone. Nat. Mater. 6, 263–268 (2007).
Poundarik, A. A. et al. Dilatational band formation in bone. Proc. Natl Acad. Sci. USA 109, 19178–19183 (2012).
Mori, S. & Burr, D. Increased intracortical remodeling following fatigue damage. Bone 14, 103–109 (1993).
Duncan, R. & Turner, C. Mechanotransduction and the functional response of bone to mechanical strain. Calc. Tissue Int. 57, 344–358 (1995).
Lanyon, L. E. & Rubin, C. Static vs dynamic loads as an influence on bone remodelling. J. Biomech. 17, 897–905 (1984).
Carter, D., Blenman, P. & Beaupre, G. Correlations between mechanical stress history and tissue differentiation in initial fracture healing. J. Orthopaed. Res. 6, 736–748 (1988).
Ehrlich, P. & Lanyon, L. Mechanical strain and bone cell function: a review. Osteopor. Int. 13, 688–700 (2002).
Diab, T., Sit, S., Kim, D., Rho, J. & Vashishth, D. Age-dependent fatigue behaviour of human cortical bone. Eur. J. Morphol. 42, 53–59 (2005).
Diab, T., Condon, K. W., Burr, D. B. & Vashishth, D. Age-related change in the damage morphology of human cortical bone and its role in bone fragility. Bone 38, 427–431 (2006).
Diab, T. & Vashishth, D. Morphology, localization and accumulation of in vivo microdamage in human cortical bone. Bone 40, 612–618 (2007).
Schaffler, M., Choi, K. & Milgrom, C. Aging and matrix microdamage accumulation in human compact bone. Bone 17, 521–525 (1995).
Zioupos, P., Gresle, M. & Winwood, K. Fatigue strength of human cortical bone: age, physical, and material heterogeneity effects. J. Biomed. Mater. Res. 86, 627–636 (2008).
Norman, T. L. & Wang, Z. Microdamage of human cortical bone: incidence and morphology in long bones. Bone 20, 375–379 (1997).
Laird, C. & Smith, G. Crack propagation in high stress fatigue. Phil. Mag. 7, 847–857 (1962).
Suresh, S. Fatigue of Materials (Cambridge Univ. Press, Cambridge, 1998).
Anderson, T. L. Fracture Mechanics: Fundamentals and Applications (CRC, Boca Raton, 2005).
Broek, D. Elementary Engineering Fracture Mechanics (Springer Science & Business Media, 2012).
Robertson, S. W. & Ritchie, R. O. In vitro fatigue–crack growth and fracture toughness behavior of thin-walled superelastic nitinol tube for endovascular stents: a basis for defining the effect of crack-like defects. Biomaterials 28, 700–709 (2007).
Zwas, S. T., Elkanovitch, R. & Frank, G. Interpretation and classification of bone scintigraphic findings in stress fractures. J. Nucl. Med. 28, 452–457 (1987).
Milgrom, C. et al. Multiple stress fractures: A longitudinal study of a soldier with 13 lesions. Clin. Orthopaed. Rel. Res. 192, 174–179 (1985).
Carter, D. & Caler, W. A cumulative damage model for bone fracture. J. Orthopaed. Res. 3, 84–90 (1985).
Nalla, R. K., Kruzic, J. J., Kinney, J. H. & Ritchie, R. O. Aspects of in vitro fatigue in human cortical bone: time and cycle dependent crack growth. Biomaterials 26, 2183–2195 (2005).
Ritchie, R. O., Kinney, J. H., Kruzic, J. J. & Nalla, R. K. A fracture mechanics and mechanistic approach to the failure of cortical bone. Fatig. Fract. Eng. Mater. Struct. 28, 345–371 (2005).
Paris, P. C. & Erdogan, F. A critical analysis of crack propagation laws. J. Basic Eng. 528–534 (1963).
Pattin, C., Caler, W. & Carter, D. Cyclic mechanical property degradation during fatigue loading of cortical bone. J. Biomech. 29, 69–79 (1996).
Genant, H. K. et al. Interim report and recommendations of the world health organization task-force for osteoporosis. Osteopor. Int. 10, 259–264 (1999).
Schuit, S. et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam study. Bone 34, 195–202 (2004).
Hui, S. L., Slemenda, C. W. & Johnston, C. C. Jr Age and bone mass as predictors of fracture in a prospective study. J. Clin. Invest. 81, 1804 (1988).
Allolio, B. Risk factors for hip fracture not related to bone mass and their therapeutic implications. Osteopor. Int. 9, S9–S17 (1999).
Sandor, T., Felsenberg, D. & Brown, E. Comments on the hypotheses underlying fracture risk assessment in osteoporosis as proposed by the world health organization. Calc. Tissue Int. 64, 267–270 (1999).
Mccreadie, B. R. & Goldstein, S. A. Biomechanics of fracture: is bone mineral density sufficient to assess risk? J. Bone Miner. Res. 15, 2305–2308 (2000).
Heaney, R. P. Is the paradigm shifting? Bone 33, 457–465 (2003).
Ritchie, R. O., Buehler, M. J. & Hansma, P. Plasticity and toughness in bone. Phys. Today 62, 41–47 (2009).
Zioupos, P. & Currey, J. Changes in the stiffness, strength, and toughness of human cortical bone with age. Bone 22, 57–66 (1998).
McCalden, R., McGeough, J. & Barker, M. et al. Age-related changes in the tensile properties of cortical bone: the relative importance of changes in porosity, mineralization, and microstructure. JBJS 75, 1193–1205 (1993).
Burstein, A. H., Reilly, D. T. & Martens, M. Aging of bone tissue: mechanical properties. JBJS 58, 82–86 (1976).
Zimmermann, E. A. et al. Age-related changes in the plasticity and toughness of human cortical bone at multiple length scales. Proc. Natl Acad. Sci. USA 108, 14416–14421 (2011).
Launey, M. E., Buehler, M. J. & Ritchie, R. O. On the mechanistic origins of toughness in bone. Annu. Rev. Mater. Res. 40, 25–53 (2010).
Eppell, S. J., Smith, B., Kahn, H. & Ballarini, R. Nano measurements with micro-devices: mechanical properties of hydrated collagen fibrils. J. R. Soc. Interf. 3, 117–121 (2006).
Ker, R. in Collagen: Structure and Mechanics 111–131 (Springer, New York, 2008).
Manhard, M. K. et al. MRI-derived bound and pore water concentrations as predictors of fracture resistance. Bone 87, 1–10 (2016).
Tang, S. Y., Herber, R.-P., Ho, S. P. & Alliston, T. Matrix metalloproteinase–13 is required for osteocytic perilacunar remodeling and maintains bone fracture resistance. J. Bone Miner. Res. 27, 1936–1950 (2012).
Thurner, P. J. et al. Osteopontin deficiency increases bone fragility but preserves bone mass. Bone 46, 1564–1573 (2010).
Boskey, A., DiCarlo, E., Paschalis, E., West, P. & Mendelsohn, R. Comparison of mineral quality and quantity in iliac crest biopsies from highand low-turnover osteoporosis: an FT-IR microspectroscopic investigation. Osteopor. Int. 16, 2031–2038 (2005).
Alliston, T. Biological regulation of bone quality. Curr. Osteopor. Rep. 12, 366–375 (2014).
Vashishth, D. et al. Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone 28, 195–201 (2001).
Sell, D. R. & Monnier, V. Structure elucidation of a senescence crosslink from human extracellular matrix. implication of pentoses in the aging process. J. Biol. Chem. 264, 21597–21602 (1989).
Bailey, A. J. Molecular mechanisms of ageing in connective tissues. Mech. Aging Dev. 122, 735–755 (2001).
Boskey, A. L. & Coleman, R. Aging and bone. J. Dent. Res. 89, 1333–1348 (2010).
Saito, M. & Marumo, K. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteopor. Int. 21, 195–214 (2010).
Eyre, D. R., Dickson, I. & Van Ness, K. Collagen cross-linking in human bone and articular cartilage. age-related changes in the content of mature hydroxypyridinium residues. Biochem. J. 252, 495–500 (1988).
Saito, M., Marumo, K., Fujii, K. & Ishioka, N. Single-column high-performance liquid chromatographic-fluorescence detection of immature, mature, and senescent cross-links of collagen. Analyt. Biochem. 253, 26–32 (1997).
Nyman, J. S. et al. Age-related effect on the concentration of collagen crosslinks in human osteonal and interstitial bone tissue. Bone 39, 1210–1217 (2006).
Odetti, P. et al. Advanced glycation end products and bone loss during aging. Ann. NY Acad. Sci. 1043, 710–717 (2005).
Ott, C. et al. Role of advanced glycation end products in cellular signaling. Redox Biol. 2, 411–429 (2014).
Zhou, Z. et al. Regulation of osteoclast function and bone mass by rage. J. Exp. Med. 203, 1067–1080 (2006).
Miyata, T. et al. Advanced glycation end products enhance osteoclast-induced bone resorption in cultured mouse unfractionated bone cells and in rats implanted subcutaneously with devitalized bone particles. J. Am. Soc. Nephrol. 8, 260–270 (1997).
Wang, X., Shen, X., Li, X. & Agrawal, C. M. Age-related changes in the collagen network and toughness of bone. Bone 31, 1–7 (2002).
Garnero, P. et al. Extracellular post-translational modifications of collagen are major determinants of biomechanical properties of fetal bovine cortical bone. Bone 38, 300–309 (2006).
Siegmund, T., Allen, M. R. & Burr, D. B. Failure of mineralized collagen fibrils: modeling the role of collagen cross-linking. J. Biomech. 41, 1427–1435 (2008).
Tang, S. & Vashishth, D. Non-enzymatic glycation alters microdamage formation in human cancellous bone. Bone 46, 148–154 (2010).
Tang, S. & Vashishth, D. The relative contributions of non-enzymatic glycation and cortical porosity on the fracture toughness of aging bone. J. Biomech. 44, 330–336 (2011).
Torres, A. M. et al. Material heterogeneity in cancellous bone promotes deformation recovery after mechanical failure. Proc. Natl Acad. Sci. USA 113, 2892–2897 (2016).
Silva, M. J. et al. Type 1 diabetes in young rats leads to progressive trabecular bone loss, cessation of cortical bone growth, and diminished whole bone strength and fatigue life. J. Bone Miner. Res. 24, 1618–1627 (2009).
Ionova-Martin, S. et al. Changes in cortical bone response to high-fat diet from adolescence to adulthood in mice. Osteopor. Int. 22, 2283–2293 (2011).
Bajaj, D., Geissler, J. R., Allen, M. R., Burr, D. B. & Fritton, J. C. The resistance of cortical bone tissue to failure under cyclic loading is reduced with alendronate. Bone 64, 57–64 (2014).
Barth, H. D. et al. Characterization of the effects of X-ray irradiation on the hierarchical structure and mechanical properties of human cortical bone. Biomaterials 32, 8892–8904 (2011).
Schwartz, A. V. et al. Pentosidine and increased fracture risk in older adults with type 2 diabetes. J. Clin. Endo. Metab. 94, 2380–2386 (2009).
Kotha, S., Hsieh, Y.-F., Strigel, R., Müller, R. & Silva, M. Experimental and finite element analysis of the rat ulnar loading model—correlations between strain and bone formation following fatigue loading. J. Biomech. 37, 541–548 (2004).
Stadelmann, V. A., Bonnet, N. & Pioletti, D. P. Combined effects of zoledronate and mechanical stimulation on bone adaptation in an axially loaded mouse tibia. Clin. Biomech. 26, 101–105 (2011).
Robling, A. G., Burr, D. B. & Turner, C. H. Skeletal loading in animals. J. Musculoskelet. Neur. Inter. 1, 249–526 (2001).
Martin, R. B. in Musculoskeletal Fatigue and Stress Fractures 183–201 (CRC, Boca Raton, 2000).
Burger, E. H., Klein-Nulend, J., Van Der Plas, A. & Nijweide, P. J. Function of osteocytes in bone—their role in mechanotransduction. J. Nutr. 125, 2020S (1995).
Santos, A., Bakker, A. D. & Klein-Nulend, J. The role of osteocytes in bone mechanotransduction. Osteopor. Int. 20, 1027–1031 (2009).
Martin, B. Mathematical model for repair of fatigue damage and stress fracture in osteonal bone. J. Orthopaed. Res. 13, 309–316 (1995).
Burr, D. B., Martin, R. B., Schaffler, M. B. & Radin, E. L. Bone remodeling in response to in vivo fatigue microdamage. J. Biomech. 18, 189–200 (1985).
Scully, T. & Besterman, G. Stress fracture–a preventable training injury. Milit. Med. 147, 285 (1982).
Cardoso, L. et al. Osteocyte apoptosis controls activation of intracortical resorption in response to bone fatigue. J. Bone Miner. Res. 24, 597–605 (2009).
Kennedy, O. D. et al. Activation of resorption in fatigue-loaded bone involves both apoptosis and active pro-osteoclastogenic signaling by distinct osteocyte populations. Bone 50, 1115–1122 (2012).
Bélanger, L. F. Osteocytic osteolysis. Calc. Tissue Int 4, 1–12 (1969).
Qing, H. & Bonewald, L. F. Osteocyte remodeling of the perilacunar and pericanalicular matrix. Int. J. Oral Sci. 1, 59 (2009).
Qing, H. et al. Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation. J. Bone Miner. Res. 27, 1018–1029 (2012).
Bonewald, L. F. The amazing osteocyte. J. Bone Miner. Res. 26, 229–238 (2011).
Frost, H. M. In vivo osteocyte death. J. Bone Joint Surg. Am. 42, 138–143 (1960).
Dunstan, C. R., Evans, R. A., Hills, E., Wong, S. Y. & Higgs, R. J. Bone death in hip fracture in the elderly. Calc. Tissue Int. 47, 270–275 (1990).
Xiong, J. & O’Brien, C. A. Osteocyte rankl: new insights into the control of bone remodeling. J. Bone Miner. Res. 27, 499–505 (2012).
Dodd, J., Raleigh, J. & Gross, T. S. Osteocyte hypoxia: a novel mechanotransduction pathway. Am. J. Physiol. Cell. Physiol. 277, C598–C602 (1999).
Fowler, T. W. et al. Glucocorticoid suppression of osteocyte perilacunar remodeling is associated with subchondral bone degeneration in osteonecrosis. Sci. Rep. 7, 44618 (2017).
Milovanovic, P. et al. Osteocytic canalicular networks: morphological implications for altered mechanosensitivity. ACS Nano 7, 7542–7551 (2013).
Vashishth, D., Verborgt, O., Divine, G., Schaffler, M. & Fyhrie, D. Decline in osteocyte lacunar density in human cortical bone is associated with accumulation of microcracks with age. Bone 26, 375–380 (2000).
Busse, B. et al. Decrease in the osteocyte lacunar density accompanied by hypermineralized lacunar occlusion reveals failure and delay of remodeling in aged human bone. Aging Cell 9, 1065–1075 (2010).
Voide, R. et al. Time-lapsed assessment of microcrack initiation and propagation in murine cortical bone at submicrometer resolution. Bone 45, 164–173 (2009).
Buettmann, E. G. & Silva, M. J. Development of an in vivo bone fatigue damage model using axial compression of the rabbit forelimb. J. Biomech. 49, 3564–3569 (2016).
Nurzenski, M. K. et al. Geometric indices of bone strength are associated with physical activity and dietary calcium intake in healthy older women. J. Bone Miner. Res. 22, 416–424 (2007).
Nguyen, T. et al. Lifestyle factors and bone density in the elderly: implications for osteoporosis prevention. J. Bone Miner. Res. 9, 1339–1346 (1994).
Devine, A., Dhaliwal, S. S., Dick, I. M., Bollerslev, J. & Prince, R. L. Physical activity and calcium consumption are important determinants of lower limb bone mass in older women. J. Bone Miner. Res. 19, 1634–1639 (2004).
Thacker, S. B., Gilchrist, J., Stroup, D. F. & Kimsey, C. D. The prevention of shin splints in sports: a systematic review of literature. Med. Sci. Sports Exer. 34, 32–40 (2002).
Busse, B. et al. Vitamin d deficiency induces early signs of aging in human bone, increasing the risk of fracture. Sci. Transl. Med. 5, 193ra88–193ra88 (2013).
Chung, M. et al. Vitamin D and calcium: a systematic review of health outcomes. Evid. Rep. Technol. Assess. 183, 1–420 (2009).
Rolvien, T. et al. Vitamin D regulates osteocyte survival and perilacunar remodeling in human and murine bone. Bone 103, 78–87 (2017).
Bishitz, Y. et al. Noncontact optical sensor for bone fracture diagnostics. Biomed. Optics Exp. 6, 651–657 (2015).
Hvid, I. & Linde, F. in Mechanical Testing of Bone and the Bone-Implant Interface 241–246 (CRC, Boca Raton, 1999).
Diez-Perez, A. et al. Microindentation for in vivo measurement of bone tissue mechanical properties in humans. J. Bone Miner. Res. 25, 1877–1885 (2010).
Gallant, M. A., Brown, D. M., Organ, J. M., Allen, M. R. & Burr, D. B. Reference-point indentation correlates with bone toughness assessed using whole-bone traditional mechanical testing. Bone 53, 301–305 (2013).
Hansma, P. et al. The bone diagnostic instrument ii: indentation distance increase. Rev. Sci. Instrum. 79, 064303 (2008).
Allen, M. R., McNerny, E., Organ, J. M. & Wallace, J. M. True gold or pyrite: a review of reference point indentation for assessing bone mechanical properties in vivo. J. Bone Miner. Res. 30, 1539–1550 (2015).
Diez-Perez, A. et al. Recommendations for a standard procedure to assess cortical bone at the tissue-level in vivo using impact microindentation. Bone Rep. 5, 181–185 (2016).
Hansen, U., Zioupos, P., Simpson, R., Currey, J. D. & Hynd, D. The effect of strain rate on the mechanical properties of human cortical bone. J. Biomech. Eng. 130, 011011 (2008).
Zimmermann, E. A., Gludovatz, B., Schaible, E., Busse, B. & Ritchie, R. O. Fracture resistance of human cortical bone across multiple lengthscales at physiological strain rates. Biomaterials 35, 5472–5481 (2014).
Garnero, P., Sornay-Rendu, E., Claustrat, B. & Delmas, P. D. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J. Bone Miner. Res. 15, 1526–1536 (2000).
We acknowledge financial support from the Swiss National Science Foundation grants PBELP2_141095 and P300P2_167583 (C.A.), from NIH-NIDCR R01 DE019284 (T.A.) and from DOD PRORP OR130191 (T.A.). R.O.R. was supported through the Mechanical Behavior of Materials Program (KC13) at the Lawrence Berkeley National Laboratory by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, Materials Sciences and Engineering Division, under contract no. DE-AC02-05CH11231.
The authors declare no competing financial interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Acevedo, C., Stadelmann, V.A., Pioletti, D.P. et al. Fatigue as the missing link between bone fragility and fracture. Nat Biomed Eng 2, 62–71 (2018). https://doi.org/10.1038/s41551-017-0183-9
This article is cited by
Fracture Toughness: Bridging the Gap Between Hip Fracture and Fracture Risk Assessment
Current Osteoporosis Reports (2023)
Multiscale Effects of Collagen Damage in Cortical Bone and Dentin
Fatigue behavior of cortical bone: a review
Acta Mechanica Sinica (2021)
Fourier Transform Infrared Spectroscopy of Bone Tissue: Bone Quality Assessment in Preclinical and Clinical Applications of Osteoporosis and Fragility Fracture
Clinical Reviews in Bone and Mineral Metabolism (2019)