Curr Osteoporos Rep (2014) 12:189–193 DOI 10.1007/s11914-014-0200-9
BIOMECHANICS (M SILVA AND P ZYSSET, SECTION EDITORS)
Atypical Femoral Fractures, Bisphosphonates, and Mechanical Stress Per Aspenberg & Jörg Schilcher
Published online: 11 March 2014 # Springer Science+Business Media New York 2014
Abstract Atypical fractures are stress fractures occurring in the femoral shaft and closely related to bisphosphonate use. We here discuss their radiographic definition and different putative etiologies, apart from mechanical stress. Long time reduction of skeletal remodeling because of bisphosphonate use is thought to allow time for the bone to deteriorate mechanically, resulting in reduced toughness. However, the risk of atypical fracture diminishes rapidly after cessation of treatment, which suggests more acute effects of bisphosphonate use. Microdamage normally accumulates at areas of high stress. Possibly, ongoing bisphosphonate use reduces the ability to resorb and replace areas of microdamage by targeted remodeling. This could lead to crack propagation beyond a point of no return, ending in macroscopic stress fracture.
described in military recruits in the Prussian army. Fatigue fractures in the lower extremity are now a common problem in athletes, normally referred to as stress fractures. They appear as thin cracks that only seldom lead to a complete, displaced fracture, probably because pain inhibits the last catastrophic loading cycles. The crack is often too thin to be seen on radiographs, and the diagnosis depends on clinical signs and the visible callus reaction on radiographs. If a complete, displaced fracture occurs, the fracture surface looks as if there had been a transverse cut, at a perfectly right angle to the traction forces, half-way through the bone [1]. The remainder of the fracture, on the compression side, looks as a normal fracture. This is completely in agreement with the broken railway axles, where a crack has grown at right angle to the direction of the mechanical force until the remainder of the structure broke.
Keywords Atypical femoral fractures . Bisphosphonates . Bone remodeling . Osteoporosis . Bone fragility Atypical Fractures Appear Introduction: Stress Fractures In the middle of the 19th century, rail-road accidents killed a great number of people, causing fear and turmoil. Many of these accidents were caused by sudden fractures of wheel axles. It was a mystery how these sturdy steel axles could suddenly break while not loaded more than usual. The problem was solved by a young German engineer, August Wöhler, who set up systematic full-scale experiments. He was the first to describe how repeated moderate loading caused material fatigue and formation of small cracks that grow for each loading cycle until the whole structure breaks. Not much later, “marching fractures” resulting from bone fatigue were P. Aspenberg (*) : J. Schilcher Department of Clinical and Experimental Medicine, Orthopedics, Faculty of Health Science, Linköping University, 581 85 Linköping, Sweden e-mail: [email protected]
Between 2005 and 2008, reports started to appear in the literature, describing stress fractures of the femoral shaft in elderly women [2–4]. Most of these patients had prodromal pain, and the fractures had displaced with a minimal trauma. The authors were astounded to find this type of fracture in patients who did not overload their bones as extremely as athletes do, and it was soon suspected that bisphosphonates were to blame. Several case series reported that the vast majority of these patients had been taking bisphosphonates for a considerable time. Soon, however, authors with a background outside orthopedics questioned the existence of a specific subcategory of fractures and the association with bisphosphonates [5, 6]. After a few years of hot debate, there is now almost consensus that these fractures exist and are caused mainly by bisphosphonates [7••]. During this debate, the term “atypical fracture” emerged [8] and was coined by the American Society of Bone and Mineral Research (ASBMR) [9].
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What is an Atypical Fracture? When the atypical fractures were first described, it was their typical stress fracture appearance that caused the attention [3, 4]. Indeed, already in 2009, we described both the absolute and relative bisphosphonate-associated risk of femoral stress fractures based on radiographic appearance in a defined Swedish population [10]. Much of the confusion and debate those days emerged when researchers started using diagnosis registers, where fractures are classified according to location, but not type [5]. A task force appointed by the ASBMR defined criteria for diagnosis in 2010 [9], but these were initially somewhat vague, which may have contributed to the confusion [1]. More recently, it has been shown that the angle of the fracture line to the lateral cortical surface in femoral shaft fractures shows a dichotomous distribution: either the angle is close to 90°, or it is around 45°, and seldom in between [11•]. Seventy-three percent of the patients with an angle of 90°±15° in that study were taking a bisphosphonate, but only 13 % of the others did. Moreover, 77 % of these patients had signs of a callus reaction that obviously had preceded the displacement. Therefore, the best definition of an atypical fracture, or at least the most specific, is probably a lateral fracture angle between 75° and 105° in combination with signs of a callus reaction that might be very discrete. However, with the increasing awareness of atypical fractures, a large and probably increasing number of patients become diagnosed with incomplete fractures before they become displaced, based on thigh pain and a typical, distinctly localized callus reaction at the lateral cortex.
Curr Osteoporos Rep (2014) 12:189–193
We believe these histologic findings suggest an explanation for the absence of healing. As first described by Perren et al [14], too narrow fracture gaps can preclude healing. The small deformations that always occur with physiological loading will lead to very small changes in the width of a fracture gap. If the fracture gap is narrow, a small change in width might still be of the same order of magnitude as the gap itself. Thus, physiological loading will more or less open and close the gap for each walking step. Strains of this magnitude will destroy any cell that enters the gap in an attempt to fill it with new tissue. If the poor healing ability has a mechanical explanation, there should not be much point in trying to stimulate healing with drugs such as PTH [15]. We have experience from a few cases with incomplete fracture, where we took a large biopsy, comprising almost the entire fracture. The created defects healed uneventfully, and remarkably, the patients reported immediate pain relief after this procedure. We believe this effect may be due to the removal of the crack, but it could also be due to the fact that we stabilized the bone with an intramedullary nail or plate.
Evidence for Bisphosphonates as a Cause When a clear definition of atypical fractures is used, based on its nature of a stress fracture, the relative risk for bisphosphonate users is increased already after a year of use and rapidly increases with time. For all bisphosphonate users among all Swedish women above 55 years of age in 2008, the relative risk was 46 [16••]. This is actually a stronger association than between smoking and lung cancer [17]. Still, the absolute risk
Impaired Healing Stress fractures in athletes, especially in cortical shaft bone, and atypical fractures have a reputation for slow or poor healing [9, 12]. We have seen patients with an undisplaced, painful atypical fracture that remained unhealed for more than 18 months after cessation of bisphosphonate use, with no clinical or radiographic signs of improvement [1]. Notably, poor healing seems to be a consistent feature in undisplaced stress fractures, regardless if the patient uses a bisphosphonate or not. Why Don’t They Heal? We have taken biopsies of the fracture, including the fracture gap, in 4 undisplaced and 4 displaced cases [13]. A consistent finding was that the fracture gap is only 100–200 micrometer wide and completely devoid of tissue. No cells, no matrix, only small amounts of amorphous material were seen, probably a protein precipitate (Fig. 1). Contrary to expectation, the bone next to the fracture line showed signs of recent remodeling, and often had a woven, immature structure.
Fig. 1 H&E stain of a bone biopsy from an 80-year-old woman with incomplete atypical femoral fracture. The patient had used Alendronate for 5 years and reported thigh pain for several months prior to surgery. The fracture was stabilized with a plate (the curvature of the femur was not feasible for intramedullary nailing) and healed uneventfully. Note the periosteal callus (C) and the thin fracture line containing amorphous material (black arrows). Image previously published in Acta Orthop (1) under the terms of Creative Commons
Curr Osteoporos Rep (2014) 12:189–193
is low (as with lung cancer). The risk decreased rapidly after discontinuation of bisphosphonate use [16••]. This was an unexpected finding, as bisphosphonates remain in the skeleton with a half-life of many years. The very strong association between bisphosphonates and atypical fractures, in combination with a plausible etiologic connection and the effect of discontinuation, all speak for a direct etiologic role of the bisphosphonates. As with smoking and cancer, other factors may play a role [18], but these other factors are likely to be less important. There have been speculations that several other drugs, notably corticosteroids and proton-pump inhibitors [19, 21–24], increase the risk, but these have not been confirmed. In our nation-wide study [16••], no such associations were found. In contrast, there seems to be a clear association with general health and probably with a healthy life-style, as patients with atypical fractures are younger, take fewer drugs, have fewer other diagnoses, are less often depressed etc, than patients with other fractures of the femur. This is to expect: general health should be associated with higher physical activity, and because atypical fractures are a form of stress fractures, mechanical stress should contribute to the risk.
Pathophysiology: Brittle Bone? The increased risk of stress fracture with bisphosphonate use suggests a connection to reduced osteoclastic activity. Before bisphosphonates were introduced in the clinic, in the early 1990ies, there were suggestions that reduced remodeling would allow the bone tissue to become too old, and therefore brittle and susceptible to fatigue damage [25]. In counterarguments it was pointed out that postmenopausal osteoporosis is a state of increased turnover, and therefore bisphosphonates would just return the situation to a premenopause-like situation. Patients at risk of atypical fracture have been suggested to have other bone abnormalities beforehand, one of them being manifested as an increased cortical thickness [2]. No such abnormalities have been demonstrated [20, 26], and when an increased thickness has been found, it was due to the difference in age between patients with atypical and ordinary fractures [27]. There have been some attempts to demonstrate an increased brittleness in bisphosphonate users, but findings are inconsistent. In normal osteonal bone, some osteons are younger than others and therefore, less mineralized, as the last stages toward full mineralization take a long time. A variation in osteonal mineralization, crystal maturity, and collagen cross-linking creates heterogeneity in between osteons and a corresponding variation in stiffness, which protects the bone from crack propagation [28]. These variations in bone composition in healthy individuals suggest an evolutionary optimum. Bone exposed to bisphosphonate has been shown to have a more homogenous composition, reflected in a narrower distribution of cortical collagen maturity and crystallinity and
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an increase in the mineral to matrix ratio and collagen crosslinks [29, 30]. These changes have been associated with stiffening of the bone and deterioration of material properties in animal studies and humans [31, 32–34]. In vivo nanoindentation of tibiae in patients with atypical femoral fractures showed impaired bone material properties compared with control patients without fractures. However, patients with ordinary femoral fractures showed similar impairments [35]. Bone mechanical properties in the monkey femur were not influenced by different doses and types of bisphosphonates [36]. Even if atypical fractures were related to an impairment of bone mechanical properties, it is unclear if this would be due to bisphosphonate use, because of inconsistencies in the type of bone (cancellous or cortical) and the anatomic location (vertebrae, rib, or femur) that have been investigated. Other important factors in the development of stress fractures are characteristics at the whole bone level. Disadvantageous bone shape, such as a smaller diameter of the shaft, larger femoral offset, and increased curvature, are typically seen in females with fractures [37–40]. This might also play a role in the etiology of atypical femoral fractures and explain why these fractures occur in patients without bisphosphonate treatment. In combination with subtle changes in bone mechanical properties secondary to bisphosphonate treatment, these morphometrical differences might be responsible for the suggested higher risk of atypical femoral fracture in female bisphosphonate users compared with men. However, this link remains to be established.
Pathophysiology: Impaired Targeted Remodeling? Perhaps the attempts to explain the atypical fractures by increased bone brittleness are on the wrong track. Stress fractures are thought to start by accumulation of microscopic cracks [41]. Such crack formation is a part of bone physiology [42]. Normally, areas with micro-cracks are resorbed by osteoclasts and replaced with new bone by a process called “targeted remodeling” [43]. If targeted remodeling is disturbed by antiresorptive treatment, microcracks might grow, fuse and cause stress fractures [16••]. The osteoclasts are formed in response to RANKL, which is secreted by osteocytes in the region where microcracks accumulate. Microcracks tend to accumulate in old bone [44], but old bone is unlikely to contain bisphosphonate, because bisphosphonates bind to surfaces, especially new-formed surfaces, and the old bone was formed and embedded before treatment started. Therefore, it seems likely that if bisphosphonates are to disturb targeted remodeling, they have to reach the site of damage inside the bone. Only doses administered while targeted remodeling is ongoing will have this possibility. In sites with ongoing resorption the mineral is uncovered by cells and therefore, more accessible for circulating bisphosphonates, compared with other bone surfaces.
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The important role of ongoing treatment, rather than skeletal accumulation of bisphosphonates, is further supported by the observation that the risk of atypical fracture diminishes rapidly after cessation of treatment (in contrast, the reduction in risk of osteoporosis fracture seems to remain for years). This theory about ongoing treatment and atypical fracture is not falsified by the continuously increasing risk during long-time bisphosphonate treatment. The increase could be explained by an accumulation of areas with microdamage as long as targeted remodeling is inhibited. According to the here suggested pathophysiological model, weekly bisphosphonates will influence targeted remodeling, while once-yearly bisphosphonates will only reach those areas of microdamage that are undergoing remodeling at the very time-point of the injection. If this model is appropriate, onceyearly bisphosphonates should confer a lower risk of atypical fractures. Nevertheless, atypical fractures related to intravenous bisphosphonates are reported to occur in a larger proportion of patients than in orally treated patients. However, these reports are rare and include patients with malignancies [45–47], patients of varying age, inhomogeneous indications for treatment, and a history of previous oral treatment [48]. Malignant conditions are usually treated with higher and more frequent doses than in the treatment of osteoporosis, and the treatment, therefore, might have similar negative effects on targeted remodeling as weekly oral treatment. Denosumab is a relatively new antiresorptive that works by blocking RANKL, the very molecule that leads to osteoclast formation in areas of targeted remodeling. Contrary to bisphosphonates, denosumab stays in circulation for several months after an injection. Its effects on targeted remodeling might therefore be similar to weekly bisphosphonates. With injection intervals of 6 months, however, there is normally a short period of recovered osteoclast function before the next injection. Very recently, 3 cases of atypical fractures in association with denosumab have been described [49•, 50•, 51]. Interestingly, the fractures appeared after about a year on denosumab. This short time does not allow for effects on bone brittleness to develop, and is yet another argument that inhibition of the ability to deal with fresh microcracks is an important etiologic factor behind atypical fractures. The producer of denosumab warns of atypical fractures. However, they report only 2 suspected cases in a cohort of about 3500 patients on denosumab followed for 3 or 6 years [49•].
Conclusions Atypical fractures are caused mainly by bisphosphonates, either due to changes in the mechanical properties of bone or a reduced ability to deal with fresh microcracks. The risk increases with duration of use and decreases rapidly after cessation. They are
Curr Osteoporos Rep (2014) 12:189–193
uncommon, and with a correct indication (but only then), bisphosphonates prevent many more fractures than they cause. Compliance with Ethics Guidelines Conflict of Interest P Aspenberg has received research support from AddBioAB. J Schilcher declares no conflicts of interest. Human and Animal Rights and Informed Consent All studies by the authors involving animal and/or human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Schilcher J. Epidemiology, radiology and histology of atypical femoral fractures. Acta Orthop Suppl. 2013;84:1–26. 2. Lenart BA, Neviaser AS, Lyman S, Chang CC, Edobor-Osula F, Steele B, et al. Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int. 2008;20:1353–62. 3. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CYC. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metabol. 2005;90:1294–301. 4. Kwek EBK, Goh SK, Koh JSB, Png MA, Sen HT. An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? Injury. 2008;39:224–31. 5. Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res. 2009;24:1095–102. 6. Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, BucciRechtweg C, et al. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med. 2010;362:1761–71. 7.•• Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014;29:1–23. The second report of the ASBMR Task Force provides a sharper definition of the radiographic criteria for atypical fracture, and an update of the knowledge in the field. 8. Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med. 2008;358:1304–6. 9. Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, 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. 2010;25:2267–94. 10. Schilcher J, Aspenberg P. Incidence of stress fractures of the femoral shaft in women treated with bisphosphonate. Acta Orthop. 2009;80:413–5. 11.• Schilcher J, Koeppen V, Ranstam J, Skripitz R, Michaëlsson K, Aspenberg P. Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls. Bone. 2013;52:389–92. 12. Pegrum J, Crisp T, Padhiar N. Diagnosis and management of bone stress injuries of the lower limb in athletes. BMJ. 2012;344:e2511–1.
Curr Osteoporos Rep (2014) 12:189–193 13.
14.
15.
16.••
17.
18.
19. 20.
21.
22.
23.
24.
25. 26.
27. 28.
29.
30.
31.
Schilcher J, Aspenberg P, Sandberg O. Histology of Atypical Femoral Fractures. Conference Abstract. ASBMR meeting, Baltimore, USA. [Abstract number 1079]. Perren SM. Physical and biological aspects of fracture healing with special reference to internal fixation. Clin Orthop Relat Res. 1979;138:175–96. Chiang CY, Chiang CY, Zebaze RMD, Zebaze RMD, GhasemZadeh A, Ghasem-Zadeh A, et al. Teriparatide improves bone quality and healing of atypical femoral fractures associated with bisphosphonate therapy. Bone. 2012;52:1–6. Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364: 1728–37. This study descibes the relative and absolute risks of atypical fracture in a nation-wide cohort with radiographic adjuducation of fracture types. The association between bisphosphonate use and atypical fracture was strong. Michaëlsson K, Schilcher J, Aspenberg P. Comment on Compston: pathophysiology of atypical femoral fractures and osteonecrosis of the jaw. Osteoporos Int. 2012;23:2901–2. Feldstein AC, Black DD, Perrin NN, Rosales AGA, Friess DD, Boardman DD, et al. Incidence and demography of femur fractures with and without atypical features. J Bone Miner Res. 2012;27:977–86. Girgis CM, Sher D, Seibel MJ. Atypical femoral fractures and bisphosphonate use. N Engl J Med. 2010;362:1848–9. Giusti A, Hamdy NA, Hamdy NA, Dekkers OM, Dekkers OM, Ramautar SR, et al. Atypical fractures and bisphosphonate therapy: a cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features. Bone. 2011;48:966–71. Ing-Lorenzini K, Desmeules J, Plachta O, Suva D, Dayer P, Peter R. Low-energy femoral fractures associated with the long-term use of bisphosphonates. Drug Saf. 2009;32:775–85. Schneider JP. Should bisphosphonates be continued indefinitely? An unusual fracture in a healthy woman on long-term alendronate. Geriatrics. 2006;61:31–3. Demiralp B, Ilgan S, Ozgur Karacalioglu A, Cicek EI, Yildrim D, Erler K. Bilateral femoral insufficiency fractures treated with inflatable intramedullary nails: a case report. Arch Orthop Trauma Surg. 2007;127:597–601. Somford MP, Draijer FW, Thomassen BJ, Chavassieux PM, Boivin G, Papapoulos SE. Bilateral fractures of the femur diaphysis in a patient with rheumatoid arthritis on long-term treatment with alendronate: clues to the mechanism of increased bone fragility. J Bone Miner Res. 2009;24:1736–40. Ott SM. Fractures after long-term alendronate therapy. J Clin Endocrinol Metab. 2001;86:1835–6. Unnanuntana A, Ashfaq K, Ton QV, Kleimeyer JP, Lane JM. The effect of long-term alendronate treatment on cortical thickness of the proximal femur. Clin Orthop Relat Res. 2011;470:291–8. Koeppen VA, Schilcher J, Aspenberg P. Atypical fractures do not have a thicker cortex. Osteoporos Int. 2012;12:937–41. Tai K, Dao M, Suresh S, Palazoglu A, Ortiz C. Nanoscale heterogeneity promotes energy dissipation in bone. Nat Mater. 2007;6:454– 62. Donnelly E, Meredith DS, Nguyen JT, Gladnick BP, Rebolledo BJ, Shaffer AD, et al. Reduced cortical bone compositional heterogeneity with bisphosphonate treatment in postmenopausal women with intertrochanteric and subtrochanteric fractures. J Bone Miner Res. 2012;27:672–8. Saito M, Mori S, Mashiba T, Komatsubara S, Marumo K. Collagen maturity, glycation induced-pentosidine, and mineralization are increased following 3-year treatment with incadronate in dogs. Osteoporos Int. 2008;19:1343–54. Tjhia CK, Stover SM, Rao DS, Odvina CV, Fyhrie DP. Relating micromechanical properties and mineral densities in severely suppressed bone turnover patients, osteoporotic patients, and normal subjects. Bone. 2012;51:114–22
193 32.
33.
34.
35.
36.
37.
38.
39.
40. 41.
42.
43. 44. 45.
46.
47.
48.
49.•
50.•
51.
Vashishth D, Gibson GJ, Khoury JI, Schaffler MB, Kimura J, Fyhrie DP. Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone. 2001;28:195–201. Allen MR, Reinwald S, Burr DB. Alendronate reduces bone toughness of ribs without significantly increasing microdamage accumulation in dogs following 3 years of daily treatment. Calcif Tissue Int. 2008;82:354–60. Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone. 2001;28:524–31. Güerri-Fernández RC, Nogués X, Quesada Gómez JM, Torres Del Pliego E, Puig L, García-Giralt N, et al. Microindentation for in vivo measurement of bone tissue material properties in atypical femoral fracture patients and controls. J Bone Miner Res. 2013;28:162–8. Yamagami Y, Mashiba T, Iwata K, Tanaka M, Nozaki K, Yamamoto T. Effects of minodronic acid and alendronate on bone remodeling, microdamage accumulation, degree of mineralization and bone mechanical properties in ovariectomized cynomolgus monkeys. Bone. 2013;54:1–7. Beck TJ, Ruff CB, Shaffer RA, Betsinger K, Trone DW, Brodine SK. Stress fracture in military recruits: gender differences in muscle and bone susceptibility factors. Bone. 2000;27:437–44. Wang Q, Teo JW, Ghasem-Zadeh A, Seeman E. Women and men with hip fractures have a longer femoral neck moment arm and greater impact load in a sideways fall. Osteoporos Int. 2008;20:1151–6. Sasaki S, Miyakoshi N, Hongo M, Kasukawa Y, Shimada Y. Lowenergy diaphyseal femoral fractures associated with bisphosphonate use and severe curved femur: a case series. J Bone Miner Metab. 2012;30:561–7. Seeman E. Bone quality: the material and structural basis of bone strength. J Bone Miner Metab. 2008;26:1–8. Frost HM. Transient-steady state phenomena in microdamage physiology: a proposed algorithm for lamellar bone. Calcif Tissue Int. 1989;44:367–81. Vashishth D, Behiri JC, Bonfield W. Crack growth resistance in cortical bone: concept of microcrack toughening. J Biomech. 1997;30:763–9. Burr DB. Targeted and nontargeted remodeling. Bone. 2002;30:2–4. Norman TL, Wang Z. Microdamage of human cortical bone: incidence and morphology in long bones. Bone. 1997;20:375–9. Puhaindran ME, Puhaindran ME, Farooki A, Farooki A, Steensma MR, Steensma MR, et al. Atypical subtrochanteric femoral fractures in patients with skeletal malignant involvement treated with intravenous bisphosphonates. J Bone Joint Surg Am. 2011;93:1235–42. Chang ST, Tenforde AS, Grimsrud CD, O'Ryan FS, Gonzalez JR, Baer DM, et al. Atypical femur fractures among breast cancer and multiple myeloma patients receiving intravenous bisphosphonate therapy. Bone. 2012;51:524–7. Kim Y-S, Park W-C. Atypical subtrochanteric femur fracture in patient with metastatic breast cancer treated with zoledronic acid. J Breast Cancer. 2012;15:261. Powell D, Bowler C, Roberts T, Garton M, Matthews C, Mccall I, et al. Incidence of serious side effects with intravenous bisphosphonate: a clinical audit. Q J Med. 2012;105:965–71. Bone HG, Chapurlat R, Brandi M-L, Brown JP, Czerwiński E, Krieg MA, et al. The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metabol. 2013;98:4483–92. This study evaluates the effects of up to 6 years of denosumab treatment in 4550 women. No patient with atypical femoral fracture was identified. Thompson RN, Armstrong C, Heyburn G. Bilateral atypical femoral fractures in a patient prescribed denosumab—a case report. Bone. 2014;61:44–7. Aspenberg P. Denosumab and atypical femoral fractures. Acta Orthopaedica. 2013;85:1.
BIOMECHANICS (M SILVA AND P ZYSSET, SECTION EDITORS)
Atypical Femoral Fractures, Bisphosphonates, and Mechanical Stress Per Aspenberg & Jörg Schilcher
Published online: 11 March 2014 # Springer Science+Business Media New York 2014
Abstract Atypical fractures are stress fractures occurring in the femoral shaft and closely related to bisphosphonate use. We here discuss their radiographic definition and different putative etiologies, apart from mechanical stress. Long time reduction of skeletal remodeling because of bisphosphonate use is thought to allow time for the bone to deteriorate mechanically, resulting in reduced toughness. However, the risk of atypical fracture diminishes rapidly after cessation of treatment, which suggests more acute effects of bisphosphonate use. Microdamage normally accumulates at areas of high stress. Possibly, ongoing bisphosphonate use reduces the ability to resorb and replace areas of microdamage by targeted remodeling. This could lead to crack propagation beyond a point of no return, ending in macroscopic stress fracture.
described in military recruits in the Prussian army. Fatigue fractures in the lower extremity are now a common problem in athletes, normally referred to as stress fractures. They appear as thin cracks that only seldom lead to a complete, displaced fracture, probably because pain inhibits the last catastrophic loading cycles. The crack is often too thin to be seen on radiographs, and the diagnosis depends on clinical signs and the visible callus reaction on radiographs. If a complete, displaced fracture occurs, the fracture surface looks as if there had been a transverse cut, at a perfectly right angle to the traction forces, half-way through the bone [1]. The remainder of the fracture, on the compression side, looks as a normal fracture. This is completely in agreement with the broken railway axles, where a crack has grown at right angle to the direction of the mechanical force until the remainder of the structure broke.
Keywords Atypical femoral fractures . Bisphosphonates . Bone remodeling . Osteoporosis . Bone fragility Atypical Fractures Appear Introduction: Stress Fractures In the middle of the 19th century, rail-road accidents killed a great number of people, causing fear and turmoil. Many of these accidents were caused by sudden fractures of wheel axles. It was a mystery how these sturdy steel axles could suddenly break while not loaded more than usual. The problem was solved by a young German engineer, August Wöhler, who set up systematic full-scale experiments. He was the first to describe how repeated moderate loading caused material fatigue and formation of small cracks that grow for each loading cycle until the whole structure breaks. Not much later, “marching fractures” resulting from bone fatigue were P. Aspenberg (*) : J. Schilcher Department of Clinical and Experimental Medicine, Orthopedics, Faculty of Health Science, Linköping University, 581 85 Linköping, Sweden e-mail: [email protected]
Between 2005 and 2008, reports started to appear in the literature, describing stress fractures of the femoral shaft in elderly women [2–4]. Most of these patients had prodromal pain, and the fractures had displaced with a minimal trauma. The authors were astounded to find this type of fracture in patients who did not overload their bones as extremely as athletes do, and it was soon suspected that bisphosphonates were to blame. Several case series reported that the vast majority of these patients had been taking bisphosphonates for a considerable time. Soon, however, authors with a background outside orthopedics questioned the existence of a specific subcategory of fractures and the association with bisphosphonates [5, 6]. After a few years of hot debate, there is now almost consensus that these fractures exist and are caused mainly by bisphosphonates [7••]. During this debate, the term “atypical fracture” emerged [8] and was coined by the American Society of Bone and Mineral Research (ASBMR) [9].
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What is an Atypical Fracture? When the atypical fractures were first described, it was their typical stress fracture appearance that caused the attention [3, 4]. Indeed, already in 2009, we described both the absolute and relative bisphosphonate-associated risk of femoral stress fractures based on radiographic appearance in a defined Swedish population [10]. Much of the confusion and debate those days emerged when researchers started using diagnosis registers, where fractures are classified according to location, but not type [5]. A task force appointed by the ASBMR defined criteria for diagnosis in 2010 [9], but these were initially somewhat vague, which may have contributed to the confusion [1]. More recently, it has been shown that the angle of the fracture line to the lateral cortical surface in femoral shaft fractures shows a dichotomous distribution: either the angle is close to 90°, or it is around 45°, and seldom in between [11•]. Seventy-three percent of the patients with an angle of 90°±15° in that study were taking a bisphosphonate, but only 13 % of the others did. Moreover, 77 % of these patients had signs of a callus reaction that obviously had preceded the displacement. Therefore, the best definition of an atypical fracture, or at least the most specific, is probably a lateral fracture angle between 75° and 105° in combination with signs of a callus reaction that might be very discrete. However, with the increasing awareness of atypical fractures, a large and probably increasing number of patients become diagnosed with incomplete fractures before they become displaced, based on thigh pain and a typical, distinctly localized callus reaction at the lateral cortex.
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We believe these histologic findings suggest an explanation for the absence of healing. As first described by Perren et al [14], too narrow fracture gaps can preclude healing. The small deformations that always occur with physiological loading will lead to very small changes in the width of a fracture gap. If the fracture gap is narrow, a small change in width might still be of the same order of magnitude as the gap itself. Thus, physiological loading will more or less open and close the gap for each walking step. Strains of this magnitude will destroy any cell that enters the gap in an attempt to fill it with new tissue. If the poor healing ability has a mechanical explanation, there should not be much point in trying to stimulate healing with drugs such as PTH [15]. We have experience from a few cases with incomplete fracture, where we took a large biopsy, comprising almost the entire fracture. The created defects healed uneventfully, and remarkably, the patients reported immediate pain relief after this procedure. We believe this effect may be due to the removal of the crack, but it could also be due to the fact that we stabilized the bone with an intramedullary nail or plate.
Evidence for Bisphosphonates as a Cause When a clear definition of atypical fractures is used, based on its nature of a stress fracture, the relative risk for bisphosphonate users is increased already after a year of use and rapidly increases with time. For all bisphosphonate users among all Swedish women above 55 years of age in 2008, the relative risk was 46 [16••]. This is actually a stronger association than between smoking and lung cancer [17]. Still, the absolute risk
Impaired Healing Stress fractures in athletes, especially in cortical shaft bone, and atypical fractures have a reputation for slow or poor healing [9, 12]. We have seen patients with an undisplaced, painful atypical fracture that remained unhealed for more than 18 months after cessation of bisphosphonate use, with no clinical or radiographic signs of improvement [1]. Notably, poor healing seems to be a consistent feature in undisplaced stress fractures, regardless if the patient uses a bisphosphonate or not. Why Don’t They Heal? We have taken biopsies of the fracture, including the fracture gap, in 4 undisplaced and 4 displaced cases [13]. A consistent finding was that the fracture gap is only 100–200 micrometer wide and completely devoid of tissue. No cells, no matrix, only small amounts of amorphous material were seen, probably a protein precipitate (Fig. 1). Contrary to expectation, the bone next to the fracture line showed signs of recent remodeling, and often had a woven, immature structure.
Fig. 1 H&E stain of a bone biopsy from an 80-year-old woman with incomplete atypical femoral fracture. The patient had used Alendronate for 5 years and reported thigh pain for several months prior to surgery. The fracture was stabilized with a plate (the curvature of the femur was not feasible for intramedullary nailing) and healed uneventfully. Note the periosteal callus (C) and the thin fracture line containing amorphous material (black arrows). Image previously published in Acta Orthop (1) under the terms of Creative Commons
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is low (as with lung cancer). The risk decreased rapidly after discontinuation of bisphosphonate use [16••]. This was an unexpected finding, as bisphosphonates remain in the skeleton with a half-life of many years. The very strong association between bisphosphonates and atypical fractures, in combination with a plausible etiologic connection and the effect of discontinuation, all speak for a direct etiologic role of the bisphosphonates. As with smoking and cancer, other factors may play a role [18], but these other factors are likely to be less important. There have been speculations that several other drugs, notably corticosteroids and proton-pump inhibitors [19, 21–24], increase the risk, but these have not been confirmed. In our nation-wide study [16••], no such associations were found. In contrast, there seems to be a clear association with general health and probably with a healthy life-style, as patients with atypical fractures are younger, take fewer drugs, have fewer other diagnoses, are less often depressed etc, than patients with other fractures of the femur. This is to expect: general health should be associated with higher physical activity, and because atypical fractures are a form of stress fractures, mechanical stress should contribute to the risk.
Pathophysiology: Brittle Bone? The increased risk of stress fracture with bisphosphonate use suggests a connection to reduced osteoclastic activity. Before bisphosphonates were introduced in the clinic, in the early 1990ies, there were suggestions that reduced remodeling would allow the bone tissue to become too old, and therefore brittle and susceptible to fatigue damage [25]. In counterarguments it was pointed out that postmenopausal osteoporosis is a state of increased turnover, and therefore bisphosphonates would just return the situation to a premenopause-like situation. Patients at risk of atypical fracture have been suggested to have other bone abnormalities beforehand, one of them being manifested as an increased cortical thickness [2]. No such abnormalities have been demonstrated [20, 26], and when an increased thickness has been found, it was due to the difference in age between patients with atypical and ordinary fractures [27]. There have been some attempts to demonstrate an increased brittleness in bisphosphonate users, but findings are inconsistent. In normal osteonal bone, some osteons are younger than others and therefore, less mineralized, as the last stages toward full mineralization take a long time. A variation in osteonal mineralization, crystal maturity, and collagen cross-linking creates heterogeneity in between osteons and a corresponding variation in stiffness, which protects the bone from crack propagation [28]. These variations in bone composition in healthy individuals suggest an evolutionary optimum. Bone exposed to bisphosphonate has been shown to have a more homogenous composition, reflected in a narrower distribution of cortical collagen maturity and crystallinity and
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an increase in the mineral to matrix ratio and collagen crosslinks [29, 30]. These changes have been associated with stiffening of the bone and deterioration of material properties in animal studies and humans [31, 32–34]. In vivo nanoindentation of tibiae in patients with atypical femoral fractures showed impaired bone material properties compared with control patients without fractures. However, patients with ordinary femoral fractures showed similar impairments [35]. Bone mechanical properties in the monkey femur were not influenced by different doses and types of bisphosphonates [36]. Even if atypical fractures were related to an impairment of bone mechanical properties, it is unclear if this would be due to bisphosphonate use, because of inconsistencies in the type of bone (cancellous or cortical) and the anatomic location (vertebrae, rib, or femur) that have been investigated. Other important factors in the development of stress fractures are characteristics at the whole bone level. Disadvantageous bone shape, such as a smaller diameter of the shaft, larger femoral offset, and increased curvature, are typically seen in females with fractures [37–40]. This might also play a role in the etiology of atypical femoral fractures and explain why these fractures occur in patients without bisphosphonate treatment. In combination with subtle changes in bone mechanical properties secondary to bisphosphonate treatment, these morphometrical differences might be responsible for the suggested higher risk of atypical femoral fracture in female bisphosphonate users compared with men. However, this link remains to be established.
Pathophysiology: Impaired Targeted Remodeling? Perhaps the attempts to explain the atypical fractures by increased bone brittleness are on the wrong track. Stress fractures are thought to start by accumulation of microscopic cracks [41]. Such crack formation is a part of bone physiology [42]. Normally, areas with micro-cracks are resorbed by osteoclasts and replaced with new bone by a process called “targeted remodeling” [43]. If targeted remodeling is disturbed by antiresorptive treatment, microcracks might grow, fuse and cause stress fractures [16••]. The osteoclasts are formed in response to RANKL, which is secreted by osteocytes in the region where microcracks accumulate. Microcracks tend to accumulate in old bone [44], but old bone is unlikely to contain bisphosphonate, because bisphosphonates bind to surfaces, especially new-formed surfaces, and the old bone was formed and embedded before treatment started. Therefore, it seems likely that if bisphosphonates are to disturb targeted remodeling, they have to reach the site of damage inside the bone. Only doses administered while targeted remodeling is ongoing will have this possibility. In sites with ongoing resorption the mineral is uncovered by cells and therefore, more accessible for circulating bisphosphonates, compared with other bone surfaces.
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The important role of ongoing treatment, rather than skeletal accumulation of bisphosphonates, is further supported by the observation that the risk of atypical fracture diminishes rapidly after cessation of treatment (in contrast, the reduction in risk of osteoporosis fracture seems to remain for years). This theory about ongoing treatment and atypical fracture is not falsified by the continuously increasing risk during long-time bisphosphonate treatment. The increase could be explained by an accumulation of areas with microdamage as long as targeted remodeling is inhibited. According to the here suggested pathophysiological model, weekly bisphosphonates will influence targeted remodeling, while once-yearly bisphosphonates will only reach those areas of microdamage that are undergoing remodeling at the very time-point of the injection. If this model is appropriate, onceyearly bisphosphonates should confer a lower risk of atypical fractures. Nevertheless, atypical fractures related to intravenous bisphosphonates are reported to occur in a larger proportion of patients than in orally treated patients. However, these reports are rare and include patients with malignancies [45–47], patients of varying age, inhomogeneous indications for treatment, and a history of previous oral treatment [48]. Malignant conditions are usually treated with higher and more frequent doses than in the treatment of osteoporosis, and the treatment, therefore, might have similar negative effects on targeted remodeling as weekly oral treatment. Denosumab is a relatively new antiresorptive that works by blocking RANKL, the very molecule that leads to osteoclast formation in areas of targeted remodeling. Contrary to bisphosphonates, denosumab stays in circulation for several months after an injection. Its effects on targeted remodeling might therefore be similar to weekly bisphosphonates. With injection intervals of 6 months, however, there is normally a short period of recovered osteoclast function before the next injection. Very recently, 3 cases of atypical fractures in association with denosumab have been described [49•, 50•, 51]. Interestingly, the fractures appeared after about a year on denosumab. This short time does not allow for effects on bone brittleness to develop, and is yet another argument that inhibition of the ability to deal with fresh microcracks is an important etiologic factor behind atypical fractures. The producer of denosumab warns of atypical fractures. However, they report only 2 suspected cases in a cohort of about 3500 patients on denosumab followed for 3 or 6 years [49•].
Conclusions Atypical fractures are caused mainly by bisphosphonates, either due to changes in the mechanical properties of bone or a reduced ability to deal with fresh microcracks. The risk increases with duration of use and decreases rapidly after cessation. They are
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uncommon, and with a correct indication (but only then), bisphosphonates prevent many more fractures than they cause. Compliance with Ethics Guidelines Conflict of Interest P Aspenberg has received research support from AddBioAB. J Schilcher declares no conflicts of interest. Human and Animal Rights and Informed Consent All studies by the authors involving animal and/or human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Schilcher J. Epidemiology, radiology and histology of atypical femoral fractures. Acta Orthop Suppl. 2013;84:1–26. 2. Lenart BA, Neviaser AS, Lyman S, Chang CC, Edobor-Osula F, Steele B, et al. Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int. 2008;20:1353–62. 3. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CYC. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metabol. 2005;90:1294–301. 4. Kwek EBK, Goh SK, Koh JSB, Png MA, Sen HT. An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? Injury. 2008;39:224–31. 5. Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res. 2009;24:1095–102. 6. Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, BucciRechtweg C, et al. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med. 2010;362:1761–71. 7.•• Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014;29:1–23. The second report of the ASBMR Task Force provides a sharper definition of the radiographic criteria for atypical fracture, and an update of the knowledge in the field. 8. Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med. 2008;358:1304–6. 9. Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, 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. 2010;25:2267–94. 10. Schilcher J, Aspenberg P. Incidence of stress fractures of the femoral shaft in women treated with bisphosphonate. Acta Orthop. 2009;80:413–5. 11.• Schilcher J, Koeppen V, Ranstam J, Skripitz R, Michaëlsson K, Aspenberg P. Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls. Bone. 2013;52:389–92. 12. Pegrum J, Crisp T, Padhiar N. Diagnosis and management of bone stress injuries of the lower limb in athletes. BMJ. 2012;344:e2511–1.
Curr Osteoporos Rep (2014) 12:189–193 13.
14.
15.
16.••
17.
18.
19. 20.
21.
22.
23.
24.
25. 26.
27. 28.
29.
30.
31.
Schilcher J, Aspenberg P, Sandberg O. Histology of Atypical Femoral Fractures. Conference Abstract. ASBMR meeting, Baltimore, USA. [Abstract number 1079]. Perren SM. Physical and biological aspects of fracture healing with special reference to internal fixation. Clin Orthop Relat Res. 1979;138:175–96. Chiang CY, Chiang CY, Zebaze RMD, Zebaze RMD, GhasemZadeh A, Ghasem-Zadeh A, et al. Teriparatide improves bone quality and healing of atypical femoral fractures associated with bisphosphonate therapy. Bone. 2012;52:1–6. Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364: 1728–37. This study descibes the relative and absolute risks of atypical fracture in a nation-wide cohort with radiographic adjuducation of fracture types. The association between bisphosphonate use and atypical fracture was strong. Michaëlsson K, Schilcher J, Aspenberg P. Comment on Compston: pathophysiology of atypical femoral fractures and osteonecrosis of the jaw. Osteoporos Int. 2012;23:2901–2. Feldstein AC, Black DD, Perrin NN, Rosales AGA, Friess DD, Boardman DD, et al. Incidence and demography of femur fractures with and without atypical features. J Bone Miner Res. 2012;27:977–86. Girgis CM, Sher D, Seibel MJ. Atypical femoral fractures and bisphosphonate use. N Engl J Med. 2010;362:1848–9. Giusti A, Hamdy NA, Hamdy NA, Dekkers OM, Dekkers OM, Ramautar SR, et al. Atypical fractures and bisphosphonate therapy: a cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features. Bone. 2011;48:966–71. Ing-Lorenzini K, Desmeules J, Plachta O, Suva D, Dayer P, Peter R. Low-energy femoral fractures associated with the long-term use of bisphosphonates. Drug Saf. 2009;32:775–85. Schneider JP. Should bisphosphonates be continued indefinitely? An unusual fracture in a healthy woman on long-term alendronate. Geriatrics. 2006;61:31–3. Demiralp B, Ilgan S, Ozgur Karacalioglu A, Cicek EI, Yildrim D, Erler K. Bilateral femoral insufficiency fractures treated with inflatable intramedullary nails: a case report. Arch Orthop Trauma Surg. 2007;127:597–601. Somford MP, Draijer FW, Thomassen BJ, Chavassieux PM, Boivin G, Papapoulos SE. Bilateral fractures of the femur diaphysis in a patient with rheumatoid arthritis on long-term treatment with alendronate: clues to the mechanism of increased bone fragility. J Bone Miner Res. 2009;24:1736–40. Ott SM. Fractures after long-term alendronate therapy. J Clin Endocrinol Metab. 2001;86:1835–6. Unnanuntana A, Ashfaq K, Ton QV, Kleimeyer JP, Lane JM. The effect of long-term alendronate treatment on cortical thickness of the proximal femur. Clin Orthop Relat Res. 2011;470:291–8. Koeppen VA, Schilcher J, Aspenberg P. Atypical fractures do not have a thicker cortex. Osteoporos Int. 2012;12:937–41. Tai K, Dao M, Suresh S, Palazoglu A, Ortiz C. Nanoscale heterogeneity promotes energy dissipation in bone. Nat Mater. 2007;6:454– 62. Donnelly E, Meredith DS, Nguyen JT, Gladnick BP, Rebolledo BJ, Shaffer AD, et al. Reduced cortical bone compositional heterogeneity with bisphosphonate treatment in postmenopausal women with intertrochanteric and subtrochanteric fractures. J Bone Miner Res. 2012;27:672–8. Saito M, Mori S, Mashiba T, Komatsubara S, Marumo K. Collagen maturity, glycation induced-pentosidine, and mineralization are increased following 3-year treatment with incadronate in dogs. Osteoporos Int. 2008;19:1343–54. Tjhia CK, Stover SM, Rao DS, Odvina CV, Fyhrie DP. Relating micromechanical properties and mineral densities in severely suppressed bone turnover patients, osteoporotic patients, and normal subjects. Bone. 2012;51:114–22
193 32.
33.
34.
35.
36.
37.
38.
39.
40. 41.
42.
43. 44. 45.
46.
47.
48.
49.•
50.•
51.
Vashishth D, Gibson GJ, Khoury JI, Schaffler MB, Kimura J, Fyhrie DP. Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone. 2001;28:195–201. Allen MR, Reinwald S, Burr DB. Alendronate reduces bone toughness of ribs without significantly increasing microdamage accumulation in dogs following 3 years of daily treatment. Calcif Tissue Int. 2008;82:354–60. Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone. 2001;28:524–31. Güerri-Fernández RC, Nogués X, Quesada Gómez JM, Torres Del Pliego E, Puig L, García-Giralt N, et al. Microindentation for in vivo measurement of bone tissue material properties in atypical femoral fracture patients and controls. J Bone Miner Res. 2013;28:162–8. Yamagami Y, Mashiba T, Iwata K, Tanaka M, Nozaki K, Yamamoto T. Effects of minodronic acid and alendronate on bone remodeling, microdamage accumulation, degree of mineralization and bone mechanical properties in ovariectomized cynomolgus monkeys. Bone. 2013;54:1–7. Beck TJ, Ruff CB, Shaffer RA, Betsinger K, Trone DW, Brodine SK. Stress fracture in military recruits: gender differences in muscle and bone susceptibility factors. Bone. 2000;27:437–44. Wang Q, Teo JW, Ghasem-Zadeh A, Seeman E. Women and men with hip fractures have a longer femoral neck moment arm and greater impact load in a sideways fall. Osteoporos Int. 2008;20:1151–6. Sasaki S, Miyakoshi N, Hongo M, Kasukawa Y, Shimada Y. Lowenergy diaphyseal femoral fractures associated with bisphosphonate use and severe curved femur: a case series. J Bone Miner Metab. 2012;30:561–7. Seeman E. Bone quality: the material and structural basis of bone strength. J Bone Miner Metab. 2008;26:1–8. Frost HM. Transient-steady state phenomena in microdamage physiology: a proposed algorithm for lamellar bone. Calcif Tissue Int. 1989;44:367–81. Vashishth D, Behiri JC, Bonfield W. Crack growth resistance in cortical bone: concept of microcrack toughening. J Biomech. 1997;30:763–9. Burr DB. Targeted and nontargeted remodeling. Bone. 2002;30:2–4. Norman TL, Wang Z. Microdamage of human cortical bone: incidence and morphology in long bones. Bone. 1997;20:375–9. Puhaindran ME, Puhaindran ME, Farooki A, Farooki A, Steensma MR, Steensma MR, et al. Atypical subtrochanteric femoral fractures in patients with skeletal malignant involvement treated with intravenous bisphosphonates. J Bone Joint Surg Am. 2011;93:1235–42. Chang ST, Tenforde AS, Grimsrud CD, O'Ryan FS, Gonzalez JR, Baer DM, et al. Atypical femur fractures among breast cancer and multiple myeloma patients receiving intravenous bisphosphonate therapy. Bone. 2012;51:524–7. Kim Y-S, Park W-C. Atypical subtrochanteric femur fracture in patient with metastatic breast cancer treated with zoledronic acid. J Breast Cancer. 2012;15:261. Powell D, Bowler C, Roberts T, Garton M, Matthews C, Mccall I, et al. Incidence of serious side effects with intravenous bisphosphonate: a clinical audit. Q J Med. 2012;105:965–71. Bone HG, Chapurlat R, Brandi M-L, Brown JP, Czerwiński E, Krieg MA, et al. The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metabol. 2013;98:4483–92. This study evaluates the effects of up to 6 years of denosumab treatment in 4550 women. No patient with atypical femoral fracture was identified. Thompson RN, Armstrong C, Heyburn G. Bilateral atypical femoral fractures in a patient prescribed denosumab—a case report. Bone. 2014;61:44–7. Aspenberg P. Denosumab and atypical femoral fractures. Acta Orthopaedica. 2013;85:1.
