Hypophosphatasia and the risk of atypical femur fractures: a case-control study

Timothy Bhattacharyya, Smita Jha, Hongying Wang, Daniel L Kastner, Elaine F Remmers, Timothy Bhattacharyya, Smita Jha, Hongying Wang, Daniel L Kastner, Elaine F Remmers

Abstract

Background: Case reports have linked adult hypophosphatasia as a possible cause of atypical femur fractures (AFF) associated with bisphosphonate use. Adult hypophosphatasia is an asymptomatic genetic condition which results in low alkaline phosphatase and elevated pyridoxal phosphate. We conducted a case-control study to assess the role of hypophosphatasia and atypical femur fracture.

Methods: We recruited 13 control patients who took long term bisphosphonates without complication and 10 patients who sustained atypical femur fractures (mean bisphosphonate use, 9 years both cohorts). Patients underwent clinical exam and measurement of alkaline phosphatase and pyridoxal phosphate (PLP) levels. In addition, DNA was extracted and the ALPL gene was sequenced in both cohorts.

Results: Low alkaline phosphatase levels (<55 U/L) were seen in 5/10 AFF patients and 5/13 control patients. Two control patients demonstrated low alkaline phosphatase levels and elevated PLP. The alkaline phosphatase (ALPL) gene exons and intron splice sites were sequenced in the atypical femur fracture and control cohorts and no coding mutations were identified in any subjects. Atypical femur fracture patients demonstrated more varus hip alignment (p < 0.048) with no significant difference in mechanical axis.

Conclusions: We found no evidence of hypophosphatasia as a risk factor for atypical femur fractures. Laboratory findings of mildly low alkaline phosphatase activity were equally common in atypical and control cohorts and may be due to long term bisphosphonate use.

Trial registration: Clinicaltrials.gov number NCT01360099 . Prospectively registered May 20, 2011. First patient enrolled June 14, 2011.

References

    1. Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364(18):1728–1737. doi: 10.1056/NEJMoa1010650.
    1. Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster DW, 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):1–23. doi: 10.1002/jbmr.1998.
    1. Aspenberg P, Schilcher J. Atypical femoral fractures, bisphosphonates, and mechanical stress. Curr Osteoporos Rep. 2014;12(2):189–193. doi: 10.1007/s11914-014-0200-9.
    1. Hagen JE, Miller AN, Ott SM, Gardner M, Morshed S, Jeray K, Alton TB, Ren D, Abblitt WP, Krieg JC. Association of atypical femoral fractures with bisphosphonate use by patients with varus hip geometry. J Bone Joint Surg Am. 2014;96(22):1905–1909. doi: 10.2106/JBJS.N.00075.
    1. Koh JS, Goh SK, Png MA, Ng AC, Howe TS. Distribution of atypical fractures and cortical stress lesions in the femur: implications on pathophysiology. Singap Med J. 2011;52(2):77–80.
    1. Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, Bucci-Rechtweg C, Cauley J, Leung PC, Boonen S, Santora A, et al. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med. 2010;362(19):1761–1771. doi: 10.1056/NEJMoa1001086.
    1. Napoli N, Schwartz AV, Palermo L, Jin JJ, Wustrack R, Cauley JA, Ensrud KE, Kelly M, Black DM. Risk factors for subtrochanteric and diaphyseal fractures: the study of osteoporotic fractures. J Clin Endocrinol Metab. 2013;98(2):659–667. doi: 10.1210/jc.2012-1896.
    1. Chen F, Wang Z, Bhattacharyya T. Absence of femoral cortical thickening in long-term bisphosphonate users: implications for atypical femur fractures. Bone. 2014;62:64–66. doi: 10.1016/j.bone.2014.01.011.
    1. Sutton RA, Mumm S, Coburn SP, Ericson KL, Whyte MP. “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res. 2012;27(5):987–994. doi: 10.1002/jbmr.1565.
    1. Edwards BJ, Bunta AD, Lane J, Odvina C, Rao DS, Raisch DW, McKoy JM, Omar I, Belknap SM, Garg V, et al. Bisphosphonates and nonhealing femoral fractures: analysis of the FDA Adverse Event Reporting System (FAERS) and international safety efforts: a systematic review from the Research on Adverse Drug Events And Reports (RADAR) project. J Bone Joint Surg Am. 2013;95(4):297–307. doi: 10.2106/JBJS.K.01181.
    1. Dell RM, Adams AL, Greene DF, Funahashi TT, Silverman SL, Eisemon EO, Zhou H, Burchette RJ, Ott SM. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res. 2012;27(12):2544–2550. doi: 10.1002/jbmr.1719.
    1. Park-Wyllie LY, Mamdani MM, Juurlink DN, Hawker GA, Gunraj N, Austin PC, Whelan DB, Weiler PJ, Laupacis A. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA. 2011;305(8):783–789. doi: 10.1001/jama.2011.190.
    1. Schilcher J, Koeppen V, Aspenberg P, Michaëlsson K. Risk of atypical femoral fracture during and after bisphosphonate use. Acta Orthop. 2015;86(1):100–107. doi: 10.3109/17453674.2015.1004149.
    1. Wang Z, Bhattacharyya T. Trends in Incidence of Subtrochanteric Fragility Fractures and Bisphosphonate Use Among the US Elderly, 1996–2007. J Bone Miner Res. 2011;26(3):553–560. doi: 10.1002/jbmr.233.
    1. Thompson RN, Armstrong CL, Heyburn G. Bilateral atypical femoral fractures in a patient prescribed denosumab–a case report. Bone. 2014;61:44–47. doi: 10.1016/j.bone.2013.12.027.
    1. Jha S, Wang Z, Laucis N, Bhattacharyya T. Trends in Media Reports, Oral Bisphosphonate Prescriptions, and Hip Fractures 1996–2012: An Ecological Analysis. J Bone Miner Res. 2015;30(12):2179–87. doi: 10.1002/jbmr.2565.
    1. Vaisman DN, McCarthy AD, Cortizo AM. Bone-specific alkaline phosphatase activity is inhibited by bisphosphonates: role of divalent cations. Biol Trace Elem Res. 2005;104(2):131–140. doi: 10.1385/BTER:104:2:131.
    1. Gertz BJ, Holland SD, Kline WF, Matuszewski BK, Porras AG. Clinical pharmacology of alendronate sodium. Osteoporos Int. 1993;3(Suppl 3):S13–S16. doi: 10.1007/BF01623002.

Source: PubMed

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