Skip to main content
SpringerLink
Log in

Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

Recent evidence has linked long-term bisphosphonate use with insufficiency fractures of the femur in postmenopausal women. In this case–control study, we have identified a significant association between a unique fracture of the femoral shaft, a transverse fracture in an area of thickened cortices, and long-term bisphosphonate use. Further studies are warranted.

Introduction

Although clinical trials confirm the anti-fracture efficacy of bisphosphonates over 3–5 years, the long-term effects of bisphosphonate use on bone metabolism are unknown. Femoral insufficiency factures in patients on prolonged treatment have been reported.

Methods

We performed a retrospective case–control study of postmenopausal women who presented with low-energy femoral fractures from 2000 to 2007. Forty-one subtrochanteric and femoral shaft fracture cases were identified and matched by age, race, and body mass index to one intertrochanteric and femoral neck fracture each.

Results

Bisphosphonate use was observed in 15 of the 41 subtrochanteric/shaft cases, compared to nine of the 82 intertrochanteric/femoral neck controls (Mantel–Haenszel odds ratio (OR), 4.44 [95% confidence interval (CI) 1.77–11.35]; P = 0.002). A common X-ray pattern was identified in ten of the 15 subtrochanteric/shaft cases on a bisphosphonate. This X-ray pattern was highly associated with bisphosphonate use (OR, 15.33 [95% CI 3.06–76.90]; P < 0.001). Duration of bisphosphonate use was longer in subtrochanteric/shaft cases compared to both hip fracture controls groups (P = 0.001).

Conclusions

We found a significantly greater proportion of patients with subtrochanteric/shaft fractures to be on long-term bisphosphonates than intertrochanteric/femoral neck fractures. Bisphosphonate use was highly associated with a unique X-ray pattern. Further studies are warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M (1995) Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 333:1437–1443

    Article  PubMed  CAS  Google Scholar 

  2. Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP, Rodriguez-Portales JA, Downs RW, Gupta J, Santora AC, Liberman UA, Alendronate Phase III Osteoporosis Treatment Study Group (2004) Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 350:1189–1199

    Article  PubMed  CAS  Google Scholar 

  3. Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR, FLEX Research Group (2006) Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 296:2927–2938

    Article  PubMed  CAS  Google Scholar 

  4. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY (2005) Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 90:1294–1301

    Article  PubMed  CAS  Google Scholar 

  5. Goh SK, Yang KY, Koh JS, Wong MK, Chua SY, Chua DT, Howe TS (2007) Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br 89:349–353

    Article  PubMed  Google Scholar 

  6. Kwek EB, Goh SK, Koh JS, Png MA, Howe TS (2008) An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? Injury 39:224–231

    Article  PubMed  Google Scholar 

  7. Visekruna M, Wilson D, McKiernan FE (2008) Severely suppressed bone turnover and atypical skeletal fragility. J Clin Endocrinol Metab 93:2948–2952

    Article  PubMed  CAS  Google Scholar 

  8. Neviaser AS, Lenart BA, Lane JM, Lorich DG (2007) Nontraumatic femoral shaft fractures associated with alendronate use. Orthopedic Trauma Association Annual Meeting, Boston, MA.

  9. Neviaser AS, Lane JM, Lenart BA, Edobor-Osula F, Lorich DG (2008) Low-energy femoral shaft fractures associated with alendronate use. J Orthop Trauma 22:346–350

    Article  PubMed  Google Scholar 

  10. Lenart BA, Lorich DG, Lane JM (2008) Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 358:1304–1306

    Article  PubMed  CAS  Google Scholar 

  11. Garnero P, Shih WJ, Gineyts E, Karpf DB, Delmas PD (1994) Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab 79:1693–1700

    Article  PubMed  CAS  Google Scholar 

  12. Hughes DE, Wright KR, Uy HL, Sasaki A, Yoneda T, Roodman GD, Mundy GR, Boyce BF (1995) Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 10:1478–1487

    PubMed  CAS  Google Scholar 

  13. Kavanagh KL, Guo K, Dunford JE, Wu X, Knapp S, Ebetino FH, Rogers MJ, Russell RG, Oppermann U (2006) The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci U S A 103:7829–7834

    Article  PubMed  CAS  Google Scholar 

  14. Chavassieux P, Seeman E, Delmas PD (2007) Insights into material and structural basis of bone fragility from diseases associated with fractures: how determinants of the biomechanical properties of bone are compromised by disease. Endocr Rev 28:151–164

    Article  PubMed  CAS  Google Scholar 

  15. Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ (2000) Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone 27:687–694

    Article  PubMed  CAS  Google Scholar 

  16. Currey JD (1984) Effects of differences in mineralization on the mechanical properties of bone. Philos Trans R Soc Lond B Biol Sci 304:509–518

    Article  PubMed  CAS  Google Scholar 

  17. Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB (2001) Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 28:524–531

    Article  PubMed  CAS  Google Scholar 

  18. Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB (2000) Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 15:613–620

    Article  PubMed  CAS  Google Scholar 

  19. Li J, Mashiba T, Burr DB (2001) Bisphosphonate treatment suppresses not only stochastic remodeling but also the targeted repair of microdamage. Calcif Tissue Int 69:281–286

    Article  PubMed  CAS  Google Scholar 

  20. Komatsubara S, Mori S, Mashiba T, Li J, Nonaka K, Kaji Y, Akiyama T, Miyamoto K, Cao Y, Kawanishi J, Norimatsu H (2004) Suppressed bone turnover by long-term bisphosphonate treatment accumulates microdamage but maintains intrinsic material properties in cortical bone of dog rib. J Bone Miner Res 19:999–1005

    Article  PubMed  CAS  Google Scholar 

  21. Burr DB, Turner CH, Naick P, Forwood MR, Ambrosius W, Hasan MS, Pidaparti R (1998) Does microdamage accumulation affect the mechanical properties of bone? J Biomech 31:337–345

    Article  PubMed  CAS  Google Scholar 

  22. Danova NA, Colopy SA, Radtke CL, Kalscheur VL, Markel MD, Vanderby R, McCabe RP, Escarcega AJ, Muir P (2003) Degradation of bone structural properties by accumulation and coalescence of microcracks. Bone 33:197–205

    Article  PubMed  CAS  Google Scholar 

  23. Diab T, Vashishth D (2005) Effects of damage morphology on cortical bone fragility. Bone 37:96–102

    Article  PubMed  CAS  Google Scholar 

  24. Schaffler MB, Choi K, Milgrom C (1995) Aging and matrix microdamage accumulation in human compact bone. Bone 17:521–525

    Article  PubMed  CAS  Google Scholar 

  25. Wenzel TE, Schaffler MB, Fyhrie DP (1996) In vivo trabecular microcracks in human vertebral bone. Bone 19:89–95

    Article  PubMed  CAS  Google Scholar 

  26. Allen MR, Gineyts E, Leeming DJ, Burr DB, Delmas PD (2008) Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra. Osteoporos Int 19:329–337

    Article  PubMed  CAS  Google Scholar 

  27. Ruppel ME, Miller LM, Burr DB (2008) The effect of the microscopic and nanoscale structure on bone fragility. Osteoporos Int 19:1251–1265

    Article  PubMed  CAS  Google Scholar 

  28. Siegmund T, Allen MR, Burr DB (2008) Failure of mineralized collagen fibrils: modeling the role of collagen cross-linking. J Biomech 41:1427–1435

    Article  PubMed  Google Scholar 

  29. Schatzker J, Tile M (eds) (1995) The rationale of operative fracture care. Springer, London.

  30. Gehlbach SH, Avrunin JS, Puleo E, Spaeth R (2007) Fracture risk and antiresorptive medication use in older women in the USA. Osteoporos Int 18:805–810

    Article  PubMed  CAS  Google Scholar 

  31. Stafford RS, Drieling RL, Hersh AL (2004) National trends in osteoporosis visits and osteoporosis treatment, 1988–2003. Arch Intern Med 164:1525–1530

    Article  PubMed  Google Scholar 

  32. Salminen S, Pihlajamaki H, Avikainen V, Kyro A, Bostman O (1997) Specific features associated with femoral shaft fractures caused by low-energy trauma. J Trauma 43:117–122

    Article  PubMed  CAS  Google Scholar 

  33. Salminen ST, Pihlajamaki HK, Avikainen VJ, Bostman OM (2000) Population based epidemiologic and morphologic study of femoral shaft fractures. Clin Orthop Relat Res 372:241–249

    Article  PubMed  Google Scholar 

  34. Boivin G, Meunier PJ (2002) Changes in bone remodeling rate influence the degree of mineralization of bone. Connect Tissue Res 43:535–537

    Article  PubMed  CAS  Google Scholar 

  35. Eriksen EF, Melsen F, Sod E, Barton I, Chines A (2002) Effects of long-term risedronate on bone quality and bone turnover in women with postmenopausal osteoporosis. Bone 31:620–625

    Article  PubMed  CAS  Google Scholar 

  36. Roschger P, Rinnerthaler S, Yates J, Rodan GA, Fratzl P, Klaushofer K (2001) Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women. Bone 29:185–191

    Article  PubMed  CAS  Google Scholar 

  37. Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S (2003) Bisphosphonate-induced osteopetrosis. N Engl J Med 349:457–463

    Article  PubMed  CAS  Google Scholar 

  38. Rossini M, Gatti D, Zamberlan N, Braga V, Dorizzi R, Adami S (1994) Long-term effects of a treatment course with oral alendronate of postmenopausal osteoporosis. J Bone Miner Res 9:1833–7

    Article  PubMed  CAS  Google Scholar 

  39. Stock JL, Bell NH, Chesnut CH 3rd, Ensrud KE, Genant HK, Harris ST, McClung MR, Singer FR, Yood RA, Pryor-Tillotson S, Wei L, Santora AC 2nd (1997) Increments in bone mineral density of the lumbar spine and hip and suppression of bone turnover are maintained after discontinuation of alendronate in postmenopausal women. Am J Med 103:291–297

    Article  PubMed  CAS  Google Scholar 

  40. Burr DB (2002) Targeted and nontargeted remodeling. Bone 30:2–4

    Article  PubMed  CAS  Google Scholar 

  41. Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T (1999) Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest 104:1363–74

    Article  PubMed  CAS  Google Scholar 

  42. Allen MR, Iwata K, Phipps R, Burr DB (2006) Alterations in canine vertebral bone turnover, microdamage accumulation, and biomechanical properties following 1-year treatment with clinical treatment doses of risedronate or alendronate. Bone 39:872–879

    Article  PubMed  CAS  Google Scholar 

  43. Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S, HORIZON Recurrent Fracture Trial (2007) Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 357:1799–1809

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Rose Mary Fisher and the entire Metabolic Bone Disease Service at the Hospital for Special Surgery are acknowledged. Thanks are also due to Dr. Margaret Peterson for statistical expertise and Drs. Felicia Cosman and Richard S. Bockman for their critical review of the manuscript and expert advice.

Funding/support

This study was supported by The Charles Cohn Foundation, Inc. and NIH Grant R01-ARO41325 “FT-IR Microscopy of Mineral Structure in Osteoporosis.”

Conflicts of interest

Joseph M. Lane has been on speaker’s bureau for Eli Lilly, Proctor and Gamble, GlaxoSmithKline, and Roche Pharmaceuticals.

Author information

Authors and Affiliations

  1. Hospital for Special Surgery, 535 E. 70th St., New York, NY, 10021, USA

    B. A. Lenart, A. S. Neviaser, C. C. Chang, F. Edobor-Osula, B. Steele, D. G. Lorich & J. M. Lane

  2. Weill Medical College, Cornell University, New York, NY, USA

    B. A. Lenart, C. C. Chang, F. Edobor-Osula, B. Steele, D. G. Lorich & J. M. Lane

  3. Medical Orthopedic Trauma Service, NewYork Presbyterian Hospital–Weill Cornell Medical Center, New York, NY, USA

    A. S. Neviaser, D. G. Lorich & J. M. Lane

  4. Mechanical & Aerospace Engineering, Cornell University, 219A Upson Hall, Ithaca, NY, 14853, USA

    M. C. H. van der Meulen

  5. Methodology & Statistics Core, Hospital for Special Surgery, 535 E. 70th St., New York, NY, 10021, USA

    S. Lyman

Authors
  1. B. A. Lenart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. S. Neviaser
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Lyman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. C. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. Edobor-Osula
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B. Steele
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. C. H. van der Meulen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D. G. Lorich
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J. M. Lane
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. M. Lane.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lenart, B.A., Neviaser, A.S., Lyman, S. et al. Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int 20, 1353–1362 (2009). https://doi.org/10.1007/s00198-008-0805-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-008-0805-x

Keywords

Search

Navigation