Copyright © 2009 by The Journal of Bone and Joint Surgery, Inc.
Commentary & Perspective
Commentary & Perspective by
Joseph M. Lane, MD, and Benjamin F. Ricciardi, MD*,
Hospital for Special Surgery, New York, NY
Posted November 2009
Capeci et al. have reported on bilateral low-energy simultaneous or sequential
femoral fractures in patients on long-term alendronate therapy. This paper adds
to a growing list of patients who have presented with single or bilateral fractures
after having received continuous long-term treatment (more than five years) with
any one of a variety of bisphosphonates1-5. The fractures are characterized
by a transverse primary fracture with an associated cortical beak and a thickened
underlying cortex. They occur primarily in the subtrochanteric region or the
upper diaphysis, and initiate on the lateral cortex if incomplete. The pre-fracture
state often is not recognized due to simultaneous spinal abnormalities and symptoms
that are assumed to be due to sciatica. These fractures commonly occur bilaterally,
so involvement of one limb necessitates examination of the contralateral side.
While there is a growing recognition of this association, the majority of low-energy
subtrochanteric fractures are still related to osteoporosis and not bisphosphonate
use6. Controversy remains as to the role of bisphosphonates as an
etiologic factor in these fractures, appropriate diagnosis measures, the form
of both medical and surgical treatment, and how best to approach the incomplete
fracture.
Bisphosphonates have had a tremendous impact on the treatment of osteoporosis.
Both the oral and intravenous bisphosphonates have been shown to decrease the
risk of vertebral fractures by 50% to 70% and hip fractures by 30% to 50%7-11.
They have played a key role in lowering the true rate of hip fractures in both
women and men over the last decade. They are currently the first line of treatment
for osteoporosis. They work best in the setting of corrected calcium and vitamin-D
levels and can be administered in daily, weekly, monthly, or yearly doses. Oral
agents may cause indigestion and intravenous agents may cause influenza-like
symptoms with the first intravenous dosing, but side effects are usually mild.
Hip fractures are associated with an increased risk of mortality in both the
acute period and after long-term follow-up, and treatment with these agents may
limit these adverse events12,13. Care and concern for patients with
these rare and unusual late-presenting femoral fractures should not preclude
the rational use of bisphosphonates for the treatment of osteoporosis.
The optimal management of patients with these fractures remains controversial.
The authors provide preliminary data on individuals who continued bisphosphonates
compared with those who stopped the medication upon diagnosis of the fracture.
Three of the six femurs in patients who remained on alendronate went on to fracture
and five out of six needed surgical procedures. Among those femurs in individuals
in whom the alendronate was halted, two of the eight went on to fracture and
five ultimately needed surgical stabilization. These limited numbers suggest
that patients who present with stress fractures and who have been receiving long-term
bisphosphonate therapy may be able to stop the drugs to increase the chance of
avoiding surgery with conservative treatment; however, many go on to require
surgery, indicating that further medical interventions may be warranted upon
discovery of these fractures.
The mechanism of these fractures remains unclear at this time. The predominant
theory is that long-term suppression of bone turnover leads to accumulated microdamage
and decreased bone mechanical properties14,15. Remodeling is necessary
for fracture-healing to occur, and continuing the bisphosphonate may impair this
process. Interestingly, anabolic agents such as teriparatide may be beneficial
in the treatment of these stress fractures because they reactivate bone turnover
in bisphosphonate-treated patients and may have positive effects on fracture-healing16-20. Only future prospective trials will definitively provide evidence-based treatment
strategies.
Many questions remain unanswered concerning these low-energy atypical femoral
fractures. What is the definition for these low-energy specific femoral fractures?
What is the evidence that the bisphosphonates are an etiologic factor? What is
the pathophysiology—microdamage, aging collagen, a unique subpopulation genetically?
What are the appropriate diagnostic interventions—radiographs, bone scans, magnetic
resonance imaging? What is the appropriate drug regimen? Until these issues are
resolved, clinicians must be aware of the occurrence of femoral subtrochanteric
and diaphyseal fractures in the setting of prolonged bisphosphonate therapy.
Patients with thigh pain who are currently being treated with bisphosphonates
should undergo imaging studies, their calcium and vitamin-D levels should be
corrected to a normal range, the bisphosphonate should be stopped, and use of
an anabolic agent should be considered.
Note: The authors wish to give special thanks to the Cohn Foundation for their continued support of research into metabolic bone disease.
*The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.
References
1. Goh SK, Yang KY, Koh JS, Wong MK, Chua SY, Chua DT, Howe TS. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br. 2007;89:349-53.
2. Kwek EB, Goh SK, Koh JS, Png MA, Howe TS. An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? Injury. 2008;39(2):224-31.
3. Neviaser AS, Lane JM, Lenart BA, Edobor-Osula F, Lorich DG. Low-energy femoral shaft fractures associated with alendronate use. J Orthop Trauma. 2008;22:346-50.
4. Sayed-Noor AS, Sjödén GO. Case reports: two femoral insufficiency fractures after long-term alendronate therapy. Clin Orthop Relat Res. 2009;467:1921-6.
5. Lenart BA, Neviaser AS, Lyman S, Chang CC, Edobor-Osula F, Steele B, van der Meulen MC, Lorich DG, Lane JM. Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int. 2009;20:1353-62.
6. 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
7. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures: Fracture Intervention Trial Research Group. Lancet. 1996;348:1535-41.
8. Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280:2077-82.
9. McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, Adami S, Fogelman I, Diamond T, Eastell R, Meunier PJ, Reginster JY; Hip Intervention Program Study Group. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344:333-40.
10. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR; HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-22.
11. Bilezikian JP. Efficacy of bisphosphonates in reducing fracture risk in postmenopausal osteoporosis. Am J Med. 2009;122(2 Suppl):S14-21.
12. Lyles KW, Colón-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. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-809.
13. Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA. 2009;301:513-21.
14. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90:1294-301.
15. 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.
16. Nakajima A, Shimoji N, Shiomi K, Shimizu S, Moriya H, Einhorn TA, Yamazaki M. Mechanisms for the enhancement of fracture healing in rats treated with intermittent low-dose human parathyroid hormone (1-34). J Bone Miner Res. 2002;17:2038-47.
17. Ettinger B, San Martin J, Crans G, Pavo I. Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. J Bone Miner Res. 2004;19:745-51.
18. Alkhiary YM, Gerstenfeld LC, Krall E, Westmore M, Sato M, Mitlak BH, Einhorn TA. Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34). J Bone Joint Surg Am. 2005;87:731-41.
19. Barnes GL, Kakar S, Vora S, Morgan EF, Gerstenfeld LC, Einhorn TA. Stimulation of fracture-healing with systemic intermittent parathyroid hormone treatment. J Bone Joint Surg Am. 2008;90 Suppl 1:120-7.
20. Aspenberg P, Genant HK, Johansson T, Nino AJ, See K, Krohn K, García-Hernández PA, Recknor CP, Einhorn TA, Dalsky GP, Mitlak BH, Fierlinger A, Lakshmanan MC. Teriparatide for Acceleration of Fracture Repair in Humans: A prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J Bone Miner Res. 2009 Jul 13. [E-pub ahead of print]
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