By Corey O. Montgomery, MD; John W. Bracey, MD; and Larry J. Suva, PhD
Bisphosphonates (BPs) are chemically stable analogues of inorganic pyrophosphate. Studies on the role of inorganic pyrophosphate in the control of soft-tissue and skeletal mineralization resulted in the discovery that these compounds could inhibit calcification. This realization triggered additional studies to determine whether these compounds could inhibit other physiologic processes, such as bone resorption.
Fig.1 An AP radiograph showing a completed and displaced fracture, characteristic of an atypical fracture in a patient treated with BP.
BPs: the good
BPs can be classified into two broad groups, based on their distinct molecular modes of action. BPs such as etidronate and clodronate, which do not contain nitrogen, are metabolically incorporated into nonhydrolysable analogues of adenosine triphosphate (ATP). These analogues, in turn, interfere with ATP-dependent intracellular pathways.
The more recently available and highly potent nitrogen-containing BPs (such as pamidronate, alendronate, risedronate, ibandronate, and zoledronate) are not metabolized in the same way. This group inhibits key enzymes of the mevalonate/cholesterol biosynthetic pathway by targeting farnesyl pyrophosphate synthase.
BPs were approved by the U.S. Food and Drug Administration (FDA) in 1995 and are commonly used to prevent and treat osteoporosis and other bone diseases such as Paget’s disease and metastatic disease. BPs have been proven to significantly reduce the risk of hip or spine fractures in older women and significantly improve the quality of life in patients with metastatic bone cancer.
In general, the reduction in vertebral fractures is greater than for nonvertebral fractures. A remarkable decrease in hip fractures of up to 40 percent has been achieved with the use of alendronate, risedronate, and zoledronate. Given the efficacy of BPs in managing osteoporosis and metastatic bone disease, researchers are exploring their use in the treatment of a myriad of other conditions.
The efficacy of using BPs as carriers to deliver other pharmacologic agents directly to the bone is well known. The use of BPs as direct antitumor agents or as agents that can extend lifespan is still being explored. Some day, synergistic antitumor effects may be achievable in the presence of other chemotherapeutic agents or in the adjuvant setting in breast cancer.
BPs: the bad
Recently, a growing number of case reports and small clinical series have suggested that BP therapy of more than 5 years may suppress normal bone remodeling to such an extent that endogenous bone repair is decreased. Such a scenario would likely result in increased fracture risk. Indeed, fractures resulting from suppressed bone turnover have been referred to as “atypical” and have been seen in sites that are less frequently associated with osteoporotic fractures, such as the subtrochanteric femur (Fig. 1).
These atypical femoral fractures are usually sustained via a low- or no-energy mechanism and often occur in the presence of an existing and characteristic stress fracture. A large cohort analysis examining the risk of atypical femoral fractures with bisphosphonate use found a statistically significant increase in such fractures. The results showed an absolute risk of 5 per 10,000 patient-years, similar to that reported in other studies.
Although the magnitude of the absolute risk may be small and the observations reassuring, patients who sustain these fractures may experience significant consequences—both clinically and personally. Although it has not been proven that BP use causes these unusual fractures, they do occur in disproportionate levels among patients taking the drugs, especially those who have taken them for more than 5 years.
Similar correlations have also been noted with the use of BPs and the occurrence of osteonecrosis of the jaw (ONJ), defined as the presence of exposed bone in the maxillofacial region that did not heal within 8 weeks after identification by a healthcare provider. A multidisciplinary group concluded that the risk of ONJ associated with oral osteoporosis BPs was between 1 in 10,000 and < 1 in 100,000 patient-treatment years, due to the correlation between the development of ONJ and the length of time on oral osteoporosis BPs. The risk of ONJ in cancer patients treated with high-dose intravenous BPs, however, was in the range of 1 to 10 per 100 patients.
As yet, however, insufficient evidence exists to confirm a direct causal link between BP use and the development of ONJ. Indeed, the ongoing investigation of the mechanism(s) responsible for either ONJ or atypical fractures remains hindered by a lack of any reproducible or relevant preclinical models.
BPs: the unidentified
Despite the clear and pronounced clinical benefits of BP therapy, these issues have led the FDA to require significant label modifications. In 2010, all drug manufacturers were required to add a warning to the labels of BP drugs about a small but significantly increased risk of atypical subtrochanteric femur fractures.
The FDA also required that all BPs used to prevent or treat osteoporosis include a label warning that optimal duration of use has not been determined and that patients should continue taking the drugs unless their doctors advise otherwise. Because the atypical fractures are primarily observed in the orthopaedic setting, orthopaedic surgeons can be leaders in determining the details of the natural history and the potential mechanism(s).
In September 2011, an FDA panel suggested that labels for BPs be updated to clarify how long patients should take these drugs to gain the greatest benefit and incur the least risk. As of this writing, exact wording for the revised labels has not been released, but is anticipated.
The FDA panel did not specify a maximum duration for the use of BPs, noting that more data are needed on their long-term effectiveness and safety. All existing clinical trial data regarding BP use are based on a maximum of 5 years of treatment, although BPs have been used in the treatment of osteoporosis since 1995.
Given the growing concerns regarding treatment length and potential BP side effects, perhaps new diagnostic and procedural codes should be developed for atypical femur fractures—as was recently done with the coding of ONJ. This would improve the quality of case reporting and enable better review of medical records. Similarly, an international registry of patients experiencing atypical femur fractures would enable surgeons and physicians to identify and track cases and facilitate future research into these fractures.
We believe that the identification and treatment of an atypical femur fracture falls to the orthopaedic surgeon and involves a thorough evaluation and discussion with the patient about the risks and benefits of ongoing BP use. The surgeon’s role should also include counseling and guidance for any patient taking the drug. Regardless of what decision is made, the ultimate goal of understanding and preventing atypical fractures will likely come from the care of patients and from the ongoing investigation into the mechanism(s) responsible for the fractures.
Disclosure information: Dr. Suva—no conflicts; Drs. Montgomery and Bracey—no information available.
Corey O. Montgomery, MD; John W. Bracey, MD; and Larry J. Suva, PhD, are affiliated with the Department of Orthopaedic Surgery, Center for Orthopaedic Research at the University of Arkansas for Medical Sciences Winthrop P. Rockefeller Cancer Institute.
Bisphosphonate Update References
- Fleisch H, Russell RG, Straumann, F. Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature. 1966 Nov 26;212(5065):901-903.
- Francis MD, Russell RG, Fleisch, H. Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo. Science. 1969 Sep 19;165(899):1264-1266.
- Fleisch H, Russell RG, Simpson B, Mühlbauer RC. Prevention by a diphosphonate of immobilization “osteoporosis” in rats. Nature. 1969 Jul 12;223(5202):211-2.
- Russell RG, Fleisch H. Inorganic pyrophosphate and pyrophosphatases in calcification and calcium homeostasis. Clin Orthop Relat Res. 1970 Mar-Apr;69:101-17.
- Russell RG. Bisphosphonates: The first 40 years. Bone. 2011 Jul;49(1):2-19.
- Ebetino FH, Hogan AM, Sun S, Tsoumpra MK, Duan X, Triffitt JT, et al. The relationship between the chemistry and biological activity of the bisphosphonates. Bone. 2011 Jul;49(1):20-33.
- Rogers MJ, Watts DJ, Russell RG, Ji X, Xiong X, Blackburn GM, et al. Inhibitory effects of bisphosphonates on growth of amoebae of the cellular slime mold Dictyostelium discoideum. J Bone Miner Res. 1994 Jul;9(7):1029-1039.
- Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G, Rogers MJ. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res. 1998 Apr;13(4):581-589.
- Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP, et al; Alendronate Phase III Osteoporosis Treatment Study Group. Ten years experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004 Mar 18;350(12):1189-1199.
- Tonino RP, Meunier PJ, Emkey R, Rodriguez-Portales JA, Menkes CJ, Wasnich RD, et al. Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. Phase III Osteoporosis Treatment Study Group J Clin Endocrinol Metab. 2000 Sep;85(9):3109-3115.
- Adami S Baroni MC, Broggini M, Carratelli L, Caruso I, Gnessi L, Laurenzi M, Lombardi A, Norbiato G, Ortolani S, et al. Treatment of postmenopausal osteoporosis with continuous daily oral alendronate in comparison with either placebo or intranasal salmon calcitonin. Osteoporos Int. 1993;3 Suppl 3:S21-27.
- Brown JE, Cook RJ, Lipton A, Costa L, Coleman RE. Prognostic factors for skeletal complications from metastatic bone disease in breast cancer. Breast Cancer Res Treat. 2010 Oct;123(3):767-779.
- Costa L, Major PP. Effect of bisphosphonates on pain and quality of life in patients with bone metastases. Nat Clin Pract Oncol. 2009 Mar;6(3):163-174..
- Daubine F, LeGall C, Gasser J, Green J, Clezardin P. Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst. 2007 Feb 21;99(4):322-330.
- Fournier PG Daubiné F, Lundy MW, Rogers MJ, Ebetino FH, Clézardin P. Lowering bone mineral affinity of bisphosphonates as a therapeutic strategy to optimize skeletal tumor growth inhibition in vivo. Cancer Res. 2008 Nov 1;68(21):8945-8953.
- Varela I, Pereira S, Ugalde AP, Navarro CL, Suárez MF, Cau P, et al. Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat Med. 2008 Jul;14(7):767-772.
- Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S, Menzel C, Jakesz R, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009 Feb 12;360(7):679-691
- Banffy MB, Vrahas MS, Ready JE, Abraham JA. Nonoperative versus prophylactic treatment of bisphosphonate-associated femoral stress fractures. Clin Orthop Relat Res. 2011 Jul;469(7):2028-2034.
- Schilcher J, Michaelsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011 May 5;364(18):1728-1737.
- Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med. 2008 Mar 20;358(12):1304-1306.
- Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007 Oct;22(10):1479-1491.
- Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, Cheung AM. 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 Nov;25(11):2267-2294.
- Sellmeyer DE. Atypical fractures as a potential complication of long-term bisphosphonate therapy. JAMA. 2010 Oct 6;304(13):1480-1484.
- Lenarz CJ, Moed BR. Atypical anterior wall fracture of the acetabulum: case series of anterior acetabular rim fracture without involvement of the pelvic brim. J Orthop Trauma. 2007 Sep;21(8):515-522.
- Horning JA, Czajka J, Uhl RL. Atypical diaphyseal femur fractures in patients with prolonged administration of bisphosphonate medication for osteoporosis. Orthopedics. 2010 Dec;33(12):902.
- Leung F, Lau TW, To M, Luk KD, Kung AW. Atypical femoral diaphyseal and subtrochanteric fractures and their association with bisphosphonates. BMJ Case Rep. 2009;2009.
- Lee JK. Bilateral atypical femoral diaphyseal fractures in a patient treated with alendronate sodium. Int J Rheum Dis. 2009 Jul;12(2):149-154.
- Puah KL, Tan MH. Bisphosphonate-associated atypical fracture of the femur: Spontaneous healing with drug holiday and re-appearance after resumed drug therapy with bilateral simultaneous displaced fractures—a case report. Acta Orthop. 2011 Jun;82(3):380-382.
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