Is the time for consolidation of fractures associated with bisphosphonates higher?
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Published:
Nov 12, 2019
Keywords:
Bisphosphonates, atypical femoral fractures, osteoporosis.
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Abstract
Introduction: Bisphosphonates evolved as the mainstay for the treatment of osteoporosis, reducing the incidence of fractures. Recently, several publications described the occurrence of low-energy atypical femur fractures associated with the use of bisphosphonates. The objective of this work was to study the average time of consolidation of the atypical femoral fractures caused by the consumption of bisphosphonates compared with a control group.Materials and Methods: We retrospectively evaluated 34 patients with atypical femoral fractures of which 16 patients had undergone treatment with bisphosphonates for at least 5 years, treated between 2006 and 2017, and stabilized with a cephalomedullary nail, and were compared with a control group of similar characteristics.Results: All the patients were female. The average age was 74 years. 22 presented subtrochanteric fractures while 12 were diaphyseal. 14% of the subjects who took bisphosphonates and received surgical treatment, required a revision versus 5.5% of the control group. The average time of consolidation was higher in those treated with bisphosphonates (8.5 months vs. 6 months), this being statistically significant (p <0.001).Conclusions: The benefit of treatment with bisphosphonates in the prevention of fractures is greater than the risk of atypical fractures. However, it is important to evaluate the risk-benefit in each patient at the beginning and the duration of the treatment, taking into account that despite this, the healing time is longer.
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Vanoli, F., Gentile, L., Juarez, A. B., Eluani, M. S., Pioli, I., & Allende, B. L. (2019). Is the time for consolidation of fractures associated with bisphosphonates higher?. Revista De La Asociación Argentina De Ortopedia Y Traumatología, 84(4), 320-327. https://doi.org/10.15417/issn.1852-7434.2019.84.4.917
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Clinical Research
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References
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2. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 1999;282:1344-52. https://doi.org/10.1001/jama.282.14.1344
3. Hosking D, Chilvers CE, Christiansen C, Ravn P, Wasnich R, Ross P, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group. N Engl J Med 1998;338:485-92. https://doi.org/10.1056/NEJM199802193380801
4. Karpf DB, Shapiro DR, Seeman E, Ensrud KE, Johnston CC Jr, Adami S, et al. Prevention of nonvertebral fractures by alendronate: a meta-analysis. Alendronate Osteoporosis Treatment Study Groups. JAMA 1997;277:1159-64. https://doi.org/10.1001/jama.1997.03540380073035
5. Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, et al. 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 1995;333:1437-43. https://doi.org/10.1056/NEJM199511303332201
6. Riggs BL, Melton LJ III. The prevention and treatment of osteoporosis. N Engl J Med 1992;327:620-7. https://doi.org/10.1056/NEJM199208273270908
7. Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Robinson V, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 2008;CD001155. . https://doi.org/10.1002/14651858.CD001155.pub2
8. Cao Y, Mori S, Mashiba T, Westmore MS, Ma L, Sato M, et al. Raloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats. J Bone Miner Res 2002;17:2237-46. https://doi.org/10.1359/jbmr.2002.17.12.2237
9. Isaacs JD, Shidiak L, Harris IA, Szomor ZL. Femoral insufficiency fractures associated with prolonged bisphosphonate therapy. Clin Orthop Relat Res 2010;468:3384-92. https://doi.org/10.1007/s11999-010-1535-x
10. Mashiba T, Hui S, Turner CH, Mori S, Johnston CC, Burr DB. Bone remodeling at the iliac crest can predict the changes in remodeling dynamics, microdamage accumulation, and mechanical properties in the lumbar vertebrae of dogs. Calcif Tissue Int 2005;77:180-5. https://doi.org/10.1007/s00223-005-1295-x
11. Mashiba T, Mori S, Burr DB, Komatsubara S, Cao Y, Manabe T, Norimatsu H. The effects of suppressed bone remodeling by bisphosphonates on microdamage accumulation and degree of mineralization in the cortical bone of dog rib. J Bone Miner Metab 2005;23(Suppl):36-42. https://doi.org/10.1007/BF03026321
12. Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci 1999;96:133-8. https://doi.org/10.1073/pnas.96.1.133
13. 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;13:581-9. https://doi.org/10.1359/jbmr.1998.13.4.581
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;90:1294-1301. https://doi.org/10.1210/jc.2004-0952
15. Ahn JK, Lee J, Cha HS, Koh EM. Non-traumatic fracture of the femoral shaft in a patient taking long-term bisphosphonate therapy. Rheumatol Int 2011;31:973-5. https://doi.org/10.1007/s00296-010-1477-3
16. Aspenberg P. Bisphosphonate-induced fractures: nature strikes back? Acta Orthop 2008;79:459-60. https://doi.org/10.1080/17453670710015427
17. Goh S-K, 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. https://doi.org/10.1302/0301-620X.89B3.18146
18. Chan SS, Rosenberg ZS, Chan K, Capeci C. Subtrochanteric femoral fractures in patients receiving long-term alendronate therapy: imaging features. AJR Am J Roentgenol 2010;194(6):1581-6. https://doi.org/10.2214/AJR.09.3588
19. Weil YA, Rivkin G, Safran O, Liebergall M, Foldes AJ. The outcome of surgically treated femur fractures associated with long-term bisphosphonate use. J Trauma 2011;71(1):186-90. https://doi.org/10.1097/TA.0b013e31821957e3
20. Egol KA, Park JH, Rosenberg ZS, Peck V, Tejwani NC. Healing delayed but generally reliable after bisphosphonate-associated complete femur fractures treated with IM nails. Clin Orthop Relat Res 2014;472(9):2728-34. https://doi.org/10.1007/s11999-013-2963-1
21. Prasarn ML, Ahn J, Helfet DL, Lane JM, Lorich DG. Bisphosphonate-associated femur fractures have high complication rates with operative fixation. Clin Orthop Relat Res 2012;470(8):2295-301. https://doi.org/10.1007/s11999-012-2412-6
22. Kang JS, Won YY, Kim JO, Min BW, Lee KH, Park KK, et al. Atypical femoral fractures after anti-osteoporotic medication: a Korean multicenter study. Int Orthop 2014;38(6):1247-53. https://doi.org/10.1007/s00264-013-2259-9
23. Grady MK, Watson JT, Cannada LK. Treatment of femoral fracture nonunion after long-term bisphosphonate use. Orthopedics 2012;35(6):e991-5. https://doi.org/10.3928/01477447-20120525-51
24. Sasaki S, Miyakoshi N, Hongo M, Kasukawa Y, Shimada Y. Low-energy diaphyseal femoral fractures associated with bisphosphonate use and severe curved femur: a case series. J Bone Miner Metab 2012;30(5):561-7. https://doi.org/10.1007/s00774-012-0358-0
25. 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):1-23. https://doi.org/10.1002/jbmr.1998
26. Whelan DB, Bhandari M, McKee MD, Guyatt GH, Kreder HJ, Stephen D, et al. Interobserver and intraobserver variation in the assessment of the healing of tibial fractures after intramedullary fixation. J Bone Joint Surg Br 2002;84(1):15-8. https://doi.org/10.1302/0301-620x.84b1.11347
27. Morris C, Einhorn T. Bisphosphonates in Orthopaedic Surgery. J Bone Joint Surg Am 2005;87:1609-618. https://doi.org/10.2106/JBJS.D.03032
28. Gehrig L, Lane J, O’Connor M. Osteoporosis: management and treatment strategies for orthopaedic surgeons. J Bone Joint Surg Am 2008;90(6):1362-74. PMID: 18519332
29. Lyles K, Colón-Emeric C, Magaziner J, Adachi J, Pieper C. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357:1799-809. https://doi.org/10.1056/NEJMoa074941
30. Capeci C, Tejwani N. Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term Alendronate therapy. J Bone Joint Surg Am 2009;91:2556-61. https://doi.org/10.2106/JBJS.H.01774
31. Puhaindran M, Farooki A, Steensma M, Hameed M, Healey J, Boland P. Atypical sub-trochanteric femoral fractures in patients with skeletal malignant involvement treated with intravenous bisphosphonates. J Bone Joint Surg Am 2011;93:1235-42. https://doi.org/10.2106/JBJS.J.01199
32. Rio M, Salonia P, Gabas D, Gotter G, Barrera Oro F. Fracturas de fémur asociadas al consumo prolongado de alendronato. Informe de dos casos. Rev Asoc Argent Ortop Traumatol 2011;76:74-76. http://www.scielo.org.ar/pdf/raaot/v76n1/v76n1a12.pdf
33. Fowler J, Criner K, Craig M. Prophylactic intramedullary fixation for bisphosphonate-related subtrochanteric stress fracture. Orthopedics 2012;35(6):e954-7. https://doi.org/10.3928/01477447-20120525-41
34. Yoon R, Beebe K, Benevenia J. Prophylactic bilateral intramedullary femoral nails for bisphosphonate-associated signs of impending subtrochanteric hip fracture. Orthopedics 2010;33(4). https://doi.org/10.3928/01477447-20100225-21
35. Banffy M, Vrahas M, Ready J, Abraham J. Nonoperative versus prophylactic treatment of bisphosphonate-associated femoral stress fractures. Clin Orthop Relat Res 2011;469(7):2028-34. https://doi.org/10.1007/s11999-011-1828-8
36. Thompson RN, Phillips JR, McCauley SH, Elliott JR, Moran CG. Atypical femoral fractures and bisphosphonate treatment: experience in two large United Kingdom teaching hospitals. J Bone Joint Surg Br 2012;94(3):385-90. https://doi.org/10.1302/0301-620X.94B3.27999
37. Unnanuntana A, Saleh A, Mensah KA, Kleimeyer JP, Lane JM. Atypical femoral fractures: what do we know about them? AAOS Exhibit Selection. J Bone Joint Surg Am 2013;95:e8(1-13). https://doi.org/10.2106/JBJS.L.00568
38. Issack PS. Bisphosphonate-associated subtrochanteric femoral fracture with profound proximal cortical thickening and canal narrowing requiring blade-plate fixation. A report of two cases. J Bone Joint Surg Case Connect 2014;24:e87. https://doi.org/10.2106/JBJS.CC.N.00026
39. Shane E, Burr D, Ebling 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. https://doi.org/10.1002/jbmr.253
2. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 1999;282:1344-52. https://doi.org/10.1001/jama.282.14.1344
3. Hosking D, Chilvers CE, Christiansen C, Ravn P, Wasnich R, Ross P, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group. N Engl J Med 1998;338:485-92. https://doi.org/10.1056/NEJM199802193380801
4. Karpf DB, Shapiro DR, Seeman E, Ensrud KE, Johnston CC Jr, Adami S, et al. Prevention of nonvertebral fractures by alendronate: a meta-analysis. Alendronate Osteoporosis Treatment Study Groups. JAMA 1997;277:1159-64. https://doi.org/10.1001/jama.1997.03540380073035
5. Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, et al. 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 1995;333:1437-43. https://doi.org/10.1056/NEJM199511303332201
6. Riggs BL, Melton LJ III. The prevention and treatment of osteoporosis. N Engl J Med 1992;327:620-7. https://doi.org/10.1056/NEJM199208273270908
7. Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Robinson V, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 2008;CD001155. . https://doi.org/10.1002/14651858.CD001155.pub2
8. Cao Y, Mori S, Mashiba T, Westmore MS, Ma L, Sato M, et al. Raloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats. J Bone Miner Res 2002;17:2237-46. https://doi.org/10.1359/jbmr.2002.17.12.2237
9. Isaacs JD, Shidiak L, Harris IA, Szomor ZL. Femoral insufficiency fractures associated with prolonged bisphosphonate therapy. Clin Orthop Relat Res 2010;468:3384-92. https://doi.org/10.1007/s11999-010-1535-x
10. Mashiba T, Hui S, Turner CH, Mori S, Johnston CC, Burr DB. Bone remodeling at the iliac crest can predict the changes in remodeling dynamics, microdamage accumulation, and mechanical properties in the lumbar vertebrae of dogs. Calcif Tissue Int 2005;77:180-5. https://doi.org/10.1007/s00223-005-1295-x
11. Mashiba T, Mori S, Burr DB, Komatsubara S, Cao Y, Manabe T, Norimatsu H. The effects of suppressed bone remodeling by bisphosphonates on microdamage accumulation and degree of mineralization in the cortical bone of dog rib. J Bone Miner Metab 2005;23(Suppl):36-42. https://doi.org/10.1007/BF03026321
12. Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci 1999;96:133-8. https://doi.org/10.1073/pnas.96.1.133
13. 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;13:581-9. https://doi.org/10.1359/jbmr.1998.13.4.581
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;90:1294-1301. https://doi.org/10.1210/jc.2004-0952
15. Ahn JK, Lee J, Cha HS, Koh EM. Non-traumatic fracture of the femoral shaft in a patient taking long-term bisphosphonate therapy. Rheumatol Int 2011;31:973-5. https://doi.org/10.1007/s00296-010-1477-3
16. Aspenberg P. Bisphosphonate-induced fractures: nature strikes back? Acta Orthop 2008;79:459-60. https://doi.org/10.1080/17453670710015427
17. Goh S-K, 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. https://doi.org/10.1302/0301-620X.89B3.18146
18. Chan SS, Rosenberg ZS, Chan K, Capeci C. Subtrochanteric femoral fractures in patients receiving long-term alendronate therapy: imaging features. AJR Am J Roentgenol 2010;194(6):1581-6. https://doi.org/10.2214/AJR.09.3588
19. Weil YA, Rivkin G, Safran O, Liebergall M, Foldes AJ. The outcome of surgically treated femur fractures associated with long-term bisphosphonate use. J Trauma 2011;71(1):186-90. https://doi.org/10.1097/TA.0b013e31821957e3
20. Egol KA, Park JH, Rosenberg ZS, Peck V, Tejwani NC. Healing delayed but generally reliable after bisphosphonate-associated complete femur fractures treated with IM nails. Clin Orthop Relat Res 2014;472(9):2728-34. https://doi.org/10.1007/s11999-013-2963-1
21. Prasarn ML, Ahn J, Helfet DL, Lane JM, Lorich DG. Bisphosphonate-associated femur fractures have high complication rates with operative fixation. Clin Orthop Relat Res 2012;470(8):2295-301. https://doi.org/10.1007/s11999-012-2412-6
22. Kang JS, Won YY, Kim JO, Min BW, Lee KH, Park KK, et al. Atypical femoral fractures after anti-osteoporotic medication: a Korean multicenter study. Int Orthop 2014;38(6):1247-53. https://doi.org/10.1007/s00264-013-2259-9
23. Grady MK, Watson JT, Cannada LK. Treatment of femoral fracture nonunion after long-term bisphosphonate use. Orthopedics 2012;35(6):e991-5. https://doi.org/10.3928/01477447-20120525-51
24. Sasaki S, Miyakoshi N, Hongo M, Kasukawa Y, Shimada Y. Low-energy diaphyseal femoral fractures associated with bisphosphonate use and severe curved femur: a case series. J Bone Miner Metab 2012;30(5):561-7. https://doi.org/10.1007/s00774-012-0358-0
25. 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):1-23. https://doi.org/10.1002/jbmr.1998
26. Whelan DB, Bhandari M, McKee MD, Guyatt GH, Kreder HJ, Stephen D, et al. Interobserver and intraobserver variation in the assessment of the healing of tibial fractures after intramedullary fixation. J Bone Joint Surg Br 2002;84(1):15-8. https://doi.org/10.1302/0301-620x.84b1.11347
27. Morris C, Einhorn T. Bisphosphonates in Orthopaedic Surgery. J Bone Joint Surg Am 2005;87:1609-618. https://doi.org/10.2106/JBJS.D.03032
28. Gehrig L, Lane J, O’Connor M. Osteoporosis: management and treatment strategies for orthopaedic surgeons. J Bone Joint Surg Am 2008;90(6):1362-74. PMID: 18519332
29. Lyles K, Colón-Emeric C, Magaziner J, Adachi J, Pieper C. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357:1799-809. https://doi.org/10.1056/NEJMoa074941
30. Capeci C, Tejwani N. Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term Alendronate therapy. J Bone Joint Surg Am 2009;91:2556-61. https://doi.org/10.2106/JBJS.H.01774
31. Puhaindran M, Farooki A, Steensma M, Hameed M, Healey J, Boland P. Atypical sub-trochanteric femoral fractures in patients with skeletal malignant involvement treated with intravenous bisphosphonates. J Bone Joint Surg Am 2011;93:1235-42. https://doi.org/10.2106/JBJS.J.01199
32. Rio M, Salonia P, Gabas D, Gotter G, Barrera Oro F. Fracturas de fémur asociadas al consumo prolongado de alendronato. Informe de dos casos. Rev Asoc Argent Ortop Traumatol 2011;76:74-76. http://www.scielo.org.ar/pdf/raaot/v76n1/v76n1a12.pdf
33. Fowler J, Criner K, Craig M. Prophylactic intramedullary fixation for bisphosphonate-related subtrochanteric stress fracture. Orthopedics 2012;35(6):e954-7. https://doi.org/10.3928/01477447-20120525-41
34. Yoon R, Beebe K, Benevenia J. Prophylactic bilateral intramedullary femoral nails for bisphosphonate-associated signs of impending subtrochanteric hip fracture. Orthopedics 2010;33(4). https://doi.org/10.3928/01477447-20100225-21
35. Banffy M, Vrahas M, Ready J, Abraham J. Nonoperative versus prophylactic treatment of bisphosphonate-associated femoral stress fractures. Clin Orthop Relat Res 2011;469(7):2028-34. https://doi.org/10.1007/s11999-011-1828-8
36. Thompson RN, Phillips JR, McCauley SH, Elliott JR, Moran CG. Atypical femoral fractures and bisphosphonate treatment: experience in two large United Kingdom teaching hospitals. J Bone Joint Surg Br 2012;94(3):385-90. https://doi.org/10.1302/0301-620X.94B3.27999
37. Unnanuntana A, Saleh A, Mensah KA, Kleimeyer JP, Lane JM. Atypical femoral fractures: what do we know about them? AAOS Exhibit Selection. J Bone Joint Surg Am 2013;95:e8(1-13). https://doi.org/10.2106/JBJS.L.00568
38. Issack PS. Bisphosphonate-associated subtrochanteric femoral fracture with profound proximal cortical thickening and canal narrowing requiring blade-plate fixation. A report of two cases. J Bone Joint Surg Case Connect 2014;24:e87. https://doi.org/10.2106/JBJS.CC.N.00026
39. Shane E, Burr D, Ebling 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. https://doi.org/10.1002/jbmr.253