Abstract
Purpose
Osteogenesis imperfecta (OI) has been treated with bisphosphonates for many years, with some clear clinical benefits. In adults, there are reports of a new pattern of atraumatic subtrochanteric fractures with bisphosphonate treatment. This study assesses if bisphosphonate treatment leads to an altered pattern of femoral fractures.
Methods
Retrospective review of imaging for a cohort of 176 bisphosphonate-treated OI patients to identify the locations of femoral fractures over a two-year period, as compared to a historical control group managed pre-bisphosphonates.
Results
Sixteen femoral fractures were identified in this time period in the bisphosphonate-treated group. All but two were within the subtrochanteric region. In comparison, the historical group—composed of 26 femoral fractures—had a more widespread fracture pattern, with the most frequent location being the mid-diaphysis. Many of the subtrochanteric fractures in the treatment group occurred with minimal trauma.
Conclusions
It appears that concerns over the treatment of the adult osteoporotic population with bisphosphonates are amplified and mirrored in OI. It is possible that the high bending moments in the proximal femur together with altered mechanical properties of cortical bone secondary to the use of this group of drugs increase the risk of this type of injury, which warrants further modification of surgical management of the femur.
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References
Shapiro F (1985) Consequences of an osteogenesis imperfecta diagnosis for survival and ambulation. J Pediatr Orthop 5:456–462
Roughley PJ, Rauch F, Glorieux FH (2003) Osteogenesis imperfecta—clinical and molecular diversity. Eur Cell Mater 5:41–47; discussion 47
King JD, Bobechko WP (1971) Osteogenesis imperfecta—an orthopaedic description and surgical review. J Bone Joint Surg Br 53-B:72–89
Dent JA, Paterson CR (1991) Fractures in early childhood: osteogenesis imperfecta or child abuse? J Pediatr Orthop 11(2):184–186
Fritz JM, Guan Y, Wang M, Smith PA, Harris GF (2009) A fracture risk assessment model of the femur in children with osteogenesis imperfecta (OI) during gait. Med Eng Phys 31(9):1043–1048
Garrison JG, Slaboch CL, Niebur GL (2009) Density and architecture have greater effects on the toughness of trabecular bone than damage. Bone 44(5):924–929
Glorieux FH (2007) Experience with bisphosphonates in osteogenesis imperfecta. Paediatrics 119(Suppl 2):S163–S165
Drake MT, Clarke BL, Khosla S (2008) Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 83(9):1032–1045
Castillo H, Samson-Fang L (2008) Effects of bisphosphonates in children with osteogenesis imperfecta: an AACPDM systematic review. Dev Med Child Neurol 51:17–29
Roelofs AJ, Coxon FP, Ebetino FH, Lundy MW, Henneman ZJ, Nancollas GH, Sun S, Blazewska KM, Bala JL, Kashemirov BA, Khalid AB, McKenna CE, Rogers MJ (2010) Fluorescent risendronate analogues reveal bisphosphonate uptake by bone marrow monocytes and localization around osteocytes in vivo. J Bone Miner Res 25(3):606–616
Reinholz GG, Getz B, Pederson L, Sanders ES, Subramaniam M, Ingle JN, Spelsberg TC (2002) Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts. Cancer Res 60:6001–6007
Fromigue O, Body JJ (2002) Bisphosphonates influence the proliferation and the maturation of normal human osteoblasts. J Endocrinol Invest 25:539–546
Im GI, Qureshi SA, Kenney J, Rubash HE, Shanbhag AS (2004) Osteoblast proliferation and maturation by bisphosphonates. Biomaterials 25:4105–4115
von Knoch F, Jaquiery C, Kowalsky M, Schaeren S, Alabre C, Martin I, Rubash HE, Shanbhag AS (2005) Effects of bisphosphonates on proliferation and osteoblast differentiation of human bone marrow stromal cells. Biomaterials 26:6941–6949
Giuliani N, Pedrazzoni M, Negri G, Passeri G, Impicciatore M, Girasole G (1998) Bisphosphonates stimulate formation of osteoblast precursors and mineralized nodules in murine and human bone marrow cultures in vitro and promote early osteoblastogenesis in young and aged mice in vivo. Bone 22:455–461
Poyrazoglu S, Gunoz H, Darendeliler F, Bas F, Tutunculer F, Eryilmaz SK, Bundak R, Saka N (2008) Successful results of pamidronate treatment in children with osteogenesis imperfecta with emphasis on the interpretation of bone mineral density for local standards. J Pediatr Orthop 28(4):483–487
Plotkin H, Rauch F, Bishop NJ, Montpetit K, Ruck-Gibis J, Travers R, Glorieux FH (2000) Pamidronate treatment of severe osteogenesis imperfecta in children under 3 years of age. J Clin Endocrinol Metab 85(5):1846–1850
Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R (1998) Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 339(14):947–952
Bajpai A, Kabra M, Gupta N, Sharda S, Ghosh M (2007) Intravenous pamidronate therapy in osteogenesis imperfecta: response to treatment and factors influencing outcome. J Pediatr Orthop 27(2):225–227
Letocha AD, Cintas HL, Troendle JF, Reynolds JC, Cann CE, Chernoff EJ, Hill SC, Gerber LH, Marini JC (2005) Controlled trial of pamidronate in children with types III and IV osteogenesis imperfecta confirms vertebral gains but not short-term functional improvement. J Bone Miner Res 20(6):977–986
Sakkers R, Kok D, Engelbert R et al (2004) Skeletal effects and functional outcome with olpadronate in children with osteogenesis imperfecta: a 2 year randomised placebo-controlled study. Lancet 363:1427–1431
Gatti D, Antoniazzi F, Prizzi R et al (2005) Intravenous neridronate in children with osteogenesis imperfecta: a randomized controlled study. J Bone Miner Res 20:758–763
Seikaly MG, Kopanati S, Salhab N et al (2005) Impact of alendronate on quality of life in children with osteogenesis imperfecta. J Pediatr Orthop 25:786–791
Antoniazzi F, Zamboni G, Lauriola S, Donaldi L, Adami S, Tato L (2006) Early bisphosphonate treatment in infants with severe osteogenesis imperfecta. J Pediatr 149:174–179
Letocha AD, Cintas HL, Troendle JF et al (2005) Controlled trial of pamidronate in children with types III and IV osteogenesis imperfecta confirms vertebral gains but not short-term functional improvement. J Bone Miner Res 20:977–986
Kok DH, Sakkers RJ, Janse AJ, Pruijs HE, Verbout AJ, Castelein RM, Engelbert RH (2007) Quality of life in children with osteogenesis imperfecta treated with oral bisphosphonates (olpadronate): a 2-year randomized placebo-controlled trial. Eur J Pediatr 166(11):1155–1161
Huang RP, Ambrose CG, Sullivan E, Haynes RJ (2006) Functional significance of bone density measurements in children with osteogenesis imperfecta. J Bone Joint Surg Am 88(6):1324–1330
Phillipi CA, Remmington T, Steiner RD (2008) Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev 4:CD005088
Marini JC (2003) Do bisphosphonates make children’s bones better or brittle? N Engl J Med 349(5):423–426
Li C, Mori S, Li J, Kaji Y, Akiyama T, Kawanishi J, Norimatsu H (2001) Long-term effect of incadronate disodium (YM-175) on fracture healing of femoral shaft in growing rats. J Bone Miner Res 16(3):429–436
Munns CF, Rauch F, Zeitlin L, Fassier F, Glorieux FH (2004) Delayed osteotomy but not fracture healing in paediatric osteogenesis imperfecta patients receiving pamidronate. J Bone Miner Res 19(11):1779–1786
Smith EJ, Little DG, Briody JN, McEvoy A, Smith NC, Eisman JA, Gardiner EM (2005) Transient disturbance in physeal morphology is associated with long-term effects of nitrogen-containing bisphosphonates in growing rabbits. J Bone Miner Res 20(10):1731–1741
Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S (2003) Bisphosphonate-induced osteopetrosis. N Engl J Med 349(5):457–463
Yoon RS, Hwang JS, Beebe KS (2011) Long-term bisphosphonate usage and subtrochanteric insufficiency fractures: a cause for concern? J Bone Joint Surg Br 93(10):1289–1295
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(3):349–353
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(2):224–231
De Das S, Setiobudi T, Shen L, De Das S (2010) A rational approach to management of alendronate-related subtrochanteric fractures. J Bone Joint Surg Br 92(5):679–686
Edwards MH, McCrae FC, Young-Min SA (2010) Alendronate-related femoral diaphysis fracture—what should be done to predict and prevent subsequent fracture of the contra lateral side? Osteoporos Int 21(4):701–703
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(5):346–350
Lenart BA, Lorich DG, Lane JM (2008) Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 358(12):1304–1306
Schilcher J, Aspenberg P (2009) Incidence of stress fractures of the femoral shaft in women treated with bisphosphonate. Acta Orthop 80(4):413–415
Park-Wyllie LY, Mamdani MM, Juurlink DN, Hawker GA, Gunraj N, Austin PC, Whelan DB, Weiler PJ, Laupacis A (2011) Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA 305(8):783–789
Abrahamsen B, Eiken P, Eastell R (2009) Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res 24(6):1095–1102
Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, Bucci-Rechtweg C, Cauley J, Leung PC, Boonen S, Santora A, de Papp A, Bauer DC (2010) Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med 362(19):1761–1771
Watts NB, Diab DL (2010) Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab 95(4):1555–1565
Bishop N, Harrison R, Ahmed F, Shaw N, Eastell R, Campbell M, Knowles E, Hill C, Hall C, Chapman S, Sprigg A, Rigby A (2010) A randomized, controlled dose-ranging study of risendronate in children with moderate and severe osteogenesis imperfecta. J Bone Miner Res 25(1):32–40
Evans KD, Lau ST, Oberbauer AM, Martin RB (2003) Alendronate affects long bone length and growth plate morphology in the oim mouse model for osteogenesis imperfecta. Bone 32(3):268–274
Zeitlin L, Rauch F, Plotkin H, Glorieux FH (2003) Height and weight development during four years of therapy with cyclical intravenous pamidronate in children and adolescents with osteogenesis imperfecta types I, III, and IV. Paediatrics 111(5 Pt 1):1030–1036
Rauch F, Travers R, Plotkin H, Glorieux FH (2002) The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta. J Clin Invest 110(9):1293–1299
Rao SH, Evans KD, Oberbauer AM, Martin RB (2008) Bisphosphonate treatment in the oim mouse model alters bone modelling during growth. J Biomech 41(16):3371–3376
Kashii M, Hashimoto J, Nakano T, Umakoshi Y, Yoshikawa H (2008) Alendronate treatment promotes bone formation with a less anisotropic microstructure during intramembranous ossification in rats. J Bone Miner Metab 26(1):24–33
Lin JH (1996) Bisphosphonates: a review of their pharmacokinetic properties. Bone 18(2):75–85
Weber M, Roschger P, Fratzl-Zelman N, Schöberl T, Rauch F, Glorieux FH, Fratzl P, Klaushofer K (2006) Pamidronate does not adversely affect bone intrinsic material properties in children with osteogenesis imperfecta. Bone 39(3):616–622
Uveges TE, Kozloff KM, Ty JM, Ledgard F, Raggio CL, Gronowicz G, Goldstein SA, Marini JC (2009) Alendronate treatment of the brtl osteogenesis imperfecta mouse improves femoral geometry and load response before fracture but decreases predicted material properties and has detrimental effects on osteoblasts and bone formation. J Bone Miner Res 24(5):849–859
Shahnazari M, Yao W, Dai W, Bob Wang B, Ionova-Martin SS, Ritchie RO, Heeren D, Burghardt AJ, Nicolella DP, Kimiecik MG, Lane NE (2010) Higher doses of bisphosphonates further improve bone mass, architecture, and strength but not the tissue material properties in aged rats. Bone 46(5):1267–1274
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Nicolaou, N., Agrawal, Y., Padman, M. et al. Changing pattern of femoral fractures in osteogenesis imperfecta with prolonged use of bisphosphonates. J Child Orthop 6, 21–27 (2012). https://doi.org/10.1007/s11832-011-0380-0
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DOI: https://doi.org/10.1007/s11832-011-0380-0