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Osteoporosis International

Published in:

01-03-2011 | Original Article

Risk of femoral shaft and subtrochanteric fractures among users of bisphosphonates and raloxifene

Authors: P. Vestergaard, F. Schwartz, L. Rejnmark, L. Mosekilde

Published in: Osteoporosis International | Issue 3/2011

Abstract

Summary

Prior studies have suggested an association between bisphosphonate use and subtrochanteric fractures. This cohort study showed an increased risk of subtrochanteric and femoral shaft fractures both before and after the start of drugs against osteoporosis including bisphosphonates. This may suggest an effect of the underlying disease rather than the drugs used.

Introduction

The objective of this study is to determine the association between drugs against osteoporosis and the risk of femoral shaft and subtrochanteric fractures. No separation was made between atypical and typical fractures.

Methods

Nationwide cohort study from Denmark with all users of bisphosphonates and other drugs against osteoporosis between 1996 and 2006 (n = 103,562) as exposed group and three age- and gender-matched controls from the general population (n = 310,683). Adjustments were made for prior fracture, use of systemic hormone therapy, and use of systemic corticosteroids.

Results

After initiation of therapy, an increased risk of subtrochanteric fractures was seen for alendronate (hazard ratio (HR) = 2.41, 95% confidence interval (CI) 1.78–3.27), etidronate (HR = 1.96, 95% CI 1.62–2.36), and clodronate (HR = 20.0, 95% CI 1.94–205), but not for raloxifene (HR = 1.06, 95% CI 0.34–3.32). However, an increased risk of subtrochanteric fractures was also present before the start of alendronate (OR = 2.36, 95% CI 2.05–2.72), etidronate (OR = 3.05, 95% CI 2.59–3.58), clodronate (OR = 10.8, 95% CI 1.14–103), raloxifene (OR = 1.90, 95% CI 1.07–3.40), and strontium ranelate (OR = 2.97, 95% CI 1.07–8.27). Similar trends were seen for femoral shaft fractures and overall fracture risk. After the start of etidronate, no dose–response relationship was present (p for trend, 0.54). For alendronate, a decreasing risk was present with increasing average daily dose (p for trend, <0.01).

Conclusions

Although an increased risk of femoral shaft and subtrochanteric fractures are seen with the use of several types of bisphosphonates, the increased risk before the start of the drugs may point at an effect of the underlying disease being treated. The increased risk may, thus, perhaps be due to confounding by indication.

Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Robinson V, Coyle D, Tugwell P (2008) Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev CD001155

Cranney A, Guyatt G, Krolicki N, Welch V, Griffith L, Adachi J, Shea B, Tugwell P, Wells G (2001) A meta-analysis of etidronate for the treatment of postmenopausal osteoporosis. Osteoporos Int 12:140–151CrossRefPubMed

Cranney A, Tugwell P, Adachi J, Weaver B, Zytaruk N, Papaioannou A, Robinson V, Shea B, Wells G, Guyatt G (2002) Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis. Endocr Rev 23:517–523CrossRefPubMed

Lenart BA, Neviaser AS, Lyman S, Chang CC, Edobor-Osula F, Steele B, van der Meulen MCH, Lorich DG, Lane JM (2009) Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int 20:1353–1362CrossRefPubMed

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

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

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 24:1095–1102CrossRefPubMed

Mashiba T, Turner CH, Hirano T, Forwood MR, Jacob DS, Johnston CC, Burr DB (2001) Effects of high-dose etidronate treatment on microdamage accumulation and biomechanical properties in beagle bone before occurrence of spontaneous fractures. Bone 29:271–278CrossRefPubMed

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 28:524–531CrossRefPubMed

10.

Vestergaard P, Rejnmark L, Mosekilde L (2007) Increased mortality in patients with a hip fracture-effect of pre-morbid conditions and post-fracture complications. Osteoporos Int 18:1583–1593CrossRefPubMed

11.

Seeman E, Crans G, Diez-Perez A, Pinette K, Delmas P (2006) Anti-vertebral fracture efficacy of raloxifene: a meta-analysis. Osteoporos Int 17:313–316CrossRefPubMed

12.

O’Donnell S, Cranney A, Wells G, Adachi J, Reginster J (2006) Strontium ranelate for preventing and treating postmenopausal osteoporosis. Cochrane Database Syst Rev CD005326

13.

Alexeeva L, Burkhardt P, Christiansen C, Cooper C, Delmas P, Johnell O, Johnston C, Kanis J, Lips P, Melton L, Meunier P, Seeman E, Stepan J, Tosteson A (1994) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: report of a WHO Study Group. WHO Technical Report Series 843, Geneva

14.

Andersen T, Madsen M, Jørgensen J, Mellemkjær L, Olsen J (1999) The Danish national hospital register. Dan Med Bull 46:263–268PubMed

15.

Mosbech J, Jørgensen J, Madsen M, Rostgaard K, Thornberg K, Poulsen T (1995) The Danish national patient register: evaluation of data quality. Ugeskr Laeger 157:3741–3745PubMed

16.

Vestergaard P, Mosekilde L (2002) Fracture risk in patients with celiac disease, Crohn’s disease, and ulcerative colitis: a nation-wide follow-up study in 16,416 patients in Denmark. Am J Epidemiol 156:1–10CrossRefPubMed

17.

Vestergaard P, Rejnmark L, Mosekilde L (2005) Fracture risk associated with systemic and topical corticosteroids. J Intern Med 257:374–384CrossRefPubMed

18.

Vestergaard P, Rejnmark L, Mosekilde L (2006) Fracture reducing potential of hormone replacement therapy on a population level. Maturitas 54:285–293CrossRefPubMed

19.

Vestergaard P, Rejnmark L, Mosekilde L (2006) Socioeconomic aspects of fractures within universal public healthcare: a nationwide case–control study from Denmark. Scand J Public Health 34:371–377CrossRefPubMed

20.

Kanis J, Johnell O, De Laet C, Johansson H, Oden A, Delmas P, Eisman J, Fujiwara S, Garnero P, Kroger H (2004) A meta-analysis of previous fracture and subsequent fracture risk. Bone 35:375–382CrossRefPubMed

21.

Nieves JW, Bilezikian JP, Lane JM, Einhorn TA, Wang Y, Steinbuch M, Cosman F (2010) Fragility fractures of the hip and femur: incidence and patient characteristics. Osteoporos Int 21:399–408CrossRefPubMed

22.

Dell R, Greene D, Ott S, Silverman S, Eisemon E, Funahashi T, Adams A (2010) A retrospective analysis of atypical femur fractures in a large California HMO from the years 2007 to 2009 (Abstract). J Bone Mineral Res (suppl 1): S61

23.

Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster D, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Koval K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O’Keefe R, Papapoulos S, Sen HT, van der Meulen MCH, Weinstein RS, Whyte M (2010) Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 25(11):2267–2294CrossRefPubMed

24.

Vestergaard P, Rejnmark L, Mosekilde L (2006) Proton pump inhibitors, histamine h(2) receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int 79:76–83CrossRefPubMed

Title: Risk of femoral shaft and subtrochanteric fractures among users of bisphosphonates and raloxifene
Authors: P. Vestergaard
F. Schwartz
L. Rejnmark
L. Mosekilde
Publication date: 01-03-2011
Publisher: Springer-Verlag
Published in: Osteoporosis International / Issue 3/2011
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-010-1512-y

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Risk of femoral shaft and subtrochanteric fractures among users of bisphosphonates and raloxifene

Abstract

Summary

Introduction

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusions

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