Skip to main content

Advertisement

Log in

Association between loop diuretic use and fracture risk

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

Loop diuretic use has been shown to be associated with an increased fracture risk, but the findings have been inconsistent. The present meta-analysis suggests that loop diuretics show a significant positive association with the overall risk of total fractures and, specifically, hip fractures.

Introduction

Despite being widely used, there is limited, prospective randomized trial evidence regarding the skeletal effects of loop diuretics. Previous observational studies have reported conflicting findings regarding the association between loop diuretic use and the risk of fractures.

Methods

This meta-analysis of observational studies assessed the association between loop diuretic use and the risk of fractures. The PubMed, EMBASE, and OVID databases were searched for prospective cohort and case–control studies. Relative risks (RR) with 95 % confidence intervals (CI) were derived using random-effects models throughout the analysis.

Results

Thirteen studies (4 cohort studies and 9 case–control studies) were included, involving 842,644 participants and 108,247 fracture cases. Compared with non-users, people who had taken loop diuretics had an approximately 15 % higher risk of total fractures (95 % CI, 1.04–1.26; p < 0.01), with high heterogeneity between studies (I 2 = 80.5 %; p < 0.01). The RR was 1.14 (95 % CI, 1.08–1.19) for hip fractures and 0.99 (95 % CI, 0.93–1.05) for lower arm or wrist fractures. The RR was 1.05 (95 % CI, 1.00–1.11) in prospective cohort studies and 1.22 (95 % CI, 1.00–1.44) in case–control studies. There was no evidence of publication bias.

Conclusion

The results suggest that loop diuretics show a significant positive association with the overall risk of total fractures and hip fractures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

RR:

Relative risk

CI:

Confidence interval

HF:

Heart failure

References

  1. Michaelsson K, Nordstrom P, Nordstrom A, Garmo H, Byberg L, Pedersen NL, Melhus H (2014) Impact of hip fracture on mortality: a cohort study in hip fracture discordant identical twins. J Bone Miner Res 29:424–431

    Article  PubMed  Google Scholar 

  2. Koh GC, Tai BC, Ang LW, Heng D, Yuan JM, Koh WP (2013) All-cause and cause-specific mortality after hip fracture among Chinese women and men: the Singapore Chinese Health Study. Osteoporos Int 24:1981–1989

    Article  PubMed  Google Scholar 

  3. Gronskag AB, Romundstad P, Forsmo S, Langhammer A, Schei B (2012) Excess mortality after hip fracture among elderly women in Norway. The HUNT study. Osteoporos Int 23:1807–1811

    Article  CAS  PubMed  Google Scholar 

  4. Sheng J, Qu X, Zhang X et al (2014) Coffee, tea, and the risk of hip fracture: a meta-analysis. Osteoporos Int 25:141–150

    Article  CAS  PubMed  Google Scholar 

  5. Qu X, Huang X, Jin F, Wang H, Hao Y, Tang T, Dai K (2013) Bone mineral density and all-cause, cardiovascular and stroke mortality: a meta-analysis of prospective cohort studies. Int J Cardiol 166:385–393

    Article  PubMed  Google Scholar 

  6. Qu X, Zhang X, Qin A, Liu G, Zhai Z, Hao Y, Li H, Zhu Z, Dai K (2013) Bone mineral density and risk of breast cancer in postmenopausal women. Breast Cancer Res Treat 138:261–271

    Article  PubMed  Google Scholar 

  7. Qu X, Zhang X, Zhai Z, Li H, Liu X, Li H, Liu G, Zhu Z, Hao Y, Dai K (2014) Association between physical activity and risk of fracture. J Bone Miner Res 29:202–211

    Article  PubMed  Google Scholar 

  8. Drake MT, Murad MH, Mauck KF et al (2012) Clinical review. Risk factors for low bone mass-related fractures in men: a systematic review and meta-analysis. J Clin Endocrinol Metab 97:1861–1870

    Article  CAS  PubMed  Google Scholar 

  9. Kanis JA, Johnell O, Oden A et al (2005) Smoking and fracture risk: a meta-analysis. Osteoporos Int 16:155–162

    Article  CAS  PubMed  Google Scholar 

  10. De Laet C, Kanis JA, Oden A et al (2005) Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporos Int 16:1330–1338

    Article  PubMed  Google Scholar 

  11. Shen C, Chen F, Zhang Y, Guo Y, Ding M (2014) Association between use of antiepileptic drugs and fracture risk: a systematic review and meta-analysis. Bone 64:246–253

    Article  CAS  PubMed  Google Scholar 

  12. Lim LS, Fink HA, Kuskowski MA, Taylor BC, Schousboe JT, Ensrud KE (2008) Loop diuretic use and increased rates of hip bone loss in older men: the Osteoporotic Fractures in Men Study. Arch Intern Med 168:735–740

    Article  PubMed  Google Scholar 

  13. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D (2008) Resistant hypertension: diagnosis, evaluation, and treatment a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 51:1403–1419

    Article  CAS  PubMed  Google Scholar 

  14. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA (2002) Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 287:337–344

    Article  PubMed  Google Scholar 

  15. Rejnmark L, Vestergaard P, Heickendorff L, Andreasen F, Mosekilde L (2005) Effects of long-term treatment with loop diuretics on bone mineral density, calcitropic hormones and bone turnover. J Intern Med 257:176–184

    Article  CAS  PubMed  Google Scholar 

  16. Rose BD (1991) Diuretics. Kidney Int 39:336–352

    Article  CAS  PubMed  Google Scholar 

  17. Rejnmark L, Vestergaard P, Heickendorff L, Andreasen F, Mosekilde L (2006) Loop diuretics increase bone turnover and decrease BMD in osteopenic postmenopausal women: results from a randomized controlled study with bumetanide. J Bone Miner Res 21(1):163–170

    Article  CAS  PubMed  Google Scholar 

  18. Leipzig RM, Cumming RG, Tinetti ME (1999) Drugs and falls in older people: a systematic review and meta-analysis: II. Cardiac and analgesic drugs. J Am Geriatr Soc 47:40–50

    CAS  PubMed  Google Scholar 

  19. Arampatzis S, Gaetcke LM, Funk GC, Schwarz C, Mohaupt M, Zimmermann H, Exadaktylos AK, Lindner G (2013) Diuretic-induced hyponatremia and osteoporotic fractures in patients admitted to the emergency department. Maturitas 75:81–86

    Article  CAS  PubMed  Google Scholar 

  20. Berry SD, Zhu Y, Choi H, Kiel DP, Zhang Y (2013) Diuretic initiation and the acute risk of hip fracture. Osteoporos Int 24:689–695

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Rashiq S, Logan RF (1986) Role of drugs in fractures of the femoral neck. BMJ 292:861–863

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Cumming RG, Klineberg RJ (1993) Psychotropics, thiazide diuretics and hip fractures in the elderly. Med J Aust 158:414–417

    CAS  PubMed  Google Scholar 

  23. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283:2008–2012

    Article  CAS  PubMed  Google Scholar 

  24. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 151:W65–W94

    Article  PubMed  Google Scholar 

  25. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Open Med 3:e123–e130

    PubMed Central  PubMed  Google Scholar 

  26. Wells G, Shea B, O’connell D, Peterson J, Welch V, Losos M, Tugwell P (2011) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. URL: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

  27. McNutt LA, Wu C, Xue X, Hafner JP (2003) Estimating the relative risk in cohort studies and clinical trials of common outcomes. Am J Epidemiol 157:940–943

    Article  PubMed  Google Scholar 

  28. Zhang J, Yu KF (1998) What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA 280:1690–1691

    Article  CAS  PubMed  Google Scholar 

  29. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    Article  CAS  PubMed  Google Scholar 

  30. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    Article  PubMed  Google Scholar 

  31. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    Article  CAS  PubMed  Google Scholar 

  33. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L (2007) Performance of the trim and fill method in the presence of publication bias and between-study heterogeneity. Stat Med 26:4544–4562

    Article  PubMed  Google Scholar 

  34. Tromp A, Ooms M, Popp-Snijders C, Roos J, Lips P (2000) Predictors of fractures in elderly women. Osteoporos Int 11:134–140

    Article  CAS  PubMed  Google Scholar 

  35. Carbone LD, Johnson KC, Bush AJ, Robbins J, Larson JC, Thomas A, LaCroix AZ (2009) Loop diuretic use and fracture in postmenopausal women: findings from the Women’s Health Initiative. Arch Intern Med 169:132–140

    Article  PubMed  Google Scholar 

  36. Lim LS, Fink HA, Blackwell T, Taylor BC, Ensrud KE (2009) Loop diuretic use and rates of hip bone loss and risk of falls and fractures in older women. J Am Geriatr Soc 57:855–862

    Article  PubMed Central  PubMed  Google Scholar 

  37. Solomon DH, Mogun H, Garneau K, Fischer MA (2011) Risk of fractures in older adults using antihypertensive medications. J Bone Miner Res 26:1561–1567

    Article  CAS  PubMed  Google Scholar 

  38. Heidrich FE, Stergachis A, Gross KM (1991) Diuretic drug use and the risk for hip fracture. Ann Intern Med 115:1–6

    Article  CAS  PubMed  Google Scholar 

  39. Jensen J, Nielsen LH, Lyhne N, Hallas J, Brosen K, Gram LF (1991) Drugs and femoral neck fracture: a case–control study. J Intern Med 229:29–33

    Article  CAS  PubMed  Google Scholar 

  40. Partanen J, Heikkinen J, Jamsa T, Jalovaara P (2002) Characteristics of lifetime factors, bone metabolism, and bone mineral density in patients with hip fracture. J Bone Miner Metab 20:367–375

    Article  CAS  PubMed  Google Scholar 

  41. Rejnmark L, Vestergaard P, Mosekilde L (2006) Fracture risk in patients treated with loop diuretics. J Intern Med 259:117–124

    Article  CAS  PubMed  Google Scholar 

  42. Bilik D, McEwen LN, Brown MB et al (2010) Thiazolidinediones and fractures: evidence from translating research into action for diabetes. J Clin Endocrinol Metab 95:4560–4565

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Rejnmark L, Vestergaard P, Pedersen AR, Heickendorff L, Andreasen F, Mosekilde L (2003) Dose-effect relations of loop- and thiazide-diuretics on calcium homeostasis: a randomized, double-blinded Latin-square multiple cross-over study in postmenopausal osteopenic women. Eur J Clin Invest 33:41–50

    Article  CAS  PubMed  Google Scholar 

  44. Power ML, Heaney RP, Kalkwarf HJ, Pitkin RM, Repke JT, Tsang RC, Schulkin J (1999) The role of calcium in health and disease. Am J Obstet Gynecol 181:1560–1569

    Article  CAS  PubMed  Google Scholar 

  45. Poon IO, Braun U (2005) High prevalence of orthostatic hypotension and its correlation with potentially causative medications among elderly veterans. J Clin Pharm Ther 30:173–178

    Article  CAS  PubMed  Google Scholar 

  46. Ganz DA, Bao Y, Shekelle PG, Rubenstein LZ (2007) Will my patient fall? JAMA 297:77–86

    Article  PubMed  Google Scholar 

  47. Berry SD, Mittleman MA, Zhang Y, Solomon DH, Lipsitz LA, Mostofsky E, Goldense D, Kiel DP (2012) New loop diuretic prescriptions may be an acute risk factor for falls in the nursing home. Pharmacoepidemiol Drug Saf 21:560–563

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Nature Science Foundation of China (Grant No. 31170901), the Fund for Key National Basic Research Program of China (Grant No. 2012CB619101), and the Major Basic Research of Science and Technology Commission of Shanghai Municipality (Grant No. 11DJ1400303). The funding sources had no role in the study design, collection, analysis, or interpretation of the data, or in the writing of the report.

Conflicts of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to X. Qu or D. Gu.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplemental Fig. S1

Funnel plot of relative risk vs standard error of the log of relative risk (GIF 339 kb)

High resolution image (TIFF 117 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiao, F., Qu, X., Zhai, Z. et al. Association between loop diuretic use and fracture risk. Osteoporos Int 26, 775–784 (2015). https://doi.org/10.1007/s00198-014-2979-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-014-2979-8

Keywords

Navigation