Advertisement

Osteoporosis International

, Volume 25, Issue 1, pp 121–129 | Cite as

β-adrenergic receptor antagonists and fracture risk: a meta-analysis of selectivity, gender, and site-specific effects

  • K. A. ToulisEmail author
  • K. Hemming
  • S. Stergianos
  • K. Nirantharakumar
  • J. P. Bilezikian
Original Article

Abstract

Summary

By meta-analysis, the risk of fracture was 15 % lower in patients treated with β-adrenergic blockers compared to controls independent of gender, fracture site, and dose. This might be attributable to β1-selective blockers.

Introduction

The aim of this study is to determine by meta-analysis whether β-adrenergic blockers (BBs) reduce fracture risk and whether the effect, if demonstrable, is dependent upon selectivity, dose, gender, or fracture site.

Methods

A literature search was performed in electronic databases MEDLINE, EMBASE, and reference sections of relevant articles to identify eligible studies. Adjusted estimates of fracture risk effect size (ES) were pooled across studies using fixed or random-effects (RE) meta-analysis as appropriate. Dose-related effects were evaluated using meta-regression. To explore the relative efficacy of β1-selective blockers in comparison to nonselective BBs, adjusted indirect comparison was performed.

Results

A total of 16 studies (7 cohort and 9 case–control studies), involving 1,644,570 subjects, were identified. The risk of any fracture was found to be significantly reduced in subjects receiving BBs as compared to control subjects (16 studies, RE pooled ES = 0.86, 95 % CI 0.78–0.93; I2 = 87 %). In a sensitivity analysis limited to those studies deemed to be most robust, the BB effect to reduce fracture risk was sustained (four studies, pooled ES = 0.79, 95 % CI 0.67–0.94; I2 = 96 %). The risk of a hip fracture was lower in both women and men receiving BBs (women: pooled ES = 0.86, 95 % CI 0.80–0.91; I2 = 1 % and men: pooled ES = 0.80, 95 % CI 0.71–0.90; I2 = 0 %). Similar risk reductions were found for clinical vertebral and forearm fractures, although statistical significance was not reached. The reduction in risk did not appear to be dose-related (test for a linear trend p value 0.150). Using adjusted indirect comparisons, it was estimated that β1-selective agents were significantly more effective than nonselective BBs in reducing the risk of any fracture (six studies, β1-selective blockers vs. nonselective BBs: RE pooled ES = 0.82, 95 % CI = 0.69–0.97).

Conclusions

The findings suggest that the risk of fracture is approximately 15 % lower in patients treated with BBs compared to controls independent of gender, fracture site, and dose. This risk reduction might be associated with the effects of β1-selective blockers.

Keyword

β-adrenergic antagonists Fracture Osteoporosis 

Notes

Acknowledgments

We are thankful to Professor Dr Alan Reid (Faculty of Medical and Health Sciences, University of Auckland, New Zealand) who kindly provided additional information relevant to this review. This work was conceived during the 2011 Preceptorship Program in Metabolic Bone Diseases held at Columbia University Medical Center, New York, USA.

Conflicts of interest

None

References

  1. 1.
    Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100:197–207PubMedCrossRefGoogle Scholar
  2. 2.
    Ma Y, Nyman JS, Tao H, Moss HH, Yang X, Elefteriou F (2011) Beta2-adrenergic receptor signaling in osteoblasts contributes to the catabolic effect of glucocorticoids on bone. Endocrinology 152:1412–1422PubMedCrossRefGoogle Scholar
  3. 3.
    Takeda S, Karsenty G (2008) Molecular bases of the sympathetic regulation of bone mass. Bone 42:837–840PubMedCrossRefGoogle Scholar
  4. 4.
    Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G (2002) Leptin regulates bone formation via the sympathetic nervous system. Cell 111:305–317PubMedCrossRefGoogle Scholar
  5. 5.
    Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M, Clement K, Vaisse C, Karsenty G (2005) Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434:514–520PubMedCrossRefGoogle Scholar
  6. 6.
    Patel MS, Elefteriou F (2007) The new field of neuroskeletal biology. Calcif Tissue Int 80:337–347PubMedCrossRefGoogle Scholar
  7. 7.
    Elefteriou F (2005) Neuronal signaling and the regulation of bone remodeling. Cell Mol Life Sci 62:2339–2349PubMedCrossRefGoogle Scholar
  8. 8.
    Elefteriou F (2008) Regulation of bone remodeling by the central and peripheral nervous system. Arch Biochem Biophys 473:231–236PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Toulis KA, Anastasilakis AD, Polyzos SA, Makras P (2011) Targeting the osteoblast: approved and experimental anabolic agents for the treatment of osteoporosis. Horm (Athens) 10:174–195Google Scholar
  10. 10.
    Lopez-Sendon J, Swedberg K, McMurray J, Tamargo J, Maggioni AP, Dargie H, Tendera M, Waagstein F, Kjekshus J, Lechat P, Torp-Pedersen C (2004) Expert consensus document on beta-adrenergic receptor blockers. Eur Heart J 25:1341–1362PubMedCrossRefGoogle Scholar
  11. 11.
    Wiens M, Etminan M, Gill SS, Takkouche B (2006) Effects of antihypertensive drug treatments on fracture outcomes: a meta-analysis of observational studies. J Intern Med 260:350–362PubMedCrossRefGoogle Scholar
  12. 12.
    Rejnmark L, Vestergaard P, Mosekilde L (2006) Treatment with beta-blockers, ACE inhibitors, and calcium-channel blockers is associated with a reduced fracture risk: a nationwide case–control study. J Hypertens 24:581–589PubMedCrossRefGoogle Scholar
  13. 13.
    Yang S, Nguyen ND, Center JR, Eisman JA, Nguyen TV (2011) Association between beta-blocker use and fracture risk: the Dubbo Osteoporosis Epidemiology Study. Bone 48:451–455PubMedCrossRefGoogle Scholar
  14. 14.
    Meisinger C, Heier M, Lang O, Doring A (2007) Beta-blocker use and risk of fractures in men and women from the general population: the MONICA/KORA Augsburg cohort study. Osteoporos Int 18:1189–1195PubMedCrossRefGoogle Scholar
  15. 15.
    Bonnet N, Gadois C, McCloskey E, Lemineur G, Lespessailles E, Courteix D, Benhamou CL (2007) Protective effect of beta blockers in postmenopausal women: influence on fractures, bone density, micro and macroarchitecture. Bone 40:1209–1216PubMedCrossRefGoogle Scholar
  16. 16.
    de Vries F, Souverein PC, Cooper C, Leufkens HG, van Staa TP (2007) Use of beta-blockers and the risk of hip/femur fracture in the United Kingdom and The Netherlands. Calcif Tissue Int 80:69–75PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Solomon DH, Mogun H, Garneau K, Fischer MA (2011) Risk of fractures in older adults using antihypertensive medications. J Bone Miner Res 26:1561–1567PubMedCrossRefGoogle Scholar
  18. 18.
    Sosa M, Saavedra P, Gomez de Tejada MJ, Mosquera J, Perez-Cano R, Olmos JM, Munoz-Torres M, Amerigo MJ, Moro MJ, Diaz-Curiel M, Alegre J, Malouf J, Del Pino J, Nogues X, Torrijos A (2011) Beta-blocker use is associated with fragility fractures in postmenopausal women with coronary heart disease. Aging Clin Exp Res 23:112–117PubMedGoogle Scholar
  19. 19.
    Song HJ, Lee J, Kim YJ, Jung SY, Kim HJ, Choi NK, Park BJ 2012 beta1 selectivity of beta-blockers and reduced risk of fractures in elderly hypertension patients. BoneGoogle Scholar
  20. 20.
    Turker S, Karatosun V, Gunal I (2006) Beta-blockers increase bone mineral density. Clin Orthop Relat Res 443:73–74PubMedCrossRefGoogle Scholar
  21. 21.
    Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF (2006) Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med 166:241–246PubMedCrossRefGoogle Scholar
  22. 22.
    Reid IR (2008) Effects of beta-blockers on fracture risk. J Musculoskelet Neuronal Interact 8:105–110PubMedGoogle Scholar
  23. 23.
    Ilic K, Obradovic N, Vujasinovic-Stupar N (2013) The relationship among hypertension, antihypertensive medications, and osteoporosis: a narrative review. Calcif Tissue Int 92:217–227PubMedCrossRefGoogle Scholar
  24. 24.
    Schlienger RG, Kraenzlin ME, Jick SS, Meier CR (2004) Use of beta-blockers and risk of fractures. JAMA 292:1326–1332PubMedCrossRefGoogle Scholar
  25. 25.
    Peacock M, Buckwalter KA, Persohn S, Hangartner TN, Econs MJ, Hui S (2009) Race and sex differences in bone mineral density and geometry at the femur. Bone 45:218–225PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Riggs BL, Melton Iii LJ III, Robb RA, Camp JJ, Atkinson EJ, Peterson JM, Rouleau PA, McCollough CH, Bouxsein ML, Khosla S (2004) Population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites. J Bone Miner Res 19:1945–1954PubMedCrossRefGoogle Scholar
  27. 27.
    Khosla S, Riggs BL, Atkinson EJ, Oberg AL, McDaniel LJ, Holets M, Peterson JM, Melton LJ 3rd (2006) Effects of sex and age on bone microstructure at the ultradistal radius: a population-based noninvasive in vivo assessment. J Bone Miner Res 21:124–131PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Peacock M, Koller DL, Lai D, Hui S, Foroud T, Econs MJ (2009) Bone mineral density variation in men is influenced by sex-specific and non sex-specific quantitative trait loci. Bone 45:443–448PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Greenland S, Longnecker MP (1992) Methods for trend estimation from summarized dose–response data, with applications to meta-analysis. Am J Epidemiol 135:1301–1309PubMedGoogle Scholar
  30. 30.
    Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D’Amico R, Bradburn M, Eastwood AJ (2005) Indirect comparisons of competing interventions. Health Technol Assess 9:1–134, iii-ivPubMedGoogle Scholar
  31. 31.
    Pasco JA, Henry MJ, Sanders KM, Kotowicz MA, Seeman E, Nicholson GC (2004) Beta-adrenergic blockers reduce the risk of fracture partly by increasing bone mineral density: Geelong Osteoporosis Study. J Bone Miner Res 19:19–24PubMedCrossRefGoogle Scholar
  32. 32.
    Reid IR, Gamble GD, Grey AB, Black DM, Ensrud KE, Browner WS, Bauer DC (2005) beta-Blocker use, BMD, and fractures in the study of osteoporotic fractures. J Bone Miner Res 20:613–618PubMedCrossRefGoogle Scholar
  33. 33.
    Rejnmark L, Vestergaard P, Kassem M, Christoffersen BR, Kolthoff N, Brixen K, Mosekilde L (2004) Fracture risk in perimenopausal women treated with beta-blockers. Calcif Tissue Int 75:365–372PubMedCrossRefGoogle Scholar
  34. 34.
    Levasseur R, Dargent-Molina P, Sabatier JP, Marcelli C, Breart G (2005) Beta-blocker use, bone mineral density, and fracture risk in older women: results from the Epidemiologie de l’Osteoporose prospective study. J Am Geriatr Soc 53:550–552PubMedCrossRefGoogle Scholar
  35. 35.
    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 229:29–33PubMedCrossRefGoogle Scholar
  36. 36.
    van Staa TP, Dennison EM, Leufkens HG, Cooper C (2001) Epidemiology of fractures in England and Wales. Bone 29:517–522PubMedCrossRefGoogle Scholar
  37. 37.
    Bazelier M, de Boer A, de Vries F (2012) Acid suppressants and hip fracture: duplicate publication bias? Bone 49:920, author reply 921CrossRefGoogle Scholar
  38. 38.
    Aitken SJ, Landao-Bassonga E, Ralston SH, Idris AI (2009) Beta2-adrenoreceptor ligands regulate osteoclast differentiation in vitro by direct and indirect mechanisms. Arch Biochem Biophys 482:96–103PubMedCrossRefGoogle Scholar
  39. 39.
    Kondo H, Togari A (2011) Continuous treatment with a low-dose beta-agonist reduces bone mass by increasing bone resorption without suppressing bone formation. Calcif Tissue Int 88:23–32PubMedCrossRefGoogle Scholar
  40. 40.
    Nagao M, Feinstein TN, Ezura Y, Hayata T, Notomi T, Saita Y, Hanyu R, Hemmi H, Izu Y, Takeda S, Wang K, Rittling S, Nakamoto T, Kaneko K, Kurosawa H, Karsenty G, Denhardt DT, Vilardaga JP, Noda M (2011) Sympathetic control of bone mass regulated by osteopontin. Proc Natl Acad Sci U S A 108:17767–17772PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Hanyu R, Wehbi VL, Hayata T, Moriya S, Feinstein TN, Ezura Y, Nagao M, Saita Y, Hemmi H, Notomi T, Nakamoto T, Schipani E, Takeda S, Kaneko K, Kurosawa H, Karsenty G, Kronenberg HM, Vilardaga JP, Noda M (2012) Anabolic action of parathyroid hormone regulated by the beta2-adrenergic receptor. Proc Natl Acad Sci U S A 109:7433–7438PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Rodrigues WF, Madeira MF, da Silva TA, Clemente-Napimoga JT, Miguel CB, Dias-da-Silva VJ, Barbosa-Neto O, Lopes AH, Napimoga MH (2012) Low dose of propranolol down-modulates bone resorption by inhibiting inflammation and osteoclast differentiation. Br J Pharmacol 165:2140–2151PubMedCrossRefGoogle Scholar
  43. 43.
    Bonnet N, Benhamou CL, Malaval L, Goncalves C, Vico L, Eder V, Pichon C, Courteix D (2008) Low dose beta-blocker prevents ovariectomy-induced bone loss in rats without affecting heart functions. J Cell Physiol 217:819–827PubMedCrossRefGoogle Scholar
  44. 44.
    Pierroz DD, Bonnet N, Bianchi EN, Bouxsein ML, Baldock PA, Rizzoli R, Ferrari SL (2012) Deletion of beta-adrenergic receptor 1, 2, or both leads to different bone phenotypes and response to mechanical stimulation. J Bone Miner Res 27:1252–1262PubMedCrossRefGoogle Scholar
  45. 45.
    de Vries F, Pouwels S, Bracke M, Leufkens HG, Cooper C, Lammers JW, van Staa TP (2007) Use of beta-2 agonists and risk of hip/femur fracture: a population-based case–control study. Pharmacoepidemiol Drug Saf 16:612–619PubMedCrossRefGoogle Scholar
  46. 46.
    Schmitt CP, Obry J, Feneberg R, Veldhuis JD, Mehls O, Ritz E, Schaefer F (2003) Beta1-adrenergic blockade augments pulsatile PTH secretion in humans. J Am Soc Nephrol 14:3245–3250PubMedCrossRefGoogle Scholar
  47. 47.
    Majumdar SR, Ezekowitz JA, Lix LM, Leslie WD (2012) Heart failure is a clinically and densitometrically independent risk factor for osteoporotic fractures: population-based cohort study of 45,509 subjects. J Clin Endocrinol Metab 97:1179–1186PubMedCrossRefGoogle Scholar
  48. 48.
    Cruickshank JM (1980) The clinical importance of cardioselectivity and lipophilicity in beta blockers. Am Heart J 100:160–178PubMedCrossRefGoogle Scholar
  49. 49.
    Yang S, Nguyen ND, Eisman JA, Nguyen TV (2012) Association between beta-blockers and fracture risk: a Bayesian meta-analysis. Bone 51:969–974PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2013

Authors and Affiliations

  • K. A. Toulis
    • 1
    Email author
  • K. Hemming
    • 2
  • S. Stergianos
    • 3
  • K. Nirantharakumar
    • 2
    • 4
  • J. P. Bilezikian
    • 5
  1. 1.Department of Endocrinology424 General Military HospitalThessalonikiGreece
  2. 2.Department of Public Health, Epidemiology and BiostatisticsUniversity of BirminghamBirminghamUK
  3. 3.Department of Internal MedicineSundsvall HospitalSundsvallSweden
  4. 4.Institute of Digital HealthcareUniversity of WarwickCoventryUK
  5. 5.Department of Medicine, Division of Endocrinology, Metabolic Bone Diseases Unit, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA

Personalised recommendations