Abstract
There is a growing list of medications used to treat non-skeletal disorders that cause bone loss and/or increase fracture risk. This review discusses glucocorticoids, drugs that reduce sex steroids, antidiabetic agents, acid-reducing drugs, selective serotonin reuptake inhibitors, and heparin. A number of drugs are known to cause bone loss, increase fracture risk, or both. These drugs should be used in the lowest dose necessary to achieve the desired benefit and for the shortest time necessary, but in many cases, long-term treatment is required. Effective countermeasures are available for some.
Similar content being viewed by others
References
Saag KG, Emkey R, Schnitzer TJ et al (1998) Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. N Engl J Med 339:292–299
Cohen S, Levy RM, Keller M et al (1999) Risedronate therapy prevents corticosteroid-induced bone loss—a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 42:2309–2318
Reid DM, Hughes R, Laan RFJM et al (2000) Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. J Bone Miner Res 15:1006–1013
Reid DM, Devogelaer J-PJP, Saag K et al (2009) Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy randomised controlled trial. Lancet 373:1253–1263. doi:10.1016/S0140-6736(09)60250-6
Saag KG, Shane E, Boonen S et al (2007) Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 357:2028–2039
Compston J (2010) Management of glucocorticoid-induced osteoporosis. Nat Rev Rheumatol 6:82–88
Weinstein RS (2011) Glucocorticoid-induced bone disease. N Engl J Med 365:62–70
Seibel MJ, Cooper MS, Zhou H (2013) Glucocorticoid-induced osteoporosis: mechanisms, management, and future perspectives. Lancet Diabetes Endocrinol 1:59–70
Frenkel B, White W, Tuckermann J (2015) Glucocorticoid-induced osteoporosis. Adv Exp Med Biol 872:179–215
Whittier X, Saag KG (2016) Glucocorticoid-induced osteoporosis. Rheum Dis Clin N Am 42:177–189
Grossman JM, Gordon R, Ranganath VK et al (2010) American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res 62:1515–1526
Buckley L, Guyatt G, Fink HA et al (2017) 2017 American College of Rheumatology Guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheumatol 69. doi:10.1002/art.40137
Rejnmark L, Vestergaard P, Heickendorff L et al (2006) Loop diuretics increase bone turnover and decrease BMD in osteopenic postmenopausal women: results from a randomized controlled study with bumetanide. J Bone Min Res 21:163–170
Rejnmark L, Vestergaard P, Mosekilde L (2006) Fracture risk in patients treated with loop diuretics. J Intern Med 259:117–124
Carbone LD, Johnson KC, Bush AJ et al (2009) Loop diuretic use and fracture in postmenopausal women: findings from the Women’s Health Initiative. Arch Intern Med 169:132–140
Verbalis JG, Barsony J, Sugimura Y et al (2010) Hyponatremia-induced osteoporosis. J Bone Miner Res 25:554–563. doi:10.1359/jbmr.090827
Ayus JC, Bellido T, Negri AL (2017) Hyponatremia and fractures: should hyponatremia be further studied as a potential biochemical risk factor to be included in FRAX algorithms? Osteoporos Int:1543–1548. doi:10.1007/s00198-017-3907-5
Ott SM, LaCroix AZ, Scholes D et al (2008) Effects of three years of low-dose thiazides on mineral metabolism in healthy elderly persons. Osteoporos Int 19:1315–1322
LaCroix AZ, Weinpahl J, White LR et al (1990) Thiazide diuretic agents and the incidence of hip fracture. N Engl J Med 322:286–290
Paik JM, Rosen Uharold N, Gordon CM, Curhan GC (2016) Diuretic use and risk of vertebral fracture in women. Am J Med 129:1299–1306
Kaunitz AM, Miller PD, Rice VM et al (2006) Bone mineral density in women aged 25–35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation. Contraception 74:90–99
Kaunitz AM, Arias R, McClung M (2008) Bone density recovery after depot medroxyprogesterone acetate injectable contraception use. Contraception 77:67–76
Cundy T, Cornish J, Roberts H, Reid IR (2002) Menopausal bone loss in long-term users of depot medroxyprogesterone acetate contraception. Am J Obstet Gynecol 186:978–983
Kyvernitakis I, Kostev K, Nassour T et al (2016) The impact of depot medroxyprogesterone acetate on fracture risk: a case-control study from the UK. Osteoporos Int 27:1–7
Furr BJA, Woodburn JR (1988) Luteinizing hormone-releasing hormone and its analogues: a review of biological properties and clinical uses. J Endocrinol Investig 11:535–557
Gonadotropin-releasing hormone agonist. https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone_agonist https://en.wikipedia.org/wiki/Gonadotropin-releasi
Gonadotropin-releasing hormone antagonist. https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone_antagonist https://en.wikipedia.org/wiki/Gonadotropin-releasi
Ezzati M, Carr BR (2015) Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain. Women's Health (Lond Engl) 11:19–28
Melis GB, Neri M, Corda V et al (2016) Overview of elagolix for the treatment of endometriosis. Expert Opin Drug Metab Toxicol 12:581–588
Casper RF (2015) Basic understanding of gonadotropin-releasing hormone-agonist triggering. Fertil Steril 103:867–869
Youssef MAFM, Van der Veen F, Al-Inany HG et al (2016) The updated Cochrane Review 2014 on GnRH agonist trigger: an indispensable piece of information for the clinician. Reprod BioMed Online 32:259–260
Park HK, Lee HS, Ko JH et al (2012) The effect of gonadotrophin-releasing hormone agonist treatment over 3 years on bone mineral density and body composition in girls with central precocious puberty. Clin Endocrinol 77:743–748
Alessandri SB, Pereira Fde A, Villela RA et al (2012) Bone mineral density and body composition in girls with idiopathic central precocious puberty before and after treatment with a gonadotropin-releasing hormone agonist. Clinics (Sao Paulo) 67:591–596
Tafi E, Leone Roberti Maggiore U, Alessandri F et al (2015) Advances in pharmacotherapy for treating endometriosis. Expert Opin Pharmacother 16:2465–2483
Berlanda N, Somigliana E, Vigano P, Vercellini P (2016) Safety of medical treatments for endometriosis. Expert Opin Drug Saf 15:21–30
Chabbert-Buffet N, Esber N, Bouchard P (2014) Fibroid growth and medical options for treatment. Fertil Steril 102:630–639
Pontis A, D’Alterio MN, Pirarba S et al (2016) Adenomyosis: a systematic review of medical treatment. Gynecol Endocrinol 32:696–700
Tsai H-W, Wang P-H, Huang B-S et al (2016) Low-dose add-back therapy during postoperative GnRH agonist treatment. Taiwan J Obstet Gynecol 55:55–59
Taylor HS, Giudice LC, Lessey BA et al (2017) Treatment of endometriosis-associated pain with elagolix, and oral GnRH inhibitor. N Engl J Med 377:28–40
Greenspan SL, Coates P, Sereika SM et al (2005) Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer. J Clin Endocrinol Metab 90:6410–6417
Morgans AK, Fan KH, Koyama T et al (2014) Bone complications among prostate cancer survivors: long-term follow-up from the prostate cancer outcomes study. Prostate Cancer Prostatic Dis 17:338–342
Wang A, Obertova Z, Brown C et al (2015) Risk of fracture in men with prostate cancer on androgen deprivation therapy: a population-based study in New Zealand. BMJ Cancer 15:837
Garg A, Leitzel K, Ali S, Lipton A (2015) Antiresorptive therapy in the management of cancer treatment-induced bone loss. Curr Osteoporos Rep 13:73–77
Smith MR, Morton RA, Barnette KG et al (2010) Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer. J Urol 184:1316–1321
Smith MR, Egerdie B, Hernandiz-Toriz N et al (2009) Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 361:1745–1755
Damji AN, Bies K, Alibhai SMH, Jones JM (2015) Bone health management in men undergoing ADT: examining enablers and barriers to care. Osteoporos Int 26:951–959
McCloskey E (2006) Effects of third-generation aromatase inhibitors on bone. Eur J Cancer 42:1044–1051
Chebowski RT, Haque R, Hedlin H et al (2015) Benefit/risk for adjuvant breast cancer therapy with tamoxifen or aromatase inhibitor use by age and race/ethnicity. Breast Cancer Res Treat 154:609–616
Bouvard B, Soulie P, Hoppe E et al (2014) Fracture incidence after 3 years of aromatase inhibitor therapy. Ann Oncol 25:843–847
Majithia N, Atherton PJ, Lafky JM et al (2016) Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy: a 5-year follow-up. Support Care Cancer 24:1219–1226
Greenspan SL, Vujevich KT, Brufsky A et al (2015) Prevention of bone loss with risedronate in breast cancer survisors: a randomized, controlled clinical trial. Osteoporos Int 26:1857–1864
Ellis GK, Bone HG, Chebowski R et al (2009) Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analysis of a Phase 3 study. Breast Cancer Res Treat 118:81–87
Gnant M, Pfeiler G, Dubsky PC et al (2015) Adjuvant denosumab in breast cancer (ABSCG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386:433–443
Hadji P, Aapro MS, Body J-J et al (2017) Management of aromatase inhibitor-associated bone loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: joint position statement of the IOF, CABS, ECTS, IEG, ESCEO, IMS, and SIOG. J Bone Oncol 7:1–12
Coleman R, Body J-J, Aapro M et al (2014) Bone health in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 25(Suppl 3):124–137
Fan Y, Wei F, Lang Y, Liu Y (2016) Diabetes mellitus and risk of hip fractures: a meta-analysis. Osteoporos Int 27:219–228. doi:10.1007/s00198-015-3279-7
Janghorbani M, Van Dam RM, Willett WC, Hu FB (2007) Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol 166:495–505
Ali AA, Weinstein RA, Scott SA et al (2005) Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology 2005:1226–1235
Lecka-Czernik B, Acker-Bicknell C, Adamo ML et al (2007) Activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) by rosiglitzaone suppresses components of the insulin-like growth factor regulatory system in vitro and in vivo. Endocrinology 148:903–911
Grey A, Bolland M, Gamble G et al (2007) The peroxisome-proliferator-activated receptor gamma agonist rosiglitazone decreased bone formation and bone mineral density in healthy postmenopausal women: a randomized controlled trial. J Clin Endocrinol Metab 92:1305–1310
Bilezikian JP, Watts NB, Usiskin K et al (2016) Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin. J Clin Endocrinol Metab 101:44–51
Watts NB, Bilezikian JP, Usiskin K et al (2016) Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 101:157–166
Dombrowski S, Kostev K, Jacob L (2017) Use of dipeptidyl peptidase-4 inhibitors and risk of bone fracture in patients with type 2 diabetes in Germany—a retrospective analysis of real-world data. Osteoporos Int. doi:10.1007/s00198-017-4051-y
Grisso JA, Kelsey JL, O’Brien LA et al (1997) Risk factors for hip fracture in men. Am J Epidemiol 145:786–793
Vestergaard P, Rejnmark L, Mosekilde L (2006) Proton pump inhibitors, histamine H2 receptor antagonists and other antacid medications and the risk of fracture. Calcif Tissue Res 79:76–83
van der Hoorn MM, Tett SE, de Vries OJ, Peeters GM (2015) The effect of dose and type of proton pump inhibitor use on the risk of fractures and osteoporosis treatment in Australian women: a prospective cohort study. Bone 81:675–682
Zhou B, Huang Y, Li H et al (2016) Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporos Int 27:339–347. doi:10.1007/s00198-015-3365-x
O’Connell MB, Madden DM, Murray AM et al (2005) Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover drial. Am J Med 120:778–781
Solomon DH, Diem SJ, Ruppert K et al (2015) Bone mineral density changes among women initiating proton pump inhibitors or H2 receptor antagonists: a SWAN cohort study. J Bone Miner Res 30:232–239
Lewis JR, Barre D, Zhu K et al (2014) Long-term proton pump inhibitor therapy and falls and fractures in elderly women: a prospective cohort study. J Bone Miner Res 39:2489–2497
Thaler HW, Sterke CS, van der Cammen TJ (2016) Association of proton pump inhibitor use with recurrent falls and risk of fractures in older women: a study of medication use in older fallers. J Nutr 20:77–81
Pouwels S, Lalmohamed A, Souverein P et al (2011) Use of proton pump inhibitors and risk of hip/femur fracture: a population-based case-control study. Osteoporos Int 22:903–910
Brozek W (2017) Use of proton pump inhibitors and mortality after hip fracture in a nationwide study. Osteoporos Int 28:1587–1595
Lee RH, Lyles KW, Colon-Emeric CS (2010) A review of the effect of anticonvulsant medications on bone mineral density and fracture risk. Am J Geriatr Pharmacother 8:34–46
Beerhorst K, van der Kruijs SJ, Verschuure P et al (2015) Bone disease during chronic antiepileptic drug therapy: general versus specific risk factors. J Neurol Sci 331:19–25
Crawford P (2005) Best practice guidelines for the management of women with epilepsy. Epilepsia 46:117–124
Elliott JO (2009) Possible methods for the prevention of bone loss in persons with epilepsy. Expert Rev Neurother 9:797–812
Lateigne A, Sheu YH, Sturmer T et al (2015) Serotonin-norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor use and risk of fractures: a new-user cohort study among US adults aged 50 years and older. CNS Drugs 29:245–252
Sheu YH, Lateigne A, Sturmer T et al (2015) SSRI use and risk of fractures among postmenopausal women without mental disorders. Inj Prev 21:397–403
Diem SJ, Blackwell TL, Stone KL et al (2007) Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch Intern Med 167:1240–1245
Feuer AJ, Demmer RT, Thai A, Vogiatzi MG (2015) Use of selective serotonin reuptake inhibitors and bone mass in adolescents: an NHANES study. Bone 78:28–33
Haney EM, Chan BK, Diem SJ et al (2007) Association of low bone mineral density with selective serotonin reuptake inhibitors in older men. Arch Intern Med 167:1251–1256
Warden SJ, Robling AG, Haney EM et al (2010) The emerging role of serotonin (5-hydroxytryptamine) in the skeleton and its mediation of the skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5). Bone 46:4–12
Lee S-H, Hsu W-T, Lai C-C et al (2017) Use of antipsychotics increased the risk of fracture: a systematic review and meta-analysis. Osteoporos Int 28:1167–1178
deSweit M, Ward P, Fidler A et al (1983) Prolonged heparin therapy in pregnancy causes bone demineralisation. Br J Obstet Gynaecol 90:1129–1134
Dalhman T (1993) Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin. Am J Obstet Gynecol 168:1265–1270
Barbour LA, Kick S, Steiner J et al (1994) A prospective study of heparing-induced osteoporosis in pregnancy using bone densitometry. Am J Obstet Gynecol 170:862–869
Ozdemir D, Tam AA, Dirikoc A et al (2015) Postpartum osteoporosis and vertebral fractures in two patients treated with enoxaparin during pregnancy. Osteoporos Int 26:415–418
Veronese N, Bano G, Bertozzo G et al (2015) Vitamin K antagonists use and fracture risk: results from a systemic review and meta-analysis. J Thromb Haemost 13:1665–1675
Lau WC, Chan EW, Cheung CL et al (2017) Association between dabigatran vs warfarin and risk of osteoporotic fractures among patients with nonvalvular atrial fibrillation. JAMA 317:1151–1158
Steffel J, Giugliano RP, Braunwald E et al (2016) Edoxaban versus warfarin in atrial fibrillation patients at risk of falling: ENGAGE AF-TIMI 48 analysis. J Am Coll Cardiol 68:1169–1178
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Stock options/holdings, royalties, company owner, patent owner, official role: OsteoDynamics, co-founder, stockholder. Honoraria for lectures the past year: Amgen, Merck, Shire. Consulting fees received in the past year: AbbVie, Amgen, Janssen, Merck, Radius, Sanofi.
Rights and permissions
About this article
Cite this article
Watts, N.B. Adverse bone effects of medications used to treat non-skeletal disorders. Osteoporos Int 28, 2741–2746 (2017). https://doi.org/10.1007/s00198-017-4171-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-017-4171-4