Advertisement

Bisphosphonate Therapy for Osteoporosis: Benefits, Risks, and Drug Holiday

Published:November 21, 2012DOI:https://doi.org/10.1016/j.amjmed.2012.06.023

      Abstract

      The amino-bisphosphonates are first-line therapy for the treatment of most patients with osteoporosis, with proven efficacy to reduce fracture risk at the spine, hip, and other nonvertebral skeletal sites. Further, bisphosphonates have been associated with a significant decrease in morbidity and increase in survival. Following the use of bisphosphonates in millions of patients in clinical practice, some unexpected possible adverse effects have been reported, including osteonecrosis of the jaw, atypical femur fractures, atrial fibrillation, and esophageal cancer. Because bisphosphonates are incorporated into the skeleton and continue to exert an antiresorptive effect for a period of time after dosing is discontinued, the concept of a drug holiday has emerged, whereby the risk of adverse effects might be decreased while the patient still benefits from antifracture efficacy. Patients receiving bisphosphonates who are not at high risk for fracture are potential candidates for a drug holiday, while for those with bone mineral density in the osteoporosis range or previous history of fragility fracture, the benefits of continuing therapy probably far outweigh the risk of harm.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Russell R.G.
        • Watts N.B.
        • Ebetino F.H.
        • Rogers M.J.
        Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy.
        Osteoporos Int. 2008; 19: 733-759
        • MacLean C.
        • Newberry S.
        • Maglione M.
        • et al.
        Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis.
        Ann Intern Med. 2008; 148: 197-213
        • Siris E.S.
        • Pasquale M.K.
        • Wang Y.
        • Watts N.B.
        Estimating bisphosphonate use and fracture reduction among US women aged 45 years and older, 2001-2008.
        J Bone Miner Res. 2011; 26: 3-11
        • Black D.M.
        • Cummings S.R.
        • Karpf D.B.
        • et al.
        Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures.
        Lancet. 1996; 348: 1535-1541
        • Cummings S.R.
        • Black D.M.
        • Thompson D.E.
        • et al.
        Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial.
        JAMA. 1998; 280: 2077-2082
        • Harris S.T.
        • Watts N.B.
        • Genant H.K.
        • et al.
        Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial.
        JAMA. 1999; 282: 1344-1352
        • Reginster J.
        • Minne H.W.
        • Sorensen O.H.
        • et al.
        Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis.
        Osteoporos Int. 2000; 11: 83-91
        • McClung M.R.
        • Geusens P.
        • Miller P.D.
        • et al.
        Effect of risedronate on the risk of hip fracture in elderly women.
        N Engl J Med. 2001; 344: 333-340
        • Black D.M.
        • Delmas P.D.
        • Eastell R.
        • et al.
        Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.
        N Engl J Med. 2007; 356: 1809-1822
        • Lyles K.W.
        • Colon-Emeric C.S.
        • Magaziner J.S.
        • et al.
        Zoledronic acid and clinical fractures and mortality after hip fracture.
        N Engl J Med. 2007; 357: 1799-1809
        • Ensrud K.E.
        • Barrett-Connor E.L.
        • Schwartz A.
        • et al.
        Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension.
        J Bone Miner Res. 2004; 19: 1259-1269
        • Black D.M.
        • Schwartz A.V.
        • Ensrud K.E.
        • et al.
        Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
        JAMA. 2006; 296: 2927-2938
        • Mellstrom D.D.
        • Sorensen O.H.
        • Goemaere S.
        • Roux C.
        • Johnson T.D.
        • Chines A.A.
        Seven years of treatment with risedronate in women with postmenopausal osteoporosis.
        Calcif Tissue Int. 2004; 75: 462-468
        • Bone H.G.
        • Hosking D.
        • Devogelaer J.P.
        • et al.
        Ten years' experience with alendronate for osteoporosis in postmenopausal women.
        N Engl J Med. 2004; 350: 1189-1199
        • Chesnut III, C.H.
        • Skag A.
        • Christiansen C.
        • et al.
        Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis.
        J Bone Miner Res. 2004; 19: 1241-1249
        • Wang Z.
        • Bhattacharyya T.
        Trends in incidence of subtrochanteric fragility fractures and bisphosphonate use among the US elderly, 1996-2007.
        J Bone Miner Res. 2011; 26: 553-560
        • Orwoll E.
        • Ettinger M.
        • Weiss S.
        • et al.
        Alendronate for the treatment of osteoporosis in men.
        N Engl J Med. 2000; 343: 604-610
        • Wallach S.
        • Cohen S.
        • Reid D.M.
        • et al.
        Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy.
        Calcif Tissue Int. 2000; 67: 277-285
        • Nevitt M.C.
        • Thompson D.E.
        • Black D.M.
        • et al.
        Effect of alendronate on limited-activity days and bed-disability days caused by back pain in postmenopausal women with existing vertebral fractures.
        Arch Intern Med. 2000; 160: 77-85
        • Center J.R.
        • Bliuc D.
        • Nguyen N.D.
        • Nguyen T.V.
        • Eisman J.A.
        Osteoporosis medication and reduced mortality risk in elderly women and men.
        J Clin Endocrinol Metab. 2011; 96: 1006-1014
        • Sambrook P.N.
        • Cameron I.D.
        • Chen J.S.
        • et al.
        Oral bisphosphonates are associated with reduced mortality in frail older people: a prospective five-year study.
        Osteoporos Int. 2011; 22: 2551-2556
        • Dell R.
        • Greene D.
        Is osteoporosis disease management cost effective?.
        Curr Osteoporos Rep. 2010; 8: 49-55
        • Newman E.D.
        • Ayoub W.T.
        • Starkey R.H.
        • Diehl J.M.
        • Wood G.C.
        Osteoporosis disease management in a rural health care population: hip fracture reduction and reduced costs in postmenopausal women after 5 years.
        Osteoporos Int. 2003; 14: 146-151
        • Beaupre L.A.
        • Morrish D.W.
        • Hanley D.A.
        • et al.
        Oral bisphosphonates are associated with reduced mortality after hip fracture.
        Osteoporos Int. 2011; 22: 983-991
        • Bolland M.J.
        • Grey A.B.
        • Gamble G.D.
        • Reid I.R.
        Effect of osteoporosis treatment on mortality: a meta-analysis.
        J Clin Endocrinol Metab. 2010; 95: 1174-1181
        • U.S. Food and Drug Administration
        What is a serious adverse event?.
        (Accessed October 31, 2011)
        • Dowd R.
        • Recker R.R.
        • Heaney R.P.
        Study subjects and ordinary patients.
        Osteoporos Int. 2000; 11: 533-536
        • Khosla S.
        • Burr D.
        • Cauley J.
        • et al.
        Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research.
        J Bone Miner Res. 2007; 22: 1479-1491
        • Migliorati C.A.
        • Schubert M.M.
        • Peterson D.E.
        • Seneda L.M.
        Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy.
        Cancer. 2005; 104: 83-93
        • Ruggiero S.L.
        • Mehrotra B.
        • Rosenberg T.J.
        • Engroff S.L.
        Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases.
        J Oral Maxillofac Surg. 2004; 62: 527-534
        • Sarathy A.P.
        • Bourgeois Jr, S.L.
        • Goodell G.G.
        Bisphosphonate-associated osteonecrosis of the jaws and endodontic treatment: two case reports.
        J Endod. 2005; 31: 759-763
        • Olson K.B.
        • Hellie C.M.
        • Pienta K.J.
        Osteonecrosis of jaw in patient with hormone-refractory prostate cancer treated with zoledronic acid.
        Urology. 2005; 66: 658
        • Cartsos V.M.
        • Zhu S.
        • Zavras A.I.
        Bisphosphonate use and the risk of adverse jaw outcomes: a medical claims study of 714,217 people.
        J Am Dent Assoc. 2008; 139: 23-30
        • Lo J.C.
        • O'Ryan F.S.
        • Gordon N.P.
        • et al.
        Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure.
        J Oral Maxillofac Surg. 2010; 68: 243-253
        • Mavrokokki T.
        • Cheng A.
        • Stein B.
        • Goss A.
        Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia.
        J Oral Maxillofac Surg. 2007; 65: 415-423
        • Hellstein J.W.
        • Adler R.A.
        • Edwards B.
        • et al.
        Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs.
        J Am Dent Assoc. 2011; 142: 1243-1251
        • Marx R.E.
        • Cillo Jr, J.E.
        • Ulloa J.J.
        Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment.
        J Oral Maxillofac Surg. 2007; 65: 2397-2410
        • Shane E.
        • Burr D.
        • Ebeling P.R.
        • et al.
        Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research.
        J Bone Miner Res. 2010; 25: 2267-2294
        • Giusti A.
        • Hamdy N.A.
        • Papapoulos S.E.
        Atypical fractures of the femur and bisphosphonate therapy: a systematic review of case/case series studies.
        Bone. 2010; 47: 169-180
        • Schilcher J.
        • Michaelsson K.
        • Aspenberg P.
        Bisphosphonate use and atypical fractures of the femoral shaft.
        N Engl J Med. 2011; 364: 1728-1737
        • Feldstein A.
        • Black D.
        • Perrin N.
        • et al.
        Incidence and demography of femur fractures with and without atypical features.
        J Bone Miner Res. 2012; 27: 977-986
        • Kumm D.A.
        • Rack C.
        • Rutt J.
        Subtrochanteric stress fracture of the femur following total knee arthroplasty.
        J Arthroplasty. 1997; 12: 580-583
        • Niimi R.
        • Hasegawa M.
        • Sudo A.
        • Uchida A.
        Unilateral stress fracture of the femoral shaft combined with contralateral insufficiency fracture of the femoral shaft after bilateral total knee arthroplasty.
        J Orthop Sci. 2008; 13: 572-575
        • Lenart B.A.
        • Neviaser A.S.
        • Lyman S.
        • et al.
        Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study.
        Osteoporos Int. 2009; 20: 1353-1362
        • Schilcher J.
        • Aspenberg P.
        Incidence of stress fractures of the femoral shaft in women treated with bisphosphonate.
        Acta Orthop. 2009; 80: 413-415
        • Giusti A.
        • Hamdy N.A.
        • Dekkers O.M.
        • Ramautar S.R.
        • Dijkstra S.
        • Papapoulos S.E.
        Atypical fractures and bisphosphonate therapy: a cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features.
        Bone. 2011; 48: 966-971
        • Dell R.M.
        • Adams A.L.
        • Greene D.F.
        • et al.
        Incidence of atypical nontraumatic diaphyseal fractures of the femur.
        J Bone Miner Res. 2012 Jul 26; ([Epub ahead of print])https://doi.org/10.1002/jbmr.1719
        • Cummings S.R.
        • Schwartz A.V.
        • Black D.M.
        Alendronate and atrial fibrillation.
        N Engl J Med. 2007; 356: 1895-1896
        • Karam R.
        • Camm J.
        • McClung M.
        Yearly zoledronic acid in postmenopausal osteoporosis.
        N Engl J Med. 2007; 357: 712-713
        • Lewiecki E.M.
        • Cooper C.
        • Thompson E.
        • Hartl F.
        • Mehta D.
        • Papapoulos S.E.
        Ibandronate does not increase risk of atrial fibrillation in analysis of pivotal clinical trials.
        Int J Clin Pract. 2010; 64: 821-826
        • U.S. Food and Drug Administration
        Update of safety review follow-up to the October 1, 2007.
        (Accessed August 11, 2011)
        • Wysowski D.K.
        Reports of esophageal cancer with oral bisphosphonate use.
        N Engl J Med. 2009; 360: 89-90
        • Green J.
        • Czanner G.
        • Reeves G.
        • Watson J.
        • Wise L.
        • Beral V.
        Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort.
        BMJ. 2010; 341: c4444
        • Abrahamsen B.
        • Eiken P.
        • Eastell R.
        More on reports of esophageal cancer with oral bisphosphonate use.
        N Engl J Med. 2009; 360 (author reply 1791-1792): 1789
        • Solomon D.H.
        • Patrick A.
        • Brookhart M.A.
        More on reports of esophageal cancer with oral bisphosphonate use.
        N Engl J Med. 2009; 360: 1789-1790
        • Cardwell C.R.
        • Abnet C.C.
        • Cantwell M.M.
        • Murray L.J.
        Exposure to oral bisphosphonates and risk of esophageal cancer.
        JAMA. 2010 August 11; 304: 657-663
        • U.S. Food and Drug Administration
        FDA drug safety communication: ongoing safety review of oral osteoporosis drugs (bisphosphonates) and potential increased risk of esophageal cancer.
        (Accessed January 12, 2012)
        • Cryer B.
        • Bauer D.C.
        Oral bisphosphonates and upper gastrointestinal tract problems: what is the evidence?.
        Mayo Clin Proc. 2002; 77: 1031-1043
        • Greenspan S.
        • Field-Munves E.
        • Tonino R.
        • et al.
        Tolerability of once-weekly alendronate in patients with osteoporosis: a randomized, double-blind, placebo-controlled study.
        Mayo Clin Proc. 2002; 77: 1044-1052
        • Miller P.D.
        • Epstein S.
        • Sedarati F.
        • Reginster J.Y.
        Once-monthly oral ibandronate compared with weekly oral alendronate in postmenopausal osteoporosis: results from the head-to-head MOTION study.
        Curr Med Res Opin. 2008; 24: 207-213
        • Harris S.T.
        • Reginster J.Y.
        • Harley C.
        • et al.
        Risk of fracture in women treated with monthly oral ibandronate or weekly bisphosphonates: the eValuation of IBandronate Efficacy (VIBE) database fracture study.
        Bone. 2009; 44: 758-765
        • de Groen P.C.
        • Lubbe D.F.
        • Hirsch L.J.
        • et al.
        Esophagitis associated with the use of alendronate.
        N Engl J Med. 1996; 335: 1016-1021
        • Strampel W.
        • Emkey R.
        • Civitelli R.
        Safety considerations with bisphosphonates for the treatment of osteoporosis.
        Drug Saf. 2007; 30: 755-763
        • Cadarette S.M.
        • Katz J.N.
        • Brookhart M.A.
        • et al.
        Comparative gastrointestinal safety of weekly oral bisphosphonates.
        Osteoporos Int. 2009; 20: 1735-1747
        • Body J.J.
        • Pfister T.
        • Bauss F.
        Preclinical perspectives on bisphosphonate renal safety.
        Oncologist. 2005; 10: 3-7
        • Markowitz G.S.
        • Fine P.L.
        • Stack J.I.
        • et al.
        Toxic acute tubular necrosis following treatment with zoledronate (Zometa).
        Kidney Int. 2003; 64: 281-289
        • US Food and Drug Administration
        FDA drug safety communication: new contraindication and updated warning on kidney impairment for Reclast (zoledronic acid).
        (Accessed February 9, 2012)
        • Miller P.D.
        • McClung M.R.
        • Macovei L.
        • et al.
        Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study.
        J Bone Miner Res. 2005; 20: 1315-1322
        • Bock O.
        • Boerst H.
        • Thomasius F.E.
        • et al.
        Common musculoskeletal adverse effects of oral treatment with once weekly alendronate and risedronate in patients with osteoporosis and ways for their prevention.
        J Musculoskelet Neuronal Interact. 2007; 7: 144-148
        • Delmas P.D.
        • Adami S.
        • Strugala C.
        • et al.
        Intravenous ibandronate injections in postmenopausal women with osteoporosis: one-year results from the dosing intravenous administration study.
        Arthritis Rheum. 2006; 54: 1838-1846
        • Reid I.R.
        • Gamble G.D.
        • Mesenbrink P.
        • Lakatos P.
        • Black D.M.
        Characterization of and risk factors for the acute-phase response after zoledronic acid.
        J Clin Endocrinol Metab. 2010; 95: 4380-4387
        • Chesnut III, C.H.
        • McClung M.R.
        • Ensrud K.E.
        • et al.
        Alendronate treatment of the postmenopausal osteoporotic woman: effect of multiple dosages on bone mass and bone remodeling.
        Am J Med. 1995; 99: 144-152
        • Papapoulos S.E.
        • Harinck H.I.
        • Bijvoet O.L.
        • Gleed J.H.
        • Fraher L.J.
        • O'Riordan J.L.
        Effects of decreasing serum calcium on circulating parathyroid hormone and vitamin D metabolites in normocalcaemic and hypercalcaemic patients treated with APD.
        Bone Miner. 1986; 1: 69-78
        • Sharma N.S.
        • Ooi J.L.
        • Masselos K.
        • Hooper M.J.
        • Francis I.C.
        Zoledronic acid infusion and orbital inflammatory disease.
        N Engl J Med. 2008; 359: 1410-1411
        • Fraunfelder F.W.
        Ocular side effects associated with bisphosphonates.
        Drugs Today (Barc). 2003; 39: 829-835
        • Bonnick S.L.
        Going on a drug holiday?.
        J Clin Densitom. 2011; 14: 377-383
        • Black D.M.
        • Reid I.R.
        • Boonen S.
        • et al.
        The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT).
        J Bone Miner Res. 2012; 27: 243-254
        • Watts N.B.
        • Chines A.
        • Olszynski W.P.
        • et al.
        Fracture risk remains reduced one year after discontinuation of risedronate.
        Osteoporos Int. 2008; 19: 365-372
        • Schwartz A.V.
        • Bauer D.C.
        • Cummings S.R.
        • et al.
        Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial.
        J Bone Miner Res. 2010; 25: 976-982
        • Curtis J.R.
        • Westfall A.O.
        • Cheng H.
        • Delzell E.
        • Saag K.G.
        Risk of hip fracture after bisphosphonate discontinuation: implications for a drug holiday.
        Osteoporos Int. 2008; 19: 1613-1620
        • Gallagher A.M.
        • Rietbrock S.
        • Olson M.
        • van Staa T.P.
        Fracture outcomes related to persistence and compliance with oral bisphosphonates.
        J Bone Miner Res. 2008; 23: 1569-1575
        • Whitaker M.
        • Guo J.
        • Kehoe T.
        • Benson G.
        Bisphosphonates for osteoporosis—where do we go from here?.
        N Engl J Med. 2012; 366: 2048-2051
        • Bonnick S.L.
        • Shulman L.
        Monitoring osteoporosis therapy: bone mineral density, bone turnover markers, or both?.
        Am J Med. 2006; 119: S25-S31
        • Kanis J.A.
        • McCloskey E.V.
        • Johansson H.
        • Oden A.
        • Strom O.
        • Borgstrom F.
        Development and use of FRAX in osteoporosis.
        Osteoporos Int. 2010; 21: S407-S413
        • Leslie W.D.
        • Berger C.
        • Langsetmo L.
        • et al.
        Construction and validation of a simplified fracture risk assessment tool for Canadian women and men: results from the CaMos and Manitoba cohorts.
        Osteoporos Int. 2011; 22: 1873-1883