Howard A. Fink, MD, MPH; Roderick MacDonald, MS; Mary L. Forte, PhD, DC; Christina E. Rosebush, MPH; Kristine E. Ensrud, MD, MPH; John T. Schousboe, MD, PhD; Victoria A. Nelson, MSc; Kristen Ullman, MPH; Mary Butler, PhD, MBA; Carin M. Olson, MD, MS; Brent C. Taylor, MPH, PhD; Michelle Brasure, PhD, MSPH, MLIS; Timothy J. Wilt, MD, MPH
Disclaimer: The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of the Agency for Healthcare Research and Quality (AHRQ) or NIH. Therefore, no statement in this report should be construed as an official position of AHRQ, NIH, or the U.S. Department of Health and Human Services. AHRQ retains a license to display, reproduce, and distribute the data and the report from which this manuscript was derived under the terms of the agency's contract with the author.
Acknowledgment: The authors thank Jeannine Ouellette for her helpful edits during the final revisions of this manuscript.
Financial Support: This manuscript is based on research conducted by the Minnesota Evidence-based Practice Center under contract 290-2015-00008-I to the AHRQ, through an interagency agreement with the NIH Office of Disease Prevention.
Disclosures: None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report. Dr. Forte reports a government contract from the AHRQ to the Minnesota Evidence-based Practice Center to conduct this systematic review during the conduct of the study. Ms. Nelson reports grants from the AHRQ during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-0533.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor, Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Reproducible Research Statement:Study protocol: The study protocol is registered in PROSPERO (CRD42018087006) and available at https://effectivehealthcare.ahrq.gov/topics/osteoporosis-fracture-prevention/research-protocol. Statistical code: Not available. Data set: The full technical report contains search strategies, flow diagrams, evidence tables, study quality assessment tables, and detailed results (https://effectivehealthcare.ahrq.gov/topics/osteoporosis-fracture-prevention/research).
Corresponding Author: Howard A. Fink, MD, MPH, Geriatric Research Education & Clinical Center, Minneapolis VA Health Care Center, 11-G, One Veterans Drive, Minneapolis, MN 55417; e-mail, Howard.email@example.com.
Current Author Addresses: Dr. Fink: Geriatric Research Education & Clinical Center, Minneapolis VA Health Care System, 11-G, One Veterans Drive, Minneapolis, MN 55417.
Mr. MacDonald and Drs. Ensrud and Wilt: Center for Care Delivery & Outcomes Research, Minneapolis VA Health Care System, 1110, One Veterans Drive, Minneapolis, MN 55417.
Dr. Forte: University of Minnesota, Division of Health Policy and Management, School of Public Health, MMC 729 (8729A), D330-4 Mayo Memorial Building, 420 Delaware Street SE, Minneapolis, MN 55455.
Ms. Rosebush: University of Minnesota, 1260 Mayo Building, MMC 807, 420 Delaware Street SE, Minneapolis, MN 55455.
Dr. Schousboe: HealthPartners Institute, 3311 Old Shakopee Road, Bloomington, MN 55425.
Ms. Nelson and Dr. Brasure: University of Minnesota, Division of Health Policy and Management, School of Public Health, MMC 197, D330-6 Mayo Memorial Building, 420 Delaware Street SE, Minneapolis, MN 55455.
Ms. Ullman and Drs. Olson and Taylor: Center for Care Delivery & Outcomes Research, Minneapolis VA Health Care System, 152, One Veterans Drive, Minneapolis, MN 55417.
Dr. Butler: University of Minnesota, Division of Health Policy and Management, School of Public Health, MMC 729, D381 Mayo Memorial Building, 420 Delaware Street SE, Minneapolis, MN 55455.
Author Contributions: Conception and design: H.A. Fink, C.E. Rosebush, V.A. Nelson, K. Ullman, M. Butler.
Analysis and interpretation of the data: H.A. Fink, R. MacDonald, M.L. Forte, C.E. Rosebush, K.E. Ensrud, J.T. Schousboe, V.A. Nelson, K. Ullman, B.C. Taylor, T.J. Wilt.
Drafting of the article: H.A. Fink, R. MacDonald, M.L. Forte, V.A. Nelson, K. Ullman, M. Butler.
Critical revision of the article for important intellectual content: H.A. Fink, M.L. Forte, K.E. Ensrud, J.T. Schousboe, K. Ullman, M. Butler, B.C. Taylor, T.J. Wilt.
Final approval of the article: H.A. Fink, R. MacDonald, M.L. Forte, C.E. Rosebush, K.E. Ensrud, J.T. Schousboe, V.A. Nelson, K. Ullman, M. Butler, C.M. Olson, B.C. Taylor, M. Brasure, T.J. Wilt.
Provision of study materials or patients: H.A. Fink, M. Brasure.
Statistical expertise: H.A. Fink, R. MacDonald, B.C. Taylor, T.J. Wilt.
Obtaining of funding: H.A. Fink, M. Butler, T.J. Wilt.
Administrative, technical, or logistic support: H.A. Fink, V.A. Nelson, K. Ullman, M. Brasure, T.J. Wilt.
Collection and assembly of data: H.A. Fink, R. MacDonald, M.L. Forte, C.E. Rosebush, V.A. Nelson, K. Ullman, C.M. Olson, M. Brasure, T.J. Wilt.
Optimal long-term osteoporosis drug treatment (ODT) is uncertain.
To summarize the effects of long-term ODT and ODT discontinuation and holidays.
Electronic bibliographic databases (January 1995 to October 2018) and systematic review bibliographies.
48 studies that enrolled men or postmenopausal women aged 50 years or older who were being investigated or treated for fracture prevention, compared long-term ODT (>3 years) versus control or ODT continuation versus discontinuation, reported incident fractures (for trials) or harms (for trials and observational studies), and had low or medium risk of bias (ROB).
Two reviewers independently rated ROB and strength of evidence (SOE). One extracted data; another verified accuracy.
Thirty-five trials (9 unique studies) and 13 observational studies (11 unique studies) had low or medium ROB. In women with osteoporosis, 4 years of alendronate reduced clinical fractures (hazard ratio [HR], 0.64 [95% CI, 0.50 to 0.82]) and radiographic vertebral fractures (both moderate SOE), whereas 4 years of raloxifene reduced vertebral but not nonvertebral fractures. In women with osteopenia or osteoporosis, 6 years of zoledronic acid reduced clinical fractures (HR, 0.73 [CI, 0.60 to 0.90]), including nonvertebral fractures (high SOE) and clinical vertebral fractures (moderate SOE). Long-term bisphosphonates increased risk for 2 rare harms: atypical femoral fractures (low SOE) and osteonecrosis of the jaw (mostly low SOE). In women with unspecified osteoporosis status, 5 to 7 years of hormone therapy reduced clinical fractures (high SOE), including hip fractures (moderate SOE), but increased serious harms. After 3 to 5 years of treatment, bisphosphonate continuation versus discontinuation reduced radiographic vertebral fractures (zoledronic acid; low SOE) and clinical vertebral fractures (alendronate; moderate SOE) but not nonvertebral fractures (low SOE).
No trials studied men, clinical fracture data were sparse, methods for estimating harms were heterogeneous, and no trials compared sequential treatments or different durations of drug holidays.
Long-term alendronate and zoledronic acid therapies reduce fracture risk in women with osteoporosis. Long-term bisphosphonate treatment may increase risk for rare adverse events, and continuing treatment beyond 3 to 5 years may reduce risk for vertebral fractures. Long-term hormone therapy reduces hip fracture risks but has serious harms.
National Institutes of Health and Agency for Healthcare Research and Quality. (PROSPERO: CRD42018087006)
Table 1. Efficacy of Long-Term Osteoporosis Drug Treatment (>3 Years)
Table 2. Harms of Long-Term Osteoporosis Drug Treatment (>3 Years)
Table 3. Effects of Osteoporosis Drug Continuation Versus Discontinuation on Incident Fractures*
Table 4. Harms of Osteoporosis Drug Continuation Versus Discontinuation*
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Fink HA, MacDonald R, Forte ML, Rosebush CE, Ensrud KE, Schousboe JT, et al. Long-Term Drug Therapy and Drug Discontinuations and Holidays for Osteoporosis Fracture Prevention: A Systematic Review. Ann Intern Med. [Epub ahead of print 23 April 2019]:. doi: 10.7326/M19-0533
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Published: Ann Intern Med. 2019.
Emergency Medicine, Endocrine and Metabolism, Metabolic Bone Disorders.
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