Steven R Cummings1,2,3,4, Li-Yung Lui1,2, Richard Eastell5, Isabel E Allen4. 1. San Francisco Coordinating Center, San Francisco, California. 2. California Pacific Medical Center Research Institute, San Francisco. 3. Department of Medicine, University of California San Francisco, San Francisco. 4. Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco. 5. Sheffield Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
Abstract
IMPORTANCE: Previous studies have reported that drug treatments, particularly treatment with bisphosphonates, is associated with reduced overall mortality rates in addition to decreased fracture risk. If so, drug treatments should be recommended for this reason alone, regardless of a patient's risk of fracture. OBJECTIVE: To assess whether randomized clinical trials demonstrate that treatment with bisphosphonates, particularly zoledronate, is associated with reduced mortality rates. DATA SOURCES: Science Direct, MEDLINE, Embase, and the Cochrane Library were searched for randomized placebo-controlled clinical trials of drug treatments for osteoporosis published after 2009 and published or in press before April 19, 2019. Conference abstracts from annual osteoporosis society meetings were also included in the search. STUDY SELECTION: Included studies were clinical trials that (1) were randomized and placebo-controlled; (2) studied drug treatments with proven antifracture efficacy; (3) used agents at the approved dose for treatment of osteoporosis; and (4) had a duration of 1 year or more. Abstracts from the literature searches were reviewed for inclusion and exclusion criteria, and mortality rate data were abstracted from the article by 1 researcher and validated by a second. A total of 2045 records were screened; 38 (1.8%) were included in the meta-analyses. DATA EXTRACTION AND SYNTHESIS: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist was followed for abstracting data and assessing data quality and validity. Data were pooled using random-effects models, and between-study variability was assessed using the I2 index. The risk of bias for each study was assessed, and funnel plots and Egger and Begg statistics were used to evaluate publication bias. MAIN OUTCOMES AND MEASURES: Associations of all drug treatments, particularly bisphosphonate and zoledronate treatments, with overall mortality. RESULTS: Of 38 clinical trials that included 101 642 unique participants, 38 were included in the meta-analyses of all drug treatments (45 594 participants randomized to placebo; 56 048 to treatment); 21 clinical trials, of bisphosphonate treatments (20 244 participants randomized to placebo; 22 623 to treatment); and 6 clinical trials, of zoledronate treatments (6944 participants randomized to placebo; 6926 to treatment). No significant association was found between all drug treatments for osteoporosis and overall mortality rate (risk ratio [RR], 0.98; 95% CI, 0.91-1.05; I2 = 0%). Clinical trials of bisphosphonate treatment (RR, 0.95; 95% CI, 0.86-1.04) showed no significant association with overall mortality. Also, clinical trials of zoledronate treatment (RR, 0.88; 95% CI, 0.68-1.13) showed no association with overall mortality rate; however, evidence existed for heterogeneity of the results (I2 = 48.2%). CONCLUSIONS AND RELEVANCE: Results of this meta-analysis suggest that bisphosphonate treatment may not be associated with reduced overall mortality rates in addition to decreased fracture risk and should only be recommended to reduce fracture risk. Additional trials are needed to clarify whether treatment with zoledronate reduces mortality rates.
IMPORTANCE: Previous studies have reported that drug treatments, particularly treatment with bisphosphonates, is associated with reduced overall mortality rates in addition to decreased fracture risk. If so, drug treatments should be recommended for this reason alone, regardless of a patient's risk of fracture. OBJECTIVE: To assess whether randomized clinical trials demonstrate that treatment with bisphosphonates, particularly zoledronate, is associated with reduced mortality rates. DATA SOURCES: Science Direct, MEDLINE, Embase, and the Cochrane Library were searched for randomized placebo-controlled clinical trials of drug treatments for osteoporosis published after 2009 and published or in press before April 19, 2019. Conference abstracts from annual osteoporosis society meetings were also included in the search. STUDY SELECTION: Included studies were clinical trials that (1) were randomized and placebo-controlled; (2) studied drug treatments with proven antifracture efficacy; (3) used agents at the approved dose for treatment of osteoporosis; and (4) had a duration of 1 year or more. Abstracts from the literature searches were reviewed for inclusion and exclusion criteria, and mortality rate data were abstracted from the article by 1 researcher and validated by a second. A total of 2045 records were screened; 38 (1.8%) were included in the meta-analyses. DATA EXTRACTION AND SYNTHESIS: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist was followed for abstracting data and assessing data quality and validity. Data were pooled using random-effects models, and between-study variability was assessed using the I2 index. The risk of bias for each study was assessed, and funnel plots and Egger and Begg statistics were used to evaluate publication bias. MAIN OUTCOMES AND MEASURES: Associations of all drug treatments, particularly bisphosphonate and zoledronate treatments, with overall mortality. RESULTS: Of 38 clinical trials that included 101 642 unique participants, 38 were included in the meta-analyses of all drug treatments (45 594 participants randomized to placebo; 56 048 to treatment); 21 clinical trials, of bisphosphonate treatments (20 244 participants randomized to placebo; 22 623 to treatment); and 6 clinical trials, of zoledronate treatments (6944 participants randomized to placebo; 6926 to treatment). No significant association was found between all drug treatments for osteoporosis and overall mortality rate (risk ratio [RR], 0.98; 95% CI, 0.91-1.05; I2 = 0%). Clinical trials of bisphosphonate treatment (RR, 0.95; 95% CI, 0.86-1.04) showed no significant association with overall mortality. Also, clinical trials of zoledronate treatment (RR, 0.88; 95% CI, 0.68-1.13) showed no association with overall mortality rate; however, evidence existed for heterogeneity of the results (I2 = 48.2%). CONCLUSIONS AND RELEVANCE: Results of this meta-analysis suggest that bisphosphonate treatment may not be associated with reduced overall mortality rates in addition to decreased fracture risk and should only be recommended to reduce fracture risk. Additional trials are needed to clarify whether treatment with zoledronate reduces mortality rates.
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