Summary: In this prospective cohort of 6120 participants aged 50+, nitrogen-bisphosphonates but not non-nitrogen bisphosphonates were associated with a significant 34% mortality risk reduction compared to non-treated propensity score matched controls. These findings open new avenues for research into mechanistic pathways. Introduction: Emerging evidence suggests that bisphosphonates (BP), first-line treatment of osteoporosis, are associated with reduced risks for all-cause mortality. This study aimed to determine the association between different BP types and mortality risk in participants with or without a fracture. Methods: A prospective cohort study of users of different BPs matched to non-users by propensity score (age, gender, co-morbidities, fragility fracture status) and time to starting the BP medication from the population-based Canadian Multicentre Osteoporosis Study from nine Canadian centres followed from 1995 to 2013. Mortality risk for bisphosphonate users vs matched non-users was assessed using pairwise multivariable Cox proportional hazards models. Results: There were 2048 women and 308 men on BP and 1970 women and 1794 men who did not receive medication for osteoporosis. The relationship between BP and mortality risk was explored in three separate 1:1 propensity score-matched cohorts of BP users and no treatment (etidronate, n = 599, alendronate, n = 498, and risedronate n = 213). Nitrogen BP (n-BP) (alendronate and risedronate) was associated with lower mortality risks [pairwise HR, 0.66 (95% CI, 0.48–0.91)] while the less potent non-n-BP, etidronate, was not [pairwise HR: 0.89 (95% CI, 0.66–1.20)]. A direct comparison between n-BP and etidronate (n = 340 pairs) also suggested a better survival for n-BP [paired HR, 0.47 (95%CI, (95% CI, 031–0.70)] for n-BP vs. etidronate]. Conclusion: Compared to no treatment, nitrogen but not non-nitrogen bisphosphonates appear to be associated with better survival.
Bibliographical noteFunding Information:
Funding information The Canadian Multicentre Osteoporosis Study was funded by the Canadian Institutes of Health Research (CIHR); Merck Frosst Canada Ltd.; Eli Lilly Canada Inc.; Novartis Pharmaceuticals Inc.; The Alliance: Sanofi-Aventis & Procter and Gamble Pharmaceuticals Canada Inc.; Servier Canada Inc.; Amgen Canada Inc.; The Dairy Farmers of Canada and The Arthritis Society.
Conflicts of interest DB, TT, TvG, CB, DG, RGJ, LL, CSK, SMK and JCP have no competing interests to declare. JDA has received research grants and/or personal fees from Amgen, Eli Lilly, Merck, Actavis and AgNovos. JvdB has received grants and/or personal fees from Amgen, MSD and Eli Lilly. JAE has consulted for and/or received research funding from Amgen, deCode, Merck Sharp and Dohme and Sanofi-Aventis. PG was advisory member for Amgen, has received speaker fee and/or research grants from Amgen, Pfizer, MSD, UCB, Abbott, Lilly, BMS, Novartis, Roche and Will Pharma. DAH has consulted for and/or received speaker fee and/or research funding from Amgen, Merck and Eli Lilly. TVN has received honoraria for consulting and symposia from Merck Sharp and Dohme, Roche, Servier, Sanofi-Aventis and Novartis. JRC has consulted for and/or given educational talks for Merck Sharp and Dohme, Amgen, Actavis and Sanofi-Aventis.
DB, TT, TvG, JAE and JRC designed the study. DB, TT, JAE and JRC analysed the data. DB, TT and JRC drafted the manuscript. All authors contributed to the interpretation of the data and revision of the manuscript. JRC had primary responsibility for final content and acts as guarantor. All authors read and approved the final manuscript. The funding sources had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; nor did they have a role in preparation, review, or approval of the manuscript and the decision to submit for publication.
This work was supported by the National Health Medical Research Council Australia Projects 1070187, 1008219, and 1073430. Other funding bodies were an Osteoporosis Australia-Amgen grant; the Bupa Health Foundation (formerly MBF Foundation); the Mrs. Gibson and Ernst Heine Family Foundation; and untied grants from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Servier and Novartis. DB was supported by an ANZBMS mid-career gap fellowsip.
- Mortality risk
- Prospective study