Association of Alendronate and Risk of Cardiovascular Events in Patients With Hip Fracture

Sing, Chor‐Wing; Wong, Angel; Kiel, Douglas P.; Cheung, Eric F.C.; Lam, Joanne K.Y.; Cheung, Tik Shing; Chan, Esther W.; Kung, A. W. C.; Wong, Ian C K; Cheung, Ching‐Lung

doi:10.1002/jbmr.3448

Cited by 76 publications

(58 citation statements)

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“…Therefore, osteoclast inhibitors, such as bisphosphonates and inhibitors of RANKL, inhibit reactivation of dormant micrometastases in animal models, (33) and reduce persistence of tumor cells in bone marrow in women with breast cancer. (38)(39)(40) Alendronate reduced carotid artery intima-media thickness in a nonrandomized but controlled study of 72 women, (41) and zoledronate has been shown to reduce both high-density lipoprotein (HDL) cholesterol and carotid artery intima-media thickness in a randomized trial of 60 postmenopausal women. (36) There is also a substantial body of preclinical and observational evidence that bisphosphonates reduce the risk of vascular disease.…”

Section: Discussionmentioning

confidence: 99%

“…(37) Longitudinal, nonrandomized studies have shown that bisphosphonate use is associated with 28% to 75% reductions in incident myocardial infarction, though these findings could be subject to bias. (38)(39)(40) Alendronate reduced carotid artery intima-media thickness in a nonrandomized but controlled study of 72 women, (41) and zoledronate has been shown to reduce both high-density lipoprotein (HDL) cholesterol and carotid artery intima-media thickness in a randomized trial of 60 postmenopausal women. (42) A recent meta-analysis of 61 trials in patients with either malignant or benign conditions (the latter mainly osteoporosis) suggested bisphosphonate reduced arterial wall calcification (two trials), cardiovascular mortality (10 trials; risk ratio 0.81; 95% CI, 0.64 to 1.02), and all-cause mortality (48 trials; risk ratio 0.90; 95% CI, 0.84 to 0.98), but without a significant change in total cardiovascular events (risk ratio 1.03; 95% CI, 0.91 to 1.17), stroke (risk ratio 1.06; 95% CI, 0.82 to 1.35), or myocardial infarction (risk ratio 0.82; 95% CI, 0.57 to 1.17).…”

Section: Discussionmentioning

confidence: 99%

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Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women

Reid

Horne

Mihov

et al. 2019

Journal of Bone and Mineral Research

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We recently showed that zoledronate prevented fractures in older women with osteopenia (hip T-scores between −1.0 and −2.5). In addition to fewer fractures, this study also suggested that women randomized to zoledronate had fewer vascular events, a lower incidence of cancer, and a trend to lower mortality. The present analysis provides a more detailed presentation of the adverse event data from that study, a 6-year, double-blind trial of 2000 women aged >65 years recruited using electoral rolls. They were randomly assigned to receive four infusions of either zoledronate 5 mg or normal saline at 18-month intervals. Supplements of vitamin D, but not calcium, were provided. There were 1017 serious adverse events in 443 participants in the placebo group, and 820 events in 400 participants in those randomized to zoledronate (relative risk = 0.90; 95% CI, 0.81 to 1.00). These events included fractures resulting in hospital admission. Myocardial infarction occurred in 39 women (43 events) in the placebo group and in 24 women (25 events) in the zoledronate group (hazard ratio 0.60 [95% CI, 0.36 to 1.00]; rate ratio 0.58 [95% CI, 0.35 to 0.94]). For a prespecified composite cardiovascular endpoint (sudden death, myocardial infarction, coronary artery revascularization, or stroke) 69 women had 98 events in the placebo group, and 53 women had 71 events in the zoledronate group (hazard ratio 0.76 [95% CI, 0.53 to 1.08]; rate ratio 0.72 [95% CI, 0.53 to 0.98]). Total cancers were significantly reduced with zoledronate (hazard ratio 0.67 [95% CI, 0.51 to 0.89]; rate ratio 0.68 [95% CI, 0.52 to 0.89]), and this was significant for both breast cancers and for non-breast cancers. Eleven women had recurrent or second breast cancers during the study, all in the placebo group. The hazard ratio for death was 0.65 (95% CI, 0.40 to 1.06; p = 0.08), and 0.51 (95% CI, 0.30 to 0.87) in those without incident fragility fracture. These apparent beneficial effects justify further appropriately powered trials of zoledronate with these nonskeletal conditions as primary endpoints.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women

Reid

Horne

Mihov

et al. 2019

Journal of Bone and Mineral Research

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“…Studies reported that patients treated with intravenous N-BPs had a significant reduction in LDL-C level[43][44][45][46] although studies examining patients treated with oral N-BP gave inconsistent results47 . Use of N-BPs was also associated with lower risk of cardiovascular mortality and incident myocardial infarction in hip fracture patients48 . Mevalonate pathway is the possible link between bone and lipid metabolism.Our MR analyses demonstrated that decrease in LDL-C level was causally associated with increase in BMD but not fracture.…”

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confidence: 89%

Positive effects of low LDL-C and statins on bone mineral density: an integrated epidemiological observation analysis and Mendelian Randomization study

Cheung

et al. 2019

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BackgroundLow-density lipoprotein cholesterol (LDL-C) is suggested to play a role in osteoporosis but its association with bone metabolism remains unclear. Effects of LDL-C-lowering drugs on bone are also controversial. We aim to determine whether LDL-C is linked causally to BMD and assess the effects of LDL-C-lowering drugs on BMD. MethodsAssociation between blood lipid levels and BMD was examined by epidemiological observation analyses in US representative cohort NHANES III (N=3,638) and Hong Kong Osteoporosis Study (HKOS; N=1,128). Two-sample Mendelian Randomization (MR), employing genetic data from GWAS of blood lipids (N=188,577), total body BMD (TB-BMD) (N=66,628) and estimated BMD (eBMD) (N=142,487), was performed to infer causality between blood lipids and BMD. Genetic proxies for LDL-C-lowering drugs were used to examine the drugs' effects on BMD. ResultsIn NHANES III cohort, each SD decrease in LDL-C was associated with 0.045 SD increase in femoral neck BMD (95% CI: 0.009 to 0.081; P=0.015). A similar increase in BMD was observed in HKOS at femoral neck and lumbar spine. In MR analysis, decrease in genetically predicted LDL-C was associated with increase in TB-BMD [estimate per SD decrease, 0.038 (95% CI: 0.002 to 0.074); P=0.038] and eBMD [0.076 (0.042 to 0.111); P=1.20x10 -5 ]. Reduction of TB-BMD was causally associated with increased LDL-C P a g e 3 [0.035 (0.033 to 0.066); P=0.034]. Statins' LDL-C-lowering proxies were associated with increased TB-BMD [0.18 (0.044 to 0.316); P=9.600x10 -3 ] and eBMD [0.143 (0.062 to 0.223); P=5.165x10 -4 ]. ConclusionsNegative causal association exists between LDL-C level and BMD. Statins' LDL-Clowering effect increases BMD, suggesting its protective effect on bone.

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confidence: 99%

“…Sing and colleagues (1) observed that individuals on alendronate (ALN) treatment had a 67% reduction in the risk of cardiovascular (CVD) mortality and 45% reduction in the risk of myocardial infarction (MI). These remarkable effect sizes deserve more explanations, and here we would like to offer an alternative interpretation relating to bias.…”

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confidence: 99%

Association Between Alendronate and All-Cause Mortality and Cardiovascular Mortality Among Hip Fracture: An Alternative Explanation

Tran

Nguyen

2018

Journal of Bone and Mineral Research

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Sing and colleagues (1) observed that individuals on alendronate (ALN) treatment had a 67% reduction in the risk of cardiovascular (CVD) mortality and 45% reduction in the risk of myocardial infarction (MI). These remarkable effect sizes deserve more explanations, and here we would like to offer an alternative interpretation relating to bias.In the study, the treated group included patients who had been on more than one anti-osteoporosis medication, and these patients were analyzed as being censored at the time of switching medication. These patients contributed to the time of follow-up in the treated group (ie, the denominator of the mortality rate), but they did not experience any event of interest because they were censored at the switching time (ie, the numerator was 0). It is not possible to examine the magnitude and direction of this bias because of no detail on how many patients had been on multiple medications. However, in the Canadian Multicentre Osteoporosis Study, we found that as many as 40% of treated patients had been given more than one anti-osteoporosis medication during the study period (2) and that including these treated patients would substantially inflate the effect size. Thus, we expect that if the censoring data were handled more sensibly, the treatment effect would be lower than reported.We consider that a more sensible question to ask is that given the data at hand, what is the chance that ALN reduces CVD mortality risk at the level of clinical significance? This question can be addressed by a Bayesian analysis, (3) which takes into account prior knowledge of the effect size and existing data. Two recent meta-analyses (4)(5)(6) suggest that bisphosphonates reduced the risk of mortality by 1% to 20% (Table 1). Using results of previous meta-analyses as prior information and given the authors' data, our analysis suggests that there is a very low probability (almost 0) that ALN reduces all-cause mortality risk or CVD mortality risk by more than 50% (Table 1). Moreover, there is less than one-third chance that ALN reduces all-cause mortality risk or CVD mortality risk by more than 30%. Even with the most optimistic prior information, there is less than 90% chance that ALN is associated with a 15% or greater reduction in CVD mortality and all-cause mortality risks.In summary, our interpretation of Sing and colleagues' data is that the large observed risk reduction in mortality associated with alendronate could be attributable to the treatment of censoring data. When considered in relation to existing data, Sing and colleagues' data suggest that in hip fracture patients, alendronate is statistically associated with reduced mortality risk, but the magnitude of association is likely modest. References1. Sing CW, Wong AY, Kiel DP, et al. Association of alendronate and risk of cardiovascular events in patients with hip fracture. J Bone Miner Res. Outcome Prior relative risk (RR) and 95% confidence interval (CI) Posterior RR and 95% CI RR < 0.5 RR < 0.7 RR < 0.85 Cardiovascular (CVD) mortality (4) 0...

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Association of Alendronate and Risk of Cardiovascular Events in Patients With Hip Fracture

Cited by 76 publications

References 46 publications

Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women

Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women

Positive effects of low LDL-C and statins on bone mineral density: an integrated epidemiological observation analysis and Mendelian Randomization study

Association Between Alendronate and All-Cause Mortality and Cardiovascular Mortality Among Hip Fracture: An Alternative Explanation

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