Treatment with zoledronic acid for osteoporosis may be associated with an increased risk for heart failure, fracture, and mortality compared with the use of oral bisphosphonates or no treatment, according to study results published in Bone. However, no increase in cardiovascular mortality was noted with zoledronic acid use.

The HORIZON-PFT trial ( Identifier: NCT00049829) reported a significant reduction in vertebral, hip, and nonvertebral fractures with 3 annual doses of 5 mg zoledronic acid in women with postmenopausal osteoporosis. However, aside from these benefits, there was a significant increase in atrial fibrillation serious adverse events with zoledronic acid, leading the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) to request longer follow-up of the skeletal and cardiovascular safety of zoledronic acid.

The goal of the current study was to assess cardiovascular and skeletal risks associated with zoledronic acid use for osteoporosis in real-world users.

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Based on data from nationwide registries in Sweden and Denmark, the researchers identified adults treated with zoledronic acid or oral bisphosphonates, as well as patients who did not receive treatment with anti-osteoporosis drugs. They matched zoledronic acid users 1:3 to the comparison groups separately for each country and calendar year by propensity score quintiles. The study cohort included a total of 8760 zoledronic acid users, including 8739 who were compared with individuals who received oral bisphosphonates between 2007 and 2012 (n=25,577) and 8731 who were compared with individuals who received no osteoporosis treatment (n=25,924).

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The primary outcomes included cardiovascular disease and skeletal complications. Upon completion of the study, all-cause mortality and cardiovascular mortality were added as post hoc outcomes.

Atrial fibrillation and arrhythmias were more common in zoledronic acid users (32.1 and 37.0 patients per 1000 patient-years, respectively) compared with bisphosphonate users (30.8 and 34.6 patients per 1000 patient-years, respectively) or untreated individuals (28.6 and 32.6 per 1000 patients-years, respectively). Fractures were also more common in zoledronic acid or bisphosphonate users (30.7 and 30.5 per 1000 person-years, respectively) compared with untreated individuals (21.7 per 1000 person-years).

The risk for heart failure was significantly higher with zoledronic acid use compared with bisphosphonate treatment (adjusted hazard ratio [aHR], 1.17; 95% CI, 1.04-1.32) or no treatment (aHR, 1.38; 95% CI, 1.24-1.54). In a similar fashion, the risk for all-cause mortality was higher with zoledronic acid use compared with bisphosphonate treatment (aHR, 1.24; 95% CI, 1.15-1.34) or no treatment (aHR, 1.09; 95% CI, 1.01-1.18). As for cardiovascular mortality, there was no difference with the use of zoledronic acid vs bisphosphonates, whereas cardiovascular mortality was lower in zoledronic acid users than in the control group (aHR, 0.87; 95% CI, 0.77-0.98).

The results also indicated increased risk for skeletal outcomes with zoledronic acid. Compared with oral bisphosphonates, zoledronic acid use was associated with increased risk for fracture of the subtrochanteric femur or the femoral shaft (aHR, 1.91; 95% CI, 1.38-2.64) and non-hip femur fracture (aHR, 1.57; 95% CI, 1.20-2.04). However, there was no significant difference in the overall fracture risk between the groups. In the crude analysis, the risk for osteonecrosis of the jaw was higher in zoledronic acid users (aHR, 2.21; 95% CI, 1.03-4.74) compared with bisphosphonate users. Compared with the control group, risk for all fracture types and osteomyelitis and osteonecrosis of the jaw was higher with zoledronic acid treatment.

Sensitivity analyses produced similar findings with no substantial changes in event rates.

The researchers acknowledged several study limitations, including the observational design; missing data on treatment indication, bone mineral density, and compliance with treatment; and lack of primary care records.

“Taken together, these findings are compatible with a higher base risk for mortality, fractures and heart failure in patients who begin [zoledronic acid] treatment for osteoporosis,” concluded the researchers.

Disclosure: This study was supported by Novartis AG, Switzerland. Please see the original reference for a full list of authors’ disclosures.


Rubin KH, Möller S, Choudhury A, et al. Cardiovascular and skeletal safety of zoledronic acid in osteoporosis observational, matched cohort study using Danish and Swedish health registries [published online February 22, 2020]. Bone. doi:10.1016/j.bone.2020.115296

This article originally appeared on Endocrinology Advisor