*Purpose: Coronary artery calcium (CAC) scoring using non-contrast cardiac CT is a well-established, noninvasive imaging biomarker for detecting subclinical atherosclerosis and stratifying cardiovascular disease (CVD) risk in asymptomatic populations. Nitrogen-containing bisphosphonates (NCBs), widely used for osteoporosis treatment, have been shown in preclinical studies to modulate vascular calcification through inhibition of farnesyl pyrophosphate synthase in the mevalonate pathway. However, clinical evidence on their cardiovascular effects remains limited and inconsistent. This study emulated a target trial to evaluate the association of NCB initiation with CAC progression assessed by cardiac CT, and with incident CVD outcomes, in a large multi-ethnic cohort of postmenopausal women.
*Methods and Materials: Among 6,814 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 1, we excluded men (due to insufficient male NCB users), premenopausal women, and prevalent users of NCBs, hormone replacement therapy, raloxifene, or calcitonin. To emulate randomization, we performed propensity score matching among 166 NCB initiators and 1,571 non-users based on FRAX variables (age, race, BMI, LDL cholesterol, alcohol use, smoking, steroid use), and baseline CAC score. This yielded a final analytic cohort of 165 NCB users matched to 473 non-users (1:3). Baseline CAC was measured using electron beam or multidetector CT, and follow-up CAC measurements with cardiac-gated multidetector CT. CAC progression was assessed using linear mixed-effects models. Incident cardiovascular disease (CVD) was evaluated using Cox proportional hazards models.
*Results: NCB initiation was not associated with CAC progression in the overall cohort (-0.01 per year, 95% CI: -0.05 to 0.01). Among participants with baseline eGFR < 65 mL/min/1.73 m², NCB use was associated with slower CAC progression (0.06 log transformed CAC Agatston units per year less than non-users, 95% CI: -0.12 to -0.007). No significant associations with CVD events were observed (HR: 0.90, 95% CI: 0.60-1.36) in the overall cohort or kidney function subgroups.
*Conclusions: Incident NCB use among postmenopausal women, was associated with reduced CAC progression only in those with impaired kidney function. However, the effect size was small and did not translate into a decreased risk of subsequent cardiovascular events.
*Clinical Relevance/Application: The observed attenuation of CAC progression among postmenopausal women with impaired kidney function initiating NCB therapy highlights a potential vascular benefit in this high-risk subgroup, warranting further investigation in prospective studies.

Elena Ghotbi MD

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