Osteoporotic fracture risks of thiazides and dihydropyridines in angiotensin modulator users

Summary: This study examined the impact of thiazide and RAAS antihypertensive medications vs DHP-RAAS medications on fracture risk. The close alignment of such settings with clinical use, combined with the potential bone benefits of ACEis and ARBs, provides enhanced accuracy in bone health evidence. Purpose: To determine whether thiazides, combined with either angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB), offer bone-protective benefits compared with dihydropyridine (DHP) drugs combined with ACEi or ARB. Methods: This retrospective cohort study was conducted on the US Collaborative Network from the TriNetX database on March 5th, 2024. It included hypertensive ACEi or ARB users under thiazide or DHP drug treatments spanning from January 1st, 2015, to December 31st, 2022, with exclusion criteria applied. The primary outcome is a composite typical osteoporotic fracture (TOPF). Kaplan Meier analyses were performed after 1:1 propensity-score matching (PSM) with a 5-year follow-up. Besides investigating fracture-related outcomes in thiazide-ACEi/ARB and DHP-ACEi/ARB users, this study explores whether the effects differ between ACEi and ARB users. Subgroup analyses were also performed, and the heterogeneity among the results was assessed using Cochran’s Q-tests. Results: Post-PSM results yield 54,240 patients per cohort in the primary analysis, aging 61.5 ± 12.2 versus 61.4 ± 13.7 (thiazide-ACEi/ARB versus DHP-ACEi/ARB) with predominantly white ethnicity. Thiazide-ACEi/ARB users exhibit lower TOPF risk than DHP-ACEi/ARB users (hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.61–0.70), and such benefits from thiazides are similar between ACEi and ARB users (ACEi: HR = 0.69; ARB: HR = 0.67, Cochran’s Q-test p-value = 0.78). Additionally, the effects of thiazides reveal significant heterogeneity between patients with and without inflammatory polyarthropathy (ICD-10, M05-M14) and benzodiazepine usage (Cochran’s Q-test p-value = 0.01, 0.04). Conclusion: Thiazides are associated with lower risks of typical osteoporotic fractures compared to DHP drugs in patients treated with ACEi or ARB, while such benefits may diminish in those with a diagnosis of inflammatory polyarthropathy and benzodiazepine usage.