Background/Purpose: Experimental studies have implicated a role for the Renin Angiotensin Aldosterone System (RAAS) in osteoporosis. However, the relationship of pharmacological inhibition of the RAAS to skeletal health is controversial.

Therefore, the purpose of this study was to determine the relationship of use of RAAS Inhibitors (Angiotensin Receptor Blockers (ARBs), Angiotensin Converting Enzyme Inhibitors (ACE), Direct Renin Inhibitors, Selective Aldosterone Receptor Blockers and RAAS inhibitors in combination with other antihypertensive medications) to incident fractures, changes in bone mineral density (BMD) and body composition measurements in postmenopausal women.

Methods: 155,565 women from the WHI Observational study (OS) and Clinical Trials (CT) were included. The BMD and body composition analyses included the 11,437 women with a Dual Energy X-ray Absorptiometry measurement. Change in BMD and body composition were modeled using linear regression. Cox proportional hazards models were fit for each fracture outcome. Change in RAAS inhibitor use over time was evaluated by entering use as a time dependent exposure variable. Unadjusted and models adjusted for demographic and clinical covariates and medication use associated with osteoporosis and a final multivariable model adjusted for all covariates plus BMD were determined.

Results: There were 13,749 (9%) users and 141,816 (91%) nonusers of RAAS inhibitors at the baseline visit of WHI. In 16.8 years of follow-up there were 34,276 total fractures, 2,912 (annualized percentage 2.20%) in the baseline users of RAAS inhibitors, 31,364 (annualized percentage 2.16%) in baseline nonusers. In unadjusted models with time-dependent covariate defined as any prior use of RAAS inhibitors, there was a significant positive association of RAAS inhibitor use with all (HR 1.05 (95% CI 1.01, 1.09)), other (HR 1.11. (1.06-1.16)) and composite fragility fractures (HR 1.11 (95% CI 1.03, 1.20)) and a significant negative association with forearm fractures (HR 0.89 (0.82, 0.97)). In final multivariable models including baseline BMD, there was no significant association of use of RAAS inhibitors with all fractures or any fracture site (clinical vertebral, forearm, hip or composite fractures (hip, humerus, clavicle, scapula)), (p> 0.13 for all) or with change in BMD of the total hip, femoral neck or lumbar spine from baseline to three (p> 0.20 for all) or six years (p>0.70 for all). There was no significant association of RAAS inhibitor use with changes in total body, lean body mass or fat mass from baseline to three (p=0.06, p=0.24, p=0.09 respectively) or six years (p=0.41, p=0.08 and p=0.95 respectively).

Conclusion: In postmenopausal women, use of RAAS inhibitors does not appear to be importantly related to osteoporosis endpoints. However, there may be differences among individual classes of RAAS inhibitors and their relationship to skeletal health, which deserve further exploration.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-association-of-raas-inhibitor-use-with-osteoporosis-findings-from-the-womens-health-initiative/