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Thiazide-type diuretics reduce risk for hip, pelvic fractures

Thiazide-type diuretic therapy was associated with a lower risk for hip and pelvic fractures compared with other antihypertensive medications, according to study results published in JAMA Internal Medicine.

“Hypertension and osteoporotic fractures are age-related disorders whose incidences increase rapidly after the age of 65 years,” Rachel Puttnam, MD, from the division of endocrinology at the Kaiser Permanente of Georgia, and colleagues wrote. “The conditions are interrelated because people with hypertension have more osteoporotic fractures than people without hypertension. A meta-analysis revealed that many nonrandomized, observational studies suggest that therapy with thiazide-type diuretics improves bone strength and reduces fracture risk.”

“[However], data from randomized clinical trials are lacking,” they added.

Puttnam and colleagues performed a secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) to determine the association between thiazide diuretic therapy for the treatment of hypertension and fracture risk. They utilized trial data from the Veterans Affairs and Medicare claims databases, focusing on hip and pelvic fracture hospitalizations. Participants in this trial (n = 22,180; mean age, 70.4 years; 43% female; 49.9%, 31.2% black, 19.1% other ethnicity), recruited between February 1994 and January 1998, were randomly assigned to receive first-step therapy with either a thiazide-type diuretic (chlorthalidone), an angiotensin-converting enzyme inhibitor (lisinopril) or a calcium channel blocker (amlodipine besylate). During the trial, patients were followed for up to 8 years, and post-trial follow-up lasted up to 5 years for participants with available data.

A total of 338 fractures were documented during the trial. Adjusted analysis showed that patients treated with chlorthalidone had a 21% reduced risk for fracture compared with patients treated with either lisinopril or amlodipine besylate (HR = 0.79; 95% CI, 0.63-0.98; P = .04). This benefit was driven by the comparison of chlorthalidone and lisinopril, where there was a significantly lower risk of fracture following treatment with chlorthalidone (HR = 0.75; 95% CI, 0.58-0.98; P = .04); there was no significant difference compared with those in the amlodipine besylate group (HR = 0.82; 95% CI, 0.63-1.08). In the in-trial plus posttrial cohort, patients who received chlorthalidone had a lower cumulative incidence of fractures that was nonsignificant (HR = 0.87; 95% CI, 0.74-1.03; P = .10) compared to patients who received lisinopril or amlodipine besylate. Similar results were observed in sensitivity analyses where the researchers used 1 year after randomization as the baseline.

“The present results of short-term and long-term fracture protection with thiazide antihypertensive therapy compared with other antihypertensive medications strongly recommend use of a thiazide for hypertension treatment in addition to its long track record of cardiovascular protection,” Puttnam and colleagues concluded.

In a related editorial, Cathleen S. Colón-Emeric, MD, MHS, and Richard Lee, MD, MHS, both from Duke University School of Medicine, wrote that the results of ALLHAT alleviated important concerns of unmeasured confounders of prior observational studies due to its large sample size and randomization. However, these findings most likely do not insinuate that patients treated with antihypertension medications other than thiazide-type diuretics are at an increased risk for fracture.

“Is the dual benefit of thiazides a happy coincidence or related to a common underlying mechanism of action in vascular tissue and bone?” Colón-Emeric and Lee wrote. “The science here is thin, and additional studies examining the overlap between cardiovascular disease and metabolic bone disease may help us develop other pleiotropic agents with a beneficial effect on both systems. Although we have avoided complexity in the case of choosing antihypertensive medications, we have yet to reach genius-level understanding that explains the complex interactions among bone, vascular disease, and the drugs that treat them.” – by Alaina Tedesco

Disclosure: Puttnam and colleagues report funding from the National Heart, Lung, and Blood Institute. Colón-Emeric and Lee do not report any relevant financial disclosures.