Thiazide type diuretics are known to improve bone strength and reduce risk of fractures. Many observational studies have suggested this advantage of diuretics regarding bone strength. There is probably a positive effect on calcium balance and direct stimulation of osteoblasts. Beta-blockers may also reduce fracture risk but the jury is till out on the mechanism. Studies have shown that ACE inhibitors by blocking local angiotensin production that increases osteoclast activity increase bone strength. Some studies suggest lower fracture risk with ACE inhibitors but all do not agree. Little data is available on effect of calcium channel blockers on bone durability.

The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a large randomized trial that compared efficacy of antihypertensive drugs in preventing mortality, myocardial infarction, and stroke. The trial recorded that amlodipine (calcium channel blocker), lisinopril (ACE inhibitor), doxazosin (a-receptor blocker) were not superior to the diuretic chorthalidone in prevention of coronary events, or any other cardiovascular or renal outcomes. Chlorthalidone was superior to amlodipine,lisinopril,and doxazosin in preventing heart failure and to lisinopril (blacks only) and doxazosin in preventing strokes.


ALLHAT was a randomized, double blind; active controlled comparing chlorthalidone (n=15,255), amlodipine (n=9048), doxazosin (9061) and lisinopril (9054). The doxazosin arm was stopped early because of a higher risk of cardiovascular disease. All patients had at least 1 additional risk factor such as previous myocardial infarction or stroke, left ventricular hypertrophy by ECG or echo, history of type 2 diabetes, current cigarette smoking and low high-density lipoprotein cholesterol level.


JAMA (21st November 2016;online) has published a secondary analysis of the ALLHAT trial, which, shows that patients on chorthalidone had a lower risk of fracture than those on lisinopril or amlodipine (HR 0.87). The ALLHAT trial originally included 22,180 patients who were followed for an average 4.9 years and post trial follow up. Crucially, several groups of participants at high risk for fracture such as those with active coronary artery disease, heart failure and chronic kidney disease. Hence results cannot ne extrapolated to such groups.


A total of 22,180 participants were followed for 8 years. After trial completion ore than 16,000 patients for whom claims data were available were followed for up to 5 additional years. There were 338 fractures that occurred. During the trial, risk of fracture was significantly lower in patients assigned to chlorthalidone vs. lisinopril (HR 0.75; P=0.04) but not significantly lower than in those in the amlodioine group (HR 0.82; P=0.17).


During the entire trial and post trial follow up, the cumulative incidence of fractures was nonsignificantly lower in participants randomized to receive chorthalidone vs. lisinopril or amlodipine (HR 0.87;P=0.10) and vs. each medication separately.


The investigators acknowledged the potential for bias and cross over among groups, with 81% of the chlorthalidone, 80% of the amlodipine, and 73% of the lisinopril groups persisting with their respective medication at 5 years. After trial completion 16,662


The investigators found that in their post hoc analysis of an older cohort randomly assigned to 3 classes of first step antihypertensive medication, the risk of hip and pelvic fractures during in-trial follow up was lowest with the diuretic chorthalidone compared with amlodipine or lisinopril. This finding was consistent in all subgroup comparisons. They cite a meta-analysis of 21 case-control and cohort studies that concluded treatment with thiazide diuretics was associated with 24% lower risk of hip fractures compared with other antihypertensive agents (HR 0.76).


This secondary analysis of a randomized clinical trial confirms previous observational reports that use of thiazide type diuretics is associated with significantly lower risk of hip and pelvic fractures compared with a ACE inhibitor or a calcium channel blocker, and the effect last for a number of years. The risk of fracture was significantly more in patients randomized to lisinopril but not significantly more in those on amlodipine compared to chorthalidone.



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