THIAZIDE EFFECTS ON BONE AND ARTERIES

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Estrogen-deficient postmenopausal women develop both osteoporosis and coronary artery atherosclerosis (CAA). Consequently, drugs with potential for use in treating osteoporosis must also be evaluated for their effect on CAA. Like women, surgically postmenopausal macaques develop osteopenia and CAA. The primary objective of this study is to evaluate, in surgically postmenopausal monkeys, whether a commonly prescribed antihypertensive drug (hydrochlorothiazide) can prevent postmenopausal bone loss. A complementary objective is to evaluate the effects of the thiazide on CAA. The goals are: 1) to determine if daily thiazide therapy protects against the bone loss seen in surgically postmenopausal monkeys, and to determine if thiazide therapy is as effective as hormonal (estrogen and progesterone) replacement therapy (HRT) in protecting against postmenopausal bone loss; 2) to determine if concurrent thiazide therapy and HRT provides additive increases in bone volume, density, and strength in surgically postmenopausal macaques; 3) to study mechanisms by which these compounds may prevent bone loss; and 4) to evaluate whether long- term thiazide treatment affects diet-induced CAA in surgically menopausal monkeys. A prospective trial of this nature cannot be done in human beings because of the invasive nature, expense, and complicating and uncontrolled variables. Experiment: 100 young adult female cynomolgus macaques will be divided into 4 groups of 25 animals each: Group 1) ovariectomized (OVX), untreated; Group 2) OVX, treated with hydrochlorothiazide for 24 months; Group 3) OVX, treated for 24 months with HRT; Group 4) OVX, treated with hydrochlorothiazide and HRT daily for 24 months. Throughout the 24-month trial, blood pressure, serum and urinary chemistry, serum and urinary markers of bone turnover, plasma lipids, noninvasive densitometry, radiography, histomorphometric analysis of bone biopsies, sex hormone levels, and body measurements will be evaluated. At the end of the trial, all monkeys will be necropsied and the groups compared for bone parameters and CAA extent by histomorphometry.