Skeletal effects of moexipril, an angiotensin-converting enzyme (ACE) inhibitor, and hydrochlorothiazide (HCTZ), a thiazide diuretic, were studied in ovariectomized (OVX) spontaneously hypertensive rats (SHR). Moexipril (10 mg/kg per day), HCTZ (10 mg/kg per day), alone or in combination, as well as 17 alpha-estradiol (30 micrograms/kg per day) were given to OVX SHR immediately after surgery and studied for short- and long-term effects (14 and 56 days respectively). All drugs were given orally. Histomorphometric data on the secondary spongiosa of proximal tibial metaphyses (cancellous bone) and tibiofibular junctions of tibial shafts (cortical bone) were analyzed. Ovariectomy induced cancellous bone loss in SHR by inducing negative bone balance. Estrogen prevented ovariectomy-induced cancellous bone loss in the SHR by reducing bone turnover and partially suppressing the coupling of bone formation to resorption on the endocortical surface. HCTZ reduced blood pressure after 1 week of treatment, yet this effect was no lower than that seen in controls after 3 weeks of treatment. Two weeks of HCTZ transiently prevented ovariectomy-induced increases in bone turnover rate and eroded surface. This delayed ovariectomy induced trabecular bone loss in the proximal tibial metaphysis, but had no effect on the tibial shaft. Like HCTZ, moexipril also reduced blood pressure after the first week of treatment but it had no apparent effect on either the proximal tibial metaphysis or the tibial shaft. A combination of moexipril and HCTZ exhibited a much more potent hypotensive effect and had the same effect on bone mass and dynamic end-points as HCTZ alone. Our data indicate that (1) HCTZ treatment has some transient beneficial effects on both antihypertension and osteoprotection in hypertensive osteopenic rats, (2) the combination of moexipril with HCTZ improved the antihypertensive effect but did not potentiate or hamper the osteoprotective effect of HCTZ, and (3) the skeletal effect of estrogen is not impacted by the hypertensive state. These findings are relevant for the use of ACE inhibitor and thiazide diuretics, alone or in combination, in antihypertensive therapy in postmenopausal women.