Ovariectomy rapidly induces strong osteoclast differentiation, leading to a marked loss of cancellous bone in the rat appendicular skeleton. As we found that histamine inhibition prevented periosteal bone resorption in rats, we tested the hypothesis that cimetidine, an H(2) receptor antagonist, prevents the osteoclastic burst and subsequent trabecular bone loss in this setting. Forty female Sprague-Dawley rats were ovariectomized (ovx) or sham-operated. Rats from each group received daily intramuscular injections of cimetidine (125 mg/kg per day) or vehicle. The animals were killed 14 days after surgery, and their femora were processed for morphometry. Cimetidine had no effect on serum estradiol levels in the control and ovx rats. BV/TV was reduced by 36% in the ovx rats, and by 10% in the cimetidine treated rats (p < 0.01). Tb.N and Tb.Wi were significantly reduced by 30% in the ovx rats and by 15% ovx-treated ones. OcS/BS did not change in the treated ovx rats, but increased 3.7-fold in the untreated ovx ones (p < 0.001). The N.Oc/TBPm increased markedly in the ovx rats (2.6-fold, p < 0.0001 vs. controls), but only slightly in the cimetidine-treated animals (+18%, p < 0.05 vs. controls), with a significant difference between the cimetidine-treated and -untreated ovx animals (p < 0.001). Cimetidine had no effect on these parameters in sham-operated animals. These results show that histamine inhibition by an H(2) receptor antagonist partially prevents the consequences of castration on cancellous bone, possibly by an action on osteoclast differentiation. Interestingly, cimetidine had no effect on basal resorption along trabecular bone. Histamine inhibition by H(2) blockers warrants further investigation in this model of osteopenia.