It seems that exercise can partially prevent estrogen deficiency-induced bone loss by suppressing bone resorption and increasing bone formation. While it is still debated whether decreased bone resorption or increased bone formation is the main reason behind exercise-induced bone mass elevation, our results support the involvement of both events. Estrogen exerts its anti-osteoporotic activity by directly or indirectly regulating bone resorption. While there is convincing evidence that estrogen, acting via estrogen receptor a, stimulates osteoclast apoptosis and suppresses osteoblasts apoptosis, estrogen has been shown to act on MSCs and osteoblasts to regulate the expression of cytokines and growth factors that control osteoclast differentiation and activity. Since long-term HRT has adverse effects, caution is expected in choosing HRT for prevention and treatment of osteoporosis in women. On the other hand, a number of studies have shown that appropriate intensities of exercise can increase serum levels of estradiol and testosterone, which helps to improve osteoblast proliferation and activity, leading to an increase in bone mass and density. However, some clinical studies showed that the estrogen levels were unchanged in response to exercise. This discrepancy could be caused by the difference in the intensities of exercise, the age and ethnicity of the patients, or both. Nevertheless, this study shows that wheel running increases serum E2 in ovariectomized rats, which can slow down bone loss induced by ovariectomy. In addition, the levels of CT, an inhibitor of osteoclast differentiation and activity, are also decreased after ovariectomy, likely due to estrogen shortage. Indeed, previous studies have shown that estrogen stimulates the synthesis of CT. We found that exercise also increases the levels of CT in ovariectomized rats, which might be a BAY 73-4506 755037-03-7 result of increased estrogen. We found that the OVX group rats showed higher levels of BGP and PTH than the control group. BGP is a hormone-like peptide synthesized and secreted by osteoblasts and is significantly increased in the serum of postmenopausal women. It has prominerilization function and is an indicator of in vivo bone formation rate. Thus, it is possible that estrogen regulates bone formation and bone resorption thorugh these two hormones as well. The observation that supplementation with diethylstilbestrol reversed the alteration in BGP and PTH expression in ovariectomized rats suggests that estrogen deficiency is the underlying cause for the change in BGP and PTH levels. In addition, we found that exercise decreases the levels of BGP in ovariectomized rats, which might be due to the increase in the E2 levels. Our study further showed that the protein and mRNA levels of the bone marrow IL-1b and osteoblastic IL-6 and COX-2 were increased in ovariectomized rats. The change in the levels of these proteins was highly related to E2, as there is no significant difference between the DES-OVX group and the sham-operated group. Charatcharoenwitthaya et al. demonstrated that in humans, like in rodents, part of the effects of estrogen deficiency on increased bone resorption is mediated by IL-1.