Nitric oxide (NO) is known to affect bone metabolism. Previous animal studies have shown that NO donor therapy can prevent ovariectomy (OVX)‐induced as well as corticosteroid‐induced bone loss. Therefore, we have carried out a 1‐year human, randomized, controlled pilot clinical study to assess the efficacy of nitroglycerin (NG) in the prevention of estrogen‐deficiency‐induced bone loss in women. We observed that NG ointment, when applied to the skin once a day (within 4 weeks of undergoing oophorectomy), mimicked estrogen replacement therapy in prevention of bone loss. The primary outcome of bone mineral density (BMD) was not different in the two groups at the end of 1 year. Urinary N‐telopeptide levels were significantly decreased after administration of either estrogen or NG. Although estrogen decreased serum osteocalcin and bone‐specific alkaline phosphatase levels, NG therapy significantly increased these two markers of bone formation. Further, it was revealed that for up to 1 year, these doses of NG did not result in tachyphylaxis. This study showed for the first time that NG is as effective as estrogen in preventing bone loss in these surgically induced menopausal women. Additionally, the dose of NG used in this study was three to four times less than that generally used to affect cardiovascular homeostasis. Although in this randomized clinical study only a small number of patients was examined, data are encouraging. If these data hold true in large randomized, controlled clinical trials, then NG could emerge as an efficacious, cost‐effective, affordable, safe, and convenient form of therapy (especially as an alternative therapy to hormone‐replacement therapy [HRT]) for prevention of postmenopausal bone loss.