Rationale for using nitric oxide donor therapy for prevention of bone loss and treatment of osteoporosis in humans.

Nitric oxide (NO) is a ubiquitous molecule involved in most cellular functions. While osteocytes communicate between bone cells, diffusible small molecules-H(+) and NO-are involved in short-term regulation of bone metabolism. Studies conducted over the past two decades have demonstrated the regulatory role of NO in bone metabolism. Circulating NO products are significantly lower in postmenopausal women, and estrogen supplementation restores this. Skeletal beneficial effects of estrogen are abolished with NO-synthase enzyme inhibitors, suggesting some estrogenic skeletal effects are mediated through NO/cGMP pathway. Since estrogen/hormone replacement therapy (HRT) has potential adverse effects, supplementing NO directly is sensible. NO is also involved with other cellular functions, such as isoprenylation of the Rho GTPase that stimulates Rho-PK (the functioning Rho-PK in turn inactivates something that would otherwise turn on the BMP-2/Cbfa1-Runx-2 cycle), and likely to be the final common pathway of other agents including statins. The first human study using nitroglycerine in the prevention of oophorectomy-induced bone loss demonstrated an equivalent efficacy to estrogen in the prevention of bone loss. A randomized NIH-funded NOVEL clinical study is currently assessing the effectiveness of topically administered nitroglycerine in the prevention of postmenopausal bone loss. If efficacy of nitroglycerine is confirmed, it may become a highly cost-effective and safe alternative therapy to treat osteoporosis. Nitroglycerine has beneficial effects in multiple systems, especially the cardiovascular system. If results of this study confirm our hypothesis, it is plausible that nitroglycerine therapy may supplant estrogen replacement and SERMs in preventing and treating postmenopausal osteoporosis.