Osteoporosis — literally “porous bone”— is the most common metabolic bone disease. Characterized by bone loss and deterioration of bone quality, it leads to bone fragility and an increased risk of fractures. It is responsible for approximately 1.6 million fractures, primarily of the hip, spine and wrist each year, and for medical expenses of $20 billion annually in this country. Not only do a high percentage of patients who experience a broken hip require permanent nursing care, these fractures are also a significant cause of morbidity and mortality in elderly people. Until recently, little could be offered to these individuals to slow or halt the progression of osteoporosis, and it was accepted as part of the aging process. Today, an increasing number of highly effective medications that reduce the risk of osteoporotic fractures by half are available to help treat osteoporosis. However, these agents are very costly and have significant adverse effects, such as upper gastrointestinal irritation/ulceration, constipation, enhanced arterial and venous thrombosis, and increased fracture incidence with over-treatment. Some studies have shown that nitroglycerin, a commonly used heart medication, may preserve bone density. Our group is currently investigating whether a nitroglycerin-based ointment would be effective in reducing bone thinning in menopausal women.
Unlike some diseases, osteoporosis can be easily diagnosed and treated. The keys to preventing fractures are a bone-healthy lifestyle, early detection of the disease by bone mineral density (BMD) testing, elimination of secondary causes of bone loss and prevention of falls. In the past, many women relied on hormone replacement therapy (HRT) after menopause to reduce the risk of heart disease and osteoporosis. However, the Women’s Health Initiative (WHI) study recently demonstrated that, although effective in fracture prevention, HRT may actually increase the risk of stroke, heart disease and breast cancer. In addition, some postmenopausal women have additional side effects, and
others cannot afford HRT or other expensive medications that combat osteoporosis. Thus, finding a cost-effective alternative therapy is essential.
Nitroglycerin is a common heart medication used to dilate blood vessels, decrease blood pressure, improve circulation and control angina. Studies conducted by our group over the past 18 years in laboratories and clinics have shown that nitroglycerin may preserve the skeletal system, and thus slow or prevent the bone-thinning process.
The Regional Osteoporosis Center at UMDNJ-Robert Wood Johnson Medical School (RWJMS) provides state-of-the-art bone mineral density testing, which is an integral part of a new clinical trial known as the NOVEL study. [The acronym NOVEL stands for “Nitroglycerin as an Option: Value in Early Bone Loss.”] This five-year study is funded by the National Institute of Arthritis and Musculoskeletal Diseases at the National Institutes of Health. The RWJMS site has a unique focus. We asked the questions: Can Nitro-Bid® ointment, which contains nitroglycerin, stop bone thinning in menopausal women? Can this be an alternative to estrogen and HRT therapy?
Figures 1 through 3: Maturation of an Osteoclast
Treatment consists of a daily application of Nitro-Bid® ointment (manufactured by E. Fougera & Co., a division of Altana Pharmaceuticals) or a placebo ointment to the arms or legs. Nitroglycerin (NTG) is 1,2,3-propantriol, an organic vasodilator nitrate. Nitroglycerin ointment has been on the market for more than 25 years and its adverse effects are well documented. In addition to a patent (US patent # 5,898,038; PCT pending), an IND application has been filed with the Food and Drug Administration for the administration of this ointment under this protocol for the indications of osteoporosis prevention and treatment. It is supplied as USP 2%, is in 60-gram tubes and should be stored at 15-30°C (59-86°F). The average NTG dose used in clinical practice to treat angina ranges from 15 to 30 mg, 2 to 3 times a day (>60 mg of NTG/day, or bio-equivalent for other nitrates); however, the NTG dose used in this NOVEL study is only 20 mg per day.
All participants receive 630 mg of elemental calcium and 400 IU of vitamin D daily (Citracal-D®, Mission Pharmacal), providing an estimated total daily intake of 1,400 mg calcium and 800 IU vitamin D per day. In this randomized, double-blind, controlled clinical study, the results of bone mineral density tests of women using only calcium and vitamin D will be compared with those using the active nitroglycerin ointment and taking
calcium and vitamin D supplements. This ointment is far less expensive than the U.S. Food and Drug Administration approved drugs for osteoporosis.
As a nitric oxide (NO) donor, nitroglycerin has a beneficial effect on controlling bone destruction while improving bone formation. In addition, at physiological doses, NO decreases the stickiness of platelets, which is responsible for clogging arteries. Evidence is also accumulating that, at physiological doses, NO may also prevent cell death in vital organs such as heart, brain and pancreatic beta cells. The most common, only significant, adverse effect of nitroglycerin is the occurrence of mild headache in about 10% of the subjects who use this ointment. The dose of nitroglycerin used in this study is about one quarter of that routinely used in angina patients. Since menopause leads to NO deficiency, there is a plausible biological basis for use of NO replacement therapy (NO supplementation). Well-established exogenous NO sources, such as nitroglycerin ointment, constitute a practical way to supplement NO when the body cannot generate enough for normal biological functions.
For postmenopausal women who cannot tolerate or afford costly HRT and other FDA-approved medications, nitroglycerin treatment could be utilized for less than $5 a month. Our preliminary human studies demonstrated that the efficacy of nitroglycerin in preventing postmenopausal bone loss is equivalent to Premarin®, and that nitroglycerin has beneficial additive effects on bone mineral density when co-administered with some established anti-osteoporosis therapies. This is yet another exciting area to be explored.
Sunil Wimalawansa, MD, PhD, MRCPath, FRCP, DSc, is a professor of medicine, chief of the Division of Endocrinology, Metabolism & Nutrition, and director of the Regional Osteoporosis Center at UMDNJ-Robert Wood Johnson Medical School. He also holds the distinction of University Professor. Dr. Wimalawansa received his MD from the University of Sri Lanka (1975) and his PhD from the University of London (1988), and diploma in Business of Medicine from the Johns Hopkins School of Business (1999). He has received several awards from national and international societies. He has been involved in many volunteer humanitarian and social development activities over the past 35 years. He serves on several national review committees, including NIH, DEA and NASA, and several other national and international committees and advisory panels. His main focus of research is metabolic bone disease, in particular osteoporosis and biochemical and molecular approaches to basic cardiovascular disease, including gene therapy.§