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Make No Bones About Nitroglycerin
Abstract & Commentary
By Rahul Gupta, MD, MPH, FACP, Clinical Assistant Professor, West Virginia University School of Medicine, Charleston, WV. Dr. Gupta reports no financial relationship to this field of study
Synopsis: In a two-year study, postmenopausal women randomized to nitroglycerin ointment group had significant increases in areal BMD at the lumbar spine, total hip, and femoral neck and decreased bone resorption.
Source: Jamal SA, et al. Effect of nitroglycerin ointment on bone density and strength in postmenopausal women: A randomized trial. JAMA 2011;305:800-807.
Osteoporosis is both common and serious. it is estimated that by the year 2025, total expenditure resulting from osteoporosis will exceed $19 billion.1 It is also clear that the patients that are most likely to benefit from therapy are those at the highest risk for osteoporosis-related fractures. The National Osteoporosis Foundation recommends treatment of postmenopausal women (and men ≥ 50 years) with a history of hip or vertebral fracture or with a diagnosis of osteoporosis based upon bone mineral density (BMD) measurement (T-score ≤ -2.5).2 The guidelines also provide specific treatment recommendations for postmenopausal women with findings of osteopenia on BMD (T-score between -1 and -2.5). In addition to the non-pharmacologic therapy, several factors play a role when considering prescribing a pharmaceutical agent. Along with costs (alendronate and estrogen being generic), prescription coverage status, sex, age, menopausal status, tolerability, and patient/provider preferences are factors that can influence the choice of an agent. With the exception of teriparatide (which stimulates new bone formation), all current agents work primarily by increasing the BMD through inhibiting bone resorption.
An ideal drug for osteoporosis would be one that works to reverse osteoporosis, not just prevent it by inhibiting bone resorption as well as stimulating new bone formation. Other characteristics of an ideal agent may include a reasonable price, wide acceptability (lower serious adverse event profile), and ease of use. Some observational studies have suggested that women taking nitrates for angina may not only have higher BMD but also fewer fractures.3 Studies have demonstrated that whereas menopause-associated decreased estrogen levels increase osteoclast activity and bone turnover, resulting in bone loss, nitric oxide (NO) has an estrogen-like beneficial effect in bone, but without estrogenic adverse effects.4 However, there is a lack of data on well conducted studies examining the effect of nitrates on BMD as a therapeutic option for treatment of osteoporosis.
In this Canadian study, Jamal et al conducted a double-blind, placebo-controlled randomized trial of 243 postmenopausal women. Participants included in the study were women aged 50 years or older who were at least 1 year postmenopausal with BMD T scores between 0 and −2.0 at the lumbar spine and higher than −2.0 at the total hip. Patients were randomized to either the nitroglycerin ointment (15 mg/d) group or placebo group, each agent being applied to skin at bedtime for 24 months. Areal BMD was measured using dual-energy x-ray absorptiometry at the lumbar spine, femoral neck, and total hip at baseline, 12 months, and 24 months.
Researchers found that compared with placebo, women randomized to the nitroglycerin group had 6.7 percent significant increases in areal BMD at the lumbar spine at 2 years. Similarly, the increases at total hip and femoral neck BMD were 6.2 percent and 7 percent, respectively. The nitroglycerin group also had increased volumetric trabecular BMD in the distal radius and tibia. Nitroglycerin ointment therapy was also associated with increases in indices of bone strength. Finally, testing for markers revealed that nitroglycerin treatment was associated with significant increases in markers of bone formation while having significant reductions in markers of bone resorption. Although the incidence of serious adverse events was not different between the two groups, women in the nitroglycerin group did report a higher incidence of headaches.
This is a well-designed study that raises the issue of whether a commonly prescribed medication such as nitroglycerin may serve as an ideal anti-osteoporosis drug. The findings of increases in areal BMD at the spine and proximal femur associated with transdermal nitroglycerin therapy as well as evidence of increased bone formation and decreased bone resorption make a compelling case. Although not studied directly, the study team even suggested that nitroglycerin therapy may lead to a reduction in bone fractures (especially in long bones). This is certainly an inexpensive option for a drug that is easy to use via a variety of routes and already widely acceptable.
It is important to point out that another recent randomized study of transdermal nitroglycerin ointment did not find any substantial BMD changes at the lumbar spine, femoral neck, or total hip between postmenopausal women who received the dose of nitroglycerin in comparison with a placebo.5 However, the patient adherence in that study was much lower, unlike the current study.
There is clearly more work to be done in this field prior to recommending nitroglycerin specifically for osteoporosis prevention, treatment, or both. This includes well designed studies to evaluate the effect of various nitroglycerin preparations in patients with osteoporosis since this study excluded such individuals. In particular, evaluating the effect of this agent on osteoporosis-related fractures is critical. Eventually, while some will have to discontinue nitroglycerin due to headaches, I believe the day is not far off when we may be able to recommend nitroglycerin as an inexpensive agent against osteoporosis. Of course, I would also not be surprised if newer, more expensive NO donor agents with specific skeletal affinity and reduced incidence of headaches also made it to the market in the next few years. Until then, I think many of us should just feel better knowing that there is at least one medication on that list for our patients that is working to provide more benefits than we thought it was intended to.
1. Burge R, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res 2007;22:465-475.
2. NOF's New Clinician's Guide to Prevention and Treatment of Osteoporosis. http://www.nof.org/professionals/clinical-guidelines. Accessed March 19, 2011.
3. Rejnmark L, et al. Decreased fracture risk in users of organic nitrates: a nationwide case-control study. J Bone Miner Res 2006;21:1811–1817.
4. Wimalawansa SJ. Nitroglycerin therapy is as efficacious as standard estrogen replacement therapy (premarin) in prevention of oophorectomy-induced bone loss: A human pilot clinical study. J Bone Miner Res 2000; 15:2240–2244.
5. Wimalawansa SJ, et al. Transdermal nitroglycerin therapy may not prevent early postmenopausal bone loss. J Clin Endocrinol Metab 2009;94:3356–3364.