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Nitroglycerin Ointment and Changes in Bone Mineral Density in Postmenopausal Women
As populations worldwide age, the number of osteoporotic fractures is increasing. Nitric oxide, an inexpensive and widely available treatment, may help limit the increase. The agent can inhibit osteoclast activity and act as a signaling molecule in osteoblasts and osteocytes. Observational studies have found that older women taking nitrates intermittently for angina have higher bone mineral density (BMD) at the hip compared with nonusers and with women taking it continuously.
A short-term randomized controlled trial (RCT) found that isosorbide mononitrate taken once at bedtime decreased a marker of bone resorption and increased a marker of bone formation. No other RCT has examined the effect of nitrates on BMD, and no trial has tested the effect of nitrates on bone geometry and strength. Researchers recently conducted a single-center, double-blind, placebo-controlled randomized trial to determine if nitroglycerin increases lumbar spine BMD and to evaluate changes in hip BMD, bone geometry, and density at the radius and tibia, and markers of bone turnover. They reported results in the Journal of the American Medical Association [2011;305(8):800-807]. The trial was conducted in Toronto, Ontario, Canada, for 24 months beginning in November 2005 and completed in March 2010. Participants included 243 postmenopausal women with lumbar spine T scores between 0 and −2.0. The women were randomized to the nitroglycerin group (n=126) or the placebo group (n=117).
Compared with placebo, women randomized to the nitroglycerin group had significant increases in areal BMD at the lumbar spine (from 1.05 to 1.14 g/cm2 vs placebo from 1.06 to 1.08 g/cm2; 6.7% change; 95% confidence interval [CI], 5.2%-8.2%; P<.001), total hip (from 0.92 to 0.97 g/cm2 vs placebo from 0.93 to 0.92 g/cm2; 6.2% change; 95% CI, 5.6%-7.0%; P<.001), and femoral neck (from 0.88 to 0.93 g/cm2 vs placebo from 0.87 to 0.86 g/cm2; 7.0% change; 95% CI, 5.5%-8.5%; P<.001) at the 24-month follow-up. During the 24 months of treatment, the women in the nitroglycerin group had increases in volumetric trabecular BMD (11.9% [95% CI, 8.1%-15.7%] at the radius and 8.5% [95% CI, 4.3%-12.7%] at the tibia), cortical BMD (2.2% [95% CI, 0.6%-3.7%] at the radius and 1.5% [95% CI, 0.8%-2.3%] at the tibia), cortical thickness (13.9% [95% CI, 6.0%-21.7%] at the radius and 24.6% [95% CI, 18.9%-30.4%] at the tibia), and periosteal circumference (7.4% [95% CI, 4.3%-10.4%] at the radius and 2.9% [95% CI, 1.0%-6.8%] at the tibia).
Use of nitroglycerin was also associated with increases in indices of bone strength (10.7% and 9.8% increases in polar section modulus in the radius and tibia, respectively, and 7.3% and 14.5% increases in polar moment of inertia at the radius and tibia, respectively). At 3, 12, and 24 months, compared with placebo, use of nitroglycerin was associated with a 14.4%, 20.7%, and 34.8% increase (P<.001) in bone-specific alkaline phosphatase, a marker of bone formation, and a 20.1%, 32.8%, and 54.0% decrease (P<.001) in urine Ntelopeptide, a marker of bone resorption. Adverse events included headaches, which were reported by 35% (n=40) of women in the nitroglycerin group and 5.4% (n=6) in the placebo group during the first month of the study.
Reports of headache decreased substantially after the first year (2% [n=2] in the nitroglycerin group in the last 12 months of the study). In conclusion, the researchers summarized that “treatment with 15 mg/day of nitroglycerin for 24 months increased bone formation and decreased bone resorption, resulting in an increased areal BMD at the spine and proximal femur and increased volumetric trabecular BMD in the distal radius and tibia. Furthermore, nitroglycerin increased cortical thickness and cortical area in the radius and tibia along with statistically significant increases in periosteal diameter.” They continued by saying that “together, these findings suggest that nitroglycerin may significantly decrease the risk of fractures, including fractures in long bones, such as the hip, legs, and upper arm, which are largely composed of cortical bone.”