Nitroglycerin ointment for the prevention of postmenopausal osteoporosis.
To determine whether clinical trial data support the use of nitroglycerin for prevention of postmenopausal osteoporosis.
A literature search using MEDLINE (1966-September 2011) and EMBASE (1973-September 2011) was conducted using the search terms nitroglycerin, bone mineral density, fracture, and osteoporosis. References of identified articles were reviewed for additional citations.
All English-language articles related to the use of nitroglycerin ointment in postmenopausal women were reviewed.
Four observational studies reported significant improvements in bone mineral density of postmenopausal women with the use of nitrates. One pilot study and 2 prospective, randomized, placebo-controlled clinical trials reported conflicting results regarding the efficacy of nitroglycerin ointment.
Clinical data do not support use of nitroglycerin for this indication; its potential is limited at this time by inconclusive efficacy and a high incidence of headache. Further well-designed clinical trials demonstrating efficacy and safety of nitroglycerin ointment for prevention of postmenopausal osteoporosis are needed before this medication can be recommended for routine use.
Beckett RD, Sheehan AH
Ann Pharmacother Dec 2011
Effect of nitroglycerin ointment on bone density and strength in postmenopausal women: a randomized trial.
Nitroglycerin stimulates bone formation and inhibits bone resorption, is inexpensive, and is widely available. Its effects on bone density, bone structure, and bone strength are unknown. To determine if nitroglycerin increases lumbar spine bone mineral density (BMD) and to evaluate changes in hip BMD, bone geometry, and density at the radius and tibia, and markers of bone turnover.
A single-center, double-blind, placebo-controlled randomized trial conducted in Toronto, Ontario, Canada, for 24 months starting in November 2005 and completed in March 2010, of 243 postmenopausal women with lumbar spine T scores of between 0 and -2.0 who completed a 1-week run-in period taking nitroglycerin ointment. Intervention Nitroglycerin ointment (15 mg/d) or placebo applied at bedtime for 24 months.
Areal BMD at the lumbar spine, femoral neck, and total hip. Secondary outcomes included indices of bone geometry and strength at the distal radius and tibia, and biomarkers of bone formation (bone-specific alkaline phosphatase) and bone resorption (urine N -telopeptide).
At 2 years, women randomized to the nitroglycerin group had significant increases in areal BMD at the lumbar spine (from 1.05 to 1.14 g/cm(2) vs placebo from 1.06 to 1.08 g/cm(2); percentage change, 6.7%; 95% confidence interval [CI], 5.2%-8.2%; P < .001); total hip (from 0.92 to 0.97 g/cm(2) vs placebo from 0.93 to 0.92 g/cm(2); 6.2%; 95% CI, 5.6%-7.0%; P < .001); and femoral neck (from 0.88 to 0.93 g/cm(2) vs placebo from 0.87 to 0.86 g/cm(2); 7.0%; 95% CI, 5.5%-8.5%; P < .001). At 2 years, nitroglycerin also increased volumetric trabecular BMD (11.9% and 8.5%), cortical thickness (13.9% and 24.6%), periosteal circumference (7.4% and 2.9%), polar section modulus (10.7% and 9.8%), and polar moment of inertia (7.3% and 14.5%) at the radius and tibia, respectively (all P < .001); and increased bone-specific alkaline phosphatase by 34.8% and decreased urine N -telopeptide by 54.0% (P < .001). Incidence of serious adverse events did not differ between nitroglycerin (5 [4.2%]) and placebo (5 [4.3%]) groups. Among those women who continued treatment for 24 months, headaches were reported by 40 (35%) in nitroglycerin and 6 (5.4%) in placebo groups during the first month, decreasing substantially after 12 months.
Among postmenopausal women, nitroglycerin ointment modestly increased BMD and decreased bone resorption.
Jamal SA, Hamilton CJ, Eastell R, Cummings SR
JAMA Feb 2011
There is a published comment on this study: Nitroglycerin needs more study.
Is nitroglycerin a novel and inexpensive treatment for osteoporosis?
JAMA Feb 2011
PMID: 21343584 | Free Full Text
Despite the differences in the results of the study by Jamal et al2 compared with the largely negative study by Wimalawansa et al,11 the findings reported by Jamal et al2 should set the stage for an adequately powered, larger study using nitroglycerin ointment with fracture as an outcome. If such a study demonstrates efficacy for reducing fractures, clinicians would have a novel and inexpensive therapy for osteoporosis. The findings of the current study also should prompt development of additional nitric oxide donors with greater skeletal efficacy and a better adverse effect profile, particularly with regard to headaches.
Restoration of ovariectomy-induced osteopenia by nitroglycerin.
Nitric oxide (NO) is known to inhibit osteoclastic bone resorption. Previously, we demonstrated that the NO donor nitroglycerin (NG) prevented ovariectomy (OVX)-induced bone loss. The current study shows that NG restores ovariectomy-induced osteopenia. Twenty-four female Sprague-Dawley rats, 36 weeks of age, underwent OVX, and a further six rats were sham-operated. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometric (DXA) scanning prior to OVX, at 6 weeks postsurgery, and at 6 weeks posttreatment. OVX rats were then assigned to four groups and treated with either (1) vehicle, (2) 17-beta-estradiol, (3) NG (0.2 mg/kg/day), or (4) a combination of estrogen and NG (n = 6/group). During the first 6-week post-OVX period, there was a significant decrease in the BMD in all ovariectomized (OVXed) rats (-11.0%, P < 0.001). There were no significant changes in BMD during the entire 12-week period in sham-operated rats. During the second 6-week period (after developing bone loss), there was no further significant loss of BMD in OVXed controls. BMD loss and loss of femur weight produced by OVXed were restored by treatment with estrogen, NG, or the two agents together during the second 6-week period (P < 0.01). The effects of estrogen and NG together, however, were not additive. The BMD of rats treated with NG alone, at 12 weeks, was similar to that of animals treated with estrogen alone or with estrogen and NG, and was comparable to that of sham-operated rats. The increased urinary excretion of deoxypyridinolines caused by OVX was negated by estrogen, NG, and estrogen together with NG (P < 0.01). In contrast to estrogen, NG did not decrease the post-OVX-induced increase of serum osteocalcin levels, suggesting that NG may also have a positive effect on bone formation. In summary, the results suggest that the NO donor, NG, reverses the OVX-induced bone loss in rats, and these effects are likely due to decreased bone resorption and, perhaps, increased bone formation.
Calcif. Tissue Int. Jan 2000
Transdermal nitroglycerin therapy may not prevent early postmenopausal bone loss.
Osteoporosis is common among postmenopausal women; animal studies and human pilot studies support the concept of nitric oxide (NO) donors reducing bone mineral density loss. The objective of the study was to evaluate whether NO donor, nitroglycerin, prevents postmenopausal bone loss.
This was a 3-yr randomized, double blinded, single-center, placebo-controlled clinical trial.
The single-center study was conducted at the University of Medicine and Dentistry-Robert Wood Johnson Medical School (New Brunswick, NJ).
Participants included 186 postmenopausal women aged 40-65 yr, with lumbar bone mineral density (BMD) T-scores of 0 to -2.5.
Women, stratified by lumbar T-score (<-1.50 and >or=-1.50) and years since menopause (<or=5 and >5 yr), were randomized to receive nitroglycerin ointment (22.5 mg as Nitro-Bid) or placebo ointment received daily for 3 yr. Both groups took 630 mg daily calcium plus 400 IU vitamin D supplements.
BMD was measured at 6 months and annually by dual-energy x-ray absorptiometry. Percent change in lumbar vertebrae BMD was the primary outcome. Hip BMD, total body bone mineral content, and height were secondary outcomes.
After 36 months of therapy, changes of -2.1% in the active group (n = 88) and -2.5% in the placebo group (n = 82) in lumbar spine BMD were seen (P = 0.59; 95% confidence interval -1.001, 1.975). Secondary outcomes also did not differ by intervention arm. The active group reported more headaches compared with the placebo group (57 vs. 14%, P < 0.001). Other adverse and serious adverse events were not different.
BMD changes did not substantially differ between postmenopausal women who received the dose of nitroglycerin tested, in comparison with a placebo. Once-daily dosing with 22.5 mg of transdermal-administered nitroglycerin was not effective (compliance adjusted dose was only approximately 16 mg/d); a sub-therapeutic dose.
Wimalawansa SJ, Grimes JP, Wilson AC, Hoover DR
J. Clin. Endocrinol. Metab. Sep 2009
PMID: 19549739 | Free Full Text