Nitrates Useless for Building Bone in Postmenopausal Women

By Marilynn Larkin

May 20, 2020

NEW YORK (Reuters Health) - Nitrates did not affect postmenopausal bone density or turnover in a randomized, controlled trial.

"We did this study because several earlier studies had suggested that nitrate treatments might have positive effects on bone health," Dr. Mark Bolland of the University of Auckland, New Zealand, told Reuters Health by email. "In particular, the largest study published in JAMA reported fairly large increases in bone density over a two-year period with a nitrate preparation. The issue was important because nitrate treatments are cheap and have been used safely for a long time for patients with angina. So, if they prevented fractures, they could be an excellent treatment for osteoporosis."

"Toward the end of our trial, the JAMA paper was retracted because of misconduct by the lead author," he noted. "She...published many of the papers suggesting benefits of nitrates on bone health, so this created considerable doubt about the earlier research."

"Contrary to past results, we found no effect at all of any of the treatments on bone density or markers of bone turnover, which are the surrogate markers used to try and predict effects on fracture," he said.

Dr. Bolland and colleagues undertook a one-year, double-blind, randomized, placebo-controlled trial of three different nitrate preparations at two different doses in osteopenic postmenopausal women, with a planned one-year observational extension. The primary endpoint was change in bone mineral density (BMD) at the lumbar spine; secondary endpoints included BMD changes at other sites, changes in bone turnover markers, and adverse events.

As reported in the Journal of Bone and Mineral Research, 328 women started the trial, but 88 (27%) were unable to tolerate the medication, with more than half withdrawing because of headache. Therefore, 240 women (average age, 67.5) who tolerated low-dose oral nitrate treatment in a two-week run-in period were randomized to five different treatment groups or placebo.

During the study, 11 women (5%) withdrew, and a further 31 (13%) stopped treatment but remained in the study, having regular follow-up. Of these, 30 (15%) were in the nitrate groups and only one (2.5%) in the placebo group.

When information about the retraction of the previous trial became available, the authors decided to perform an analysis of the trial data after 12 months of active treatment.

There were no statistically significant between-group differences in changes in BMD at any site, and no consistent differences in bone turnover markers. Similarly, when the active treatment groups were pooled, no differences in changes in BMD or bone turnover markers were observed between nitrate treatment and placebo.

Because no effect was observed, the observation phase was considered redundant and the trial was stopped.

Dr. Bolland said, "The findings won't change clinical practice because patients are not prescribed nitrates for osteoporosis, but they should put an end to further clinical research on the topic. They also raise the question of why other earlier small studies found such strikingly positive results, and whether those results are valid."

Dr. Daniel Solomon, Chief, Section of Clinical Sciences, Division of Rheumatology at Brigham and Women's Hospital in Boston commented in an email to Reuters Health, "The study was well conducted and convincing. Their conclusions that nitrates have no direct beneficial effects on BMD or bone turnover in postmenopausal women are well supported by very strong negative evidence from their trial."

"To the best of my knowledge," he added, "there has not been a complete investigation of (the) somewhat suspicious findings" from the earlier studies.

"At this point, nitrates should not be considered a treatment for low BMD," he said. "However, this whole episode points out the importance of replication in science. Well described and well conducted trials always need to be tested by other investigators before we come to strong conclusions."

SOURCE: Journal of Bone and Mineral Research, online May 5, 2020.