Nitrates Do Not Affect Bone Density or Bone Turnover in Postmenopausal Women: A Randomized Controlled Trial

Abstract

Organic nitrates have been reported to have significant effects on bone mineral density (BMD) and bone turnover in previous clinical trials. However, results are inconsistent and some trials with strikingly positive results have been retracted because of scientific misconduct. As preparation for a potential fracture prevention study, we set out to determine the lowest effective dose and the most effective and acceptable nitrate preparation. We undertook a 1‐year, double‐blind, randomized, placebo‐controlled trial of three different nitrate preparations and two different doses in osteopenic postmenopausal women, with a planned 1‐year observational extension. The primary endpoint was change in BMD at the lumbar spine, and secondary endpoints included BMD changes at other sites, changes in bone turnover markers, and adverse events. A total of 240 eligible women who tolerated low‐dose oral nitrate treatment in a 2‐week run‐in period were randomized to five different treatment groups or placebo. Over 12 months, there were no statistically significant between‐group differences in changes in BMD at any site and no consistent differences in bone turnover markers. When the active treatment groups were pooled, there were also no differences in changes in BMD or bone turnover markers between nitrate treatment and placebo. Eighty‐eight (27%) women withdrew during the run‐in phase, with the majority because of nitrate‐induced headache, and 41 of 200 (21%) women randomized to nitrate treatment withdrew or stopped study medication during the 1‐year study compared with 1 of 40 (2.5%) in the placebo group. In summary, organic nitrates do not have clinically relevant effects on BMD or bone turnover in postmenopausal women and were poorly tolerated. These results call into question the validity of previous clinical research reporting large positive effects of nitrates on BMD and bone turnover. © 2020 American Society for Bone and Mineral Research.

The Efficacy of Nitrates for Bone Health: A Systematic Review and Meta-Analysis of Observational and Randomized Controlled Studies

“…The results of four randomized controlled trials on the effects of nitrates on BMD were inconsistent. There were no statistically significant differences in BMD percent change at any sites in these two RCTs compared with a placebo ( 14 , 15 ). In contrast, nitrates and alendronate had similar effects in increasing bone BMD in another two RCTs ( 16 , 25 ).…”

“…However, one cohort study found no evidence that nitrate use was related to a decreased incidence of fractures or a higher BMD (13). Furthermore, the results of two randomized controlled trials (RCTs) that examined the effects of nitroglycerin ointment on BMD were contradictory (14)(15)(16).…”

Chronic nitrate administration increases the expression the genes involved in the browning of white adipose tissue in female rats

“…According to a meta‐analysis of the prospective cohort, cross‐sectional, and clinical trial studies, the Mediterranean diet, a rich source of inorganic nitrate, has body weight‐lowering effects and decreases the risk of obesity‐related diseases in humans 34 . In contrast, organic nitrates are poorly tolerated, 35,36 increase body weight, 37 and induce tachyphylaxis following chronic use 38,39 …”

“…10 According to a meta-analysis of the prospective cohort, cross-sectional, and clinical trial studies, the Mediterranean diet, a rich source of inorganic nitrate, has body weight-lowering effects and decreases the risk of obesity-related diseases in humans. 34 In contrast, organic nitrates are poorly tolerated, 35,36 increase body weight, 37 and induce tachyphylaxis following chronic use. 38,39 Our result showed that nitrate administration to female rats increased serum NO x levels, which was positively correlated with serum progesterone but not 17β-estradiol levels.…”

The NO–cGMP–PKG pathway in skeletal remodeling

“…In this study of 240 postmenopausal women with low bone densities, no significant BMD change was noted. Of note, the withdrawal rate was quite high (∼20%) in the active treatment arm mainly due to headaches 50 …”