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Date of release: 05 October, 2009

The role of nitric oxide in prevention of osteoporosis: a novel therapy?


The role of the endothelial cell in secreting the important local regulatory substances that control the vascular system has been established for many years [1, 2]. The cells produce several smooth muscle relaxing factors such as nitric oxide (NO), which is derived from the transformation of the amino acid L-arginine by the activity of NO synthase (NOS). As well as the beneficial effects for the vascular system, in vitro and in vivo data have revealed the efficacy of nitroglycerine and nitrates on bone cells [1]. NO has a stimulatory effect on osteoblasts and bone formation with concomitant inhibition of osteoclastic bone resorption [1, 2]. It also has been proven that some of the effects of estrogen in bone are mediated via the NO pathway. Several animal studies consistently support this theory. Indeed, a body of evidence taken from a variety of animal studies has shown that NO donor therapy could prevent ovariectomy-induced as well as corticosteroid-induced bone loss [2–4]. If this is the case, it seems that NO/nitroglycerine therapy may become an affordable and cost-effective option for preventing and treating osteoporosis. Unfortunately, not all human studies have shown the same positive result [2–6]. 


One of the recent papers published by Wimalawansa and colleagues has reported on the use of transdermal nitroglycerine in postmenopausal women [7]. This single-center, randomized, double-blind, placebo-controlled clinical trial was intended to compare the effect of a NO donor compound, 2% nitroglycerine ointment, with placebo. The primary endpoint was the percentage change in lumbar vertebrae bone mineral density (BMD) from baseline to 36 months. The secondary endpoints were the changes in hip BMD, total body bone mineral content and height. 


Inclusion criteria were: lumbar spine T score of 0 to -2.5 (0 to -2.0 for women aged 61–65 years); level of 25-hydroxyvitamin D > 15 ng/ml; body mass index of 18–32 kg/m2; and achieving the prerequisite compliance with calcium and vitamin D therapy during the run-in period. Exclusion criteria were: prior spine or hip fracture; cardiac or coronary artery disease requiring medication; abnormal hepatic or renal function; metabolic bone diseases other than postmenopausal osteopenia; insulin-dependent diabetes mellitus; severe hypertension; significant migraine headaches; history of renal calculi or cancer. Participants taking the following medications were also excluded or required to undergo a wash-out period: bisphosphonates, hormone therapy, raloxifene, calcitonin, routine use of nitrates, corticosteroids and estrogen.


A total of 186 women were randomized to the study. At the end of the study, 88 participants remained in the active arm and 83 remained in the placebo arm. Participants were randomly assigned to receive either active 22.5 mg/day nitroglycerine 2% or placebo ointment and were studied for 36 months.


The result showed no significant difference for primary efficacy outcomes: at the end of study, a -2.1% (95% confidence interval (CI) -3.1 to -1.0%) change in lumbar spine BMD in the active group and a -2.5% (95% CI -3.6 to -1.4%) change in the placebo group from baseline were seen (p = 0.59). It should be noted that there were no significant treatment arm differences for any absolute BMD measurements at 36 months as well as percentage change from baseline measurements at 36 months. The active group reported more headaches compared to the placebo group (p = 0.001). Other serious adverse effects were not different between the two groups.


The authors conclude that a 3-year evaluation using randomized, controlled trial methodology did not support the effectiveness of the NO donor nitroglycerine in preventing postmenopausal decreases in BMD. Nevertheless, based on the data collected from three previous clinical studies using the nitrate product, which demonstrated a positive effect on BMD as well as bone turnover, the authors still believe that further research using higher doses of NO donor is warranted before discarding this as a novel therapy for osteoporosis.

Comment

There were at least three additional contradictory reference articles used by the authors in their comparative discussion. The first article concerned a randomized, controlled trial study design which reported equal effects on increasing lumbar BMD either after oral isosorbide mononitrate (C6H9NO6) 20 mg daily (p = 0.027) or with alendronate 70 mg once a week (p < 0.001) over a 12-month period. The percentage changes in BMD were 10.8% and 12.1% for isosorbide mononitrate and alendronate, respectively [8]. It should be noted that the participants recruited were already osteoporotic, thus differing from the subjects studied in the study by Wimalawansa and colleagues. The authors assumed that nitrate donor therapy for women who already had osteoporosis would show more positive results [7]. Another difference found between the above two studies was that the latter study was open-labeled, not placebo-controlled, and used oral isosorbide mononitrate (C6H9NO6) as the NO donor instead of transdermal nitroglycerine (C3H5N3O9) [3, 8]. This could explain the difference between the findings in the two studies. 
Another article reported on a population-based, pharmaco-epidemiological, case-controlled study involving a large number of respondents which demonstrated a reduced risk of fracture in users of organic nitrates (isosorbide mononitrate, isosorbide dinitrate/C6H8N2O8 and nitroglycerine) [9]. The use of nitrates was associated with an 11% reduced risk of any fracture (odds ratio (OR) 0.89; 95% CI 0.86–0.92) and a 15% reduced risk of hip fracture (OR 0.85; 95% CI 0.79–0.92) [4]. However, the authors stated that the results of this nationwide study must be viewed with caution because the upper limit of the CI for the risk of any fracture or hip fracture was 0.92 [5]. 
The third relevant article by the same investigators found that a NO donor from 15 mg of active nitroglycerine (ointment) was as effective as estrogen (Premarin) in inhibiting oophorectomy-induced bone loss [6, 7]. The result was encouraging in that nitroglycerine was proven to decrease osteoclast activity and stimulate osteoblast activity significantly, but, due to the small sample size (n = 8), further research involving a larger number of patients is required to generate a reliable conclusion, since inadequate or an improper number of samples (undersized or oversized) could lead to the occurrence of type I or type II errors.
In summary, based on the relatively consistent animal research and recent human studies which hitherto have shown no sufficiently convincing evidence, further well-designed studies pertaining to the efficacy of NO for bone are still required. Different NO donors and bioavailability as well as determination of the accurate treatment dosage should be taken into account as important factors to consider.

Comentario

M. Sjarief Darmasetiawan
Senior Lecturer, Division of Reproductive Endocrinology & Fertility, Department of Obstetrics & Gynecology, Gatot Soebroto Central Army Hospital, Pembangunan National University, Indonesia

    References

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    http://www.ncbi.nlm.nih.gov/pubmed/14563699

  2. Wimalawansa SJ. Nitric oxide: novel therapy for osteoporosis. Expert Opin Pharmacother 2008:9:3025-44.
    http://www.ncbi.nlm.nih.gov/pubmed/19006476

  3. Wimalawansa SJ, De Marco G, Gangula P, Yalampalli C. Nitric oxide donor alleviates ovariectomy-induced bone loss. Bone 1996;18: 301-4.
    http://www.ncbi.nlm.nih.gov/pubmed/8726385

  4. Wimalawansa SJ, Chapa MT, Yalampalli C, Zhang R, Simmons DJ. Prevention of corticosteroid-induced bone loss with nitric oxide donor nitroglycerin in male rats. Bone 1997;21:275-80.
    http://www.ncbi.nlm.nih.gov/pubmed/9276093

  5. Wimalawansa SJ. Restoration of ovariectomy-induced osteopenia by nitroglycerin. Calcif Tissue Int 2000;66:56-60.
    http://www.ncbi.nlm.nih.gov/pubmed/10602846

  6. 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;15:2240-4.
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  7. Wimalawansa SJ, Grimes SJ, Grimes JP, Wilson AC, Hoover DR. Transdermal nitroglycerin therapy may not prevent early postmenopausal bone loss. J Clin Endocrinol Metab 2009,94:3356-64. Published September 2009.
    http://www.ncbi.nlm.nih.gov/pubmed/19549739

  8. Nabhan AF, Rabie NH. Isosorbide mononitrate versus alendronate for postmenopausal osteoporosis. Int J Gynecol Obstet 2008;103:213-16.
    http://www.ncbi.nlm.nih.gov/pubmed/18805524

  9. Rejnmark L, Vestergaard P, Mosekilde L. Decreased fracture risk in users of organic nitrates: a nationwide case-control study. J Bone Miner Res 2006;21:1811-17.
    http://www.ncbi.nlm.nih.gov/pubmed/17054422