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Nitrates and osteoporosis: Which relationship?

      Osteoporosis and related risk of fracture represent a major a common clinical condition and a major health problem, especially in elderly patients creating huge costs to the health care system [
      • Cauley J.A.
      Public health impact of osteoporosis. J Gerontol A.
      ]. Moreover, osteoporotic fractures are related with a higher rate of morbidity and both short- and long-term rates of disability [
      • Golchin N.
      • Hohensee C.
      • LaCroix A.
      • Gray S.L.
      Nitrate medications, fractures, and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative.
      ]. Over the last years, several studies have documented a relationship between cardiovascular and bone health. Specifically, different risk factors are shared between cardiovascular and bone diseases, as older age, smoking habits, physical activity, alcohol intakes, diabetes and post-menopausal status [
      • Sprini D.
      • Rini G.B.
      • Di Stefano L.
      • Cianferotti L.
      • Napoli N.
      Correlation between osteoporosis and cardiovascular disease.
      ]. As known, nitrates are drugs commonly prescribed for the treatment of patients with ischemic heart disease (IHD), due their ability to cause vasodilatation and decrease both the preload and afterload. Intriguingly, some investigations have observed that organic nitrates modify the bone metabolism and for this reason they have been proposed and evaluated as drug also able to prevent osteoporosis. However, these studies have sometimes achieved conflicting results. Recently, Misra et al. have analysed a large cohort of patients (14,451 pairs of matched nitrate users and non-users with IHD, mean age 72.0 ± 7.6 years old, 41% women), reporting a 33% lower risk of hip fracture in those subjects treated with short-acting nitrates (intermittent-use) compared with those non-treated. Moreover, after adjusting the results for calcium, vitamin D use and heart failure, which is a risk factor for low bone mineral density (BMD), the protective effect of short-acting nitrates remains. Interestingly, they reported a similar protective effect of short-acting nitrates on proximal humeral fractures [
      • Misra D.
      • Peloquin C.
      • Kiel D.P.
      • Neogi T.
      • Lu N.
      • Zhang Y.
      Intermittent Nitrate Use and Risk of Hip Fracture.
      ]. Golchin et al. in their prospective study based on 139.211 postmenopausal women, aged between 50 and 79 years old, they observed no significant associations between overall nitrate use and risk of hip, wrist/arm or total fractures. More precisely, after examining the results according the type of nitrates, they found that only “as-needed” nitrate use was associated with a lower risk of wrist/arm (HR, 0.57; 95% CI 0.34–0.98) and total number of fractures (HR, 0.77; 95% CI 0.62–0.95) over the time. Furthermore, both chronic assumption of nitrates and the duration of the treatment were not associated with lower fracture risk [
      • Golchin N.
      • Hohensee C.
      • LaCroix A.
      • Gray S.L.
      Nitrate medications, fractures, and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative.
      ]. Rejnmark et al., which observed that the use of nitrates was associated with an 11% and 15% reduced risk of total and hip fractures. However, risk of hip fracture resulted lower only in women (dose-dependently) while global risk of fracture was reduced in both genders. Differencing the type of nitrates used, the same authors conclude that short-acting formulations were associated with a lower risk of fractures when compared to slow release preparations [
      • Rejnmark L.
      • Vestergaard P.
      • Mosekilde L.
      Decreased fracture risk in users of organic nitrates: a nationwide case-control study.
      ]. Jamal et al. anticipated all the present results in their pioneer investigation in 1998. Indeed, they observed that postmenopausal women using nitrates intermittently had a greater hip (difference, 2.6%; 95% CI, 0.4–6.8%) and heel (difference, 5.3%; 95% CI 2.1–11%) BMDs when compared to non-users [
      • Jamal S.A.
      • Browner W.S.
      • Bauer D.C.
      • Cummings S.R.
      Intermittent use of nitrates increases bone mineral density: the study of osteoporotic fractures.
      ]. In contrast with previous results were Wimalawansa et al., which analysed the same outcome in a randomized placebo-controlled trial (long-acting nitrates vs placebo) enrolling 186 post-menopausal women. Indeed, they observed no significant differences in BMD change from baseline after 36 months. Probably, the systematic use of long-acting formulations may not have the same beneficial effect as the intermittent use of short-acting nitrates [
      • Wimalawansa S.J.
      • Grimes J.P.
      • Wilson A.C.
      • Hoover D.R.
      Transdermal nitroglycerin therapy may not prevent early postmenopausal bone loss.
      ]. However, as suggested in another investigation, the relative low-dose of nitrates administrated, considered sub-therapeutic, could have influenced the final results [
      • Misra D.
      • Peloquin C.
      • Kiel D.P.
      • Neogi T.
      • Lu N.
      • Zhang Y.
      Intermittent Nitrate Use and Risk of Hip Fracture.
      ]. The protective effects of nitrates have been analysed also in-vitro studies. As known, nitric oxide (NO) is an endogenous free radical involved in several biological processes, as bone remodelling. It has been demonstrated that at high tissue concentration, NO is able to reduce the osteoclastic activity and enhance osteoblast formation [
      • Hukkanen M.
      • Platts L.A.
      • Lawes T.
      • Girgis S.I.
      • Konttinen Y.T.
      • Goodship A.E.
      • et al.
      Effect of nitric oxide donor nitroglycerin on bone mineral density in a rat model of estrogen deficiency-induced osteopenia.
      ]. The former process is due to the apoptosis of osteoclastic progenitors and suppression of RANK-L expression. Conversely, the real mechanism responsible of the latter biological effect is currently not completely understood [
      • Ralston S.H.
      • Todd D.
      • Helfrich M.
      • Benjamin N.
      • Grabowski P.S.
      Human osteoblast-like cells produce nitric oxide and express inducible nitric oxide synthase.
      ]. Further confirmation come from animal studies, in which nitro-glycerine (NTG) resulted able to prevents bone loss and increase BMD by about 20% [
      • Wimalawansa S.J.
      • De Marco G.
      • Gangula P.
      • Yallampalli C.
      Nitric oxide donor alleviates ovariectomy-induced bone loss.
      ]. Despite these promising results, the use of nitrates as osteoporotic agent is not currently either applied or recommended in daily clinical practice. Indeed, the absence of larger trials and definitive results create a lack of evidences in this field. Moreover, the optimal dosage of nitrates as osteoporotic agents has never been assessed. The available results suggest only that the intermittent use of short-acting nitrates is associated with a reduction in fracture and positive effect on BMD. Probably, the development of tachyphilaxis, which is frequently achieved with the continuous use of nitrates, is the pathophysiological mechanism responsible of the absence of beneficial effect on BMD and fracture prevention. However, as well known form the clinical practice, a drug-free interval is fundamental when nitrates are administered to patients with IHD. Probably, this is equally true for the effects of nitrates on bone metabolism. Further studies are needed to confirm the effects of nitrates on BMD and fracture prevention. Indeed, thanks to their relative low cost and their frequent prescription to IHD patients, they could be a valid adjuvant treatment in the prevention of BMD reduction, osteoporosis and risk fractures. However, the frequent side effects of nitrates, as hypotension, headache, etc., should be considered as potential limitation to the use of this type of pharmacological approach. Indeed, in elderly patients, hypotension and especially orthostatic hypotension, accidental falls, which are important risk factors for fractures and traumas in these frail groups of patients. Moreover, the assessment of a common beneficial dose of nitrates for both IHD and prevention of bone loss should be investigated, if the goal is to apply the same drug for different aims.

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