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The effects of organic nitrates on osteoporosis: a systematic review

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A Statement of Concern to this article was published on 01 December 2016

Abstract

Current treatments for osteoporosis are limited by lack of effect on cortical bone, side effects, and, in some cases, cost. Organic nitrates, which act as nitric oxide donors, may be a potential alternative. This systematic review summarizes the clinical data that reports on the effects of organic nitrates and bone. Organic nitrates, which act as nitric oxide donors, are novel agents that have several advantages over the currently available treatments for osteoporosis. This systematic review summarizes the clinical data that reports on the effects of organic nitrates on bone. We searched Medline (1966 to November 2012), EMBASE (1980 to November 2012), and the Cochrane Central Register of Controlled Trials (Issue 11, 2012). Keywords included nitrates, osteoporosis, bone mineral density (BMD), and fractures. We identified 200 citations. Of these, a total of 29 were retrieved for more detailed evaluation and we excluded 19 manuscripts: 15 because they did not present original data and four because they did not provide data on the intervention or outcome of interest. As such, we included ten studies in literature review. Of these ten studies two were observational cohort studies reporting nitrate use was associated with increased BMD; two were case control studies reporting that use of nitrates were associated with lower risk of hip fracture; two were randomized controlled trials (RCT) comparing alendronate to organic nitrates for treatment of postmenopausal women and demonstrating that both agents increased lumbar spine BMD. The two largest RCT with the longest follow-up, both of which compared effects of organic nitrates to placebo on BMD in women without osteoporosis, reported conflicting results. Headaches were the most common adverse event among women taking nitrates. No studies have reported on fracture efficacy. Further research is needed before recommending organic nitrates for the treatment of postmenopausal osteoporosis.

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Authors and Affiliations

  1. Women’s College Research Institute, 790 Bay Street, 7th Floor, Toronto, Ontario, M5G 1N8, Canada

    S. A. Jamal, L. S. Reid & C. J. Hamilton

  2. Department of Medicine, Women’s College Hospital, University of Toronto, 790 Bay Street, 7th Floor, Toronto, Ontario, M5G 1N8, Canada

    S. A. Jamal

  3. Department of Exercise Sciences, University of Toronto, 790 Bay Street, 7th Floor, Toronto, Ontario, M5G 1N8, Canada

    C. J. Hamilton

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  1. S. A. Jamal
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A comment to this article is available at http://dx.doi.org/10.1007/s00198-016-3852-8.

Appendix 1 search strategy

Appendix 1 search strategy

  1. a.

    Medline (PubMed) (1966 to November 2012)

    (Nitrates[53] OR nitrate[tiab] OR nitrates[tiab] OR Nitroglycerin[53] OR nitroglycerin[tiab] OR Glyceryl-Trinitrate[tiab] OR transderm-nitro[tiab] OR nitroderm[tiab] OR Nitric Oxide Donors[53] OR Nitric Oxide[53] OR Isosorbide Dinitrate[53] OR Isosorbide[53] OR oxide-donor[tiab] OR isosorbide-dinitrate[tiab] OR isosorbide[tiab] OR dinitrate[tiab] OR monoxide[tiab] OR mononitrogen[tiab] OR endogenous-nitrate[tiab] OR ((Vasodilator Agents[53] OR vasodilator[tiab] OR vasodilators[tiab] OR vasorelaxant[tiab] OR vasodilatator[tiab] OR Organic Chemicals[53] OR organic[tiab]) AND (nitrate[tiab] OR nitrates[tiab] OR nitric[tiab])) OR nitrogen-monoxide[all fields] OR mononitrate[tiab] OR organic-nitrate[tiab] OR organic-salt[tiab]) AND (osteoporosis[all fields] OR osteopenia[tiab] OR osteoporotic[tiab] OR Bone Diseases, Metabolic[53] OR Bone Density/drug effects[53] OR Bone Resorption[53] OR Bone Density Conservation Agents[53] OR bone-loss[tiab] OR bone-resorption[tiab] OR osteolysis[tiab])

    (Therapy/Broad[filter]) AND ((Nitrates[53] OR nitrate[tiab] OR nitrates[tiab] OR Nitroglycerin[53] OR nitroglycerin[tiab] OR Glyceryl-Trinitrate[tiab] OR transderm-nitro[tiab] OR nitroderm[tiab] OR Nitric Oxide Donors[53] OR Nitric Oxide[53] OR Isosorbide Dinitrate[53] OR Isosorbide[53] OR oxide-donor[tiab] OR isosorbide-dinitrate[tiab] OR isosorbide[tiab] OR dinitrate[tiab] OR monoxide[tiab] OR mononitrogen[tiab] OR endogenous-nitrate[tiab] OR ((Vasodilator Agents[53] OR vasodilator[tiab] OR vasodilators[tiab] OR vasorelaxant[tiab] OR vasodilatator[tiab] OR Organic Chemicals[53] OR organic[tiab]) AND (nitrate[tiab] OR nitrates[tiab] OR nitric[tiab])) OR nitrogen-monoxide[all fields] OR mononitrate[tiab] OR organic-nitrate[tiab] OR organic-salt[tiab]) AND (osteoporosis[all fields] OR osteopenia[tiab] OR osteoporotic[tiab] OR Bone Diseases, Metabolic[53] OR Bone Density/drug effects[53] OR Bone Resorption[53] OR Bone Density Conservation Agents[53] OR bone-loss[tiab] OR bone-resorption[tiab] OR osteolysis[tiab]))

    (Therapy/Broad[filter]) AND (Nitrates[53] OR nitrate[tiab] OR nitrates[tiab] OR Nitroglycerin[53] OR nitroglycerin[tiab] OR Glyceryl-Trinitrate[tiab] OR transderm-nitro[tiab] OR nitroderm[tiab] OR Nitric Oxide Donors[53] OR Nitric Oxide[53] OR Isosorbide Dinitrate[53] OR Isosorbide[53] OR oxide-donor[tiab] OR isosorbide-dinitrate[tiab] OR isosorbide[tiab] OR dinitrate[tiab] OR monoxide[tiab] OR mononitrogen[tiab] OR endogenous-nitrate[tiab] OR ((Vasodilator Agents[53] OR vasodilator[tiab] OR vasodilators[tiab] OR vasorelaxant[tiab] OR vasodilatator[tiab] OR Organic Chemicals[53] OR organic[tiab]) AND (nitrate[tiab] OR nitrates[tiab] OR nitric[tiab])) OR nitrogen-monoxide[all fields] OR mononitrate[tiab] OR organic-nitrate[tiab] OR organic-salt[tiab]) AND (osteoporosis[all fields] OR osteopenia[tiab] OR osteoporotic[tiab] OR Bone Diseases, Metabolic[53] OR Bone Density/drug effects[53] OR Bone Resorption[53] OR Bone Density Conservation Agents[53] OR bone-loss[tiab] OR bone-resorption[tiab] OR osteolysis[tiab]) AND Human[53]

  2. b.

    Cochrane Central Register of Controlled Trials (Issue 11, 2012)

    (Nitrates OR Nitroglycerin OR Nitric Oxide Donors OR Nitric Oxide OR Isosorbide Dinitrate OR Isosorbide OR Vasodilator Agents OR nitrate* OR nitric oxide OR nitroglycerin OR isosorbide OR dinitrate OR monoxide OR mononitrogen OR endogenous nitrate OR nitrogen monoxide OR mononitrate) AND (osteoporosis OR osteopenia OR osteoporotic OR Bone Diseases, Metabolic OR Bone Density OR Bone Resorption OR Bone Density Conservation Agents)

  3. c.

    EMBASE (Ovid) (1980 to November 2012)

    1. 1.

      nitrate$.mp. or exp nitrate/ (76389)

    2. 2.

      nitroglycerin.mp. or exp glyceryl trinitrate/ (33093)

    3. 3.

      "nitric oxide donor$".mp. or exp nitric oxide/ or exp nitric oxide donor/ (109316)

    4. 4.

      isosorbide dinitrate.mp. (8858)

    5. 5.

      (osteoporosis or osteopenia or osteoporotic).mp. (102897)

    6. 6.

      "bone density conservation agent$".mp. or exp bone density conservation agent/ (2410)

    7. 7.

      "metabolic bone disease$".mp. or exp metabolic bone disease/ (103492)

    8. 8.

      "bone resorption".mp. or exp osteolysis/ (51435)

    9. 9.

      nitric.mp. (173554)

    10. 10.

      nitrat$.mp. (80571)

    11. 11.

      9 or 10 (239764)

    12. 12.

      "vasodilator agent$".mp. (26093)

    13. 13.

      "organic chemicals".mp. (2201)

    14. 14.

      12 or 13 (28294)

    15. 15.

      11 and 14 (5042)

    16. 16.

      1 or 2 or 3 or 4 or 15 (209373)

    17. 17.

      5 or 6 or 7 or 8 (157666)

    18. 18.

      16 and 17 (880)

    19. 19.

      limit 18 to "therapy (maximizes sensitivity)" (266)

    20. 20.

      limit 19 to exclude medline journals (46)

    21. 21.

      limit 19 to human (236)

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Jamal, S.A., Reid, L.S. & Hamilton, C.J. The effects of organic nitrates on osteoporosis: a systematic review. Osteoporos Int 24, 763–770 (2013). https://doi.org/10.1007/s00198-012-2262-9

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