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.

The number of osteoporotic fractures is increasing worldwide as populations age. An inexpensive and widely available treatment is necessary to alleviate this increase in fractures. Current treatments decrease fractures at trabecular bone sites (spine) but have limited effects at cortical sites (hip, legs, forearm and upper arm)-the most common sites of osteoporotic fracture. Treatments are also limited by costs, side effects and lack of availability. Nitric oxide (NO) is a novel agent that has the potential to influence cortical bone, is inexpensive, widely available and has limited side effects. In this review, we will evaluate the in vitro and in vivo data that support the concept that NO is important in bone cell function, review the observational, case control and randomized trial data on organic nitrates and the effects of these agents on bone turnover, geometry and strength.

BackgroundOrganic nitrates uncouple bone turnover, improve bone mineral density, and improve trabecular and cortical components of bone. These changes in turnover, strength and geometry may translate into an important reduction in fractures. However, before proceeding with a large fracture trial, there is a need to identify the nitrate formulation that has both the greatest efficacy (with regards to bone turnover markers) and gives the fewest headaches. Ascertaining which nitrate formulation this may be is the purpose of the current study.Methods and designThis will be an open-label randomized, controlled trial conducted at Women’s College Hospital comparing five formulations of nitrates for their effects on bone turnover markers and headache. We will recruit postmenopausal women age 50 years or older with no contraindications to nitroglycerin. Our trial will consist of a run-in phase and a treatment phase. We will enroll 420 women in the run-in phase, each to receive all of the 5 potential treatments in random order for 2 days, each with a 2-day washout period between treatments. Those who tolerate all formulations will enter the 12-week treatment phase and be randomly assigned to one of five groups: 0.3 mg sublingual nitroglycerin tablet, 0.6 mg of the sublingual tablet, a 20 mg tablet of isosorbide mononitrate, a 160 mg nitroglycerin transdermal patch (used for 8 h), and 15 mg of nitroglycerin ointment as used in a previous trial by our group. We will continue enrolment until we have randomized 210 women or 35 women per group. Concentrations of bone formation (bone-specific alkaline phosphatase and procollagen type I N-terminal propeptide) and bone resorption (C-telopeptides of collagen crosslinks and N-terminal crosslinks of collagen) agents will be measured in samples taken at study entry (the start of the run in phase) and 12 weeks. Subjects will record the frequency and severity of headaches daily during the run-in phase and then monthly after that. We will use the ‘multiple comparisons with the best’ approach for data analyses, as this strategy allows practical considerations of ease of use and tolerability to guide selection of the preparation for future studies.DiscussionData from this protocol will be used to develop a randomized, controlled trial of nitrates to prevent osteoporotic fractures.Trial registrationClinicalTrials.gov Identifier: NCT01387672. Controlled-Trials.com: ISRCTN08860742.

Purpose: To identify barriers to, and motivations for, recruitment and retention in osteoporosis related clinical trials among postmenopausal women. Methods: We explored the self reported reasons for and against participation in clinical trials among women who expressed an interest in participating in the Nitrates and Bone Turnover (NABT) study: an ongoing randomized controlled trial based at an urban tertiary care centre (Women's College Hospital, University of Toronto). The study was designed to compare the effects of different doses and formulations of nitrates on markers of bone turnover among postmenopausal women not diagnosed and/or receiving treatment for osteoporosis. We administered a standardized interviewer questionnaire to 53 women to determine their reasons for participation in the NABT trial. To determine reasons for non-participation, we administered a questionnaire to 9 women and reviewed data collected at the time of initial assessment in 56 women who were not interested in participating in the trial. We conducted qualitative analyses using thematic coding of these responses. Results: The most common reasons for participation were: altruism (26.4%) and potential personal benefits (22.6%). The two most common reasons for non-participation included fear associated with taking medication (23.1%) and lack of time (16.9%). Conclusions: Postmenopausal women participate in clinical trials to help others and potentially themselves. Barriers to participation in trials may include the intervention being evaluated and time required to participate in the trial. Researchers should consider these motivations and barriers when recruiting postmenopausal women for RCTs.