Nitrates and bone turnover (NABT) - trial to select the best nitrate preparation: study protocol for a randomized controlled trial

Abstract

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.

Nitrate Medications, Fractures, and Change in Bone Mineral Density in Postmenopausal Women: Results from the Women's Health Initiative

“…(15) Based on this potential for tachyphylaxis, randomized controlled trials that have examined nitroglycerin effects on BMD have used once daily dosing of nitroglycerin ointment, which is a short-acting formulation. (4,11,16) In contrast, this same medication would be dosed several times a day for management of angina symptoms (e.g. maintenance therapy), which is hypothesized not to have beneficial bone effects.…”

“…(3) Organic nitrates (eg, isosorbide mononitrate, isosorbide dinitrate, nitroglycerin) are medications used to treat angina that have been proposed as potential novel therapeutic options for osteoporosis. (4,5) Serving as nitric oxide donors, these medications uncouple bone resorption and formation resulting in beneficial effects on bone metabolism. (1) In vitro and animal studies suggest that nitric oxide donors decrease bone resorption by reducing osteoclastic activity and to a lesser extent may enhance osteoblast activity (eg, leading to enhanced bone formation).…”

“…(13,14) The optimal dosing regimen to maximize bone effects remains unclear. (4) The action of nitrates on bone appears to be dosedependent and continuous exposure may cause tachyphylaxis in bone as it does with angina symptom control. In ovariectomized rats, once daily administration of nitroglycerin ointment increased BMD, whereas more frequent application did not have beneficial effects.…”

“…(15) Based on this potential for tachyphylaxis, randomized controlled trials that have examined nitroglycerin effects on BMD have used once daily dosing of nitroglycerin ointment, which is a short-acting formulation. (4,11,16) In contrast, this same medication would be dosed several times a day for management of angina symptoms (eg, maintenance therapy), which is hypothesized not to have beneficial bone effects. The difficulty in capturing the nitrate regimen that optimizes benefits to bone from data available in observational studies where frequency of as-needed use is rarely captured makes it challenging to examine the relationship between nitrates and bone outcomes.…”

Recently Retracted Clinical Trial Serves as an Important Reminder

“…The Nitroglycerin as an Option: Value in Early Bone Loss (NOVEL) study (n = 186) found BMD changes of −2.06% with nitroglycerin and −2.48% with placebo (mean difference = 0.487% [95% CI = −1.00 to 1.96]; P = 0.59) at the lumbar spine. 4 The second study, now retracted, was published by Jamal et al 5 (n = 243) and reported increased BMD at the lumbar spine (mean difference = 6.7%; 95% CI = 5.2% to 8.2%; P < 0.001), total hip (mean difference = 6.2%; 95% CI = 5.6% to 7%; P < 0.001), and femoral neck (mean difference = 7%; 95% CI = 5.5% to 8.5%; P < 0.001) with nitroglycerin compared with placebo. At the time of writing, we noted the considerable discrepancy in these results compared with NOVEL as well as observational studies and suggested many potential reasons for these differences.…”