Decreased Fracture Risk in Users of Organic Nitrates: A Nationwide Case‐Control Study

Department of Endocrinology and Metabolism, Aarhus University Hospital, Aarhus Sygehus, Tage-Hansens Gade 2, Aarhus C, Denmark. rejunmark@
Journal of Bone and Mineral Research (Impact Factor: 6.83). 12/2006; 21(11):1811-7. DOI: 10.1359/jbmr.060804
Source: PubMed


In a nationwide population-based pharmaco-epidemiological case-control study, including 124,655 subjects who had sustained a fracture during 2000 (cases) and 373,962 age- and sex-matched controls, we found an approximately 15% reduced risk of fractures in users of organic nitrates. Thus, organic nitrates may protect against osteoporosis.
Organic nitrates are widely used in the treatment of ischemic heart diseases. In addition, nitrates may affect bone. In vitro studies have shown that nitrates are able to inhibit bone resorption, and recent studies in humans have shown a positive effect on BMD and bone turnover.
We studied the effect of organic nitrates on risk of fracture. We performed a population-based pharmaco-epidemiological case-control study with fracture in 2000 as outcome and use of nitrates (isosorbide mononitrate, isosorbide dinitrate, and nitroglycerin) during the previous 5 years as exposure variable. We used nationwide computerized registers to assess individual use of nitrates and related these data to individual fracture data and information on potential confounders. In the study, we included 124,655 subjects who had sustained a fracture during 2000 (cases) and 373,962 age- and sex-matched controls.
After confounder adjustment, use of nitrates was associated with an 11% reduced risk of any fracture (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). Risk of any fracture was reduced in both men and women, but risk of hip fracture was only reduced in women. Hip fracture risk was reduced dose-dependently. Use of nitrates with a short duration of action was associated with lower risk estimates than use of slow release preparations.
Treatment with nitrates is associated with a decreased risk of fracture. Further studies should determine whether a causal relationship exists.

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    • "Of note, there have been two previous case-control studies that have reported on the effect of organic nitrates on fracture risk [47,48]. Both of these studies demonstrate that nitrate use was associated with a decreased risk of fracture, including hip fracture (by about 10% to 15%), and that the reduction in fracture risk was greatest among those using low-dose nitrates on as needed basis. "
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    ABSTRACT: Organic 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 design: This 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. Data from this protocol will be used to develop a randomized, controlled trial of nitrates to prevent osteoporotic fractures.Trial registration: Identifier: NCT01387672. ISRCTN08860742.
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