Trial Information

The Effects of Organic Nitrates on Osteoporosis: Part 2

This proposal consists of two studies. The objective of the first study is to determine
which of isosorbide mononitrate (ISMO) at 20 mg/day or nitroglycerin ointment (NTG) at 15
mg/day results in fewer headaches. The nitrate that is best tolerated will be used in a
second study with one main objective: To determine if postmenopausal women with a T-score at
the lumbar spine (L1 to L4) between 0 and -2.0 randomized to two years of treatment with
intermittent nitrates have a greater increase in spine BMD as compared to women randomized
to placebo.

I hypothesize that:

1. Women will report fewer headaches when they are randomized to intermittent NTG ointment
at 15 mg/day compared to intermittent oral ISMO at 20 mg/day.

2. After two years, women randomized to intermittent nitrates will have a greater percent
increase in lumbar spine BMD compared with women randomized to placebo.

To test these hypotheses I will execute 2 trials both of which include postmenopausal women,
aged 50 and older, with BMD T scores at the lumbar spine between 0 and -2.0. I will exclude
subjects with prior osteoporotic fractures or OP by BMD testing, subjects with current
metabolic bone or cardiovascular disease, subjects taking treatments for OP, subjects with
migraine headaches, and subjects with known hypersensitivity to nitrates. I will use
computer generated randomization to allocate subjects to treatment assignments. To avoid
bias the studies will be double-blind. The first study, which uses a crossover design, will
recruit 22 subjects who will be randomly assigned to each of NTG ointment and ISMO for one
week. In between treatments there will be a two week wash out period. Subjects will rate
headaches on a daily basis using a visual analog scale and for each subject I will calculate
the mean headache score over the 7 day treatment period for both treatments. I will then
calculate the mean headache score (considering all subjects) for NTG and the mean headache
score for ISMO. I will compare the mean headache scores for both treatments and the nitrate
preparation that is best tolerated (lowest mean score) will be used in a second placebo
controlled study (the main study) whose primary objective is to assess the effects of
intermittent nitrates on spine BMD (L1 to L4) in 280 postmenopausal women. To limit
differential drop out due to headaches among subjects randomized to nitrates, the main trial
will follow a run-in phase during which all subjects will receive nitrates for one week.
Only those subjects who do not have headaches resulting in discontinuation of the study
medication during the nitrate run-in phase will enter the main study.