• Pilot Study: Mean headache score associated with each of intermittent nitroglycerin ointment (NTG) and isosorbide mononitrate (ISMO) use [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  
• Main Study: Change from baseline in bone mineral density (BMD) at the lumbar spine over 24 months [ Time Frame: 48 months ] [ Designated as safety issue: No ]
  

• Change from baseline in total hip BMD; Change from baseline in bone formation and bone resorption markers; Adverse events and Bone microarchitecture: trabecular and cortical volumetric bone densities at the radius and tibia. [ Time Frame: 48 months ] [ Designated as safety issue: No ]
  

Drug: Nitroglycerin ointment
Pilot Study: 15 mg/day applied once daily for 2 weeks Main Study: 15 mg/day applied once daily for 24 months
Drug: Isosorbide mononitrate
Pilot study: 20 mg/day once per day for 2 weeks

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.