The Nitrate and Bone Study: Effects of Nitrates on Osteoporosis

NCT ID: NCT00252421

Last Updated: 2014-05-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 243 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-10-31
• Study Completion Date: 2010-07-31

Brief Summary

Osteoporosis or "thinning of the bones" affects in 1 in 4 Canadian women and 1 in 8 Canadian men. Moreover, while the rates of osteoporosis among Canadians are stabilizing, worldwide the number of people afflicted with osteoporosis continues to rise. The most serious complication of osteoporosis is a broken bone or fracture. Fractures due to osteoporosis can result in long hospital stays, dependence on others, and premature death. While there are several medications that prevent osteoporosis they all have side effects. For example, postmenopausal women who take hormone replacement therapy (HRT) are at increased risk of breast cancer and heart disease. In addition, drugs to prevent osteoporosis are expensive and not available worldwide. Therefore, it is essential that researchers continue to identify and test new medications for the prevention of osteoporosis.

The purpose of the research is to determine if nitrates, a group of drugs that are widely available, inexpensive, and commonly used to treat chest pain or angina, can prevent osteoporosis in women. If the researchers find that nitrates prevent osteoporosis, a widely available, inexpensive treatment for osteoporosis prevention that does not have any long term side effects would have been identified. This will improve the health of patients with osteoporosis worldwide.

Detailed Description

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.

We 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 we 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. We 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. We 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. We will then calculate the mean headache score (considering all subjects) for NTG and the mean headache score for ISMO. We 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.

Conditions

Osteoporosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Nitroglycerin

Nitroglycerin ointment 15 mg/day daily for 24 month

Group Type: ACTIVE_COMPARATOR

Nitroglycerin ointment 15 mg/day daily for 24 month

Intervention Type: DRUG

Nitroglycerin ointment 15 mg/day applied daily for 24 mth

Placebo

Placebo ointment daily for 24 month

Group Type: PLACEBO_COMPARATOR

Placebo ointment daily for 24 month

Intervention Type: DRUG

Placebo ointment applied daily for 24 mth

Interventions

Nitroglycerin ointment 15 mg/day daily for 24 month

Nitroglycerin ointment 15 mg/day applied daily for 24 mth

Intervention Type: DRUG

Placebo ointment daily for 24 month

Placebo ointment applied daily for 24 mth

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Women aged 50 and older
• Lumbar spine BMD (L1 to L4) T score between 0 and -2.0
• At least 3 years postmenopausal

Exclusion Criteria

• Prior low trauma hip or vertebral fracture
• Total hip or femoral neck T score of <-2.0
• Bone disorders other than osteopenia (e.g., hyperparathyroidism or Paget's disease)
• Treatment within six months of study entry with androgen, calcitonin, estrogen, progesterone, fluoride in a tablet form, raloxifene, tamoxifen, etidronate, prednisone or an equivalent at 5 mg/d for 12 months or greater, lithium or anticonvulsants
• Alendronate or risedronate use for at least four weeks, within the last three years
• Current treatment with nitrates
• Systolic blood pressure of =<100 mm Hg or diastolic blood pressure >=100 mm Hg at the baseline screening examination
• Abnormal electrocardiogram (ECG) at the baseline screening examination
• history of myocardial infarction, angina, valvular or congenital heart disease
• Disabling conditions that may interfere with follow-up visits
• Inability to give informed consent
• Migraine headaches
• Hypersensitivity to nitrates

• Minimum Eligible Age: 50 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Canadian Institutes of Health Research (CIHR)

OTHER_GOV

Sponsor Role: collaborator

University of Toronto

OTHER

Sponsor Role: lead

Responsible Party

Sophie Jamal

Associate Professor/Endocrinologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Sophie A. Jamal, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Women's College Hospital, St. Michael's Hospital, University of Toronto

Locations

Women's College Hospital

Toronto, Ontario, Canada

Countries

Canada

References

Jamal SA, Cummings SR, Hawker GA. Isosorbide mononitrate increases bone formation and decreases bone resorption in postmenopausal women: a randomized trial. J Bone Miner Res. 2004 Sep;19(9):1512-7. doi: 10.1359/JBMR.040716. Epub 2004 Jul 26.

Reference Type: BACKGROUND

PMID: 15312252 (View on PubMed)

Other Identifiers

ISRCTN 94484747

Identifier Type: -

Identifier Source: secondary_id

05-169

Identifier Type: -

Identifier Source: org_study_id