Nitrates and Bone Turnover; Nitrates and Bone Turnover Bisphosphonate Sub-Study

Study Overview
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Brief Summary
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Purpose: NABT: To compare five widely available nitrate formulations: (1) 15 of nitroglycerin (NTG) ointment, (2) 0.3 mg and (3) 0.6 mg of sublingual NTG, (4) 20 mg of isosorbide mononitrate (an oral tablet), and (5) 160 mg of glycerol trinitrate (a patch), for their efficacy on markers of bone formation and resorption and for the incidence and severity of headache they cause. Hypothesis: There is one ideal nitrate preparation which balances the clinical efficacy in bone remodeling against the common side effect of headache. NABT-B: To determine if nitrates affect markers of bone formation (serum BALP and P1NP) and resorption (serum CTX and urine NTX) in women who have recently discontinued treatment with alendronate, risedronate or zoledronate.

Official Title
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Nitrates and Bone Turnover (NABT): Trial to Select the Best Nitrate Preparation

Conditions
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Osteoporosis

Intervention / Treatment
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* Drug: Nitrates (NABT Main trial)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: NABT: Women aged 50 years and older whose last menstrual period occurred at least 3 years ago Women without a uterus will be eligible after age 55 NABT-B: Women aged 50 years and older whose last menstrual period occurred at least 3 years ago Women without a uterus will be eligible after age 55 Previously treated with alendronate but stopped within 2 years of study commencement; or previously treated with risedronate but stopped within 1 year of study commencement; or previously treated with zoledronate. Exclusion Criteria: NABT: A previous fracture of the hip, wrist, spine or ankle within the last 3 months; or a diagnosis of osteoporosis; A history of bone disorders such as hyperparathyroidism or Paget's disease; Treatment within 12 months of study entry with any agent that may influence bone metabolism including any hormone, anti-estrogen or raloxifene and prednisone (equivalent to 5 mg/d for 12 months or greater); Treatment with any antiresorptive agent, including alendronate, risedronate, etidronate or denosumab use for at least four weeks within the last three years; Previous treatment with intravenous zoledronate or parathyroid hormone; Current treatment with nitrates; A history of migraine headaches; A history of angina or cardiovascular disease; Inability to give informed consent; Hypersensitivity to nitroglycerin. NABT-B: A previous fracture of the hip, wrist, spine or ankle; or a self-reported diagnosis of osteoporosis; A history of bone disorders such as hyperparathyroidism or Paget's disease; Treatment within 12 months of study entry with any agent that may influence bone metabolism including any hormone, anti-estrogen or raloxifene and prednisone (equivalent to 5 mg/d for 12 months or greater); Treatment with etidronate or denosumab use for at least four weeks within the last three years and any previous treatment with parathyroid hormone; Current treatment with nitrates; A history of migraine headaches; A history of angina or cardiovascular disease; Inability to give informed consent; Hypersensitivity to nitroglycerin.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nitrol<br>Nitroglycerin Ointment 2% USP | Drug: Nitrates (NABT Main trial)<br>* nitroglycerin; isosorbide mononitrate<br>* Other names: NABT-B Sub-Study: Nitroglycerin Ointment 2%: 15mg of NTG ointment for a 3 month period;|
| Active Comparator: Nitro-Dur<br>Nitroglycerin Extended Release Patch 160mg | Drug: Nitrates (NABT Main trial)<br>* nitroglycerin; isosorbide mononitrate<br>* Other names: NABT-B Sub-Study: Nitroglycerin Ointment 2%: 15mg of NTG ointment for a 3 month period;|
| Active Comparator: Nitrostat 1<br>Nitroglycerin 0.3mg Sublingual Tablet | Drug: Nitrates (NABT Main trial)<br>* nitroglycerin; isosorbide mononitrate<br>* Other names: NABT-B Sub-Study: Nitroglycerin Ointment 2%: 15mg of NTG ointment for a 3 month period;|
| Active Comparator: Nitrostat 2<br>Nitroglycerin 0.6mg Sublingual Tablet | Drug: Nitrates (NABT Main trial)<br>* nitroglycerin; isosorbide mononitrate<br>* Other names: NABT-B Sub-Study: Nitroglycerin Ointment 2%: 15mg of NTG ointment for a 3 month period;|
| Active Comparator: ISMO<br>Isosorbide Mononitrate 20mg Oral Tablet | Drug: Nitrates (NABT Main trial)<br>* nitroglycerin; isosorbide mononitrate<br>* Other names: NABT-B Sub-Study: Nitroglycerin Ointment 2%: 15mg of NTG ointment for a 3 month period;|
| Placebo Comparator: Placebo<br>Placebo Ointment | Other: Placebo<br>* Placebo ointment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone Turnover Markers | Markers of Bone Formation: Serum Procollagen type 1 amino- terminal propeptide (P1NP) Serum Osteocalcin (OC) Serum Bone-specific alkaline phosphatase (BALP) Markers of Bone Resorption: - Serum C-telopeptides of collagen cross-links (CTX) | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Headache | Severity of headaches. Subjects recorded the severity of headaches upon awakening every day during the run-in phase using a visual analogue scale (VAS). The scale is represented by a line (continuum) 10 cm long. Subjects were asked to make a vertical line along the continuum to indicate the severity of their headache each morning upon awakening. The score is recorded in cm from 0 to 10. A vertical line marked at 0 means no headache (score recorded = 0), a vertical line marked at 10 means a terrible headache (score recorded = 10). | Run-in phase - 2 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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postmenopausal, osteoporosis, bone turnover, nitrate, headache