Osteoporosis
Conditions
Keywords
postmenopausal, osteoporosis, bone turnover, nitrate, headache
Brief summary
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.
Interventions
DRUGNitrates (NABT Main trial)
nitroglycerin; isosorbide mononitrate
OTHERPlacebo
Placebo ointment
Sponsors
The Physicians' Services Incorporated Foundation
California Pacific Medical Center
Sunnybrook Health Sciences Centre
Canadian Institutes of Health Research (CIHR)
University of Toronto
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
50 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bone Turnover Markers | 3 months | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Headache | Run-in phase - 2 days | 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). |
Countries
Canada
Participant flow
Pre-assignment details
Initial run-in period-subjects received, in random order, each of the 5 nitrate formulations for 2 days with a 2 day wash out period between formulations. There were 265 subjects enrolled in the run-in phase of the study. Out of those, 229 subjects entered the treatment phase of the study, where they were randomized to one of the 6 treatment arms.
Participants by arm
| Arm | Count |
|---|---|
| ISMO - Treatment Arm 1 Isosorbide Mononitrate 20mg Oral Tablet
Nitrates (NABT Main trial) | 39 |
| Patch (Nitro-Dur) - Treatment Arm 2 Nitroglycerin Extended Release Patch 160mg
Nitrates (NABT Main trial) | 38 |
| Ointment (Nitrol) - Treatment Arm 3 Nitroglycerin Ointment 2% USP
Nitrates (NABT Main trial) | 38 |
| 0.3 Sublingual (Nitrostat 1) - Treatment Arm 4 Nitroglycerin 0.3mg Sublingual Tablet
Nitrates (NABT Main trial) | 39 |
| 0.6 Sublingual (Nitrostat 2) - Treatment Arm 5 Nitroglycerin 0.6mg Sublingual Tablet
Nitrates (NABT Main trial) | 38 |
| Placebo Ointment - Treatment Arm 6 Placebo Ointment
Placebo: Placebo ointment Nitrates (NABT Main trial) | 37 |
| Total | 229 |
Baseline characteristics
| Characteristic | ISMO - Treatment Arm 1 | Patch (Nitro-Dur) - Treatment Arm 2 | Ointment (Nitrol) - Treatment Arm 3 | 0.3 Sublingual (Nitrostat 1) - Treatment Arm 4 | 0.6 Sublingual (Nitrostat 2) - Treatment Arm 5 | Placebo Ointment - Treatment Arm 6 | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 20 Participants | 17 Participants | 18 Participants | 16 Participants | 15 Participants | 17 Participants | 103 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 21 Participants | 20 Participants | 23 Participants | 23 Participants | 20 Participants | 126 Participants |
| Region of Enrollment Canada | 39 participants | 38 participants | 38 participants | 39 participants | 38 participants | 37 participants | 229 participants |
| Sex: Female, Male Female | 39 Participants | 38 Participants | 38 Participants | 39 Participants | 38 Participants | 37 Participants | 229 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 17 / 39 | 21 / 38 | 17 / 38 | 10 / 39 | 12 / 38 | 6 / 37 |
| serious Total, serious adverse events | 0 / 39 | 0 / 38 | 0 / 38 | 1 / 39 | 1 / 38 | 0 / 37 |
Outcome results
Primary
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)
Time frame: 3 months
Population: One subject from the Treatment Arm 3 had outlier bone turnover markers values and was excluded from the analysis. Total number of subjects analyzed in Treatment Arm 3 was therefore 32.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ISMO - Treatment Arm 1 | Bone Turnover Markers | P1NP | -4.627 Percent change from baseline | Standard Deviation 16.191 |
| ISMO - Treatment Arm 1 | Bone Turnover Markers | OC | -3.244 Percent change from baseline | Standard Deviation 12.049 |
| ISMO - Treatment Arm 1 | Bone Turnover Markers | BALP | -5.023 Percent change from baseline | Standard Deviation 11.824 |
| ISMO - Treatment Arm 1 | Bone Turnover Markers | CTX | -5.844 Percent change from baseline | Standard Deviation 26.084 |
| Patch (Nitro-Dur) - Treatment Arm 2 | Bone Turnover Markers | BALP | -0.541 Percent change from baseline | Standard Deviation 20.738 |
| Patch (Nitro-Dur) - Treatment Arm 2 | Bone Turnover Markers | OC | 3.796 Percent change from baseline | Standard Deviation 33.601 |
| Patch (Nitro-Dur) - Treatment Arm 2 | Bone Turnover Markers | P1NP | -0.405 Percent change from baseline | Standard Deviation 20.289 |
| Patch (Nitro-Dur) - Treatment Arm 2 | Bone Turnover Markers | CTX | -1.025 Percent change from baseline | Standard Deviation 32.163 |
| Ointment (Nitrol) - Treatment Arm 3 | Bone Turnover Markers | CTX | -9.699 Percent change from baseline | Standard Deviation 27.299 |
| Ointment (Nitrol) - Treatment Arm 3 | Bone Turnover Markers | BALP | -7.426 Percent change from baseline | Standard Deviation 11.056 |
| Ointment (Nitrol) - Treatment Arm 3 | Bone Turnover Markers | OC | -4.481 Percent change from baseline | Standard Deviation 14.823 |
| Ointment (Nitrol) - Treatment Arm 3 | Bone Turnover Markers | P1NP | -4.297 Percent change from baseline | Standard Deviation 16.236 |
| 0.3 Sublingual (Nitrostat 1) - Treatment Arm 4 | Bone Turnover Markers | P1NP | -6.126 Percent change from baseline | Standard Deviation 16.093 |
| 0.3 Sublingual (Nitrostat 1) - Treatment Arm 4 | Bone Turnover Markers | CTX | -0.666 Percent change from baseline | Standard Deviation 37.945 |
| 0.3 Sublingual (Nitrostat 1) - Treatment Arm 4 | Bone Turnover Markers | OC | 1.046 Percent change from baseline | Standard Deviation 21.818 |
| 0.3 Sublingual (Nitrostat 1) - Treatment Arm 4 | Bone Turnover Markers | BALP | -7.000 Percent change from baseline | Standard Deviation 19.011 |
| 0.6 Sublingual (Nitrostat 2) - Treatment Arm 5 | Bone Turnover Markers | BALP | -3.686 Percent change from baseline | Standard Deviation 17.435 |
| 0.6 Sublingual (Nitrostat 2) - Treatment Arm 5 | Bone Turnover Markers | CTX | -1.380 Percent change from baseline | Standard Deviation 52.248 |
| 0.6 Sublingual (Nitrostat 2) - Treatment Arm 5 | Bone Turnover Markers | OC | 1.033 Percent change from baseline | Standard Deviation 17.931 |
| 0.6 Sublingual (Nitrostat 2) - Treatment Arm 5 | Bone Turnover Markers | P1NP | 2.941 Percent change from baseline | Standard Deviation 36.843 |
| Placebo Ointment - Treatment Arm 6 | Bone Turnover Markers | OC | 4.247 Percent change from baseline | Standard Deviation 22.088 |
| Placebo Ointment - Treatment Arm 6 | Bone Turnover Markers | BALP | -1.648 Percent change from baseline | Standard Deviation 21.523 |
| Placebo Ointment - Treatment Arm 6 | Bone Turnover Markers | CTX | -1.783 Percent change from baseline | Standard Deviation 28.063 |
| Placebo Ointment - Treatment Arm 6 | Bone Turnover Markers | P1NP | -1.635 Percent change from baseline | Standard Deviation 16.749 |
Secondary
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).
Time frame: Run-in phase - 2 days
Population: The mean headache score considering all subjects in each of the treatment/formulation group was calculated.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ISMO - Treatment Arm 1 | Headache | ISMO | 2.1 score on a scale | Standard Deviation 2.64 |
| ISMO - Treatment Arm 1 | Headache | Patch | 3.1 score on a scale | Standard Deviation 2.98 |
| ISMO - Treatment Arm 1 | Headache | Ointment | 1.5 score on a scale | Standard Deviation 2.12 |
| ISMO - Treatment Arm 1 | Headache | 0.3 Sublingual | 0.36 score on a scale | Standard Deviation 1.18 |
| ISMO - Treatment Arm 1 | Headache | 0.6 Sublingual | 0.6 score on a scale | Standard Deviation 1.62 |