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Nitrates and Bone Turnover; Nitrates and Bone Turnover Bisphosphonate Sub-Study (NABT;NABT-B)

Primary Purpose

Osteoporosis

Status

Completed

Phase

Phase 3

Locations

Canada

Study Type

Interventional

Intervention

Nitrates (NABT Main trial)

Placebo

About this trial

This is an interventional prevention trial for Osteoporosis focused on measuring postmenopausal, osteoporosis, bone turnover, nitrate, headache

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)FemaleAccepts Healthy Volunteers

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.

Sites / Locations

Women's College Research Institute/Women's College Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Nitrol

Nitro-Dur

Nitrostat 1

Nitrostat 2

ISMO

Placebo

Arm Description

Nitroglycerin Ointment 2% USP

Nitroglycerin Extended Release Patch 160mg

Nitroglycerin 0.3mg Sublingual Tablet

Nitroglycerin 0.6mg Sublingual Tablet

Isosorbide Mononitrate 20mg Oral Tablet

Placebo Ointment

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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").

Full Information

NCT ID

NCT01387672

First Posted

June 30, 2011

Last Updated

May 6, 2015

Sponsor

University of Toronto

Collaborators

The Physicians' Services Incorporated Foundation, California Pacific Medical Center, Sunnybrook Health Sciences Centre, Canadian Institutes of Health Research (CIHR)

1. Study Identification

Unique Protocol Identification Number

NCT01387672

Brief Title

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

Acronym

NABT;NABT-B

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2015

Overall Recruitment Status

Completed

Study Start Date

September 2011 (undefined)

Primary Completion Date

December 2014 (Actual)

Study Completion Date

December 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Toronto

Collaborators

The Physicians' Services Incorporated Foundation, California Pacific Medical Center, Sunnybrook Health Sciences Centre, Canadian Institutes of Health Research (CIHR)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Osteoporosis

Keywords

postmenopausal, osteoporosis, bone turnover, nitrate, headache

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

265 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Nitrol

Arm Type

Active Comparator

Arm Description

Nitroglycerin Ointment 2% USP

Arm Title

Nitro-Dur

Arm Type

Active Comparator

Arm Description

Nitroglycerin Extended Release Patch 160mg

Arm Title

Nitrostat 1

Arm Type

Active Comparator

Arm Description

Nitroglycerin 0.3mg Sublingual Tablet

Arm Title

Nitrostat 2

Arm Type

Active Comparator

Arm Description

Nitroglycerin 0.6mg Sublingual Tablet

Arm Title

ISMO

Arm Type

Active Comparator

Arm Description

Isosorbide Mononitrate 20mg Oral Tablet

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo Ointment

Intervention Type

Drug

Intervention Name(s)

Nitrates (NABT Main trial)

Other Intervention Name(s)

NABT-B Sub-Study: Nitroglycerin Ointment 2%: 15mg of NTG ointment for a 3 month period

Intervention Description

nitroglycerin; isosorbide mononitrate

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

Placebo ointment

Primary Outcome Measure Information:

Title

Bone Turnover Markers

Description

Time Frame

3 months

Secondary Outcome Measure Information:

Title

Headache

Description

Time Frame

Run-in phase - 2 days

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sophie A Jamal, MD,PhD,FRCPC

Organizational Affiliation

Women's College Research Institute/Women's College Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Women's College Research Institute/Women's College Hospital

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 1N8

Country

Canada

12. IPD Sharing Statement

Citations:

PubMed Identifier

21343579

Citation

Jamal SA, Hamilton CJ, Eastell R, Cummings SR. Effect of nitroglycerin ointment on bone density and strength in postmenopausal women: a randomized trial. JAMA. 2011 Feb 23;305(8):800-7. doi: 10.1001/jama.2011.176.

Results Reference

background

PubMed Identifier

18800179

Citation

Jamal SA, Goltzman D, Hanley DA, Papaioannou A, Prior JC, Josse RG. Nitrate use and changes in bone mineral density: the Canadian Multicentre Osteoporosis Study. Osteoporos Int. 2009 May;20(5):737-44. doi: 10.1007/s00198-008-0727-7. Epub 2008 Sep 18.

Results Reference

background

PubMed Identifier

15312252

Citation

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.

Results Reference

background

PubMed Identifier

9797485

Citation

Jamal SA, Browner WS, Bauer DC, Cummings SR. Intermittent use of nitrates increases bone mineral density: the study of osteoporotic fractures. J Bone Miner Res. 1998 Nov;13(11):1755-9. doi: 10.1359/jbmr.1998.13.11.1755.

Results Reference

background

PubMed Identifier

19549739

Citation

Wimalawansa SJ, Grimes JP, Wilson AC, Hoover DR. Transdermal nitroglycerin therapy may not prevent early postmenopausal bone loss. J Clin Endocrinol Metab. 2009 Sep;94(9):3356-64. doi: 10.1210/jc.2008-2225. Epub 2009 Jun 23.

Results Reference

background

PubMed Identifier

24010992

Citation

Bucur RC, Reid LS, Hamilton CJ, Cummings SR, Jamal SA. Nitrates and bone turnover (NABT) - trial to select the best nitrate preparation: study protocol for a randomized controlled trial. Trials. 2013 Sep 8;14:284. doi: 10.1186/1745-6215-14-284.

Results Reference

derived

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

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