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

Osteoporosis Clinical Trial

— NABT;NABT-B  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01387672
• Other study ID #: 062011
• Status: Completed
• Phase: Phase 3
• First received: June 30, 2011
• Last updated: May 6, 2015
• Start date: September 2011
• Est. completion date: December 2014

Study information

• Verified date: May 2015
• Source: University of Toronto
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 265
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 50 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Osteoporosis

Intervention

Drug:
• Nitrates (NABT Main trial)
nitroglycerin; isosorbide mononitrate

Other:
• Placebo
Placebo ointment

Locations

Country	Name	City	State
Canada	Women's College Research Institute/Women's College Hospital	Toronto	Ontario

Sponsors (5)

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

Country where clinical trial is conducted

Canada, 

References & Publications (5)

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. — View 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. Epub 2004 Jul 26. — View 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. — View 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. Retraction in: Eastell R, Hamilton CJ, Cummings SR. JAMA. 2016 Jan 26;315(4):418-9. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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)	3 months	No
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").	Run-in phase - 2 days	No