Clinical trial NCT01387672: Nitrates and Bone Turnover; Nitrates and Bone Turnover Bisphosphonate Sub-Study
Official title: Nitrates and Bone Turnover (NABT): Trial to Select the Best Nitrate Preparation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Osteoporosis
Keywords: postmenopausal
osteoporosis
bone turnover
nitrate
headache
Lead sponsor: University of Toronto
Sponsor class: OTHER
Collaborators: name: The Physicians' Services Incorporated Foundation
name: California Pacific Medical Center
name: Sunnybrook Health Sciences Centre
name: Canadian Institutes of Health Research (CIHR)
First posted: 2011-07-04
Enrollment: 265
Sex: FEMALE
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


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.

Primary outcomes:
measure: Bone Turnover Markers
timeFrame: 3 months
Secondary outcomes:
measure: Headache
timeFrame: Run-in phase - 2 days
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Women's College Research Institute/Women's College Hospital
state: Ontario
Study officials:
affiliation: Women's College Research Institute/Women's College Hospital
name: Sophie A Jamal, MD,PhD,FRCPC
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.