If you are interested in participating in this study please read all of the following information, then follow the instructions in the “How to Participate?” section below. Here are the forms for the study:

• Consent Form for Nitrates and Bone Turnover (NABT) Study
• Patient Information Sheet

Study Title:
Nitrates and Bone Turnover (NABT): trial to select the best nitrate preparation.

Investigator(s):

Study Sponsors:

Physicians’ Services Incorporated Foundation
Ontario Academic Health Science Centres Alternate Funding Plan Innovation Fund
Canadian Institutes of Health Research
California Pacific Medical Center Research Institute

Background and Purpose of the Study:

Osteoporosis or "thinning of the bones" affects 1 in 4 Canadian women. While the rates of osteoporosis among Canadians are stabilizing, worldwide the number of people afflicted with osteoporosis continues to rise.  The most serious complication of osteoporosis is a broken bone or fracture.  Fractures due to osteoporosis can result in long hospital stays, dependence on others, and premature death.  While there are several medications that prevent osteoporosis they all have side effects and most cannot rebuild bone. In addition, drugs to prevent osteoporosis are expensive and not available worldwide.  Therefore, it is essential that researchers continue to identify and test new medications for the prevention of osteoporosis. 

A previous study by our research group determined that nitrates, common and inexpensive agents used to treat chest pain or angina can increase bone strength by forming new bone.  Nitrates are extremely safe medications and the only side effect, while common, is the development of headaches.  Nitrates are available in a large number of doses and formulations.  It is possible that there is one dose and formulation that result in few headaches and a large improvement in bone formation.  Our current study aims to identify this ideal nitrate by comparing the effects of five different formulations of nitrates on headaches and bone formation.  The nitrate formulation and dose that gives the greatest change in bone formation, together with the least headaches will subsequently be tested in a trial to prevent osteoporotic fractures.

Who Can Participate?

Participation in this study is completely voluntary.  You must meet the following inclusion and exclusion criteria to be eligible to participate.

What does participation entail?

The study will consist of 2 different phases: (1) a Run-In Phase lasting 18 days and (2) an Intervention Phase lasting 90 days.  Participation in the study will require a total time commitment of approximately 4 months and will involve 3 study visits to Women’s College Hospital. 

Prior to the first study visit, you will be screened for eligibility by the study coordinator. 

Please note that for the duration of the study you will be asked to refrain from taking the following prescription medications that affect your bones: 

• Calcitonin                                           
• Estrogen                                              
• Progesterone                                       
• Raloxifene                                          
• Tamoxifen                                          
• Corticosteroids                                   
• Zoledronic Acid                                            
• Alendronate
• Risedronate
• Etidronate
• Parathyroid Hormone
• Denosumab
• Nitrates
• Viagra, Cialis or Levitra (while not prescribed to women, these drugs cannot be used with nitrates as they may lead to severe hypotension, circulatory collapse or death)

You will also be asked to refrain from participating in other research studies.

A brief description of each study visit is outlined below: 

Visit 1: At your first study visit, you will receive a package containing 5 different formulations of nitroglycerin: (1) a 0.3mg sublingual nitroglycerin tablet; (2) a 0.6mg sublingual nitroglycerin tablet; (3) a 20mg oral tablet of isosorbide mononitrate; (4) a 160mg nitroglycerin transdermal patch and (5) 15mg of nitroglycerin ointment.  You  will be asked to take each of these 5 formulations in a randomly determined but assigned order for 2 days, each with a 2-day break in between treatments.  This will take a total of 18 days.  The study coordinator will explain how to properly administer each treatment and will provide you with specific written instructions to take home with you.  You will also be given a Visual Analogue Scale (VAS) which you will use at home to evaluate the frequency and severity of headaches if they occur and a Ranking Form.  We will call you once at the start of the run-in phase to keep note of your progress and answer any questions you may have at this time.  We will also be available to you by telephone and e-mail Monday-Friday from 9 to 5 for any additional inquiries throughout the run-in period.  Finally, you will be asked to provide a blood sample (about 60 ml or 4 tablespoons of blood) and urine sample for the measurement of bone turnover markers.  Visit 1 will last approximately half an hour.

Visit 2:  At the end of 18 days you will come back to Women’s College Hospital so that we can find out how you are doing.  If you had intolerable headaches while taking the 5 nitrate formulations, you will be withdrawn from the study.  If  you did not have headaches or had mild headaches that were tolerable during the run-in phase, we will enter you into the intervention phase of the study.  If you are continuing on, the study coordinator will administer a brief Food Frequency Questionnaire (FFQ) in order to determine how much calcium and vitamin D you need based on your current dietary intake.  If you require additional supplements, a 3 month supply of calcium and vitamin D will be provided and you will be given specific written instructions on how to take the supplements.  At this point, we will also randomly (or by chance) assign you to receive one of 6 different interventional treatments by using a computer program: (1) a 0.3mg sublingual nitroglycerin tablet; (2) a 0.6mg sublingual nitroglycerin tablet; (3) a 20mg oral tablet of isosorbide mononitrate; (4) a 160mg nitroglycerin transdermal patch; (5) 15mg of nitroglycerin ointment or (6) a placebo ointment.  You will have an equal chance of being assigned to any of the 6 treatments.  The placebo ointment is an inactive ointment that will look and smell exactly like the nitroglycerin ointment. You will be asked to take your assigned medication once daily for 3 months.  Specific written instructions on how to administer the medication assigned to you will be provided.  Visit 2 will last approximately half an hour.  In between Visit 2 and Visit 3 we will call you every month, at a time that is convenient to you, to make sure you are feeling well and answer any questions you might have.  We will also be available to you by telephone and e-mail Monday to Friday from 9 to 5.

Visit 3: After 3 months we will ask you to come back to Women’s College Hospital for your final study visit.  You will be asked to provide a blood sample (about 60 ml or 4 tablespoons of blood) and urine sample for the measurement of bone turnover markers.   You will also be asked to return any unused calcium and vitamin D or study medication.  Visit 3 will take approximately half an hour. 

The study timeline is summarized in the chart below: