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.

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.

The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)