Women

The Effects of Organic Nitrates on Osteoporosis: A Randomized Controlled Trial [ISRCTN94484747]

Sophie A Jamal1, Celeste J Hamilton1, Dennis Black2 & Steven R Cummings3

1Department of Medicine, University of Toronto and Division of Endocrinology and Metabolism, St. Michael's Hospital, Toronto, Canada

2Department of Epidemiology and Biostatistics, University of California, San Francisco, USA

3California Pacific Medical Center Research Institute, San Francisco, USA

Published 9 26 April 2006

Trials 2006, 7:10 doi:10.1186/1745-6215-7-10

Abstract & Article

Background

Osteoporotic fractures are common and are associated with increased morbidity, mortality and health care costs. The most effective way to moderate increases in health care costs and the sickness and premature death associated with osteoporotic fractures, is to prevent osteoporosis. Several lines of evidence suggest that nitrates, drugs typically prescribed for the treatment of angina, may be effective in preventing postmenopausal osteoporosis.

Methods

We have designed a multicentre randomized controlled trial to determine the effects of nitrates on bone. The trial consists of two studies. The objective of the first study is to determine whether isosorbide mononitrate at 20 mg/day or nitroglycerin ointment at 15 mg/day leads to fewer headaches. The nitrate that is best tolerated will be used in a second study with one main objective: To determine if postmenopausal women with a T-score at the lumbar spine (L1 to L4) between 0 and -2.0 randomized to two years of treatment with intermittent nitrates have a greater increase in spine bone mineral density as compared to women randomized to placebo.

We hypothesize that: 1. Women will report fewer headaches when they are randomized to intermittent nitroglycerin ointment at 15 mg/day compared to intermittent oral isosorbide mononitrate at 20 mg/day, and, 2. After two years, women randomized to intermittent nitrates will have a greater percent increase in lumbar spine bone mineral density compared with women randomized to placebo.

Discussion

We have completed our pilot study and found that transdermal nitroglycerin was associated with fewer headaches than oral isosorbide mononitrate. We are currently recruiting patients for our second main study.

1.0 Background

1.1 The burden of illness due to osteoporosis

Osteoporosis (OP) is characterized by a reduction in bone mass and disruption of skeletal microarchitecture leading to an increased susceptibility to fracture with minimal trauma. In Canada, one in four women have OP and in 1993 the total expenditure for fractures was in excess of 1.3 billion dollars [1,2]. The average length of stay in an acute care hospital after a hip fracture is three weeks; one of four patients must remain in long-term care institutions for at least one year; and one of three returns home but must depend on other people or devices for mobility. Furthermore, after a hip fracture there is up to a 20% increased risk of mortality [3].

As elderly men and women are the fastest growing group in the world and the incidence of OP fractures increases exponentially with age, the number of men and women with OP fractures is expected to increase dramatically over the next 50 years in Canada and world wide [3]. Assuming current demographic trends continue, the annual incidence of hip fractures worldwide could exceed 21 million in 2050 [4]. The most effective way to moderate increases in health care costs and the sickness and premature death associated with OP fractures, is to prevent OP.

Pharmacologic agents to prevent OP include estrogen replacement therapy (ERT), bisphosphonates (alendronate, risedronate, and etidronate), and selective estrogen receptor modulators (raloxifene). These medications decrease bone resorption. The resultant unopposed bone formation increases bone mineral density (BMD) and decreases fracture rates. Each medication has adverse effects, often resulting in discontinuation. For example, a randomized controlled trial (RCT) of the bisphosphonate alendronate reported that at 2 years, 60% of participants were adherent [5]. Bisphosphonates, if taken improperly, can cause gastrointestinal irritation and esophageal ulceration [6,7]. In addition, bisphosphonates cannot be prescribed for patients with impaired renal clearance, yet these patients are at particularly high risk for fractures [7-10].

Estrogen (with or without a progestin) reduces the risk of all types of fractures by 25ЁC33% but with risks that outweigh its potential benefits for fractures in the vast majority of women [8]. Raloxifene is associated with a 3-fold increase in thromboembolic disease, an increase in hot flushes, leg cramps, leg swelling, and an influenza-like syndrome [9,10].

Pharmacologic treatments are expensive: raloxifene and bisphosphonates cost > $700 Canadian/year, are either unavailable or unaffordable outside of North America and Western Europe, and of uncertain safety when used long-term (> 10 years). The limitations of the current therapies have fuelled interest in alternatives. An optimal agent would be one that decreases bone resorption while also increasing bone formation to have maximal effects on BMD and ultimately fracture, is convenient to take, inexpensive, has minimal adverse effects, is safe for long-term use, and is available world wide. One potential agent is nitric oxide in the form of organic nitrate, the subject of this randomized trial.

This randomized trial consists of two studies. The objective of the first study is to determine whether isosorbide mononitrate (ISMO) at 20 mg/day or nitroglycerin ointment (NTG) at 15 mg/day results in fewer headaches. The nitrate that is best tolerated will be used in a second study with one main objective: To determine if postmenopausal women with a T-score at the lumbar spine (L1 to L4) between 0 and -2.0 randomized to two years of treatment with intermittent nitrates have a greater increase in spine BMD as compared to women randomized to placebo.

1.2 Nitric oxide influences osteoclast and osteoblast activity

Nitric oxide (NO) is a short-lived free radical involved in the regulation of many physiological processes, including bone remodeling [11,12]. There are three sources of NO (Figure 1). First, NO can be

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