Uncovering the Genetic Basis of Osteoporosis

Philip Dopp, BSc

The disturbing statistics with regard to the prevalence of osteoporosis among older women are well known. By 65 years of age, one in four women have experienced an osteoporotic fracture, and the rate of incidence rises to one in two by the age of 75. The incidence of hip fractures among women in the United States is 2 per 1000 patient years by the age of 65 and 30 per 1000 patient years by the age of 85.1 More importantly, hip fractures in the elderly are associated with a high mortality rate. Both men and women are between two and five times more likely to die during the first 12 months following a hip fracture when compared to age and sex matched controls without hip fractures. Given this and other serious consequences, there is much interest in discovering factors that can prevent or slow the rate of development of this disease.¹

Pathophysiology of Osteoporosis
Osteoporosis is the generalized, progressive diminution in bone tissue mass per unit volume which causes skeletal weakness, even though the remaining bone is normal morphologically. It is well known that factors that decrease bone mineral density (BMD) and increase the risk of osteoporotic fractures include family history, white race, female gender, estrogen deficiency, low dietary levels of calcium and vitamin D, limited physical activity or immobility and medications such as corticosteroids.^1,2 Currently, there has been an increased interest in determining the role that genetic factors play in the pathogenesis of osteoporosis.

Miacalcin: A New Drug Option for Treating Established Osteoporosis

Anna Liachenko, BSc, MSc

Canadian postmenopausal women now have a new drug option for treatment of established osteoporosis and/or relief of pain associated with osteoporotic fractures--synthetic salmon calcitonin administered as a nasal spray (Miacalcin Nasal Spray or Miacalcin NS). Already available in over 70 countries, the drug was approved in Canada in September of 1999. The nasal spray is very safe and has been shown in various studies to increase bone mineral density (BMD) in vertebrae, the primary site of fractures in postmenopausal osteoporosis. Several months ago a large clinical trial confirmed that Miacalcin NS lowers the risk of vertebral fractures, making it an important agent for osteoporotic therapy.⁶

Calcitonin is a peptide hormone secreted by the thyroid gland and its secretion is under the direct control of blood calcium levels. In humans, no definite effects on calcium levels are seen in states of calcitonin deficiency or excess. Calcitonin was discovered over 35 years ago by Dr. Harold Copp at the University of British Columbia. Secretion calcitonin is estrogen-dependent and is decreased after menopause.^7,8 Osteoporotics have lower levels of serum calcitonin than both premenopausal and healthy menopausal females. It is likely that the deficiency in the hormone plays some role in postmenopausal bone loss, and studies have found that calcitonin counteracts both early and established osteoporosis.

Fourteen vegetables significantly inhibit bone resorption in rats

A study in the September 23rd issue of Nature by Drs Roman C Muhlbauer and Feng Li of the University of Bern in Switzerland showed that a variety of salads, herbs and cooked vegetables can alter bone metabolism in rats. In particular, a mixture of 500 mg each of onion and Italian parsley, and a mixture of lettuce, tomato, cucumber, arrugula, onion, garlic, wild garlic, common parsley, Italian parsley and dill significantly inhibited bone resorption indicating that the effect was additive. Furthermore, when male rats were fed one gram of dry onion per day, bone resorption was inhibited by 20 percent. That was slightly higher than the effect of calcitonin, at doses comparable to what is used to treat postmenopausal women. If these results could be duplicated in humans, then consuming some of these vegetables on a daily basis could be an "effective and inexpensive way to decrease the incidence of osteoporosis."

Further Reading: Nature 1999;401:343-4.

Novel drug reduced incidence of osteoporotic fracture up to half

In one of the largest late-stage clinical programs ever conducted, the investigational pyridinyl bisphosphonate drug risedronate (Actonel) reduced the incidence of new vertebral fractures by up to 49 percent, and lowered the risk of osteoporosis related non-vertebral fractures by up to 39 percent. The results were presented at the annual meeting of the Endocrine Society.

Professor Richard Eastell, professor of bone metabolism at the University of Sheffield, UK, presented safety data from five clinical studies that enrolled a total of 5,226 post-menopausal women. The proportion of women reporting GI side effects was similar in the risedronate and placebo groups. Currently, risedronate is not available in Canada. For the full article see Nature 1999;397:315-23.

Gene discovery may lead to osteoporosis cure

After twenty years of searching, Toronto researchers have located a gene in mice called opgl, that can activate mature osteoclasts and mediate osteoclastogenesis. The tumour-necrosis-factor family molecule osteoprotegerin ligand (OPGL), is an important factor for osteoclast maturation in vivo. Mice who lack the opgl gene exhibited severe osteopetrosis, stunted growth, defective tooth eruption and a complete lack of lymph nodes. Scientists also discovered that the gene was necessary for T- and B-cell maturation. Interestingly researchers found that OPGL secreted from activated T cells may "directly modulate osteoclastogenesis and the activity of mature osteoclasts." Although the implications of this discovery for humans are as yet undetermined, this may bring scientists one step closer to finding a cure for osteoporosis and T-cell-mediated arthritis.

For the full article see Nature 1999;397:315-23.

Risedronate and Etidronate both effective for treating corticosteroid-induced osteoporosis

A 12 month, double-blind, placebo-controlled, randomized, multicentre study by Jencen and colleagues demonstrated that 5 mg/day of risedronate (Actonel) given for twelve months was effective in significantly increasing bone mineral density and lowering the risk of vertebral fractures, for patients on chronic corticosteroid therapy. From the abstract it is unclear if these fractures were clinically symptomatic, radiologically detected, or both. Risedronate prevents bone loss by inhibiting bone resorption. It represents a new type of biphosphonate which is hoped to have less gastrointestinal complications than other bisphosphonates, however, residronate is not available in Canada at this time.

Adachi and colleagues pooled results from two similarly designed, randomized, double-blind, placebo controlled trials examining the effectiveness of Etidronate (Didrocal) (which is available in Canada). Intermittent cyclical therapy with etidronate in patients recently starting corticosteroids proved to be effective in preventing bone loss in men, pre- and post-menopausal women. This data supports previously published studies employing a bisphosphonate to decrease the loss of bone mineral density with chronic systemic corticosteroid use.

Abstracts are available at http://ex2.excerptamedica.com/98ac

Calcitonin Relieves Vertebral Fracture Pain

How Many Bones Must be Broken?

Lilia Malkin, BSc

A fracture is often the first clinical sign of osteoporosis (OP), the silent disease of skeletal fragility characterized by decreased bone mass and deterioration of bone tissue that results in an increased vulnerability to fractures.

The bone mineral density (BMD) criterion frequently used to define osteoporosis was set in 1994 by the World Health Organization (WHO) as more than 2.5 standard deviations below the "young adult mean." An estimated 1.4 million Canadians suffer from OP. In the population aged 50 and over, approximately one in four women and one in eight men are affected. The incidence of the disease increases with age: 70 percent of women have osteoporosis by the age of 80. Predictably, the fracture risk rises with age, with women at higher risk due to both more extensive bone loss and longer average life span. Osteoporotic fractures make a significant contribution to morbidity and mortality in the geriatric population. For instance, the mortality rates within one year of hip fracture are estimated at between 12 and 37 percent, while the average death rate in octogenarians is 2.6 percent per year.

Unfortunately, OP is often asymptomatic prior to the occurrence of a fragility fracture, a break that occurs in the absence of major trauma to the affected bone. The best predictor of fracture risk is low bone density.