Bone Research - A Structural Support - An important Mineral Depot

The adult human skeleton contains slightly more than 200 bones, ranging from the interlocking complexities of the spine to the tiny resonators that allow us to hear sound to the marrow-filled long bones of our limbs. Not only does the skeleton provide structural support for muscles and protection for vital organs, it also acts as a depot for essential minerals, such as calcium, phosphorous and magnesium.

Despite its apparent durability, bone tissue is constantly being broken down and reformed. Among other things, this turnover is necessary for growth, repair of microfractures from everyday mechanical stress and maintaining general health. The skeleton stores 99 per cent of the body's calcium. The remaining one per cent circulates freely in the bloodstream, where it's involved in such diverse activities as muscle contractions, nerve-impulse transmissions and blood clotting.

Usually, in any given year, up to a third of the adult skeleton is remodeled by two types of cells whose opposing actions are kept in balance by a complex mix of hormones and chemical factors. Osteoblasts are the bone builders; they cruise along the bone surface secreting collagen and then mineralizing it with calcium and phosphorus. Osteoclasts are recruited to damaged parts of the bone's surface where they resorb the proteins and calcium and then release it into the bloodstream. Peak bone mass for men and women is attained in their mid-thirties and plateaus for about another 10 years, during which time bone formation approximately equals bone resorption.

From Osteoporosis to Paget's Disease

After age 60, however, osteoblast activity typically slows down. Meanwhile, declining levels of estrogen in women and testosterone in men have the opposite effect on osteoclasts, which begin to resorb bone at an accelerated pace. This sets the stage for one of the most common bone diseases, osteoporosis - when the net rate of bone resorption exceeds the rate of bone formation, resulting in less bone mass. Eventually, a person's bones can become so thin and brittle that they fracture as a result of a simple movement or a minor fall. Common fracture sites include the spine, wrists and hips. What's more, a long list of medical conditions - such as hyperthyroidism, leukemia or chronic liver disease - as well as medications (most notably prednisone) can also cause osteoporosis.

Approximately 1.4 million Canadians are currently affected by osteoporosis, and this number is increasing as the population ages. By age 65, one in every two women will have osteoporosis; by age 75, one in two will have experienced an osteoporotic fracture; and by age 90, one in three will have experienced a hip fracture (approximately twice the incidence rate for men). Women who have had an osteoporotic fracture are two to six times more likely than other women to report difficulty in daily-living activities such as stair climbing, reaching, bending, lifting and walking. Of those older people who experience a hip fracture, between 18 and 28 per cent will die within a year of related complications-primarily from pulmonary embolism or stroke due to immobilization, pneumonia or blood poisoning from bed sores.

Although many people confuse the two, osteoarthritis (OA) has quite a different effect on bone than osteoporosis. Instead of loss of bone mass, OA tends to do the opposite. Unusual mechanical forces set off by crumbling cartilage destabilize the joint and promote exuberant repair by osteoblasts. Over time, the bone directly beneath joint cartilage often becomes increasingly dense, which some researchers theorize reduces the shock-absorbing qualities of the cartilage and increases the potential for pitting and cracking. Another result of these poorly functioning glide-surfaces is remodeling of the joint margins into bony spurs that restrict range of motion and irritate surrounding soft tissue.

By contrast, rheumatoid arthritis (RA) corrodes bone and cartilage. In RA and other types of inflammatory disease, the acids and enzymes released by immune cells can eat away bone until, after three to five years, it becomes a fragile filigree. Many of the same processes of bone resorption are also involved in periodontal disease.

Bone is also particularly vulnerable to cancers that spread from other sites, notably breast and prostate cancers, as well as myeloma (when cancerous plasma cells invade the marrow and surrounding bone). At present, cancer metastasis to bone is incurable.

There are also diseases of abnormal calcification and bone formation. Sometimes, calcium circulating in the blood attaches to cholesterol deposits on arterial walls, forming a hard, brittle cover over plaque formations, which significantly raises the risk of stroke. FOP (fibrodysplasia ossificans progessiva), on the other hand, is an extremely rare genetic disorder that causes painful bony nodules to form in muscles, tendons, ligaments and other connective tissues.

Other inherited disorders include osteogenesis imperfecta, which causes weak bones that break easily because of poor quality collagen or underproduction of collagen, and Paget's disease, which is characterized by abnormal bone resorption followed by hyperactive bone formation.

A Reputation for Innovation

Canada's bone researchers have an international reputation for innovation that is disproportionate to their number. For example, Canadian research into hormones led to the discovery of calcitonin, which is crucial to regulating bone and calcium metabolism. Current basic science includes improving our knowledge about how osteoblasts and osteoclasts signal one another, locating and describing the genes that control bone development, understanding why bone's microenvironment provides a "safe sanctuary" to migrating tumors, and learning how to coax stem cells into becoming skeletal tissue.

On the clinical front, investigators are searching for more agents that stimulate bone formation or block resorption by exploiting hormones such as leptin (a hormone secreted by fat cells and usually associated with control of body weight) or by enlisting existing drugs such as statins (which seem to actually stimulate bone growth) or by exploring the protective properties of different SERMS (selective estrogen receptor modulators). In genetic bone diseases, scientists have discovered a method in the lab for suppressing the gene in osteogenesis imperfecta that causes weakened collagen. A known bone resorption inhibitor, bisphosphonate, has also been found to improve the clinical symptoms of osteogenesis imperfecta in children. And several possible sites on three different chromosomes have been identified that may be involved with Paget's disease.

Yet, there is much work to be done and a myriad of questions to be answered. For example, can the agents used to prevent bone loss also reduce fracture risks in people with low bone mass? What is the best way to maximize peak bone-mass in children, teens and young adults? How can we chart the natural effects of aging on the skeleton? And, if we learn to master the factors involved in normal bone remodeling, could they be manipulated to resist tumor growth?

As a result of the support provided by IMHA, and other Institute's associated with the Canadian Institutes of Health Research, Canada's bone scientists are well positioned to tackle these and other questions requiring large-scale, long-term research. Ultimately, multi-centre trials will prove to be the most cost-effective avenue for addressing the wide array of diseases affecting the human skeleton.

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