Diseases

Osteoporosis

Osteoporosis occurs when bone breakdown happens more rapidly than bone formation. The bones get weaker, leading to fracture - particularly of the hip. Post-menopausal women are particularly at risk. Pharmaceutical research has developed many therapies including medicines that inhibit bone breakdown. More and more treatments to make old age a happier time for millions of people are under investigation.

What is osteoporosis? Top

Osteoporosis, or brittle bone disease, is a disorder of the skeleton in which there is an imbalance between bone formation and bone resorption, leading to excessive loss of bone. The weakened bones are eventually unable to support even normal activities and fractures occur, especially in the hip, wrist and vertebrae, leading to substantial pain and incapacity. Fractures in the neck of the femur are often the reason for a spiral of dependency. Osteoporosis is an insidious disease, as the affected individual feels initially well and is unaware that bone loss is taking place.

Bone is constantly being remodelled from birth to death. Many factors influence the maximum bone mineral density (BMD) reached and the rate of subsequent decline, including genetic makeup, race, gender, physical activity, nutrition and exercise (especially in childhood), and vitamin D intake. Bone remodelling is under hormonal control and the drop in level of the sex hormone oestrogen in women after the menopause greatly accelerates bone loss.

Who does osteoporosis affect? Top

In Europe, about one in four women will develop osteoporosis (post-menopausal women are especially vulnerable), as will about one in 12 (mostly elderly) men. The prevalence rates are age-dependent. It is estimated that 30 per cent of women over the age of 50, and 50 per cent of women over the age of 60 are affected. Altogether, some 19 million people in the EU are considered to suffer from osteoporosis.

The World Health Organisation estimates that the number of hip fractures worldwide due to osteoporosis is expected to rise three-fold by the middle of the next century, from 1.7 million in 1990 to 6.3 million by 2050. Osteoporosis will also create an enormous strain on healthcare organisations, due to increased morbidity and high mortality risk and the subsequent effects on quality of life, quite apart from the distress to the sufferer.

 

 

FIGURE1: Schematic diagram of bone mineral density throughout life

Present treatments Top

There are two stages in dealing with the disease: prophylaxis and therapy. Diagnosis plays a particularly important role, because serious illness can be prevented by timely treatment. So far, European countries have neither established an age at which the screening of post-menopausal women for the detection of osteoporosis should be envisaged, nor have they laid down consistent criteria when treatment should take place. The approval of the first selective oestrogen receptor modulator (SERM) in 1998 added a new class of treatment for post-menopausal osteoporosis. The therapy has been shown to reduce the rate of vertebral fractures and to have a favourable effect on blood lipid levels. It does not act on the uterus (unlike oestrogen) and so can be used safely in women who have not had a hysterectomy.

The main class of non-steroidal compounds for osteoporosis are the bisphosphonates. They act by binding to bone, where they stop cells called osteoclasts, which are involved in bone cell turnover and remodelling, from digesting the bony tissue. The first was launched in 1992. Extensive trial data has shown that these medicines are able to lower substantially the risk of fracture in the hip and spine and are authorised for both the prevention and therapy of post-menopausal osteoporosis, and for the prevention of bone loss during prolonged steroid therapy. All bisphosphonates are available in oral tablet form and are taken once weekly or once monthly.

Strontium ranelate, a dual-acting bone agent, has also been shown to reduce the risk of vertebral and hip fractures in postmenopausal osteoporosis. The compound combines the activity of anti-resorptive bisphosphonates with the anabolic action of parathyroid hormone (PTH) products. It offers an alternative to bisphosphonates and is used in those patients who are not tolerant of bisphosphonates and those worried about bisphosphonates’ long half-life. Given as an oral suspension, strontium is taken daily, in contrast with the current trend for bisphosphonates to be dosed less frequently to increase convenience and compliance.

Other medicines for osteoporosis include vitamin D products and combinations of calcium salts and vitamin D3, usually given in addition to other medicines such as bisphosphonates. Synthetic injectable forms of the natural hormone calcitonin also prevent bone resorption. They are mainly used in patients for whom HRT and bisphosphonates are unsuitable.

What’s in the development pipeline? Top

The new osteoporosis medicines under clinical development include both new compounds in existing classes of medicines that represent new approaches to treating the disease. There are further SERMs in clinical trials. They have been shown to be effective in increasing lumbar spine BMD. If they were able to reduce hip fracture rates in addition to vertebral fractures, it could expand the role of SERMs in osteoporosis.

A recombinant form of an active sub-fragment of human PTH is the first in a new class of anti-osteoporotic treatments. Other related preparations are in earlier phases, including a nasal spray and an oral compound. PTH stimulates bone formation by increasing the number and/or activity of bone-forming cells called osteoblasts. Other medicines such as the bisphosphonates work by inhibiting bone-destroying activity.

An additional bisphosphonate that is already available for treating raised levels of calcium in the blood in cancer patients is being studied to examine its ability to prevent new hip and vertebral fractures in osteoporosis. It is given by injection only once a year.

The new medicine has been shown to reduce the rate of new vertebral and non-spinal fractures in post-menopausal women by more than 50 per cent. It remains to be seen whether the beneficial effect will persist after stopping treatment and it has been suggested that it might be necessary to add a subsequent course of a bisphosphonate to lock in the gain in bone strength. Apart from the truncated formulation of PTH, there is a bio-engineered full-length version of human PTH in the late stages of clinical development.

Another new molecule under investigation is a naturally occurring protein which regulates the number and activity of osteoclasts and hence of bone resorption. It may also have application in preventing bone destruction in some types of cancer. Findings in animal experiments suggest that it might be especially effective in osteoporosis when used in combination with PTH.

The longer-term future Top

Substantial efforts are still being made to seek improved therapies for osteoporosis. Research is continuing to generate new candidates for development, either inhibitors of bone resorption or stimulators of bone formation. There is a first category with an osteoclast vitronectin receptor antagonist; other types of molecule being investigated in preclinical research include cathepsin K inhibitors, p38 mitogen-activated protein kinase inhibitors, and IL-1 receptor antagonists.

Among the stimulants of bone formation, recombinant bone morphogenetic proteins are being studied. Other studies have suggested that new statins may have promise for stimulating bone formation. The protein BEER – Bone Equilibrium Expression Regulator – is believed to be responsible for governing bone resorption. Researchers have come up with antibodies to the BEER protein, which it is hoped will promote bone formation.

Research on new targets includes inhibitors of the enzyme 12/15-lipoxygenase. Mice with over-expression of the Alox15, the gene that encodes for the enzyme, show weaker bones and low bone mass, but giving the animals an inhibitor of 12/15-lipoxygenase seems to increase both bone strength and density. These findings underscore the need to determine the cells, substrates and metabolic pathways of lipid mediators that are altered in the disease. Further research into 12/15-lipoxygenase could hasten the development of a new class of osteoporosis treatment.