OSTEOPOROSIS

What is osteoporosis?

Osteoporosis is a condition affecting the body's bones, in which there is an imbalance between bone formation and bone resorption (the breakdown and assimilation of bones by the body), leading to excessive loss of bone (Figure 1). 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. Osteoporosis is an insidious disease, as the affected individual feels well and is often unaware that bone loss is taking place until a fracture occurs.

Bone is constantly being renewed (remodelling) from birth to death (Figures 2 and 4). Many factors influence the maximum bone mineral density (BMD) reached and the rate of subsequent decline, including genetic makeup, race, 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. Osteoporosis may also develop as a result of high-dose or prolonged treatment with corticosteroids or, less commonly, some other medications, or in association with certain inflammatory, gastrointestinal or endocrine diseases.

Who does osteoporosis affect and what does it cost?

The National Osteoporosis Society has estimated that as many as 3 million people in the UK are affected by osteoporosis. The disease causes over 60,000 hip fractures, 50,000 wrist fractures and 120,000 spinal fractures each year. One woman in two and one man in five will suffer a fracture after the age of 50. The cost of treating hip fractures alone, including long-term nursing care, is estimated at £1.73 billion a year in the UK, with a recent study putting direct NHS costs at over £12,000 per case.

Present treatments and shortcomings

A wide range of hormone replacement therapy (HRT) treatments are available for managing the symptoms that arise from the fall in oestrogen level at menopause. HRT is also recognised to improve bone mineral density and reduce the risk of hip and spinal fractures. It has, however, become clear that HRT treatments may increase the risk of venous thromboembolism (see Thrombosis) and stroke, and may slightly increase the risk of breast cancer. Current medical thinking suggests that HRT use should be restricted to relief of menopausal symptoms, at the lowest effective dose, and not used long-term to protect against osteoporosis.

Raloxifene (Evista, Lilly), a selective oestrogen receptor modulator (SERM), has been introduced for the prevention and treatment of post-menopausal osteoporosis. It increases BMD and reduces the rate of vertebral (but not hip) fractures. It has been shown to have a favourable effect on blood lipid levels, but does not act on the uterus (unlike oestrogen) and so can be used safely in women who have not had a hysterectomy. It does not increase the risk of breast cancer, unlike the oestrogen in HRT, but there is still an increased risk of venous embolism. There was an increased incidence of hot flushes during the first six months of treatment in clinical trials.

The main agents used for the treatment of osteoporosis are the bisphosphonates. They act by binding to bone, where they stop cells called osteoclasts, which are involved in breaking down bone, from digesting the bony tissue (Figure 4) and thus lower the risk of fracture. Those currently available in the UK are etidronate (Didronel PMO, Procter & Gamble), alendronate (Fosamax, Merck Sharp & Dohme) and risedronate (Actonel, Procter & Gamble). Alendronate and risedronate are also available for the prevention of post-menopausal osteoporosis. Their main disadvantages are that they are not readily absorbed in the gut and have a tendency to irritate the oesophagus. All are available in oral tablet form for osteoporosis treatment (usually taken daily or once a week).

Strontium ranelate (Protelos, Servier) is an oral agent for treating osteoporosis which is effective in preventing both vertebral and hip fractures. It has a dual action, both increasing bone formation and reducing bone resorption and is effective in increasing BMD. The main side-effects observed in trials were headaches, diarrhoea and nausea. It should be used with caution in patients at raised risk of venous thromboembolism.

Teriparatide (Forsteo, Lilly) is a treatment for osteoporosis that also works in a different way. It stimulates bone formation by increasing the number and/or activity of bone-forming cells called osteoblasts (Figure 4). It is administered once daily by injection for a maximum of 18 months. Teriparatide has been shown to reduce the rate of new vertebral (but not hip) fractures in post-menopausal women by more than 50 per cent.

Other medicines for OP include calcitriol (Rocaltrol, Roche) and combinations of calcium salts and vitamin D3 (usually given in addition to other medicines such as bisphosphonates), such as Procter & Gamble's Cacit D3 and Calcichew D3 Forte from Shire. Synthetic salmon calcitonin (a naturally occurring hormone) also prevents bone resorption. It is available from Novartis (Miacalcic) as a nasal spray, but is mainly used in patients for whom HRT and bisphosphonates are unsuitable.

What's in the development pipeline?

Preotact, developed by NPS Pharmaceuticals and Nycomed, is an injectable preparation of human parathyroid hormone that has been shown to reduce the risk of new vertebral fractures in women with or without pre-existing fractures resulting from osteoporosis. Other related preparations are in earlier phases, including a nasal spray (CHS13340, Chugai, at Phase 2), an oral compound in Phase 1 trial (768974, GSK/Unigene) and BA058 (Radius), which is also in Phase 1.

Three new selective oestrogen receptor modulators are in Phase 3 trial and are potential alternatives to raloxifene. Lasofoxifene (Oporia, Pfizer) has been shown to be effective in increasing lumbar spine BMD. Bazedoxifene (Viviant, Wyeth) has also been studied for its ability to reduce the incidence of new vertebral fractures in postmenopausal osteoporosis. Wyeth also has a Phase 3 trial in progress in which bazedoxifene is given together with oestrogen for prevention of osteoporosis. Meanwhile, arzoxifene (LY353381, Lilly) is also in Phase 3 trial for vertebral fracture reduction.

An additional bisphosphonate is also in Phase 3 trial. Zoledronate (Zometa, Novartis) is already available for treating raised levels of calcium in the blood in cancer and a trial is examining its ability to prevent new hip and vertebral fractures in osteoporosis. This bisphosphonate is given by injection only once a year.

Amgen's compound AMG-162 (denosumab) represents a new approach to the problem of bone destruction in osteoporosis. It is a monoclonal antibody that is directed against a naturally occurring regulator of bone resorption. It is in Phase 3 trials in osteoporosis and is also being studied in other disorders, such as rheumatoid arthritis, in which it may prevent bone destruction.

Other new approaches are in earlier phase trials. Novartis has an inhibitor of bone resorption (AAE 581) in Phase 2 trial, as does Merck Sharp & Dohme (MK-0822). GSK has another such inhibitor 462795 (relacatib) at Phase 1. Also at Phase 1 are other compounds from GSK (751689) and Ligand and TAP Pharmaceuticals (LGD2941).

FOR FURTHER INFORMATION CONTACT:

THE NATIONAL OSTEOPOROSIS SOCIETY
Camerton
Bath, BA2 0PJ
Phone: 01761 472 721 (Helpline)
Website: www.nos.org.uk