Osteoporosis and metabolic bone diseases

Osteoporosis is a very common disease caused by loss of bone. The bones become thin and are thus much more liable to fracture.

Causes

The maximum amount of bone in the skeleton (peak bone mass) is achieved soon after linear growth ceases, usually in the late teens. Peak bone mass is largely determined by genetic (inherited) factors, and thus a family history of osteoporosis may signify increased risk for developing the disease. The skeleton is kept healthy throughout life by processes which remove old bone tissue and replace it with new bone tissue (bone remodelling). The two processes of bone breakdown and bone formation usually balance each other so that bone mass is neither lost nor gained. Bone loss, which may result in osteoporosis, occurs when the process of bone breakdown exceeds that of bone formation. Bone loss occurs in all women following the menopause, and postmenopausal osteoporosis eventually affects 1 in 3 women. In men, bone loss occurs gradually with aging. Other causes of osteoporosis include overactive thyroid or parathyroid glands, certain cancers and leukaemias, rheumatoid arthritis, and treatments such as corticosteroids. Osteoporosis is less common in men, but can be due to lack of testosterone.

Effects

Bone loss itself does not cause any symptoms, and people losing bone for any reason are not aware of it. Fractures most commonly occur in the spine, wrist and hip, but can also occur in the ribs, pelvis, shoulder and ankle. Fracture causes immediate and often quite severe pain at the site. This pain can persist for several weeks but eventually resolves. More persistent pain, usually in the back, is usually due to bony deformity which produces a local arthritis, or sometimes due to microscopic fractures continually occurring. Osteoporotic fractures usually heal quite normally. Hip fracture is the most important osteoporotic fracture because it requires hospitalisation and usually a surgical operation, and it carries an increased early death rate.

Diagnosis

Osteoporosis may be suspected in someone who sustains a fracture after fairly minimal trauma. An X-ray may reveal the presence of spinal fractures but osteoporosis is often difficult to detect on plain X-rays in those who have not yet fractured. The best diagnostic procedure is to have a measurement of bone mineral density. This is performed on a dual-energy X-ray absorptiometry (DEXA) machine. It is a non-invasive procedure which takes just a few minutes to perform, and gives an almost negligible radiation exposure. Other procedures, such as using ultrasound (sound-wave) assessments, are less reliable.

Treatment

Diet and exercise alone are not able to prevent or treat osteoporosis. Most treatments for osteoporosis are with drugs that reduce bone breakdown, and hence prevent bone loss. When such drugs are first given, there is often a gain in bone mass, because the reduction in bone breakdown exceeds that in formation, and thus a “positive” bone balance exists for some months or even years. There are now some drugs which primarily increase bone formation rather than just reducing breakdown.

Hormone replacement therapy (HRT) prevents bone breakdown, and may also increase bone formation to some extent. It is very effective in preventing the development of osteoporosis and fractures in postmenopausal women. It is usually given to those identified as being at increased risk, and is as safe and effective as any other currently available treatment (see Menopause and HRT section). It can also be used for the treatment of osteoporosis in women who already have the disease. It does not have the same long term adverse effects as the bisphosphonates and other drugs (see below).

Bisphosphonates are drugs which prevent bone breakdown by acting directly on the bone cells responsible for this. They are usually given as a once weekly tablet, although newer drugs can be given as an intravenous injection every three months or an intravenous infusion once a year. They are very effective in reducing the risk of fractures in people who have got osteoporosis. There are rare adverse effects such as atrial fibrillation (a heart rhythm disorder that can lead to a stroke), and inflammatory eye disease. Other rare adverse events relate to long term (>5 years) use. They include osteonecrosis of the jaw (ONJ) and atypical femoral fractures. ONJ is where a small area of the jaw bone ulcerates and dies. This usually follows a dental extraction and is more common with intravenous bisphosphonates and in cancer sufferers. Atypical femoral fractures are transverse fractures of the thigh bone that can occur spontaneously or after minimal trauma, and may be preceded by pain in the thigh. They are thought to be due to excessive suppression of bone remodelling leading to accumulation of fatigue damage in susceptible individuals. As yet we do not know how to detect these individuals. A drug-free “holiday” is often recommended after about 5 years of treatment to reduce these risks. Bisphosphonates are retained in the skeleton for many years, so the really long term effects of these drugs remain unknown. For this reason I believe their use in people younger than 60 or even 65 years should be restricted.

Denosumab is an antibody that blocks the main signal driving the cells which break down bone. It is given as an injection under the skin just once every 6 months. It is as effective as the bisphosphonates in preventing fractures and is not retained in the skeleton, so it may be more suitable for younger patients. It can slightly increase the risk of infections, such as of the throat or urinary tract, and so should be avoided in people prone to infections. ONJ and atypical femoral fractures may rarely occur with long term use. Again, a drug-free “holiday” is often recommended after about 5 years of treatment to reduce these risks. However, there are some concerns that there may be a rebound increase in fracture risk after stopping denosumab.

Teriparatide is a drug related to parathyroid hormone which increases bone formation quite dramatically, and thus reduces fractures in those with osteoporosis. It has to be given by daily injection under the skin, and is very expensive.

Selective estradiol receptor modulators (SERMs) are drugs which act like weak oestrogens in some tissues and like anti-oestrogens in other tissues. They can prevent and treat osteoporosis in postmenopausal women, but do not prevent hip fractures.

Anabolic steroids may reduce bone breakdown and increase bone formation, and can be used for treatment of osteoporosis. They usually have to be given by injection into a muscle every 3 weeks, and have a number of side-effects which precludes their widespread use.

Calcium + vitamin D is not effective by itself for either the prevention or treatment of osteoporosis and fractures (except in the very elderly and housebound individuals), but is used as an adjunct in certain situations, such as in patients taking corticosteroids. It can increase the risk of kidney stones and there have been debatable concerns about adverse effects on the heart.

Romosozumab is an antibody that blocks a natural inhibitor (sclerostin) of a major signal for bone formation. It rapidly reduces fracture risk but some adverse cardiovascular effects have arisen in clinical trials. However, it is now approved for use in the UK for the treatment of severe osteoporosis. Antibodies against other natural inhibitors of this signal are also under development.

Osteoporosis and metabolic bone diseases

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