The incidence of osteoporosis-related fractures is increasing worldwide. The age and sex specific increase in fracture risk reflects partly the increasing age of the general population. However, there is an additional increased incidence in fracture rate, which is not explicable on the basis of age alone. There is much speculation as to the potential cause of this increase but no certain explanation.
Although osteoporosis is defined both in terms of low bone mass and qualitative changes in bone, other factors are important in the causation of fractures, particularly the propensity to falls. In some patients, such non-skeletal risk factors may be more important than bone mineral density itself in predicting the risk of fracture. Nevertheless, bone mineral density is the single most important determinant of liability to fractures in the general population. Measurement of bone density can be carried out with a high degree of accuracy and precision. In medical practice, diagnosis of osteoporosis is established by bone mineral density measurements. The rationale for using bone mineral density to identify patients at risk of fracture comes from studies that have shown a relationship between bone density measurement and subsequent risk of fracture. It has been shown by several prospective studies that, in general, the risk of fracture increases by between two and three for every standard deviation decrease in bone mineral density.
Before discussing the treatments available for established osteoporosis, it is important to consider primary prevention. This can be applied on a population-wide basis with the emphasis on modification of lifestyle to ensure better "bone health". In this area, advice relating to alcohol consumption, weight-bearing exercise and cessation of smoking, as well as life-long adequate calcium and vitamin D intake, are most apt. In practice, this approach is dependent on the level of public awareness of the risk of osteoporosis and the support of primary care groups, health authorities and charitable bodies, such as the National Osteoporosis Society. The success of the approach is closely dependent on the response of the general population itself to such initiatives and to the impact lifestyle amendment has on fracture risk. Therefore, although intuitively appropriate, the effectiveness of this approach is not established.1 The alternative is to use selective case-finding techniques employing the criteria indicated above to identify patients at potential risk of osteoporosis.
Secondary prevention or treatment is indicated in patients with low bone mineral density who may or may not have an osteoporotic fracture. This article deals with the drugs commonly used in the treatment of osteoporosis in women, as these are better established than those for men.
Hormone replacement therapy Hormone replacement therapy (HRT) has been available for almost 50 years and is available in many different preparations. The description HRT encompasses preparations containing oestrogen alone or those which may also contain a progestogen. Tibolone is a gonadomimetic drug with a molecular structure that is different to natural oestrogens and it is, therefore, referred to as a synthetic oestrogen. However, this agent usually falls within the global description of HRT.
Selective oestrogen receptor modulators Drugs in this class (eg, raloxifene, tamoxifen) possess both oestrogenic and anti-oestrogenic effects. Tamoxifen has relatively weak oestrogenic activity but there is evidence that bone loss is slowed in women who receive tamoxifen for breast cancer.7,8,9 Tamoxifen has no licence for use in osteoporosis.
Bisphosphonates Bisphosphonates are structural analogues of pyrophosphate and bind strongly to hydroxyapatite crystal in bone. They have the effect of inhibiting bone resorption. Many analogues have been tested and are in the process of current development. Cyclical etidronate and alendronate are in common use for both prevention and treatment of osteoporosis.
Calcium The evidence for the beneficial effects of calcium on bone mineral density has been largely confined to women in their 70s or older. Many studies have shown that supplements of calcium are capable of slowing the rate of bone loss in women after the menopause at a variety of different skeletal sites.16 This effect is produced by a reduction in bone turnover due to a transient incremental effect on serum calcium. This reduces parathyroid hormone production and increases activation of bone remodelling sites. The increased bone mineral density may last for up to three years.17
Vitamin D and derivatives In the elderly, increased bone loss is often associated with secondary hyperparathyroidism, itself contributed to by vitamin D deficiency. Vitamin D leads to suppression of parathyroid hormone and a decrease in bone loss.
Calcitonin This polypeptide hormone with antiresorptive effects is licensed for use in the treatment of postmenopausal osteoporosis. In practice, its widespread use has been limited because of adverse effects that have affected compliance. Its use can be in the acute phase, where analgesic effects on patients with vertebral fractures have been demonstrated, and it may retard bone loss at a time of immobilisation.23 The evidence for its anti-fracture effects is largely based on the nasal spray preparation. Overall, the studies suggest a decrease in fracture rate of at least 30 per cent.1 Studies have indicated that calcitonin may prevent bone loss or, alternatively, increase bone density at the lumbar spine in the early and late postmenopausal years. There is no evidence of any effect at cortical-rich sites, (ie, the hip). Overgaard's study showed a 75 per cent reduction in vertebral fracture rates after two years' treatment with intranasal salmon calcitonin.24
Osteoporosis is a common condition that is multifactorial in origin. It is now possible to measure bone mineral density and, thus, to categorise populations in terms of liability to fractures. Low calcium intake, lack of exercise, smoking and excessive alcohol intake may be important risk factors in individuals. Although preventive strategies appear logical, the evidence for effectiveness in this area is wanting. Treatment options should go hand-in-hand with lifestyle amendment, where appropriate.
Dr Fordham is consultant rheumatologist at South Cleveland hospital, MiddlesbroughIn this article, the incidence, implications and treatment of established osteoporosis is reviewed
Osteoporosis is defined by the World Health Organisation (WHO) as "a progressive systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture". In the United Kingdom the annual incidence of osteoporosis-related fractures is 200,000. The annual cost to the NHS has been estimated at £942m.1 The commonest fractures associated with osteoporosis are vertebral, distal radius and neck of femur. Other sites include the pelvis, distal femur and ribs. It has been estimated that the lifetime risk of fracture in a 50-year-old woman is 13 per cent for the wrist, 11 per cent for the vertebrae and 14 per cent for the femoral neck.2
Although predominantly a condition affecting women, approximately 15 per cent of vertebral fractures and 20 per cent of hip fractures affect men. The significance of osteoporosis-related fractures lies not only in the cost to the NHS but also in the cost in human terms of increased morbidity and mortality. There is a 20 per cent excess mortality at six months after hip fracture and only half of patients previously able to walk can walk independently after hip fracture.
The adverse effects on the quality of life of patients, particularly following vertebral fractures, is increasingly recognised. Many patients have continuing and long-term pain as a consequence of spinal deformity, which may persist long after the acute pain of vertebral fracture has settled. Chronic pain following vertebral fractures is caused by changes in spinal muscle and joint function and is sometimes associated with vertebral compression or radicular nerve root compression. There is some evidence that chronic pain may be improved by muscle training, in addition to the use of analgesics and non-drug treatments, such as the use of transcutaneous electrical nerve stimulation (TENS) machines.
Diagnosing osteoporosis
Peak bone mass is established in the fourth decade, after which there is a gradual age-related decline. The decline is accelerated in women after the menopause. This fact, combined with lower bone mineral density in women compared with men, partly explains the difference in incidence of fractures between the sexes.
For the purpose of establishing a diagnosis of osteoporosis, the individual bone mineral density is compared with the peak bone mass of the healthy young adult woman. This comparison is made by means of standard deviation units (T scores). A T score of –2.5 or less establishes a diagnosis of osteoporosis. Osteopaenia is indicated by T scores of –1 to –2.49. Using this definition, the prevalence of osteoporosis in western women increases from 14.8 per cent between 50-59 years of age to 70 per cent at 80-plus. Overall, according to WHO, a woman over 50 has a 30 per cent risk of having osteoporosis. In effect, the use of bone mineral density measurements enables the clinician to make an assessment of fracture risk, and thus allows targeting of patients for treatment. Knowledge of the bone mineral density measurement itself by the patient may increase compliance with treatment. Sequential bone mineral density measurements can be used as a means of monitoring the efficacy of intervention and may further aid compliance.
Common causes of osteoporosis include premature menopause, whether this be natural, surgical or the effects of chemotherapy, and long-term corticosteroid use. General medical conditions associated with secondary osteoporosis include anorexia nervosa, alcohol excess, hyperparathyroidism, thyrotoxicosis, hypogonadism, malabsorption syndromes (including coeliac disease) and myeloma. Other clinical indications for bone densitometry include patients who have had a low trauma fracture, patients who have had x-rays suggestive of osteoporosis and women with a family history of osteoporosis (particularly maternal hip fracture). Other clinical risk factors include height loss, kyphosis (increased spinal flexion, commonly seen as "dowager's hump"), and low body mass index (less than 19kg/m2).1 Patients falling into the above groups should be considered for bone densitometry by their general practitioner or physician.
Other methods used to predict fracture include ultrasonic-based techniques and computed tomography. However, at present, the gold standard technique for establishing the diagnosis of osteoporosis is dual energy absorptiometry (DXA).3
Biochemical assessment of bone turnover may ultimately prove to be a useful adjunct to physical measurements, such as ultrasound and DXA, and may aid compliance. These techniques are under development and have yet to find an established role in clinical practice. Used alone, biochemical markers cannot establish a diagnosis of osteoporosis.
Having established the diagnosis, it is important to investigate the patient, where appropriate, to exclude underlying causes of osteoporosis, such as those indicated above, prior to initiating therapy.
Prevention
Treatment
Oestrogens have a direct effect on bone mass through cellular oestrogen receptors present in bone. This action results in increased bone formation and reduced bone resorption. Oestrogens also have an indirect effect in that they increase calcium absorption and decrease renal calcium loss. Since it is known that oestrogen deficiency is associated with subsequent bone loss, HRT should be offered to all women with a premature menopause, regardless of age, provided that oestradiol levels are low and gonadotrophins are high.
In women with an intact uterus, unopposed oestrogen treatment results in an increased risk of endometrial cancer. Therefore, a combination of oestrogen with progestogen should be used. Such combinations may be cyclic, sequential, long cycle or continuous-combined.
The evidence for the effectiveness of HRT is mainly based on retrospective epidemiological studies using changes in bone mineral density as a surrogate for fracture reduction. Randomised, controlled studies are difficult to carry out because of the necessary size of the patient population to be studied and because such studies need to be long term. Clinical trials have shown that the rate of bone loss in postmenopausal women is usually reduced in women taking HRT and, if it is started shortly after the menopause, maintenance or incremental increases in bone mass may occur. As indicated, the evidence for fracture prevention comes from trials which have been of short duration and have been observational. Such studies have shown that osteoporosis-related fractures at non-hip sites may fall if HRT is given.4 It has been estimated that, over three to five years, HRT may decrease vertebral fractures by 50 per cent and non-vertebral fractures by 25 per cent. These effects may be greater with longer-term use (over 10 years). The effects of HRT on bone density reverse after treatment is withdrawn.
The evidence would suggest that the minimum effective dose for preservation of lumbar spine bone for conjugated equine oestrogens is 0.65mg per day and for transdermal oestradiol is 50µg per day.5 These doses maintain bone density at the hip in approximately 80-85 per cent of white women. Oestradiol values achieved by implant therapy probably increase bone density.
Another potential beneficial effect of HRT is reduced risk of cardiovascular disease. However, the increased risk of breast cancer after prolonged use of HRT is a significant distraction to many women. The current advice is that short-term use of HRT is not associated with a detectable increase in breast cancer but that longer term use, possibly for five years but most probably from above 10 years, may be associated with an increased risk of breast cancer.1
Tibolone may be used as an alternative to conventional oestrogen therapy in women in whom cyclical bleeding is unacceptable. Although the effects of tibolone on calcium metabolism are similar to those of oestrogens, the evidence of its effectiveness on fracture rates is less certain than for oestrogens. Nevertheless, studies have shown significant increases in spinal bone mineral density over a two-year treatment period in women with established osteoporosis - a figure comparable to the effects of oestrogens.6 Use of tibolone should be restricted to women who are at least one year post-menopause.
The use of HRT in clinical practice is limited by problems of poor compliance. Only about 50 per cent of patients continue treatment beyond a year. The increasing variety and range of HRT preparations, however, may improve compliance.
Raloxifene has a positive effect on bone metabolism. It inhibits resorption of bone and it has reduced oestrogenic activity on the uterus, with the consequence that menstruation does not usually occur. Evidence suggests that raloxifene prevents bone loss and decreases vertebral fractures in postmenopausal women.10 However, the effect on bone mass is less than that of oestrogens. Raloxifene also reduces the risk of breast cancer but, like HRT, may increase the risk of venous thromboembolic events.11
The Multiple Outcomes of Raloxifene Evaluation (MORE) study showed fracture reduction similar to that achieved with HRT and bisphosphonates.10 At present, there are no data available relating to effects on non-vertebral fractures, including the hip. Raloxifene has lipid lowering effects and may, therefore, reduce the risk of atherosclerosis. The role of raloxifene in the management of osteoporosis is, as yet, unclear in routine clinical practice. Its present licence is for the prevention of vertebral fractures.
The evidence to date is that there is at least maintenance of bone mineral density over the short-term, of perhaps three years, with an average increase in spinal bone mineral density of between 6-8 per cent. At the femoral neck, bone mineral density increases of 4 per cent are seen after three years of treatment. The effectiveness of such drugs on fracture rates has been demonstrated by the studies of Storm et al.12 In their study of cyclical etidronate and calcium plus vitamin D, there was a decrease in vertebral fracture rates during a period of 60-150 weeks. Watts et al demonstrated similar reductions in the number of vertebral fractures when data were pooled from two treatment groups compared with that from two placebo groups.13 A large international study of alendronate showed significant reduction in the rate of new vertebral fractures (48 per cent) and a 21 per cent reduction in the rate of non-vertebral fractures.14 The fracture intervention trial (FIT) showed reductions of 47 per cent in the vertebral deformity group (ie, those with x-ray evidence of osteoporotic collapse), 51 per cent in the rate of hip fractures and 41 per cent in the rate of wrist fractures.15
Optimal absorption of both etidronate and alendronate is necessary for their clinical effectiveness. Both should be taken with water on an empty stomach. It is recommended that alendronate is taken at least half an hour before breakfast, or other food, and that the subject should remain upright for 30 minutes after taking the drug to minimise the risk of oesophageal symptoms. Alendronate is contraindicated in patients with a high risk of oesophageal ulceration.
Cyclical etidronate is licensed for the prevention of postmenopausal osteoporosis at all skeletal sites, as well as the prevention of corticosteroid-induced osteoporosis. It is probable that further bisphosphonates will be marketed in the next year. Alendronate is licensed for use in post menopausal women to treat fractures.
There is some epidemiological evidence that high dietary intake of calcium salts decreases the risk of osteoporotic fracture.18 As for the evidence of reduction in fracture rates, this is uncertain at best, with the most impressive evidence being from a single study involving calcium and vitamin D supplementation in elderly women thought to be deficient in vitamin D.19 This study found a reduction in hip fractures of over 25 per cent and a 15 per cent reduction in other fractures.
Calcium and vitamin D may be effective in the older adult, particularly those of limited mobility living in nursing homes. The evidence for the effectiveness of such treatment in more ambulant elderly patients is not as strong.
Intramuscular injection of 150-200,000 units of vitamin D given annually to individuals who were 75 years or older resulted in a significant decrease in frequency of all fractures.20 However, these findings contrasted with a study by Lips et al in which no effect was seen on hip or other fracture rates with daily administration of 400 iu of vitamin D in men and women.21 In one large study, treatment with vitamin D reduced hip fractures by 55 per cent among elderly women with a low body mass index.22 These studies suggest that vitamin D prophylaxis in the elderly, frail, housebound patient may be worthwhile in reducing hip fractures.
The evidence of efficacy for calcitriol on vertebral fracture rates is inconsistent, and there are no published studies on the efficacy of calcitriol or alfacalcidol on hip fracture rates. Vitamin D derivatives may induce hypercalcaemia, which may cause renal impairment and renal stones. The inconclusive nature of the studies to date, together with the risk of the treatment, has curtailed widespread use of vitamin D derivatives.
Conclusion
The ideal treatment goal is to reduce the rate of fractures. However, efficacy studies of the drugs used in the prevention and treatment of osteoporosis are inconsistent and have not always included fractures as the outcome. Nevertheless, there is sufficient evidence to advocate the use of hormone replacement therapy, bisphosphonates and the other agents discussed, on a case-by-case basis.
Many of the treatments have side effects, which may reduce patient compliance. Effective agents in terms of fracture reduction, such as HRT or calcitonin, may not be acceptable to many patients because of poor tolerance. Conversely, agents with relatively small effects on fracture rates may find a wider use on the grounds of better tolerability, particularly in the elderly in whom calcium and vitamin D are increasingly being used.
References