Hospital Pharmacist Vol 7 No 3 p62-68
March 2000 Special Features

Osteoporosis

The incidence, epidemiology and aetiology of osteoporosis

By N. W. Liggett MB, MRCPI and D.M. Reid, MD, FRCP(Edin)

The special feature this month is on osteoporosis. This first article gives an overview of the disease and details the section of the population most at risk. The second article will discuss the treatments which are currently approved

Osteoporosis has become increasingly recognised as a major healthcare problem which will affect the lives of a considerable number of individuals. Asymptomatic at onset, insidious bone loss leads to the clinical consequences of painful fractures, often at the clinically relevant sites of femoral neck and vertebral bodies, causing increased mortality, increasing debility and a reduced quality of life. In addition to the personal impact of this condition, the economic consequences are dire, with costs of fracture treatment alone recently estimated to cost the exchequer nearly £1,000m annually.¹ The aim of this article is to try to help raise the profile of this common disorder and to consider the factors which are implicated in its pathogenesis.

Definition

Osteoporosis is most commonly referred to by the lay public as "thinning of the bones". However, this is not the full story.
Osteoporosis has been consistently defined by consensus conferences as - "a 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".²
Clearly, this definition relies on a pathological specimen to determine if there has been any deterioration in the bone architecture, but clinically the condition is not generally recognised until a fracture has occurred. This therefore led the World Health Organisation in 1994 to redefine osteoporosis according to bone mass.³ This is illustrated in Table 1.
Defining osteoporosis in terms of bone mass allows the condition to be diagnosed before it presents with the clinical consequences of fracture. However, the definition is essentially statistical and, therefore, with a knowledge of the natural history of bone loss with age, it is possible to give the prevalence of the disease at various ages. For example, in women it has been estimated that 15 per cent at the age of 50 will have osteoporosis, 30 per cent at the age of 70 and 40 per cent at the age of 80.⁴
Although the use of this statistically-based definition may be useful epidemiologically, it does however raise the difficulty that one in three of the female population will suffer from osteoporosis at some stage in their lives. This leads to the question of who should have their bone mass assessed to examine for the presence of osteopenia or osteoporosis. Mass population screening has not been shown to be economically viable.

Bone mass measurement

When considering the assessment of bone mass, it is known that there is no evidence that standard radiographs (X-rays) can be reliably and consistently used to diagnose or quantify osteopenia or osteoporosis.5 Osteopenia is not associated with symptoms and the first sign of the disease, clinically, is usually the occurrence of a low trauma fracture. A low trauma fracture is defined as a fracture sustained as the result of a force equivalent to the force of a fall from a height equal to, or less than, that of an ordinary chair. It is therefore necessary to use another method to measure the bone mineral density (BMD). The best validated technique available currently for measurement of BMD is dual energy X-ray absorptiometry (DXA). This uses low doses of ionising radiation and enables accurate and reproducible measurements of BMD to be made at the clinically relevant sites of hip and vertebral bodies. The results are reported in a variety of forms as shown in Figure 1 giving both the raw bone mineral content or by expressing this value statistically in terms of standard deviations (SD) in relation to the patient's age (Z score) or in relation to a young adult mean (T score). It is upon these latter results that osteoporosis is diagnosed using the WHO definition which is shown in Table 1, and treatment recommended if appropriate.

Figure 1: Dual energy X-ray absorbtiometry (DXA) report indicating osteopenia of the lumbar spine. The report shows raw bone mineral content (BMC) and the value expressed statistically in terms of standard deviations (SD) in relation to the patient's age (Z score) or in relation to a young adult mean (T score). The Z score and the T score diagnose the degree of osteoporosis using the WHO definition

At present, the strongest predictor of the risk of future osteoporotic fracture is the finding of BMD and this may account for approximately 75 per cent of the fracture risk in an individual. Generally speaking, this measurement of bone mineral content (BMC) or BMD at the site of potential future fracture produces the best predictive capacity. It has been estimated that each standard deviation age-related bone mass is associated with a 1.7 - 2.6 times increased risk of fracture at that site.⁶

Normal bone turnover

Bone is not a static tissue but is constantly undergoing a process of renewal. Remodelling is the process by which old bone is removed and subsequently replaced by new bone.This cyclical process is mediated by a complex interaction between bone resorbing cells (osteoclasts) and bone forming cells (osteoblasts). This whole process is under the control of a large number of cytokines and growth factors, many of which have multiple actions on both osteoclasts and osteoblasts and which can also be influenced by other external factors. During growth towards adulthood the rate of bone remodelling is high, with bone formation by osteoblasts exceeding osteoclastic resorption with a net increase in bone. At skeletal maturity, which occurs between the ages of 25 and 35, the peak bone mass will have been obtained. This means that the processes of remodelling are balanced and the BMD stabilises. From this age onwards, bone remodelling serves to repair areas of stress-induced microdamage in the skeleton. The areas where this remodelling takes place are called bone remodelling units. This helps to keep the skeleton in good shape to fulfil its functions. However, after about 40 years of age, osteoblastic activity begins to uncouple from osteoclastic activity with an increase in bone resorption compared to formation. This results in a gradual slow loss of bone of approximately 0.6-1.6 per cent per year. These are the rates of bone loss quoted for the non-treatment controls in most of the drug trials currently in the literature. However, in females there is a phase of accelerated bone turnover and accelerated bone loss for approximately five years immediately after the menopause due to lack of oestrogen, before slowing down to the usual rate of loss as mentioned above. Figure 2 illustrates the variation of bone mass with time.

Figure 2: The variation of bone mass with time

Activated vitamin D Activated vitamin D (1,25 dihydroxycholecalciferol) also has an active role in regulating extra-cellular calcium homeostasis, having effects on intestinal calcium absorption and calcium resorption from the kidney. It is required for normal bone turnover and vitamin D deficiency has been found to correlate with a low BMD.⁸

Sex hormones Sex hormones are important regulators of bone remodelling and in post-menopausal females oestrogen deficiency makes the major contribution to the cause of osteoporosis.

Oestrogen Oestrogen receptors have been demonstrated on cell lines of both osteoblasts and osteoclasts. However, oestrogen does not appear to act directly at these sites but appears to be mediated through locally produced cytokines, mainly through changes in interleukin-1, interleukin-6, tumour necrosis factor (TNF-a) and granulocyte/macrophage colony stimulating factor (GCSF).^9,10 It appears that oestrogen deficiency allows greater expression of these cytokines, all of which are associated with increased stimulation of bone resorption which then leads to increased bone loss and a reduction in BMD.

Androgens Androgens, like oestrogens, can directly affect and modulate bone cell function. Androgen receptors are found on osteoblast cell lines and they can cause osteoblast proliferation. Hypogonadal men, in common with post-menopausal women, have decreased calcium absorption and low vitamin D levels. The replacement of androgens with testosterone can correct these abnormalities, suggesting again that sex hormones are required for the maintenance of bone health.

Determinants

As noted above, an individual's bone mass varies throughout his or her lifetime. The bone mass of an individual at any one time is determined by:

(i) the peak bone mass that was obtained, ie, the maximum potential bone mass for an adult, usually achieved around the age of 30
and subsequently
(ii) the rate of bone loss which, in both sexes, commences in the fourth decade

Both peak bone mass and rates of loss are determined by a combination of genetic and environmental factors. Some of these will be discussed below, but it is, however, in the field of genetic predisposition that the greatest advances have been made.

Genetic determinants

The main suggestion for a genetic contribution to osteoporosis has come from the study of twins. In twin studies, monozygotic (genetically identical) twins are compared with dizygotic (non-identical) twins for a given trait. In this case, BMD was measured in the twin pairs and the similarities of BMD in each pair of twins expressed in the form of a correlation coefficient. This was done for both the monozygotic (MZ) and dizygotic (DZ) twins. If the correlation coefficient for the MZ twins is significantly greater than that of the DZ twins then this would suggest that there was a genetic component to BMD. If the correlation coefficients were the same then no genetic component would be involved. The genetic component can then be quantified to give an estimate of degree to which genetic factors contribute. In the case of BMD this has been estimated to range from 50 to 90 per cent.
There is always the danger from such studies for the analysis to overestimate the genetic contribution. This is because MZ twins may also have similar exposure to environmental factors, for example, diet, calcium intake, smoking, alcohol intake, exercise, etc. However, even taking these factors into account, the concordance appears to remain. Subsequent tests in family studies also confirm a significant genetic factor with lower BMD occurring in the daughters of known osteoporosis sufferers compared with controls with no family history of osteoporosis. Knowing that a genetic component may account for about 75 per cent of the determinant of peak bone mass leads to the question of which particular gene, or genes, may be involved.
Genetic modelling would suggest that BMD is a polygenic trait with a number of different genes possibly being responsible. These possible genes are referred to as candidate genes and the most widely studied gene to date is the vitamin D receptor (VDR) gene. The vitamin D receptor plays a central role in bone and calcium metabolism and homeostasis, as well as controlling cell differentiation in other target tissues. Vitamin D regulates the absorption of calcium from the gut, regulates bone resorption and osteoclast formation and regulates the production by osteoblasts (which form new bone) of osteocalcin, which has been used as a serum marker of new bone formation.
Morrison and colleagues first studied the VDR gene in its relationship with osteocalcin levels and found that polymorphisms in the VDR gene were associated with levels of circulating osteocalcin (and by inference osteoblast activity and bone formation).¹¹ Subsequently, in a study on Australian twins¹² they found that polymorphisms in the VDR gene apparently explained up to 75 per cent of the genetic variance of BMD. However, subsequent analysis has shown errors in the original assessments which reduced, but did not abolish, the strength of the relationship. The original findings have been supported by some workers,¹³ including workers in the UK,¹⁴ but are not supported by all.¹⁵ In some cases, the correlation between the VDR polymorphisms and BMC has been in the opposite direction to that originally demonstrated.¹⁶ Others have demonstrated that the effect is strongest in premenopausal women¹⁷ and declines with age, so no longer has a discernible effect by the age of 70.¹⁸ The lack of an effect in elderly women would support the contention that VDR alleles were unimportant in determining rates of perimenopausal bone loss as was demonstrated in a longitudinal study,¹⁹ although bone loss in the elderly has also been related to VDR alleles and, in heterozygotes only, related to calcium intake.²⁰
It is difficult to draw together all of these contrasting findings to make a cohesive story. It is unclear from the above studies whether VDR itself is linked to BMD. Perhaps the best unifying hypothesis is that it is not the VDR region of the chromosome itself which is important, but another linked gene on the same chromosome.
Candidate genes on other chromosomes have also been shown to be related to bone mass. Two of these candidates, the oestrogen receptor gene²¹ and the interleukin (IL)-6²² might more clearly be seen to have potential functional importance in the pathogenesis of osteoporosis. In a similar way, the polymorphism affecting the regulatory site in the collagen type l-A1 gene could have functional importance both in terms of the development of peak bone mass and determination of vertebral fracture risk.²³
Genetic factors are clearly important in the determination of peak bone mass and this appears to be the stage at which they exert most effect, but they could also be determinants of fracture risk which are in part independent of BMD. The excitement in the future will be whether one of these polymorphisms, or a combination of several, will come forward as a predictive test of future osteoporotic fractures.

Environmental factors

Environmental factors are also important in determining peak bone mass as well as subsequent rates of bone loss. These are sometimes referred to as the risk factors for osteoporosis and have been widely rehearsed in their relative contributions to osteoporosis and fracture risk.²⁴

Calcium Calcium is one of the most important constituents of bone and adequate intake and absorption are required to ensure that enough calcium is available to fulfil the needs of the growing skeleton. The absorption of calcium from the diet relies on two mechanisms. With a high calcium intake most calcium is absorbed passively from the gut. However, with low intakes, calcium absorption relies on an active transport system in the intestinal mucosa which is vitamin D dependent. Therefore a low calcium intake combined with a low vitamin D availability would greatly impair the amount of calcium available for bone formation.
When looking for evidence that low calcium alone influences bone mass one has to take into account that the major source of calcium intake is in the form of milk and dairy products. So how can we be sure that all of the effect of milk is in its calcium and not also through the carbohydrate, protein and fats that it contains? Studies looking at milk and dairy product intake during the skeletal growth and maturation stage of childhood and early adulthood have found a positive association between the intake of dairy products and BMD in middle-aged²⁵ and post-menopausal women, possibly correlating with calcium intake.
Johnston's study²⁶ using calcium supplementation in twins showed that before puberty a high calcium intake, of about 1600mg daily, increased BMD, compared with those with a lower calcium intake of about 900mg daily. It should be stated, however, that this improvement in BMD was not seen in pubertal children. This would support the view that a high calcium intake is needed in childhood to achieve the optimum peak bone mass and therefore help prevent subsequent osteoporosis.
An adequate calcium intake is also required to help maintain bone mass, which is borne out in population studies of calcium supplementation to slow the rate of bone loss, although supplementation was only beneficial in those taking 400mg a day or less.²⁷

Physical activity Regular exercise is known to help prevent bone loss in older adults,²⁸ while the lack of regular exercise or immobilisation will lead to bone loss.²⁹ Whether regular exercise contributes to increased peak bone mass was investigated in MZ twins and regular weight bearing exercise was found to correlate with increased BMD.³⁰

Alcohol High alcohol intake is associated with low BMD.³¹ It is directly toxic to bone by reducing bone cell proliferation and activity. Reduced serum osteocalcin levels (suggesting reduced bone formation) are found and bone biopsies confirm reduced bone formation.³² As well as a direct effect on bone, heavy alcohol consumption is also associated with poor nutrition, decreased calcium intake, reduced mobility and low vitamin D, all of which will have a compounding effect on reducing bone mass through their own individual actions.

Smoking There are several studies showing an adverse effect on bone from cigarette smoking, including findings from a study in twins and a study in post-menopausal women.^33,34 The potential mechanisms for this effect mainly involve oestrogen and its metabolism. Although normal oestrogen levels are found in smokers there are abnormalities of metabolism which lead to less of the biologically active metabolites being available. There is a consequent increase in the less active metabolites. Therefore the normal protective effects of oestrogen on bone are attenuated with a consequent increase in bone loss.
In addition, smoking is known to lead to an earlier menopause³⁵ and hence to earlier post-menopausal status and earlier onset of the phase of rapid bone loss. Smoking has also been associated with lower BMD in males.³⁶

Thin body type It is well recognised that thin individuals have lower bone mineral density than heavier individuals, and there may be multiple reasons for this. Fat is an important site of conversion of androgens to estrone. Therefore in post-menopausal women this site of production of even a small amount of oestrogen will help protect the bones. Additionally, increased weight will put more stress on the skeleton and help maintain BMD in a similar way to what exercise would. However, other mechanisms, and hormones and growth factors may also be at work.
It can be seen from the above that there are a number of possible influences which may affect an individual's bone mineral density and susceptibility to osteoporosis. All of these need to be considered when looking for a cause for osteoporosis in an individual, as attention to, and modification of, environmental factors may help improve the degree of further bone loss. Our genes we cannot change.

Classification

Osteoporosis can be defined as being either primary or secondary in origin. Both types are discussed below.

Primary osteoporosis This is said to exist where no other disease is present to contribute to the osteoporosis. In women 70 per cent of all osteoporosis is defined in this way, although the vast majority of this is due to post-menopausal oestrogen deficiency. In men, however, only 46 per cent of osteoporosis sufferers have no known predisposing illness but a further 16 per cent are known to have hypogonadism. ^37,38

Secondary osteoporosis This is said to exist where a pre-existing disease can be identified leading to the osteoporosis. However, in some cases this may be iatrogenic through drug administration. Table 2 gives a summary of causes.

Corticosteroid therapy This therapy is by far the commonest cause of secondary osteoporosis and accounts for osteoporosis in up to 13 per cent of male and 10 per cent of female osteoporosis sufferers.^37,38 The impact of corticosteroid-induced osteoporosis (CIOPS) as an iatrogenic cause of osteoporosis has led to the formulation of national guidelines specifically for its treatment in both the United Kingdom³⁹ and the United States. Steroids exert their effects on bone in a number of ways. They decrease osteoblast activity and also decrease their active life span. Steroids also decrease calcium absorption from the intestine and increase renal calcium loss. The resulting overall loss disturbs calcium homeostasis and therefore exerts effects through PTH and vitamin D.⁴⁰ Sex hormone production is also suppressed in steroid users,⁴¹ and the resulting hypogonadism may result in increased bone turnover and bone loss.
Similar mechanisms occur with the excess production of steroids seen in Cushing's syndrome. In this situation, successful treatment can lead to a restoration of BMD within 10 years.

Hyperthyroidism Excess production of thyroid hormone from the thyroid gland generally leads to a quickening of processes in the body with an increase in heart rate, metabolic rate, bowel motility and increased rate of bone remodelling. Both osteoblasts and osteoclasts are stimulated but the overall remodelling process becomes uncoupled, with relatively more osteoclast activity leading to increased bone loss.⁴² However, once the hyperthyroidism has been treated, the individual is at no greater risk of developing osteoporosis. This has recently been shown over a 20 year follow-up.⁴³ Although uncommon in men, hyperthyroidism accounts for 5 per cent of osteoporosis in women. Moreover, it should be noted that reduced BMD has also been noticed in patients given too much thyroxine for treatment of hypothyroidism.⁴⁴ This is yet another example of an iatrogenic cause of osteoporosis.
In addition to the above conditions, there are a small number of cases which are secondary to other medical problems. When considering treatment one would obviously have to look at treatment of the underlying condition. The following conditions serve as examples.

Hyperparathyroidism There may be an increase in parathyroid hormone levels due to increased secretion from an adenoma or carcinoma. The effects of PTH on bone will be familiar from the preceding discussion which showed that increased PTH caused increased bone loss.

Malabsorption syndrome This can lead to secondary osteoporosis through decreased vitamin D and calcium absorption from the gut, with additional actions on bone from PTH.

Anorexia nervosa Symptoms include low body weight, loss of menstruation and cyclical sex hormone production. There can also be reduced physical activity and hypercortisolism (increased corticosteroid production). These can all contribute to osteoporosis.

Alcohol abuse This was discussed earlier.

Summary

Osteoporosis is a condition which will affect one in three women, and one in 12 men, at some stage in their lives. Interest in the condition has grown exponentially over the last 10 years due to a number of factors, including the development of a reliable and reproducible tool for the measurement of bone mineral density in the form of DEXA scanning. This has allowed studies to be undertaken which have improved our understanding of the factors associated with osteoporosis along with allowing studies to evaluate if treatments are effective. The greatest advances in our understanding are in the field of genetics which may account for up to 75 per cent of an individual's BMD, but unfortunately this is a factor that we cannot modify. Having said this, however, we may in the future be able to use genetic testing to determine who might be at risk from the condition and therefore modify their risk factors from an early age to try to prevent the condition developing. In addition to prevention, a number of therapies are currently available for the prevention and treatment of osteoporosis and these will be discussed in the next article.

Dr Liggett is consultant physician with an interest in rheumatology at Craigavon Area hospital, Northern Ireland and Professor Reid is professor of rheumatology, University of Aberdeen

References