Musculoskeletal disorders, of which osteoarthritis (OA) is the most common, incur significant economic, social and psychological costs. Costs of illness have risen over recent decades accounting for up to 1-2.5% of the gross national product for those countries studied so far, including the USA, Canada, the UK, France and Australia. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. There are also significant out-of-pocket costs and loss of earnings due to changes in occupation and roles in domestic duties. Current guidelines for the management of OA of hip and knee include the recommendation of inexpensive but effective interventions. Although the guidelines have not had a specific economic evaluation, cost reductions may be expected. OA is a very common disease and will become an increasing economic burden as the population ages.

Non-pharmacological therapies are very important in osteoarthritis. Each form of this treatment should be individually devised, taking into account the anatomical distribution, the phase and the progression rate of the disease. Indications, contraindications, dosage and precautions are as important in non-pharmacological therapy as they are in drug treatment. Therapeutic exercises decrease pain, increase muscle strength and range of joint motion as well as improve endurance and aerobic capacity. Exercise programmes should be designed, conducted and regularly supervised by professionally trained physiotherapists. Weight reduction is of proven benefit in obese patients with osteoarthritis of the knee. Walking aids, crutches, shoe insoles, braces and patellar taping are useful tools in some form of osteoarthritis. Patient education and the management of the psychosocial consequences are priority tasks. Therapeutic heat and cold, electrotherapy, ultrasound, acupuncture, hydrotherapy and spa treatment are widely used, although the effects and benefits have not been fully established. Non-pharmacological therapies should undergo rigorous randomized controlled trials in a similar manner to pharmacological studies.

Although intra-articular therapy is widely used in the treatment of osteoarthritis (OA), those controlled clinical trials which include placebo groups suggest that there is little to be gained over joint aspiration alone, or even over a simple needle prick. Glucocorticoids may however offer a small additional symptom benefit over one or two weeks. Viscosupplementation may offer a slightly longer benefit. Intra-articular radiotherapy probably confers no benefit. Serious adverse effects are rare but local effects may occur in up to 10% of patients treated with viscosupplements. Future research should always include a placebo group in clinical studies, should clarify the possible benefits of viscosupplementation and should include in vitro work to consider the biological basis for possible actions of intra-articular therapy.

Therapy for osteoarthritis (OA) is aimed at relieving symptoms and at maximizing function. Therapies can be considered as either symptom modifying OA drugs (SMOADs) or as disease modifying OA drugs (DMOADs). Currently available agents fall into the category of SMOADs. Analgesic medications, particularly paracetamol and capsaicin, have proven efficacy in OA and are recommended first line therapies. Non-steroidal anti-inflammatory drugs (NSAIDs) do appear to provide extra symptomatic benefit for some patients but have greater toxicity. Newer generation NSAIDs may have safety advantages which remain to be confirmed in practice. Further therapies are being developed which aim to prevent cartilage damage and/or aid cartilage restoration, but these DMOADs remain in the experimental stage.

X-ray, magnetic resonance imaging (MRI) and arthroscopy are the methods most widely used to assess the status of osteoarthritic joints. How do these methods compare? As diagnostic tools, what is the relative sensitivity of X-ray versus MRI, arthroscopy versus MRI and arthroscopy versus X-ray? Which imaging modalities can be used for predicting progression? Scintigraphy and MRI can assess the degree of cellular activity in the tissues of a joint, which may help in prognosis. Are the methods proven and are they reliable? Recommendations for clinical trials in knee osteoarthritis, state it is essential that reproducible radiographs are obtained for reliable assessment of progression. Two radiographic views of the knee have been proposed; which provides the more reliable assessment, the knee in extension or semi-flexed? Compared with standard radiography, does microfocal radiography make a difference to patient numbers required for drug trials?

Biochemical markers for osteoarthritis (OA) may serve different purposes. Since markers reflect ongoing dynamic metabolic processes in the joint tissues (cartilage, synovium, bone, etc.), they are most likely to be useful to predict prognosis and response to treatment, to monitor response to treatment, and for disease staging. Markers are currently being used at the research level for these purposes. The goal of using these markers to assess the disease process in the OA clinical trial setting or in the clinical routine has, however, not yet been reached.

Several epidemiological studies have shown a lower incidence and prevalence of hip fractures in people with osteoarthritis (OA) and vice versa which has led to numerous studies examining the association between OA and osteoporosis more generally. There is felt to be an inverse relationship between these two diseases and the evidence for and against this association is discussed. The evidence for an association with osteoporosis is stronger for large joint OA than hand OA or primary generalized OA. A number of possible mechanisms for this association are discussed such as genetic factors, common risk factors, role of subchondral bone in cartilage damage and growth factors. The incidence and prevalence of one disease in the presence of the other is discussed. Despite the inverse relationship seen in some studies, there is currently no evidence that treatment of one disease can have a detrimental effect on the other.

The relationship between osteoarthritis and ageing raises important questions about what exactly defines 'normal' ageing and whether the pathogenesis of osteoarthritis shares common pathways with other age-associated dysfunctions, or whether osteoarthritis is a time-dependent disorder distinct from normal ageing with a separate causative mechanism at work. Theories of ageing now emphasize the stochastic nature of the ageing process, that is the role played by accumulation of essentially random cell and tissue damage, such as somatic mutations, oxidative damage and the formation of aberrant proteins. The role of genetic factors in determining longevity and predisposition to age-associated diseases is probably in programming the efficiency of somatic maintenance functions and in influencing the development of a durable soma. Gene-environment interactions, for example through lifestyle, can also be important. Many of the risk factors and mechanisms that are thought to contribute to osteoarthritis can be accommodated within this framework.

Overweight people are at high risk of developing knee osteoarthritis (OA) and may also be at increased risk of hand and hip OA. Furthermore, being overweight accelerates disease progression in knee OA. While the increased joint stress accompanying obesity may explain the strong linkage between obesity and knee OA risk, it does not necessarily explain why obese people have a high risk of disease in the hand nor why obese women are at higher comparative risk of knee disease than obese men. Unfortunately, studies of metabolic factors linked to obesity have not provided an explanation for these findings. There are a paucity of data on weight loss as a treatment for OA, but preliminary information suggests it is especially effective in knee disease and that even small amounts of weight reduction may have favourable effects.

Although for many years it was speculated that osteoarthritis was genetically determined, little data were available to support this contention. A major problem with early work was a lack of consistency in the definition of osteoarthritis. Based on a radiographical definition of osteoarthritis, which is currently the optimal method for epidemiological and genetic studies, data from a recent twin study have provided an estimate of the hereditable component of osteoarthritis to be in the order of 50 to 65%. In addition, sophisticated molecular biology techniques are being increasingly used to explore potential genetic abnormalities in cartilage and matrix components in osteoarthritis. These exciting new data are examined as we address the role of genetic factors in osteoarthritis.

Major advances have occurred in our knowledge of osteoporosis and its treatment in the past 10 years. This paper reviews aspects of the epidemiology, pathogenesis, and diagnosis of the disease that deserve further investigation. Although anti-resorption treatments such as hormone replacement therapy and bisphosphonates have been shown to reduce the incidence of osteoporotic fractures, there is room for improving available treatments. Today, there is no bone-forming agent that has been shown to decrease fracture rate, and several agents are under clinical investigation. The potential value of combined therapy will also be discussed.

In the UK and throughout Europe 10 years ago, osteoporosis was not a word that existed in the vocabulary of the general public. The majority of doctors had dismissed osteoporosis as a normal process of ageing, affecting only the very elderly and about which nothing could be done. Why should it matter that awareness of osteoporosis was so low among the general public and the medical professions? For the newly launched National Osteoporosis Society in the UK, several questions needed to be answered: if osteoporosis was not an inevitable part of growing old, was it really a disease and how could action be implemented to treat it and prevent it? If fracture numbers and their costs were so much higher than had been thought, who should be informed of this? And if there were ways of treating and preventing osteoporosis, who should be made more aware, what should they be told, and how could such awareness-raising be done and paid for? Before real action could be undertaken, a considerable awareness programme would be needed to radically-alter traditional beliefs about bone health.

Hip fractures in men account for one third of all hip fractures and have a higher mortality than in women. The public health burden will increase as the increase in the numbers of elderly men in the community increases. In addition, the age-specific incidence of hip fractures may be increasing in some, but not all, countries. Vertebral fractures may be a public health problem as recent studies suggest that the prevalence in the community is 20-30%, similar to that reported in women. Forearm fractures should probably not be regarded as a public health problem. Peak bone mass is higher in men than women because men have bigger bones. Peak bone mineral density is the same. The amount of trabecular bone lost at the spine and iliac crest during ageing is similar in men and women. Cortical bone loss is less in men because endocortical resorption is less and periosteal formation is greater. Bone loss accelerates in elderly men because endocortical resorption and increasing cortical porosity increase the surface available for resorption. Bone fragility is less in men than women because: (a) the cross-sectional surface of the bone is larger; (b) trabecular bone loss is less as a percentage of the higher peak bone mass; (c) trabecular bone loss occurs by thinning rather than perforation; and (d) periosteal appositional growth compensates for endocortical resorption by maintaining the bending strength of bone. Reduced BMD in men with fractures may be due to reduced peak bone size and mass, and bone loss. Bone loss occurs by reduced bone formation. Whether men with fractures have increased bone fragility due to reduced periosteal appositional growth during ageing is unknown. The age-related decline in testosterone, adrenal androgens, growth hormone, and insulin-like growth factor 1 may contribute to reduced bone formation and bone loss. Men with vertebral fractures often have hypogonadism or illnesses with few clinical features that should be considered with a high index of suspicion (alcoholism, myeloma, malabsorption, primary hyperparathyroidism, haemochromatosis, Cushing's disease). Secondary hyperparathyroidism may contribute to bone loss by activating bone turnover and so increasing the number of bone remodelling units with impaired bone formation in each. There is no proven treatment for osteoporosis in men because there have been no trials using anti-fracture efficacy as an end point. Testosterone replacement should be considered in men with proven hypogonadism and vitamin D deficiency should be corrected if present. Calcium supplements and bisphosphonates are reasonable options given the lack of information.

Osteoporosis in children, adolescents and corticosteroid-treated patients represent a particular problem for clinicians. In children and adolescents, the main management question is whether any specific interventions can influence attainment of peak bone mass and so decrease the chance of osteoporosis in later adult life. The role of physical activity and calcium in particular are reviewed. In adolescence, osteoporosis is usually due to idiopathic juvenile osteoporosis or secondary to amenorrhoea or anorexia nervosa. These entities, as well as the management of corticosteroid-induced osteoporosis at all ages, are discussed.

Oestrogen deficiency at the menopause leads to bone loss primarily as a result of increased bone turnover and an increase in the activity of osteoclasts. Hormone replacement therapy (HRT) reverses these changes, preventing menopausal bone loss and reducing fracture risk at the spine, hip, and wrist, although the magnitude of this reduction has not been accurately established. The optimal duration of therapy for the prevention of osteoporosis is uncertain but there is increasing evidence that life-long treatment after the menopause may be required to maintain maximum protection against fracture. The extraskeletal effects of long-term oestrogen therapy include protection against cardiovascular disease and a possible increase in the risk of breast cancer; the persistence of these effects after therapy is withdrawn is uncertain although there is some evidence that the increase in risk of breast cancer is seen only in current users. Furthermore, there is increasing evidence that the use of progestogens in combined formulations does not substantially alter either the cardiovascular benefits or the increased risk of breast cancer, although further studies are needed in this area. The emergence of 'no-bleed' preparations in recent years has increased the acceptability of HRT for some women, particularly those in older age groups. Finally, the development of tissue-selective oestrogen agonists is an exciting advance which may enable life-long therapy after the menopause to protect against cardiovascular and bone disease in the absence of significant side-effects.

The primary aim of any intervention in osteoporosis is the prevention of fractures in individuals who have not yet fractured or the prevention of the progression of the disease in individuals with fragility fractures. There is currently insufficient evidence to recommend either a population-based prevention strategy or a strategy based on general screening with treatment of those individuals identified at high risk. Identification of subjects with strong clinical risk factors for osteoporotic fractures with subsequent measurement or not of bone mineral density as well as those with fragility fractures constitute at present the most rational approach to fracture prevention. Current measures to prevent osteoporotic fractures aim mainly at influencing bone mass and bone turnover and reducing the risk and impact of falls. Interventions that can reduce effectively the frequency of osteoporotic fractures in subjects at risk are available and new or alternative interventions are being developed. Issues related to the impact of these interventions on public health and health economics need to be addressed and methods to calculate the clinical outcomes in a way allowing comparison with outcomes of interventions in other common diseases should be developed.

Osteoporosis is preventable with the various therapeutic options available today. It is therefore important to reach the patient who needs to be treated. If based only on clinical risk factors there is much room for therapeutic misassignation in both directions: too many and too few treatments. Generally speaking, only bone mass measurement can yield the correct risk for future fracture, and clinical factors taken alone might be misleading. Clinical factors can be used to modulate the therapeutic intervention based on assessment of bone mass. In very elderly people with several risk factors (poor vision, poor balance and awkward gait, use of psychotropic drugs, etc), bone mass measurements probably become less crucial in therapeutic decision, because factors other than bone mineral have also to be actively assessed. All in all, the use of cut offs of bone mineral density balanced with the clinical decision based on an individual examination, will allow assessment of the therapeutic level in a particular patient. A therapeutic intervention will never be an all or nothing phenomenon based on computerized data.

The recent development of specific and sensitive biochemical markers reflecting the overall rate of bone formation and bone resorption, has markedly improved the non-invasive assessment of bone turnover in various metabolic bone diseases, especially osteoporosis. The immunoassay of human osteocalcin recognizing the intact molecule and its major proteolytic fragment, along with that of bone alkaline phosphatase, are currently the most sensitive markers to assess bone formation. For bone resorption, the total urinary excretion of pyridinoline crosslinks measured by high pressure liquid chromatography has shown its superiority over all other markers for the clinical assessment of osteoporosis. The recent development of immunoassays recognizing either the free pyridinoline crosslinks or pyridinoline crosslinked-type I collagen peptides in urine and serum should allow a broad use of this sensitive resorption marker. Recent studies, some of them still in progress, define the clinical use of these markers: first, to improve the prognostic assessment of post-menopausal women in combination with bone mass measurement, i.e. their risk of developing osteoporosis and, ultimately, fractures and, second, to monitor the efficacy of anti-resorption drugs.

Osteoporosis is a systematic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue. This leads to diminished biomechanical competence of the skeleton and is associated with low-trauma or atraumatic fractures. In the past decade, considerable progress has been made in the development of methods for assessing the skeleton non-invasively, so that osteoporosis can be better managed. While dual X-ray absorptiometry (DXA) is still the preferred methodology, several limitations will be addressed. Another densitometric technique which is widely accepted for diagnosis of spinal osteoporosis is single energy QCT. Measurements of vertebral trabecular bone mineral density (BMD) demonstrate larger percentage decrements between vertebrally-fractured subjects and normal controls, and confer higher relative risks for vertebral fracture than either anteroposterior or lateral DXA measurements. As an emerging alternative to photon absorptiometry techniques, there is a growing interest in the use of quantitative ultrasound (QUS) measurements for the non-invasive assessment of osteoporotic fracture risk in the management of osteoporosis. The attractiveness of QUS lies in the fact that indirect and in vitro experience has suggested that ultrasound may give information not only about BMD but also about architecture and elasticity. Whether or not combining QUS and DXA improve fracture prediction is still unclear and needs further analysis. Due to the growing evidence supporting the use of QUS in osteoporosis and the large number of QUS devices already on the market, a general clinical consensus on the application of QUS is urgently needed. Other techniques that are less widely used for the management of osteoporosis. For example, peripheral quantitative computed tomography, quantitative magnetic resonance (QMR) and magnetic resonance microscopy are promising tools for the evaluation of the skeleton. For example, the ability of QMR and high resolution magnetic resonance imaging has been explored and shows promise as a technique for assessing trabecular bone structure in osteoporosis.

Bone mass at any point in life represents a balance between the amount of bone laid down during growth and development and the amount of bone lost with ageing. At a cellular level, these changes in bone mass occur as the result of bone remodelling; a process whereby bone resorbing cells (osteoclasts) and bone forming cells (osteoblasts) remove and replace small packets of bone at discrete points throughout the skeleton. This process is in turn regulated by a complex interaction between genetic factors and environmental influences such as nutrition and exercise, which affect bone cell function both directly and indirectly by altering the production of local and systemic hormones that modulate bone cell activity. In this chapter, I shall review the relative importance of genetic and environmental factors in regulating bone growth, peak bone mass, and bone loss. Discussion of the genetic aspects shall focus on recent data linking polymorphisms in candidate genes to bone mass and bone loss, and on the possible role which gene-environment interactions may have in regulating these processes.