Clinical Review - Osteoporosis

Contributed by Professor John A Kanis, professor emeritus in metabolic bone diseases, and director of WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, and Dr Eugene McCloskey, reader in adult bone disease, University of Sheffield

Typical sites of osteoporotic fracture: wrist (left), spine (centre) and hip (right)
Typical sites of osteoporotic fracture: wrist (left), spine (centre) and hip (right)

Section 1 Epidemiology and aetiology
Epidemiology

The clinical significance of osteoporosis lies in the fractures that arise. In the UK, osteoporosis results in more than 200,000 fractures each year, causing severe pain and disability to individuals at an annual cost to the NHS of over £1.73 billion.

More than one-third of adult women and one in five men will sustain one or more osteoporotic fractures in their lifetime. Common sites of fracture include the vertebral bodies, distal radius, proximal femur and the proximal humerus.

Hip fractures alone account for more than 20 per cent of orthopaedic bed occupancy in the UK, and the majority of the direct health service cost of osteoporosis.

Approximately 50 per cent of patients suffering a hip fracture can no longer live independently and 20 per cent die within 12 months of the fracture.

Fractures in patients aged over 60 years account for more than two million hospital bed days in England each year. This exceeds the bed occupancy attributable to diabetes, IHD, heart failure or COPD. The ageing of the UK population will double the number of osteoporotic fractures over the next 50 years if changes are not made in present practice.

Already, the admission rate for hip fractures has increased in England by 2.1 per cent per year since 1999, while hospital bed days have increased by 5.9 per cent a year.

Aetiology
The most common cause of osteoporosis arises from estrogen deficiency that begins some years before the time of menopause. The skeleton comprises approximately 20 per cent trabecular bone and 80 per cent cortical bone and undergoes a continual process of resorption and formation, governed by the activity of bone cells in bone remodelling units.

Approximately 10 per cent of the adult skeleton is remodelled every year.

Estrogen deficiency accelerates the normal turnover of bone tissue, but the net activity of bone resorbing cells (osteoclasts) is greater than that of bone forming cells (osteoblasts). This gives rise to thinning of the cortices of bones, thinning of trabecular bone and loss of trabecular elements (see below).

The architectural changes weaken bone disproportionately compared with the loss of skeletal mass.

The rate of loss of bone tissue is particularly rapid around the time of menopause giving rise to postmenopausal osteoporosis, but bone loss continues throughout later life in men as well as women.

Many other disorders can give rise to osteoporosis (see box) by accelerating bone loss.

Secondary osteoporosis
Relatively common causes of secondary osteoporosis

Endocrine malignancy drugs

  • Thyrotoxicosis
  • Primary hyperparathyroidism
  • Cushing's syndrome
  • Hypogonadism, including anorexia nervosa
  • Type-1 diabetes

Gastrointestinal

  • Malabsorption syndrome, e.g. coeliac disease, partial gastrectomy
  • Inflammatory bowel disease
  • Liver disease, e.g. primary biliary cirrhosis

Rheumatological

  • Rheumatoid arthritis
  • Ankylosing spondylitis

Malignancy

  • Multiple myeloma
  • Cancer-treatment-induced bone loss (see drugs)

Drugs

  • Glucocorticoids
  • Anticonvulsants
  • Heparin
  • Aromatase inhibitors
  • Androgen-deprivation therapy

 

Section 2 Diagnosis
Clinical features

The clinical features of osteoporosis are a consequence of the fractures that arise. Non-vertebral fractures are easily detected by the associated acute pain and deformity, both of which resolve well with appropriate management.

In contrast, vertebral fractures are often undiagnosed due to a relative lack of symptoms (detected on X-ray only) or the attribution of back pain to other causes.

Multiple vertebral fractures commonly cause symptoms and may give rise to a thoracic kyphosis (unkindly termed dowager's hump) and long-term morbidity.

The diagnosis of osteoporosis relies on quantitative assessment of bone mineral density (BMD), usually by central dual energy X-ray absorptiometry (DXA).

BMD at the femoral neck provides the reference site. It is defined as a value for BMD 2.5 standard deviations (SD) or more below the young female adult mean (T-score ≤ -2.5 SD).

Severe osteoporosis (established osteoporosis) describes osteoporosis in the presence of one or more fragility fractures.

There are a number of other indications for bone densitometry including monitoring of treatment, determining the extent of bone loss and assessment of suitability for certain treatments.

Diagnostic thresholds differ from intervention thresholds for several reasons. First, the fracture risk varies at different ages, even with the same T-score. Other factors that determine intervention thresholds include the presence of clinical risk factors and the cost and benefits of treatment.

Investigations
The aims of the clinical history, physical examination and clinical tests are to: exclude diseases that mimic osteoporosis (e.g. osteomalacia, myeloma); identify secondary causes of osteoporosis and contributory factors; assess the risk of subsequent fractures and select the most appropriate form of treatment.

Relevant tests are shown in the box.

Investigation in osteoporosis

Routine

  • History and physical examination.
  • FBC, ESR or CRP, serum calcium, albumin, creatinine, phosphate, alkaline phosphatase and liver transaminases.
  • TFTs.
  • Bone densitometry (DXA).

Other investigations, if indicated

  • Lateral radiographs of lumbar and thoracic spine/DXA-based vertebral imaging.
  • Protein immunoelectrophoresis and urinary Bence-Jones proteins.
  • Serum testosterone, sex-hormone binding globulin, FSH, LH (in men).
  • Serum prolactin.
  • 24-hour urinary cortisol/dexamethasone suppression test.
  • Endomysial and/or tissue transglutaminase antibodies (coeliac disease).
  • Isotope bone scan.
  • Markers of bone turnover, when available.
  • Urinary calcium excretion.

Section 3 Management

Acute fracture
The management of acute fracture is not different from that of a non-osteoporotic fracture. It is important to restore mobility as soon as possible since immobilisation is an important cause of bone loss.

Lifestyle advice
Lifestyle advice includes intakes of 1,000mg/day of calcium, 800IU of vitamin D and of 1g/kg body weight of protein.

Smoking and high intakes of alcohol are recognised risk factors for fractures and are to be avoided.

Many fractures occur after a fall and strategies to avoid falls should be considered.

Assessing fracture risk
The longer term management of osteoporosis requires the assessment of future fracture risk which, in turn, determines the need for intervention.

At present there is no accepted policy for population screening in the UK to identify individuals with osteoporosis or those at high risk of fracture.

Rather, patients are identified opportunistically using a case-finding strategy on the finding of a previous fragility fracture or the presence of significant clinical risk factors (CRFs).

Some of these risk factors act independently of BMD to increase fracture risk (see box), whereas others increase fracture risk through their association with low BMD (see box, section 1).

Algorithms that integrate the weight of CRFs for fracture risk have been developed by the WHO. The FRAX tool (www.shef.ac.uk/FRAX) computes the 10-year probability of hip fracture or major osteoporotic fracture.

The National Osteoporosis Guideline Group (NOGG) has recently published a new management guideline (see figure) that integrates FRAX with clinical management algorithms.

The approach adopts the previous guidance in that treatment should be considered when an individual's probability of fracture is comparable to or exceeds that of a woman of the same age who has already sustained a low trauma fracture.

The guideline suggests that fracture probability should be assessed with FRAX in postmenopausal women and in men aged 50 years or more with CRFs where assessment would influence management.

Women with a prior fragility fracture can be considered for treatment without the need for further risk assessment, although BMD measurement may sometimes be appropriate, particularly in younger postmenopausal women.

In the presence of other CRFs, the 10-year probability of a major osteoporotic fracture (clinical spine, hip, forearm or humerus) should be determined using FRAX.

Men and women with probabilities below the lower assessment threshold (left-hand figure) can be reassured. Those with probabilities above the lower assessment threshold but below the upper assessment threshold can be considered for testing with BMD using DXA and have their fracture probability reassessed. Men and women with probabilities above the upper assessment threshold (right-hand figure) should be considered for treatment.

In men and women who require a BMD test, fracture probabilities should be re-computed with FRAX. Treatment can be considered in those in whom fracture probabilities lie above the intervention threshold.

Clinical risk factors for osteoporosis

  • Age
  • Sex
  • Low BMI (≤19kg/m2)
  • Previous fragility fracture, particularly of the hip, wrist and spine including morphometric vertebral fracture
  • Parental history of hip fracture
  • Current glucocorticoid treatment (any dose, by mouth for three months or more)
  • Current smoking
  • Alcohol intake of three or more units daily
  • Secondary causes of osteoporosis including: RA; untreated hypogonadism in men and women; prolonged immobility; organ transplantation; type-1 diabetes; hyperthyroidism; gastrointestinal disease; chronic liver disease; COPD
  • Falls (not accommodated in the FRAX algorithm)

Section 4 Pharmacological interventions
Bisphosphonates, strontium ranelate, raloxifene and parathyroid hormone peptides have been shown to reduce the risk of vertebral fracture when given with calcium and vitamin D.

Some have been shown to also reduce the risk of non-vertebral fractures, in some cases specifically at the hip (see box).

Alendronate is the first-line treatment in the majority of patients.

In patients who are intolerant of alendronate or in whom it is contraindicated, other bisphosphonates, strontium ranelate or raloxifene may provide appropriate treatment options.

The high cost of parathyroid hormone peptides restricts their use to those at very high risk, particularly for vertebral fractures.

Alendronate, risedronate, zoledronate and teriparatide are also approved for treatment of men at high risk of fracture. Alendronate is approved for the prevention and treatment of glucocorticoid-induced osteoporosis.

Risedronate and etidronate are approved for the prevention and treatment of glucocorticoid-induced osteoporosis in postmenopausal women while zoledronate is approved for the treatment of osteoporosis associated with long-term systemic glucocorticoid therapy in postmenopausal women and in men at increased risk of fracture. Teriparatide is approved for treatment of glucocorticoid-induced osteoporosis in men and women at increased risk of fracture.

Other approved treatments for postmenopausal women include calcitonin, calcitriol, etidronate and HRT.

In the near future, therapies will include other SERMs and a novel monoclonal antibody therapy, denosumab, which inhibits osteoclast activity.

Resources

  • Compston J, Cooper A, Cooper C et al; National Osteoporosis Guideline Group (NOGG). Guidelines for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK. Maturitas 2009; 62: 105-8.
  • Kanis J A, Johnell O, Oden A, Johansson H, McCloskey E V. FRAX(TM) and the assessment of fracture probability in men and women from the UK. Osteoporos Int 2008; 19: 385-97.
  • Kanis J A, McCloskey E V, Johansson H, Strom O, Borgstrom F, Oden A and the National Osteoporosis Guideline Group. Case finding for the management of osteoporosis with FRAX - Assessment and intervention thresholds for the UK. Osteoporos Int 2008; 19: 1,395-1,408; Erratum Osteoporos Int 2009; 20: 499-502.
  • NICE Technology appraisal TA161. Final appraisal determination. Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. London, NICE, June 2008.
  • NICE Technology appraisal TA160. Final appraisal determination. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women. London, NICE, June 2008.
  • Royal College of Physicians and Bone and Tooth Society of Great Britain. Update on pharmacological interventions and an algorithm for management. London, Royal College of Physicians, 2000.
  • Bone and Tooth Society of Great Britain, National Osteoporosis Society and Royal College of Physicians. Glucocorticoid-induced osteoporosis. Guidelines on prevention and treatment. London, Royal College of Physicians, 2002.
  • Royal College of Physicians. Osteoporosis: clinical guidelines for the prevention and treatment. London, Royal College of Physicians, 1999.

For an archive of all GP clinical reviews visit www.healthcarerepublic.com/clinical/GP

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