Definition

Osteoporosis is a progressive systemic skeletal disease characterised by reduced bone mass/density and micro-architectural deterioration of bone tissue. Bone formation initially exceeds bone resorption, but by the third decade this has reversed resulting in a net loss of bone mass. This leads to an increased bone fragility and susceptibility to fracture.¹

Bone density values in individuals can be expressed in relation to a reference population in standard deviation (SD); when SDs are used in relation to the young healthy population, this measurement is referred to as the T-score.²

Epidemiology

The National Institute for Health and Clinical Excellence (NICE) estimates there are 2 million women who have osteoporosis in England and Wales.¹ It affects 1 in 3 women aged >50 years and 1 in 12 men aged >50 years. This results in 310,000 fractures per year in the UK at a cost of £1.7 billion. This is expected to increase to £2.1 billion by 2010. This equates to an osteoporotic fracture every 2-3 minutes and is calculated to double in the next 50 years.⁴

Risk factors

As well as increasing age and reduced BMD, other independent clinical risk factors for fracture are:¹

• Parental history of hip fracture.
• Alcohol intake of 4 or more units per day.
• Rheumatoid arthritis.

Risk factors for reduced BMD are:

• Female gender.
• Corticosteroid therapy or Cushing's syndrome.
• Ankylosing spondylitis.
• Crohn's disease.
• Untreated premature menopause (<45 years) or prolonged secondary amenorrhoea.
• Low body mass (<19 kg/m²) and anorexia nervosa.
• Poor diet (particularly if calcium-deficient) or malabsorption syndromes, e.g. coeliac disease.
• Prolonged immobilisation or a very sedentary lifestyle.
• Smoking.
• Primary hypogonadism (men and women).
• Primary hyperparathyroidism.
• Hyperthyroidism.
• Caucasian or Asian origin.
• Post transplantation.
• Chronic renal failure.

Presentation

Unfortunately, the process that leads to established osteoporosis is asymptomatic and the condition usually presents only after bone fracture.
It is important that clinicians be alert to recognise low trauma 'fragility fractures' (fracture caused by a force equivalent to the force of a fall from the a height of an ordinary chair or less).¹

Signs differ according to the fracture site. The most common is deformity and loss of height due to vertebral collapse.⁶

Investigations

• Case finding:
  • If a fragility fracture occurs this should trigger bone density measurement (although in women ≥75 years osteoporosis can be assumed and first-line treatment initiated (alendronate) without dual-energy X-ray absorptiometry (DEXA) scan if the clinician feels this is appropriate).
  • Patients with any risk factors above should be considered for DEXA scanning, particularly if there are one or more risk factors for fractures (family history, increased alcohol intake or rheumatoid arthritis).
• Diagnosis of osteoporosis centres on the assessment of BMD:³
  • Single-energy X-ray absorptiometry (SXA) and DEXA/digital X-ray radiogrammetry (DXR) assessment of mineral content of the entire skeleton and particularly at specific, vulnerable sites.
  • DEXA is regarded as the gold standard technique for diagnosis; the accuracy at the hip exceeds 90%. Residual errors arise for various reasons. Incorrect diagnosis of osteoporosis can be caused by osteomalacia, osteoarthritis or soft-tissue calcification.³
  • DXR is a relatively new technique which is much simpler and less time-consuming than DEXA. It can be carried out anywhere where there is the facility to perform a standard radiograph of the hand. It appears to have similar precision and accuracy to DEXA in terms of diagnosing osteoporosis.⁷ It is a useful screening tool for osteoporosis following Colles'/other forearm fractures, without the need for additional radiographs. (This is a cohort of patients ripe for screening who often 'slip through the net').⁸ DXR seems to be slightly less sensitive than DEXA in detecting osteoporosis.⁹
  • Other modalities used include ultrasonic measurement of bone. This can be used for the assessment of fracture risk, or selection of those in need of DEXA/DXR. It is unreliable for diagnosis of osteoporosis and is associated with underdiagnosis. Radiography is useful for selection of patients in need of screening/formal diagnosis.
• Consider the following screening blood tests in patients suffering from osteoporosis to identify treatable underlying causes:
  • FBC and erythrocyte sedimentation rate (ESR).
  • U&E, LFT, TFT, serum calcium, alkaline phosphatase.
  • Testosterone/gonadotrophins in men.
  • Serum immunoglobulins and paraproteins, urinary Bence-Jones' proteins.

Assessment of fracture risk¹⁰

Although osteoporosis indicates a high likelihood of fracture, many fragility fractures occur in people with bone density values above the defined level. Fractures can be better predicted by adding clinical risk factors that contribute to fracture risk independently of BMD.³

There is now a WHO risk calculator available (FRAX®) which calculates the ten-year probability of a major osteoporotic fracture, (with or without BMD result).^11,12 Intervention thresholds based on cost-effectiveness can then be used to make a decision about treatment.¹³

For UK populations, the recent QFracture® score may be more appropriate for fracture risk assessment.^14,15

Management¹

Patients with osteoporosis (T-score -2.5 or worse) any age:

• Consider hip protectors and assessment of ongoing risk of falls.
• Reduce polypharmacy, especially sedatives.
• Ensure adequate calcium (0.5-1 g) and vitamin D (800 IU) - supplementation may be necessary.

Further management in women who have never had an osteoporotic fragility fracture (primary prevention)

• First-line bisphosphonate (usually alendronate on the basis of cost) is only recommended in postmenopausal women aged under 65 with confirmed osteoporosis but without fragility fractures, if they have an independent clinical risk factor for fracture and at least one additional indicator of low BMD.
• Start bisphosphonates in osteoporotic women without fragility fracture once they reach age 65 if they have any independent clinical risk factor for fracture, or over the age of 70 if they just have an indicator of low BMD.
• The responsible physician may decide a DXA scan is not required in women aged 75 years or older who have two or more independent clinical risk factors for fracture or indicators of low BMD.

Second-line treatments (risedronate and etidronate) may be considered if the patient is aged over 65 and unable to take alendronate:

Third-line treatment with strontium:

Denosumab is a monoclonal antibody that reduces osteoclast activity (and hence bone breakdown) which is given by 6 monthly subcutaneous injections. It may be a suitable option in women who are unable to comply with instructions for alendronate and either risedronate or etidronate.¹⁶

Raloxifene is not recommended as a treatment option for the primary prevention of osteoporotic fragility fractures.²

Further management in women who have had an osteoporotic fragility fracture (secondary prevention)

Start first-line bisphosphonate (usually alendronate on the basis of cost), and calcium and vitamin supplementation is usually co-prescribed. If the initial alendronate is not tolerated or is inappropriate, or there is an inadequate response, the next step depends on BMD, age, whether there has been a fragility fracture and risk factors:¹

If second bisphosphonate is not an option, treat with strontium or raloxifene at these thresholds:

If strontium or raloxifene is not an option, consider referral to secondary care for assessment for teriparatide or denosumab:

Denosumab may also be a treatment option for the secondary prevention with increased risk of fractures in patients who cannot comply with the special instructions for administering alendronate, risedronate or etidronate, or have an intolerance or a contraindication to those treatments.¹⁶

Osteoporosis in men

Alendronate 70 mg is used in men, (unlicensed indication). Seek specialist advice re alternatives if this is not tolerated or if other first-line bisphosphonates are not tolerated.

Notes on treatments

• Bisphosphonates are the mainstay of treatment for osteoporosis. They are, however, poorly absorbed and need to be taken separately from food. They may cause oesophageal irritation and should be taken sitting up with plenty of water. Etidronate was the first but has been superseded by the more powerful alendronate and risedronate, both of which can be taken daily or weekly, and the newer ibandronate that can be taken monthly. Less frequent dosing may improve adherence to therapy. All bisphosphonate trials have been controlled for calcium/vitamin D and so bisphosphonates should usually have calcium/vitamin D co-prescribed. Bisphosphonates act by inhibiting the action of osteoclasts. They have been shown to be cost-effective in European studies.^17,18
  
  Zoledronic acid (Aclasta®)¹⁹ is a bisphosphonate given by a single intravenous infusion once a year, licenced for the treatment of postmenopausal osteoporosis and osteoporosis in men. It is very expensive compared with oral formulations.
• Strontium ranelate has been licensed for the prevention of osteoporotic fractures in postmenopausal women with osteoporosis. This is the first drug in a new class of dual action bone agents (DABAs). In addition to decreasing bone resorption by inhibiting osteoclast differentiation and activity, bone formation is increased by stimulation of pre-osteoblast replication leading to an increase in bone matrix synthesis.
• Raloxifene, a selective oestrogen receptor modulator (SERM), reduces postmenopausal bone loss and reduces vertebral fractures but, like hormone replacement therapy (HRT), may increase the risk of venous thromboembolism. Unlike HRT, however, it decreases the risk of breast cancer (oestrogen-positive tumours) but may exacerbate hot flushes. The CSM has advised that HRT should not be considered as first-line therapy for long-term prevention of osteoporosis, due to the increased risk of breast cancer and cardiovascular disease.
• Parathyroid hormone peptides. Teriparatide (recombinant 1-34 parathyroid hormone) reduces vertebral and non-vertebral fractures in postmenopausal women with osteoporosis.¹³ Preotact® (the full 1-84 parathyroid hormone peptide) has also been approved. Neither has been shown to reduce hip fractures. They are more expensive than other options, so are reserved for patients with severe osteoporosis who are unable to tolerate, or are unresponsive to, bisphosphonates.

Screening

See separate articles Osteoporosis Risk Assessment and Primary Prevention and Osteoporosis Case Finding in Primary Care.

Prognosis

Once osteoporosis is established and causes a fracture there is considerable associated mortality and morbidity.

• Approximately 14,000 people die per year from osteoporosis (greater than carcinoma of ovary, uterus and cervix put together).
• The mortality of hip fracture in older patients is 20% at 3 months.
• Only 50% of survivors regain full independence after fracture.
• Survivors consult their GP approximately 9 extra times in the year following their fracture.
• Only 1 in 3 vertebral fractures is diagnosed.
• One vertebral fracture increases a patient's risk of sustaining another vertebral fracture fivefold, 20% of these within a year.
• Patients who sustain a vertebral fracture consult their GP, on average, 14 extra times in the year following it.

Document references

1. Osteoporosis - secondary prevention including strontium ranelate, NICE Technology Appraisal Guideline (January 2011); Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women
2. Osteoporosis - primary prevention, NICE Technology Appraisal Guideline (January 2011); Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women
3. Kanis JA; Diagnosis of osteoporosis and assessment of fracture risk.; Lancet. 2002 Jun 1;359(9321):1929-36. [abstract]
4. Bouee S, Lafuma A, Fagnani F, et al; Estimation of direct unit costs associated with non-vertebral osteoporotic fractures in five European countries.; Rheumatol Int. 2006 Sep 5;. [abstract]
5. Richards JS, Young HA, DeSagun R, et al; Elderly African-American and Caucasian men are infrequently screened for osteoporosis.; J Natl Med Assoc. 2005 May;97(5):714-7. [abstract]
6. Smith R: Disorders of the skeleton. Oxford Texbook of Medicine, Chapter 19
7. Elliot JR, Fenton AJ, Young T, et al; The precision of digital X-ray radiogrammetry compared with DXA in subjects with normal bone density or osteoporosis.; J Clin Densitom. 2005 Summer;8(2):187-90. [abstract]
8. Reed MR, Murray JR, Abdy SE, et al; The use of digital X-ray radiogrammetry and peripheral dual energy X-ray absorptiometry in patients attending fracture clinic after distal forearm fracture.; Bone. 2004 Apr;34(4):716-9. [abstract]
9. Boonen S, Nijs J, Borghs H, et al; Identifying postmenopausal women with osteoporosis by calcaneal ultrasound, metacarpal digital X-ray radiogrammetry and phalangeal radiographic absorptiometry: a comparative study.; Osteoporos Int. 2005 Jan;16(1):93-100. Epub 2004 Jun 10. [abstract]
10. Bukhari M; The National Osteoporosis Guideline Group's new guidelines: what is new? Rheumatology (Oxford). 2009 Apr;48(4):327-9. Epub 2009 Jan 7.
11. Kanis JA, Johnell O, Oden A, et al; FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008 Apr;19(4):385-97. Epub 2008 Feb 22. [abstract]
12. WHO Fracture Risk Assessment Tool (FRAX®), World Health Organization Collaborating Centre for Metabolic Bone Diseases
13. Kanis JA, Johnell O, Oden A, et al; Intervention thresholds for osteoporosis. Bone. 2002 Jul;31(1):26-31. [abstract]
14. QFracture® - risk calculator for hip fracture or osteoporotic fracture (hip, vertebral, or distal radius fracture) over the next 10 years
15. Hippisley-Cox J, Coupland C; Predicting risk of osteoporotic fracture in men and women in England and Wales: BMJ. 2009 Nov 19;339:b4229. doi: 10.1136/bmj.b4229. [abstract]
16. Osteoporotic fractures - denosumab, NICE Technology Appraisal Guideline (October 2010)
17. Borgstrom F, Carlsson A, Sintonen H, et al; The cost-effectiveness of risedronate in the treatment of osteoporosis: an international perspective.; Osteoporos Int. 2006;17(7):996-1007. Epub 2006 Mar 29. [abstract]
18. Brecht JG, Kruse HP, Mohrke W, et al; Health-economic comparison of three recommended drugs for the treatment of osteoporosis.; Int J Clin Pharmacol Res. 2004;24(1):1-10. [abstract]
19. Summary of Product Characteristics - Aclasta® 5 mg solution for infusion (zoledronic acid), Novartis Pharmaceuticals UK Ltd; eLectronic Medicines Compendium (updated June 2009); accessed 5 Jan 2010

Internet and further reading

• QFracture® - risk calculator for hip fracture or osteoporotic fracture (hip, vertebral, or distal radius fracture) over the next 10 years
• WHO Fracture Risk Assessment Tool (FRAX®), World Health Organization Collaborating Centre for Metabolic Bone Diseases
• Osteoporosis Disease Management: What Every Orthopaedic Surgeon Should Know, British Orthopaedic Association (November 2009)

Acknowledgements