Osteoporosis

Osteoporosis is a progressive systemic skeletal disease characterised by:

• Reduced bone mass
• Microarchitectural deterioration of bone tissue

This leads to increased bone fragility and susceptibility to fracture.
It may also be defined in terms of standard deviation of bone mineral density (BMD) from the young adult reference mean - the T Score.¹

Epidemiology

It affects:

• 1 in 3 women aged >50 years
• 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. The equivalent of employing 108,000 nurses or 34,000 GP's! 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.^1,2

Risk factors

Some risk factors vary in importance according to the age of the patient:

• Corticosteroid therapy
  • Patients on corticosteroid therapy are at increased risk of fracture (compared to patients not on steroids with the same BMD)³
  • Any patient aged >65, or who has suffered a relevant previous fracture, taking any dose of steroid for >3 months, should be considered for prophylaxis/treatment, without BMD measurement
  • Any patient <65>
  • If the T score is < –1.5 treatment should be considered
  • Also consider BMD measurement in patients taking recurrent, intermittent courses of steroids as there is evidence to suggest that total cumulative dose is as important as chronicity for reducing BMD
• Primary hypogonadism (men and women)
• Primary hyperparathyroidism
• Hyperthyroidism
• Cushing's syndrome
• Premature menopause (<45>
• Prolonged secondary amenorrhoea
• Low body mass (<19 style="color: rgb(0, 0, 0); font-weight: 400; vertical-align: super; font-size: 0.75em; ">2)
• Anorexia nervosa
• Poor diet (particularly if calcium deficient)
• Malabsorption syndromes e.g. coeliac disease
• Chronic disorders associated with osteoporosis e.g. rheumatoid arthritis
• Sedentary lifestyle
• Prolonged immobilisation
• Female gender
• Aged>60
• Family history osteoporosis
• Maternal history of hip fracture
• Smoking
• Caucasian or Asian origin
• Post transplantation
• Chronic renal failure

NB Although females are at higher risk, men are also susceptible and are often inadequately screened for the disease despite having relevant risk factors. This is particularly so in older men, and should be borne in mind when designing any system to select patients for screening.⁴

Pathogenesis

Age related bone loss starts around age 40 years for men and women. It occurs as a result of increased bone breakdown by osteoclasts and decreased bone formation by osteoblasts. The role of oestrogen deficiency in menopausal and age related bone loss in women is well documented, however it is less well recognised that bone mass in elderly men is also positively related to oestrogen levels.⁵

Presentation

Unfortunately, the process that leads to established osteoporosis is asymptomatic and the condition usually presents only after bone fracture. Features differ according to the fracture site. The most common is deformity and loss of height due to vertebral collapse.⁶

Investigations

Consider the following screening blood tests in patients suffering from osteoporosis to identify treatable underlying causes:

• FBC & ESR
• U&E, LFT, TFT, serum calcium, alkaline phosphatase
• Testosterone/gonadotrophins in men
• Serum immunoglobulins and paraproteins, urinary Bence-Jones proteins

Diagnosis of osteoporosis centres on the assessment of BMD:⁷

• Single and dual X-ray absorptiometry (DXA)/Digital X-ray radiogrammetry (DXR) Assessment of mineral content of the entire skeleton and particularly at specific, vulnerable sites.
• DXA is regarded as the gold standard technique for diagnosis; the accuracy of DXA at hip exceeds 90%. Residual errors arise for various reasons. Incorrect diagnosis of osteoporosis can be caused byosteomalacia, osteoarthritis or soft tissue calcification.⁷
• DXR is a relatively new technique which is much simpler and less time-consuming than DXA. 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 DXA in terms of diagnosing osteoporosis.⁸ 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').⁹DXR seems to be slightly less sensitive than DXA in detecting osteoporosis.¹⁰

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 DXA/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.

Diagnosis of osteoporosis

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.⁷

General diagnostic categories proposed by WHO/International Osteoporosis Foundation:7 Normal:- hip BMD greater than the lower limit of normal (taken as 1 SD below the young adult female reference mean (T score ≥ –1)) Low bone mass (osteopenia):- hip BMD between 1 and 2.5 SD below the young adult female reference mean (T score less than –1 but above –2.5) Osteoporosis :- hip BMD 2.5 SD or more below the young adult female reference mean (T score ≤ –2.5) Severe osteoporosis:- hip BMD 2.5 SD or more below the young adult female reference mean in the presence of one or more fragility fractures (T score ≤ –2.5 PLUS fracture)

For diagnosis, measurement at the hip is the gold standard, since it has the highest predictive value for hip fracture. Greater experience of the use of DXR may mean that rigid diagnostic criteria based on hand measurements are developed in the near future.

Diagnosis in men

Risk of hip fractures is similar in men and women for any given BMD, so similar cut-off value for hip BMD can be used ( 2.5 SD or more below ( T score ≤ –2.5, obviously using different reference value for different population).⁷

Assessment of fracture risk

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 bone mineral density.⁷ Intervention thresholds based on cost effectiveness can then be used to make a decision about treatment.¹¹

Assessment of BMD is performed by DXA and quantitative ultrasound.
Risk of fracture in elderly women roughly doubles for each SD reduction in BMD measured by DXA.

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).^12,13

Management

Interpreting DEXA scan results T score ≥ –1.0 (Normal) Lifestyle advice to include taking regular exercise (especially weight-bearing as suggested below*), to stop smoking and to avoid excessive alcohol. T –1.0 to –2.5 (Osteopenia) Offer lifestyle advice as above. Offer treatment if previous fracture. T ≤ –2.5 (Osteoporosis) Offer lifestyle advice as above. Offer treatment.1,3

Treatment

Consider hip protectors.
Ensure adequate calcium (0.5-1g) and Vit D (800iu) intake. Vitamin D is required for calcium metabolism and may reduce the tendency to falling.
Reduce polypharmacy, especially sedatives.

• 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.^14,15
• Strontium ranelate has been licensed for the prevention of osteoporotic fractures in post-menopausal women with osteoporosis. This is the first drug in a new class of Dual Action Bone Agents (DABA). 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 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 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.¹¹ Preotact (the full 1-84 parathyroid hormone peptide) has also been approved. Neither have 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.

Treatment monitoring

Routine monitoring of treatment by DXA is not recommended. Biochemical markers of bone turnover are a research tool at present, but may become clinically useful for selecting patients for treatment (patients with higher bone turnover respond better to treatment) and for monitoring the effectiveness of therapy. Markers of bone production are produced by osteoblasts and breakdown markers are collagen degradation products.

Efficacy of interventions

Treatment	Prevention of Spine Fracture	Prevention of Hip Fracture	Positive Effect on Bone Mineral Density
Alendronate	Grade A Evidence	Grade A Evidence	Grade A Evidence
Calcitonin	Grade A Evidence	Grade B Evidence	Grade A Evidence
Calcium	Grade A Evidence	Grade B Evidence	Grade A Evidence
Calcium + Vitamin D	Not Demonstrated	Grade A Evidence	Grade A Evidence
Cyclical Etidronate	Grade A Evidence	Grade B Evidence	Grade A Evidence
Hip Protectors	Not Applicable	Grade A Evidence	Not Applicable
Hormone Replacement Therapy	Grade A Evidence	Grade B Evidence	Grade A Evidence
Physical Exercise*	Not Demonstrated	Grade B Evidence	Grade A Evidence
Raloxifene	Grade A Evidence	Not Demonstrated	Grade A Evidence
Risedronate	Grade A Evidence	Grade A Evidence	Grade A Evidence
Tibolone	Not Demonstrated	Not Demonstrated	Grade A Evidence

* American College Sports Medicine Guidelines suggest 50, 2 footed jumps of 8 cm, three times a week.

• Grade A Evidence is evidence from meta-analysis of randomised controlled trials (RCTs) or at least one RCT or one well designed controlled study without randomisation.
• Grade B Evidence is from at least one other type of well designed quasi-experimental study or from well designed non-experimental descriptive study e.g. case controlled studies.¹

Screening

Clinical Knowledge Summaries recommend that those with a confirmed T score of 2.5 or less or >2 vertebral fractures (if no other cause of vertebral fracture is apparent) should be offered treatment.³ Their criteria for offering BMD measurement are:

• X-ray evidence of osteopenia or vertebral deformity
• Quantitative ultrasound of the calcaneum, or peripheral DXA/DXR of the wrist or heel suggesting osteoporosis.
• Decrease in height
• Long-term oral steroid treatment (3 months or more)
• Menopause at <45>
• History of amenorrhoea for >1 year
• Body mass index <19
• Primary hypogonadism
• Chronic disorders associated with osteoporosis e.g. rheumatoid arthritis
• Hyperthyroidism
• Maternal family history of hip fracture

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 are diagnosed.
• One vertebral fracture increases a patient's risk of sustaining another vertebral fracture 5-fold, 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.

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Document references

1. Osteoporosis - Guidelines for Treatment and Prevention, Royal College of Physicians, (January 2001)
2. 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]
3. Osteoporosis - treatment (and prevention of fragility fractures), Clinical Knowledge Summaries (2007)
4. 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]
5. Poole KE, Compston JE; Osteoporosis and its management. BMJ. 2006 Dec 16;333(7581):1251-6.
6. Smith R: Disorders of the skeleton. Oxford Texbook of Medicine, Chapter 19
7. Kanis JA; Diagnosis of osteoporosis and assessment of fracture risk.; Lancet. 2002 Jun 1;359(9321):1929-36. [abstract]
8. 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]
9. 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]
10. 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]
11. Kanis JA, Johnell O, Oden A, et al; Intervention thresholds for osteoporosis. Bone. 2002 Jul;31(1):26-31. [abstract]
12. 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]
13. WHO Fracture Risk Assessment Tool (FRAX™)
14. 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]
15. 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]

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Internet and further reading

• Management of osteoporosis, SIGN (2004)
• Osteoporosis - secondary prevention including strontium ranelate, NICE Technology Appraisal Guideline (October 2008); Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women
• Osteoporosis. Osteoporosis is a condition which causes your bones to become thin and fragile. Although there's no cure, there are ways to reduce your risk of fracture and slow down the progression of the condition. Short video from NHS Choices. (October 2007)
• WHO Fracture Risk Assessment Tool (FRAX™)