Clinical Review: Osteoporosis

A clinical review of the aetiology, diagnosis and management of osteoporosis. By Dr Mark Cooper

Osteoporosis: bisphosphonates work by reducing bone loss (Photograph: Professor P Motta)
Osteoporosis: bisphosphonates work by reducing bone loss (Photograph: Professor P Motta)

Section 1. Epidemiology and aetiology

Osteoporosis is defined as a systemic abnormality in the amount and/or architecture of bone. The consequence of osteoporosis is an increased risk of fractures with low trauma (for example, falling from standing height or less).

The focus in osteoporosis is moving away from low bone density towards treating increased fracture risk. Low trauma fractures, for example of the wrist or hip, are rare in adults under 50 years. Beyond this age there is a steep rise in risk. This increase with age is particularly dramatic for hip fractures with a 30-fold increase between age 50 and 80 years.1

Most fractures are clinically obvious but only a third of spine fractures are recognised as such since the pain is commonly attributed to other pathologies.

Bone remodelling
Low bone density is caused by failure to accrue an adequate amount of bone during growth, a loss of bone through excessive resorption or a combination of the two.

Bone is continually being remodelled by being broken down and subsequently replaced. Approximately 5% of the bone surface undergoes remodelling at any one time.

In early adulthood the amount of bone lost per cycle is similar to the amount which is replaced and thus the amount of bone in the skeleton does not change.

However, with ageing and loss of estrogen at the menopause these cycles are characterised by greater amounts of bone being removed each time and a reduced ability to refill the defects leading to bone loss and architectural deterioration.

Other factors also contribute to bone strength independent of density. These include high remodelling rates, collagen quality and bone size and shape.

Fracture risk
Much of the increase in fracture risk with age is independent of changes in bone density and the increased risk of falls is a major factor.

Smoking, excessive alcohol use, malabsorption, inflammatory disease, prolonged use of glucocorticoids, aromatase inhibitors or androgen deprivation therapy, a previous fracture and a family history of fracture are all additional important risk factors for low trauma fracture.

A previous fracture is an important predisposing factor for further fracture independent of bone density.

This is particularly so at the spine where a single fracture can adversely alter the force distribution throughout the rest of the spine, leading to other fractures (see image, below).

This domino effect can lead to rapid height loss and spinal deformity.


A fracture can alter the force distribution through the spine (Author image)

Section 2. Making the diagnosis

Osteoporosis is clinically silent until the first fracture. The condition might be suspected by the presence of a disease or medical treatment that predisposes to bone loss. Osteoporosis is strongly suggested, and increasingly defined, by the presence of multiple low trauma fractures.

Investigations and treatment should be done in the context of an individual's likely fracture risk. In general, low trauma fractures in premenopausal women are rare even in women with low bone density.

As such, attempts to diagnose osteoporosis 'early' in otherwise healthy premenopausal women without fracture are discouraged because their fracture risk will be very low in absolute terms.

Additionally, there would be no indication for osteoporosis treatment and the premature label of 'osteoporosis' can cause unwarranted distress.

Investigations
Investigations are used to rule out secondary causes of osteoporosis and/or fractures. Most causes will be clear on history and examination but multiple myeloma and covert coeliac disease are easily missed. Blood tests for U&Es, LFTs, TFTs, FBC and ESR are usually sufficient in women. In men, measuring serum testosterone is vital.

The chance of finding a secondary cause of osteoporosis is (approx) 5-30% in women but more than 50% in men.2 A strong case can be made for measuring vitamin D levels (25-hydroxyvitamin D) to exclude osteomalacia. This is definitely required in patients with symptoms and signs of muscle weakness or hypocalcaemia, or factors that predispose to vitamin D deficiency (for example, malabsorption, skin pigmentation).

Some centres also perform tests for biochemical bone turnover markers. Although useful in monitoring compliance with therapy their use is not universally recommended.

Bone density scanning
Bone density scanning using DXA is the test normally used to measure bone density (see image, below, for an example of a DXA scan).

Density is measured at the hip and lumbar spine. Hip bone mineral density gives an estimate of fracture risk at all non-spine sites and lumbar spine bone mineral density an estimate for the spine in general.


Bone density scanning using DXA
(Author image)

Quantitative CT and bone ultrasound can also be used to estimate fracture risk but their use is generally restricted to screening individuals in whom DXA might be used.

Given the importance of knowing whether spine fractures are present vertebral spine imaging is commonly employed, particularly if there is height loss or back pain.

Imaging could be with plain radiographs but many DXA scanners can now perform vertebral imaging.

FRAX algorithm
The diagnosis of osteoporosis is classically based on a DXA value of equal to or less than -2.5 SD below the young gender matched adult mean.

Increasingly fracture risk assessment algorithms are replacing the dependence on DXA.

The FRAX algorithm is most widely used and incorporates several risk factors with or without DXA information to generate a more accurate assessment of fracture risk. In the UK, the output from FRAX can guide whether DXA scanning is likely to be useful and/or whether treatment should be offered.

Section 3. Managing the condition

Treatment involves addressing underlying secondary causes where possible. There is a limited role for dietary or exercise intervention in most individuals but a healthy lifestyle is encouraged.

For women in the immediately postmenopausal period HRT might be considered but this is not commonly used because the absolute risk of fracture in these women is low and HRT has significant extraskeletal risks.

Initial medication is normally a bisphosphonate, such as alendronic acid 70mg once a week, combined with calcium and vitamin supplementation. The main adverse effect of oral bisphosphonates is upper GI intolerance. In this situation, alternatives are IV bisphosphonates (once-yearly zoledronic acid), strontium ranelate (a sachet once daily) or denosumab (a six-monthly subcutaneous injection). All these medications work by reducing bone loss.

An alternative medication, teriparatide, stimulates new bone formation. This daily subcutaneous injection costs more than other treatments. It is indicated in patients with severe osteoporosis who continue to fracture on bisphosphonate treatment.

 

Key prescribing advice
Avoid bisphosphonates in premenopausal women without specialist advice (there is little evidence in this situation, these medications are less effective in premenopausal women and they are contraindicated in pregnancy). Bisphosphonates should also be avoided in patients with significant renal impairment (eGFR <30ml/min) or existing upper GI pathology.

An increased risk of 'atypical' fractures of the subtrochanteric region of the femur and osteonecrosis of the jaw have been reported with long-term use of bisphosphonates.3

In patients with dental problems these should be managed before starting a bisphosphonate. Patients must inform their dentist of current bisphosphonate use.

These risks are time dependent and the MHRA and Food and Drug Administration recommend that the use of bisphosphonates is re-evaluated after five years of treatment.

Follow-up
Centres vary in their approach to follow-up DXA scanning. Some recommend regular scans whereas others only recommend them if the clinical situation changes.

Patients with low bone density (but not osteoporosis) are likely to need further DXA scans within two to three years.

Patients on treatment are likely to need repeat DXA scans within five years of starting treatment.

Further guidance
The drugs used to treat osteoporosis have been evaluated by NICE (see online resources). Guidelines from NICE for the management of osteoporosis are in draft form. These guidelines are heavily based on assessment of absolute fracture risk.

Section 4. Prognosis

The prognosis of osteoporosis depends on the number and type of fractures that will be sustained. Fractures at many skeletal sites will cause temporary pain and the inconvenience of an operation and/or being in plaster for a short time.

However, these events are unlikely to significantly contribute to long-term morbidity or mortality.

By contrast, fractures of the hip and spine are much more serious. Half of the elderly patients who sustain a hip fracture cannot live independently subsequently and mortality post hip fracture is up to 30% by one year.

Of individuals who sustain a vertebral fracture, 40% are left with persistent pain. Vertebral fractures are also associated with increased mortality in addition to their ability to cause deformity.

The adverse prognosis of osteoporosis can be altered significantly by currently available medical treatments. As an approximation, bisphosphonate treatment reduces the risk of vertebral fracture by (approx) 50% and hip fracture by (approx) 30%.

Section 5. Case study

A 65-year-old woman presented to her GP concerned about osteoporosis. She was well and reported no history of fractures.

However, her mother had sustained a hip fracture at the age of 68. The patient was taking no medications and her only medical history involved a DVT 10 years before.

She had not had a recent fall and her mobility was excellent. Her BMI was 22kg/m2, her menopause occurred at the age of 50, she was a non-smoker and took around four units of alcohol per day. She did report height loss of two inches (5cm).

On the basis of the FRAX calculator she had a 10-year probability of major osteoporotic fracture of around 19% and hip fracture of around 3%.

Borderline risk
This data suggested she was of borderline risk to benefit from treatment and the recommendation was that a DXA scan be performed - it demonstrated a T-score of -2.3 at the hip and -2.5 at the spine.

Owing to her height loss, a vertebral fracture assessment was also carried out during the DXA procedure which demonstrated a vertebral fracture (see image, below). Screening investigations described above were performed to rule out a secondary cause of osteoporosis.


Assessment revealed a vertebral fracture (Author image)

The presence of low bone density and a previous fracture substantially increased her estimated probability of fracture and treatment was recommended. She was advised to decrease her alcohol intake.

On the basis of NICE guidance, she was started on alendronic acid 70mg once weekly along with a calcium and vitamin D supplement.

Dyspepsia side-effect
Unfortunately she returned two weeks later having experienced significant dyspepsia for several days following each alendronic acid tablet.

This medication was therefore discontinued and alternative treatment options were considered. Strontium ranelate would normally have been an option but this medication is contraindicated in people with a history of venous thromboembolism.

After discussion with a local consultant, treatment with once-yearly zoledronic acid infusions was organised for the patient (an alternative would have been six-monthly denosumab injections).

The patient successfully had the treatment and the intention is to continue therapy for three to five years before reassessing her need for potential further treatment.

If she had further fractures of the spine despite this treatment the use of teriparatide should be considered.

Section 6. Evidence base

Clinical trials
Alendronic acid was the first bisphosphonate that was to be proven effective in fracture intervention.

  • Black DM, Cummings SR, Karpf DB et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996; 348: 1535-41.

Similar trials demonstrated effectiveness of risedronate and strontium ranelate. Ibandronate was shown to be equally effective to alendronic acid.

The HORIZON Pivotal Fracture Trial demonstrated effectiveness of once-yearly IV zoledronic acid.

The most recent medication proven to be effective is denosumab, a six-monthly subcutaneous injection.

Other notable trials were those of the Women's Health Initiative (WHI). These studies proved the effectiveness of HRT in reducing fractures but also demonstrated that HRT carried significant extraskeletal risks.

  • Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288: 321-33.

Guidelines
NICE guidance is available for the use of medications in post-menopausal women. Guidelines from NICE relating to the treatment of both women and men are in development.

More online

Reflect on this article and add notes to your CPD Organiser on MIMS Learning

    CPD IMPACT: EARN MORE CREDITS

    These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

    • Hold a strategy meeting at your practice to address how you can identify and manage at-risk patients.
    • Make a clinical poster about osteoporosis to highlight considerations such as coeliac disease.
    • Put a link to the FRAX algorithm on every computer in the practice and teach colleagues how to use it.

    References
    1. Kanis JA, Borgstrom F, de Laet C et al. Assessment of fracture risk. Osteoporosis International 2005; 16: 581–9.
    2. Premaor MO, Compston JE. Testing for secondary causes of osteoporosis. BMJ 2010; 341: c6959.
    3. Lenart BA, Lorich DG, Lane JM.  Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 2008; 358: 1304–6.

    Contributed by Dr Mark Cooper, senior clinical lecturer in endocrinology at the University of Birmingham and Queen Elizabeth Hospital Birmingham.

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