Professor Juliet Compston explains how recent advances in the assessment and treatment of osteoporosis in postmenopausal women and older men will improve care


O steoporosis is characterised by reduced bone mass and deterioration of bone structure, leading to increased risk of fragility fracture. In the UK, osteoporosis results in over 200,000 fractures each year, with an estimated cost to the health services of around £2 billion. More than one-third of women and one in five men aged 50 years or older will sustain an osteoporotic fracture during their remaining lifetime.1

NOGG guidance

In 2008, the National Osteoporosis Guideline Group (NOGG) published guidance for the diagnosis and management of osteoporosis in postmenopausal women and older men in the UK.2 Significant advances in risk assessment and treatment have been made since then, and these have been incorporated into an updated version of the guideline.1 The update contains new information on the management of glucocorticoid-induced osteoporosis, the role of calcium and vitamin D supplementation, and the benefits and risks of long-term therapy with bisphosphonates. Regulatory updates on approved pharmacological interventions and adverse effects have also been included. NOGG guidance is web-based (see www.shef.ac.uk/NOGG/) and provides a practical, stepwise approach to the management of osteoporosis in clinical practice.

Assessment of fracture risk

The 10-year probability of fracture is estimated using the Fracture Risk Assessment tool (FRAX®) (www.shef.ac.uk/FRAX/), with or without femoral neck bone mineral density (BMD),1,3 using clinical risk factors (see Box 1). The value obtained is automatically superimposed on a graph, which provides thresholds for intervention set at a probability of fracture equivalent to that of a postmenopausal woman with a history of fragility fracture (see Figure 1).1,4

Box 1: Clinical risk factors used for the assessment of fracture probability2

  • Age
  • Sex
  • Low body mass index (≤19 kg/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 ≥3 months)
  • Current smoking
  • Alcohol intake of ≥3 units per day
  • Secondary causes of osteoporosis, including:
    • rheumatoid arthritis
    • untreated hypogonadism in men and women
    • prolonged immobility
    • organ transplantation
    • type 1 diabetes
    • hyperthyroidism
    • gastrointestinal disease
    • chronic liver disease
    • chronic obstructive pulmonary disease
  • Falls.
Figure 1: Assessment and treatment thresholds without (left) or with (right) BMD test to compute fracture probability for men and women4
Assessment and treatment thresholds without (left) or with (right) BMD test to compute fracture probability for men and women
  1. Figure adapted from: Kanis J, McCloskey E, Johansson H et al and the National Osteoporosis Guideline Group (2008). Case finding for the management of osteoporosis with FRAX®—Assessment and intervention thresholds for the UK. Osteoporos Int 19: 1395–1408.
    © The International Osteoporosis Foundation and National Osteoporosis Foundation, reprinted with permission.

Significance of thresholds

Women and men with fracture probabilities below the threshold can be reassured. If the probability of fracture has been estimated without BMD and the value lies in the intermediate zone, measurement of BMD is advised so that the probability of fracture can be recomputed using the FRAX® tool. When the probability of fracture is above the threshold for intervention, treatment should be considered.1

Postmenopausal women with a previous fragility fracture should be considered for treatment without further risk assessment, although measurement of BMD may sometimes be appropriate, particularly in younger postmenopausal women.1 In men aged >50 years with or without a previous fracture, and postmenopausal women without a previous fracture, decisions about treatment should be made on the basis of the 10-year probability of a major osteoporotic fracture (hip, spine, humerus, or forearm).1

Drug treatments

Alendronate is the first-line option for most individuals. Other bisphosphonates—denosumab, raloxifene, and strontium ranelate—provide cost-effective alternative options if alendronate is contraindicated or not tolerated.5 The high cost of parathyroid hormone peptides means that their use should be restricted to patients at very high risk of fractures (particularly vertebral).

New information in the NOGG update

Assessment of fracture risk and oral glucocorticoids

The FRAX® tool assumes an average dose of prednisolone (2.5–7.5 mg/day) so may underestimate the risk of fracture in patients taking higher doses, and overestimate the risk in those taking lower doses.1 Average adjustments for postmenopausal women of all ages and men aged ≥50 years have therefore been estimated for doses of prednisolone or its equivalent as follows:6

  • <2.5 mg/day (low)
  • 2.5–7.5 mg/day (medium)
  • >7.5 mg/day (high).

When the FRAX® model for the UK is used, and the glucocorticoid box is filled, three points appear on the NOGG graphs: one for low dose, one for medium dose, and one for high dose (as defined above). The thresholds for assessment and intervention are then used as described above.2

Calcium and vitamin D

Supplementation with calcium and vitamin D is widely recommended in older people who are housebound or live in residential or nursing homes, as vitamin D deficiency and low dietary calcium intake are common in these settings.1 Supplementation is often also advocated as an adjunct to other treatments for osteoporosis, as clinical trials of these agents were performed in patients who were calcium and vitamin D replete. It has been suggested that calcium supplementation may be associated with adverse cardiovascular outcomes,7 but the studies on which this suggestion was based have been widely criticised and the putative association therefore requires further clarification.1,8-10 A longitudinal cohort study also suggested an increased risk of cardiovascular events associated with calcium supplementation, but this increase was not associated with high dietary intake of calcium.11 It may therefore be prudent to increase dietary intake of calcium and use supplementary vitamin D alone when the use of calcium and vitamin D supplementation might otherwise be considered.1,10

Osteonecrosis of the jaw

Osteonecrosis of the jaw occurs rarely in patients receiving bisphosphonate or denosumab for osteoporosis. A dental examination with appropriate preventive dentistry should be considered prior to treatment in the presence of risk factors, such as:

  • poor oral hygiene
  • dental disease
  • glucocorticoid therapy.

While patients are receiving treatment, they should avoid invasive dental procedures wherever possible, but use of bisphosphonates or denosumab should not be regarded as a contraindication to necessary dental treatment. Good oral hygiene practices should be maintained during treatment. In the vast majority of patients, the benefits of treatment outweigh the risks.1

Atypical fractures

Atypical fractures (mainly of the subtrochanteric and diaphyseal regions of the femoral shaft) have been reported rarely in patients taking bisphosphonates or denosumab for osteoporosis. These fractures are often bilateral and tend to heal poorly. During treatment with bisphosphonates or denosumab, patients should be advised to report any unexplained pain in the thigh, groin, or hip, and imaging of the femur (radiography, isotope scanning, or magnetic resonance imaging) performed if such symptoms develop. If an atypical fracture is present, the contralateral femur also should be imaged. Discontinuation of bisphosphonates or denosumab should be considered in patients who develop an atypical fracture, with alternative treatment options considered where appropriate.1

Duration and monitoring of therapy

In most patients at increased risk of fracture, treatment needs to be continued in the long term (see Figure 2). The beneficial effects of treatment with drugs other than bisphosphonates wear off soon after therapy is discontinued, but benefits may be maintained for longer periods after cessation of bisphosphonate therapy. This fact, together with concerns over possible adverse effects of long-term bisphosphonate therapy—particularly with regard to osteonecrosis of the jaw and atypical femoral fractures—has raised questions about the optimal duration of bisphosphonate treatment, and whether treatment should be discontinued as a ‘drug holiday’ in some individuals.12

On the available data, it is recommended that treatment should be reviewed after 5 years for alendronate, risedronate or ibandronate, and after 3 years for zoledronic acid.1 Alendronate, ibandronate, or risedronate treatment can generally be continued without the need for further assessment in the following groups:1

  • high-risk individuals—for example those:
    • aged ≥75 years
    • who have previously sustained a hip or vertebral fracture
    • taking continuous oral glucocorticoids at a dose ≥7.5 mg/day prednisolone or equivalent
  • individuals who sustain one or more low-trauma fractures during treatment
  • individuals with a total hip or femoral neck BMD T-score ≤–2.5 standard deviations, in whom continuation of treatment generally should be advised.

If treatment is discontinued, fracture risk should be reassessed:

  • after a new fracture, regardless of when this occurs
  • after 2 years if no new fracture occurs.

In most individuals treated with zoledronic acid, treatment should be stopped after 3 years and the case for continuation of therapy reviewed 3 years later. Individuals with a previous vertebral fracture or hip BMD T-score ≤–2.5 standard deviations may be at increased risk of vertebral fracture if treatment is stopped.1

Reassessment of the risk of fracture in treated individuals

Reassessment of the risk of fracture in treated individuals can be performed using the FRAX® tool with femoral neck BMD.13 The NOGG thresholds for intervention can then be used to guide the decision as to whether or not to stop treatment for a time. If biochemical markers of bone turnover indicate relapse from suppressed bone turnover, and BMD has decreased following withdrawal of treatment, resumption of treatment should be considered.

Figure 2: Bisphosphonates: algorithm for long-term treatment monitoring
Bisphosphonates: algorithm for long-term treatment monitoring
  • * 3 years for zoledronic acid; 5 years for other bisphosphonates
  • BMD=bone mineral density.
  • Reproduced with kind permission from the WHO Collaborating Centre for Metabolic Bone Diseases, www.shef.ac.uk/FRAX

Conclusion

In the updated NOGG osteoporosis guideline,2 new information about management of glucocorticoid-induced osteoporosis, calcium and vitamin D supplementation, and duration of bisphosphonate therapy has been added. These are all issues that arise frequently in primary care, where osteoporosis is predominantly managed. The recommendations contained in the guideline are provided to aid management decisions but do not replace clinical judgement in the care of individual patients.

  • Commissioners should consider the impact of NOGG guidance, and also the latest MHRA warnings about use of strontium, to review their local care pathways for osteoporosis
  • Now that osteoporosis risk assessments like FRAX® are included in the QOF for patients with rheumatoid arthritis, there is likely to be an increase in referrals for DXA scanning
  • Commissioners should review the potential cost benefits of giving ‘drug holidays’ against the potential need for more DXA scanning stimulated by this guidance (likely to be a cost pressure as bisphosphonates are now available generically at low acquisition costs)
  • Commissioners should look at potential community or primary care delivery programmes for drugs such as zoledronic acid and denosumab under shared-care guidelines to treat patients closer to home and avoid expensive hospital tariff charges
  • In view of the complexity of the management of osteoporosis and changes to guidance, particularly in relation to duration of therapy, commissioners should consider education programmes with their constituent practices around local care pathways
  • Tariff costs for rheumatology outpatients = £217 (new), £100 (follow up).a

NOGG=National Osteoporosis Guideline Group; QOF=quality and outcomes framework;
DXA=dual energy X-ray absorptiometry

awww.gov.uk/government/publications/payment-by-results-pbr-operational-guidance-and-tariffs

  1. National Osteoporosis Guideline Group (NOGG). Osteoporosis: clinical guidelines for prevention and treatment; executive summary. London: NOGG, 2013. Available at: www.shef.ac.uk/NOGG/NOGG_Executive_Summary.pdf
  2. Compston J, Cooper A, Cooper C et al. Guidelines for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK. Maturitas 2008; 62 (2): 105–108.
  3. FRAX website. WHO fracture risk assessment tool. Available at: www.shef.ac.uk/FRAX/ (accessed 27 June 2013).
  4. Kanis J, McCloskey E, Johansson H et al. Case finding for the management of osteoporosis with FRAX—assessment and intervention thresholds for the UK. Osteoporos Int 2008; 19 (10): 1395–1408.
  5. Kanis J, Adams J, Borgstrom F. The cost-effectiveness of alendronate in the management of osteoporosis. Bone 2008; 42 (1): 4–15.
  6. Kanis J, Johansson H, Oden A, McCloskey E. Guidance for the adjustment of FRAX according to the dose of glucocorticoids. Osteoporos Int 2011; 22 (3): 809–816.
  7. Bolland M, Avenell A, Baron J et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010; 341: c3691.
  8. Bolland M, Grey A, Avenell A et al. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 2011; 342: d2040.
  9. Abrahamsen B, Sahota O. Do calcium plus vitamin D supplements increase cardiovascular risk? BMJ 2011; 342: d2080.
  10. National Osteoporosis Society. Vitamin D and bone health: a practical clinical guideline for patient management. Bath: NOS, 2013. Available at: www.nos.org.uk/document.doc?id=1352
  11. Li K, Kaaks R, Linseisen J, Rohrmann S. Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg). Heart 2012; 98 (12): 920–925.
  12. Compston J, Bilezikian J. Bisphosphonate therapy for osteoporosis: the long and short of it. J Bone Miner Res 2012; 27: 240–242.
  13. Leslie W, Lix L, Johansson H et al. Does osteoporosis therapy invalidate FRAX for fracture prediction? J Bone Miner Res 2012; 27 (6): 1243–1251. G