New guidelines should help prevent fragility fractures in this often overlooked condition, as Dr Juliet Compston, chair of the RCP Guidelines Writing Group, explains


Glucocorticoids are widely used in the treatment of a variety of medical disorders. Data from the General Practice Research Database indicate that 1% of the adult population in the UK is taking oral glucocorticoids at any one time; in those aged 70-79 years this figure rises to 2.4%.1

Use of glucocorticoids is associated with a dose-related increased risk of fragility fracture. This risk increases rapidly after therapy starts and declines rapidly towards baseline values after therapy ceases.

The need for guidelines

The significant morbidity and mortality caused by osteoporosis-related fractures has become widely recognised in recent years. However, studies of therapeutic intervention and management guidelines have focused mainly on non-glucocorticoid treated postmenopausal women with osteoporosis.

In contrast, several studies have emphasised the low utilisation of appropriate diagnostic and therapeutic interventions in individuals treated with oral glucocorticoids.

In the General Practice Research Database study2 the use of bone active medication in such patients was very low, 5% using hormone replacement therapy and only 1.8% bisphosphonates.1 The authors of the study concluded that the current population at risk of developing fractures attributable to glucocorticoids could be as high as 350 000.

The growing realisation that bone protection is inadequate in most glucocorticoid-treated individuals has been accompanied by a significant expansion in our knowledge of glucocorticoid-induced osteoporosis.

Epidemiological studies have demonstrated that, contrary to popular belief, adverse skeletal effects of glucocorticoids are seen at doses lower than 7.5mg daily of prednisolone and that fracture risk rises rapidly after the start of treatment and falls after treatment stops. Overall, the relative risk of any non-vertebral fracture during oral glucocorticoid use is 1.33 (95% confidence intervals [CI] 1.29-1.38) and of vertebral fracture, 2.60 (95% CI 2.31-2.92).2

In addition, several large randomised controlled studies of the prevention and treatment of glucocorticoid-induced osteoporosis have been performed, resulting in the approval of three bisphosphonates in the UK for this indication.3-5

The 1999 Royal College of Physicians guidelines on the prevention and treatment of osteoporosis6 did not address in detail the specific topic of glucocorticoid-induced osteoporosis because the evidence base at the time was weak, and guidance issued by the National Osteoporosis Society in 1998 did not fulfil the criteria for fully evidence-based guidelines.7

The new guidelines from the Bone and Tooth Society of Great Britain, the National Osteoporosis Society and the Guidelines Writing Group of the Royal College of Physicians have been developed to reflect the information now available and the clinical importance of glucocorticoid-induced osteoporosis.

The aim of the guidelines is to assist all health professionals in primary and secondary care who are involved with the management of glucocorticoid-treated patients. The guidelines primarily address the use of oral glucocorticoids.

How robust is the evidence?

The guidelines were developed using strict evidence-based methodology which is detailed in the appendices of the guidelines document. It included a full systematic search for relevant literature and appraisal of the guidelines using the AGREE appraisal tool. Levels of evidence are graded from Ia to IV and recommendations from A to C (Table 1, below).

Table 1: Levels and types of evidence and grade of recommendations
Level

 

 

Type of evidence Grade
Ia Meta-analysis of randomised controlled trials A
Ib At least one randomised controlled trial A
IIa

 

 

At least one well designed, controlled study but without randomisation B
IIb

 

 

At least one well designed, quasi-experimental study B
III

 

 

At least one well designed, non-experimental descriptive study (e.g. comparative studies, correlation studies, case-control studies) B
IV Expert committee reports, opinions and/or experience of respected authorities C

Bone loss and increased fracture risk

Evidence linking oral glucocorticoid use to bone loss and increased fracture risk is strong, but there is less certainty about the skeletal effects of inhaled glucocorticoids. Nevertheless, some evidence indicates that high doses of inhaled glucocorticoids and long-term use of lower doses may result in increased bone loss.

However, one study that demonstrated increased fracture risk in individuals taking inhaled glucocorticoids also demonstrated an increased risk in those using inhaled bronchodilator drugs, suggesting the risk was related to the underlying respiratory disease rather than the glucocorticoids.8

The effects of short-term, high-dose therapy and intermittent oral glucocorticoids administered over longer periods have not been well studied.

Diagnostic evaluation

The optimal bone mineral density at which intervention should be considered in individuals taking oral glucocorticoids remains to be established. The guidelines recommend that a T score at or below –1.5 at the hip and/or spine should be used, although age should also be taken into consideration because the absolute risk of fracture for any given T score increases with age.

The decision to use a T score of –1.5, rather than –2.5 as used in postmenopausal osteoporosis, is based on evidence that fractures occur at a higher bone mineral density in glucocorticoid-induced osteoporosis than in postmenopausal osteoporosis. In glucocorticoid-treated individuals, the relative risk of fracture for any given bone mineral density is approximately twice that in the general population.9

Monitoring of therapy

The evidence base for monitoring of bone protective therapy in glucocorticoid-treated individuals using either biochemical markers of bone turnover or bone mineral density measurements is currently weak.

The spine is the preferred site for measuring bone mineral density because of the low precision error of measurement.

Pharmacological intervention

A number of randomised controlled trials of different interventions have been performed in individuals receiving glucocorticoids. Many of these have been small and the timing of intervention with respect to initiation of glucocorticoid therapy has varied.

In many of these studies, the patient population has been heterogeneous and not all underlying diseases have been well represented. For example, the issue of whether orally administered drugs are adequately absorbed in inflammatory bowel disease remains unresolved.

Grade of recommendations for the interventions are provided in Table 2 (below). These gradings refer solely to the level of evidence of efficacy, regardless of effect size. It should be noted that fracture reduction was not an end-point of any study and evidence for anti-fracture efficacy is derived from post hoc or safety analyses.

Table 2: Effect of interventions on the prevention/reduction of glucocorticoid-induced bone loss and vertebral fracture: grade of recommendations
Intervention

 

Spine BMD

 

 

Proximal femur BMD Vertebral fracture
alendronate A

 

 

A A†
alfacalcidol A

 

 

A# na
calcitonin A#

 

 

A# na
calcitriol A#

 

 

A# na
calcium nd

 

 

nd na
calcium + vitamin D A# A# na
clodronate A

 

 

A na
cyclic etidronate A A A†
fluoride A

 

 

nd na
HRT (including tibolone) A A na
pamidronate A

 

 

A na
parathyroid hormone A A na
raloxifene no data no data no data
risedronate A A A†
testosterone A na na

na not adequately assessed
† not a primary end-point
BMD bone mineral density
nd not detected
# data inconsistent

The three agents approved in the UK for the prevention and treatment of glucocorticoid-induced bone loss are cyclic etidronate, alendronate and risedronate.

Promoting best practice and improving patient care

At present, many individuals receiving glucocorticoid therapy do not undergo appropriate investigation or treatment.

The guidelines advocate primary prevention (co-administration of a bone protective agent at the time of initiation of glucocorticoid therapy) in all high-risk individuals, without the need for prior measurement of bone mineral density.

For this purpose, high-risk individuals are defined as men and women aged over 65 years and those who have sustained a fragility fracture in the past. All those in the latter category should be investigated to exclude secondary causes of osteoporosis.

Other glucocorticoid-treated individuals should undergo bone densitometry to assess fracture risk. Measurement of hip, with or without spine, bone density using dual energy X-ray absorptiometry is recommended and intervention with a bone protective agent should be considered in those with a T score of –1.5 or less. In addition, if a fragility fracture occurs during glucocorticoid therapy, this should be regarded as an indication for bone protective medication.

Implementation tools included with the guidelines include a concise guide containing the executive summary with the level of evidence and grade of recommendation indicated for each key point (Figure 1, below), grading of recommendations for the pharmacological interventions, an algorithm (Figure 2, below) and a patient information sheet.

Figure 1: Summary guidance from the concise guide
  • Glucocorticoids are widely used to treat a number of medical disorders. At any one time approximately 1% of the adult population in the UK is taking oral glucocorticoids; this figure increases to 2.4% in individuals aged 70–79 years (Level III).

     

  • The administration of oral glucocorticoids is associated with a significant increase in fracture risk at the hip and spine (Level 1a). Although the greatest increase in risk is observed with higher dose therapy, increased risk is seen even at daily doses of prednisolone less than 7.5 mg (Level III). Fracture risk increases rapidly after the onset of treatment and declines rapidly after stopping therapy (Level III).
  • Loss of bone mineral density (BMD) associated with oral glucocorticoid administration is greatest in the first few months of glucocorticoid use (Level IIa). The effects of inhaled glucocorticoids on bone mineral density are less certain, although some studies report increased bone loss with high doses (Level IIa) and long-term use of lower doses may result in significant deficits of bone mineral density (Level III).
  • Glucocorticoids contribute to the increase in fracture risk over and above the effect of low bone mineral density (Level Ia). Thus, for a given bone mineral density, the risk of fracture is higher in glucocorticoid-induced osteoporosis than in postmenopausal osteoporosis.
  • Individuals at high risk, for example those aged 65 years or over and those with a prior fragility fracture, should be advised to commence bone-protective therapy at the time of starting glucocorticoids (Grade A).
  • In other subjects receiving oral prednisolone, in whom it is intended to continue therapy for at least 3 months, bone densitometry should be considered (Grade C). A T score of –1.5 or lower may indicate the need for intervention with a bone-sparing agent (Level IV), although the effect of age on fracture probability in an individual should be taken into account when making treatment decisions (Grade C).
  • Measurement of bone mineral density using dual energy X-ray absorptiometry is recommended for assessment of fracture risk in individuals treated with glucocorticoids (Grade C). Other secondary causes of osteoporosis should be excluded in individuals with a prior fracture (Grade C).
  • General measures to reduce bone loss include reduction of the dose of glucocorticoids to a minimum, consideration of alternative formulations or routes of administration, and prescription of alternative immunosuppressive agents (Grade C). Good nutrition, an adequate dietary calcium intake and appropriate physical activity should be encouraged, and tobacco use and alcohol abuse avoided (Grade C).
  • Evidence for the efficacy of agents in the prevention and treatment of glucocorticoid osteoporosis varies but beneficial effects on bone mineral density in the spine and hip have been demonstrated for several interventions (see Table 1)(Level Ia). Fracture has not been a primary end-point of any studies of prevention or treatment of glucocorticoid-induced osteoporosis. Nevertheless, a reduction in vertebral fracture has been observed in post hoc or safety analyses of trials of etidronate, alendronate and risedronate (Level Ib).
  • The role of monitoring the effects of bone-protective agents in glucocorticoid-induced osteoporosis has not been established. However, significant treatment responses in some individuals may be detectable within one to two years by bone mineral density measurements in the spine (Level IV).

 

Figure 2: Management of glucocorticoid-induced osteoporosis in men and women

An important aspect of the algorithm is that it includes all individuals commencing oral glucocorticoid therapy who are expected to continue for a minimum of 3 months, regardless of the dose. This acknowledges the evidence for adverse skeletal effects at doses below 7.5mg prednisolone daily and the rapid onset of bone loss and increased fracture risk after starting glucocorticoids.

The guidelines are being widely disseminated to medical practitioners in primary and secondary care, and to health authorities and other organisations involved in health care policy to encourage the provision of adequate resources at national and local level.

An audit tool is currently being developed by the Clinical Effectiveness and Evaluation Unit at the Royal College of Physicians, which will focus on the management of individuals over 65 years of age.

Bone and Tooth Society of Great Britain, National Osteoporosis Society, Royal College of Physicians. Glucocorticoid-induced osteoporosis: guidelines for prevention and treatment. Copies are available, price £15, from the RCP publications department. Tel: 020 7935 1174 ext 254 or at www.rcplondon.ac.uk

References

  1. van Staa TP, Leufkens HGM, Abenhaim L et al. Use of oral corticosteroids in the United Kingdom. QJM 2000; 93: 105-11.
  2. van Staa T, Leufkens HGM, Abenhaim L et al. Use of oral corticosteroids and risk of fractures. J Bone Miner Res 2000; 15: 993-1000.
  3. Adachi JD, Bensen WG, Brown J et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 1997; 337: 382-7.
  4. Saag KG, Emkey R, Schnitzer TJ et al. Alendronate for the prevention and treatment of glucorticoid-induced osteoporosis. N Engl J Med 1998; 339: 292-9.
  5. Reid DM, Hughes RA, Laan RFJM et al. Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomised trial. J Bone Miner Res 2000; 15: 1006-13.
  6. Guideline Development Group for the Royal College of Physicians. Osteoporosis: clinical guidelines for prevention and treatment. London: Royal College of Physicians, 1999.
  7. Eastell R, Reid DM, Compston JE et al. A UK consensus group on management of glucocorticoid-induced osteoporosis: an update. J Intern Med 1998; 244: 271-92.
  8. van Staa T, Leufkens HGM, Cooper C. Use of inhaled corticosteroids and risk of fractures. J Bone Miner Res 2001; 16: 581-8.
  9. Johnell O, de Laet C, Johansson H et al. Oral corticosteroids increase fracture risk independently of BMD. Osteoporos Int 2002; 13 (suppl 1): S14.

 

 

 

Guidelines in Practice, June 2003, Volume 6(6)
© 2003 MGP Ltd
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