Assessment and management of glucocorticoid-induced osteoporosis

Transcription

1 PRESCRIBING IN PRACTICE n Assessment and management of glucocorticoid-induced osteoporosis Gerald Tracey and Tehseen Ahmed Glucocorticoid-induced osteoporosis (GIO) is the most prevalent form of secondary osteoporosis; however, many patients taking glucocorticoids are still missing out on fracture risk assessments and boneprotection therapy. This article describes the clinical features, assessment and recommended management of GIO. In 1932, Harvey Cushing wrote: The greatly compressed bodies of the vertebrae... were so soft they could easily be cut with a knife. 1 He was, of course, describing the bones of a patient suffering from a condition that was later to be termed Cushing s syndrome, a state of hypercortisolism. Today, we more commonly encounter iatrogenic cases of hypercortisolism due to the widespread use of glucocorticoids. Glucocorticoid therapy is associated with many adverse effects including loss of bone density and increased fracture risk. In fact, glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis. 2 At any one time, approximately 1 per cent of the adult population in the UK is taking oral glucocorticoids; this figure increases to 2.4 per cent in individuals aged years. 3 Pathophysiology Bone loss in GIO is biphasic. 4 The most rapid bone loss occurs in the first 6-12 months of glucocorticoid therapy. Bone loss then slows but continues at a rate Figure 1. Glucocorticoid-induced thoracic vertebral fractures faster than that seen with rmal ageing. 5 Glucocorticoids affect both cortical and trabecular bone although effects on trabecular bone predominate. In the early phase of GIO, bone resorption is increased while bone formation is reduced. Glucocorticoids have indirect effects on osteoclasts, leading to enhanced osteoclast differentiation and osteoclastogenesis. 6 Simultaneously, glucocorticoids exhibit both direct and indirect effects on osteoblasts, resulting in inhibition of osteoblast proliferation and differentiation, as well as increased apoptosis of osteoblasts. 7 With long-term use of glucocorticoids, osteoclast production is diminished but osteoclast survival is enhanced. Bone formation remains suppressed. This leads to an ongoing reduction in bone density. 8 In addition, glucocorticoids negatively affect bone via decreased calcium Prescriber 19 November 2015 z 31

2 n PRESCRIBING IN PRACTICE l Glucocorticoid osteoporosis absorption in the gastrointestinal tract, increased renal calcium loss, and reduced levels of sex hormones. Glucocorticoids and fractures The net result of glucocorticoid-induced effects on bone is loss of bone mass (up to 10 per cent in the first year) leading to subsequent increase in fracture risk. 6 Fracture risk is significantly elevated even in the first few months of therapy and fractures may occur in greater than 30 per cent of patients receiving chronic glucocorticoid therapy. 9 Fracture risk is increased for all osteoporotic fracture types and in all age groups, but fractures are more commonly seen in areas with higher proportions of trabecular bone such as the spine. 10 However, the increased fracture risk is unlikely to be the result of reduced bone density alone. There is an increased incidence of fracture for a given bone mineral density in GIO compared with postmepausal osteoporosis, suggesting that bone quality is also an issue. This may, in part, be explained by glucocorticoid-induced apoptosis of osteocytes, which are thought to play an important role in determining bone strength. 7 A large retrospective cohort study found that the relative rate of nvertebral fracture in glucocorticoid users vs nuser controls was 1.33 (95 per cent confidence intervals [CI] ), that Older age Prior history of fragility fracture Family history of osteoporosis Smoking Alcohol intake 3 units per day Low BMI Immobility Low vitamin D levels Low dietary calcium intake Hypogonadal states Malabsorption disorders Endocrine disorders, eg hyperthyroidism, diabetes, Cushing s disease, hyperparathyroidism Systemic inflammatory diseases Higher daily glucocorticoid dosages Higher cumulative glucocorticoid dosages Other medications, eg aromatase inhibitors, androgen deprivation therapy Table 1. Risk factors for compromised bone health of hip fracture 1.61 (CI ), that of forearm fracture 1.09 (CI ), and that of vertebral fracture 2.60 (CI ). 11 There does t appear to be a safe dosage of glucocorticoids in relation to fracture risk. Even dosages of prednisolone less than 2.5mg daily carry an increased risk of vertebral fractures. However, there is evidence of a dosedependent relationship between chronic glucocorticoid use and fracture risk. The increased fracture risk rapidly declines after discontinuation of gluco - corticoids. 11 Clinical features In the absence of fracture, there are particular symptoms to alert a patient to the detrimental effects of glucocorticoid on bone. Once fractures begin to occur, the symptoms and signs are the same as for any patient with osteoporosis. Vertebral fractures, in particular, are very common (see Figure 1). They can occur early after initiation of glucocorticoid therapy and can arise without any preceding trauma. New-onset acute back pain may indicate that a fracture has occurred and warrants further investigation. Some patients will be aware of height loss and a change in posture. Again, this should alert clinicians to consider investigation to exclude vertebral fracture. Finally, a significant proportion of patients will be asymptomatic and fractures may be identified as an incidental finding on imaging studies. These patients remain at high risk of further fracture and management should be similar to patients who present with symptomatic fractures. Which patient groups are most susceptible? All patients receiving medium- to longterm systemic glucocorticoids (and those receiving frequent short courses of glucocorticoids) should be considered to be at increased risk of fracture. However, those receiving higher dosages are more at risk. Also, patients with pre-existing co-morbidities and traditional risk factors associated with poor bone health will be at greater risk of fracture (see Table 1). The effects of inhaled glucocorticoids on bone health are less certain. An increased risk of fracture has t been definitively established. Assessment An assessment of bone health should be conducted in all patients already receiving or starting systemic glucocorticoid therapy. Other risk factors and co-morbidities that may lead to compromised bone health should be sought in the history. Laboratory investigations that should be considered include serum calcium profile and serum creatinine and electrolytes. Occasionally vitamin D testing is indicated, although for most patients a clinical evaluation to determine the likelihood of vitamin D deficiency/insufficiency should be adequate to inform management. Fracture risk can be estimated using web-based tools such as FRAX ( or QFracture ( Measurement of bone density using dual energy X-ray absorptiometry (DXA) scanning can help to refine fracture risk and can be incorporated into the FRAX calculation. Vertebral fracture assessment (VFA) can be performed at the same time as DXA scanning and involves only a small fraction of the radiation dose received with conventional spinal X-rays. Who to treat? The decision to commence bone protective therapy should be based on an assessment of fracture risk. However, the optimal risk at which intervention is indicated is t universally defined. Pragmatically, individuals at high risk should be advised to commence boneprotective therapy at the time of starting glucocorticoids, eg those aged 65 years or over and those with a prior fragility fracture (see Figure 2). 12 In other patients receiving systemic glucocorticoids, in whom it is intended to continue therapy for at least three months, DXA scanning should be considered. A T score of 1.5 may indicate the need for intervention with a bone-sparing agent, although the effect of age on fracture probability should be taken into account. 12 Alternatively, clinicians may refer to the National Osteoporosis Guideline Group (NOGG) intervention thresholds, 32 z Prescriber 19 November 2015

3 Glucocorticoid osteoporosis l PRESCRIBING IN PRACTICE n Already taking or initiating systemic glucocorticoid therapy Equivalent of 5mg of daily prednisolone for 3 months of the year Reduce falls risk Previous fragility fracture, or incident fracture during glucocorticoid therapy 65 years old T score > -1.5 Reassure and lifestyle advice Consider repeat DXA scan in 1-3 years to assess rate of bone loss if glucocorticoids continued Reduce falls risk Consider antiresorptive treatment, ie alendronate or risedronate Zoledronic acid or teriparatide can be considered as secondline therapy Fracture risk assessment, eg FRAX and DXA scan T score -1.5 Treatment recommended by National Osteoporosis Guidelines Group or 10 year risk of major osteoporotic fracture 20% or hip fracture 5% Reassess fracture risk and bone protective therapy on cessation of glucocorticoids or at 5 years (whichever is earlier) Figure 2. Assessment and management of glucocorticoid-induced osteoporosis (adapted from the RCP guidelines, 2002) 12 which can be accessed when making a calculation of fracture risk using the FRAX tool. Management All patients taking glucocorticoids should receive general lifestyle advice to optimise bone health (see Table 2). It is imperative to reduce the risk of falls where applicable. The glucocorticoid dosage should be reduced where possible and consideration should be given to alternative routes of administration, eg inhaled, if clinically appropriate. In selected cases, steroid-sparing medications may be indicated. Calcium and vitamin D Calcium and vitamin D supplementation is important to help slow and/or prevent bone loss but there is evidence to support a significant reduction in fractures. 13 A recommended maintenance dose of vitamin D 3 is IU daily and patients should be advised to aim for a total daily calcium intake of mg. Bisphosphonates Alendronate and risedronate are considered first-line agents for the prevention and treatment of GIO. They t only prevent bone loss but can also increase bone density in patients taking gluco - corticoids. 14,15 More importantly, studies have shown a trend towards a reduced incidence of vertebral fracture. 14,15 Efficacy in reducing fracture at other sites is unproven. For those patients who are intolerant or have contraindications to oral bisphosphonates, intraveus bisphosphonates may be an option. Zoledronic acid is a licensed and evidence-based therapy for GIO. In a ninferiority trial between oral risedronate and intraveus zoledronic acid (5mg once yearly), zoledronic acid was superior in terms of increasing lumbar bone mineral density. This study was t powered to show a reduction in fracture incidence. 16 Teriparatide Teriparatide, a recombinant human parathyroid hormone given by subcutaneous injection, stimulates bone formation, increases bone mass, and reduces the risk of vertebral and nvertebral fractures in postmepausal osteoporosis. In the context of GIO, teriparatide has been proven to be superior to daily alendronate with significantly greater increases in bone mineral density and a Prescriber 19 November 2015 z 33

4 n PRESCRIBING IN PRACTICE l Glucocorticoid osteoporosis Reducing alcohol intake to less than three units daily Smoking cessation Regular weight-bearing exercise Optimising calcium intake (aim for mg daily) Safe sun exposure: minutes three times weekly - Between 11am-3pm - Late spring/summer/early autumn - Face and arms exposed Table 2. Lifestyle measures to optimise bone health significant reduction in vertebral fracture incidence. 17 Although licensed for use in GIO, the cost of teriparatide and requirement for daily injections prohibits the widespread use of this medication. In practice, it is reserved for high-risk patients who are unable to take, have a contraindication to, or have failed treatment with bisphosphonates. HRT HRT is w largely superseded by the bisphosphonates although for younger women who are hypogonadal there may be a role for replacement of oestrogen/ progesterone. 18 SERMs Twelve months of therapy with the selective estrogen receptor modulator (SERM) KEY POINTS raloxifene has been shown to modestly increase bone mineral density at the lumbar spine and total hip compared with placebo. 19 Raloxifene is t licensed for the treatment of GIO in the UK. Desumab Desumab is a human moclonal antibody to the receptor activator of nuclear factor kappa B ligand (RANKL) licensed for treatment of osteoporosis in postmepausal women and men at increased risk of fractures. It has a potent antiresorptive action and is administered subcutaneously every six months. A recent study revealed that patients who switched from oral bisphosphonates to desumab experienced an increase in spinal bone mineral density and a decrease in bone turver markers. 20 It is t currently licensed for GIO but may be initiated in specialist bone clinics if licensed alternatives are unsuitable. Duration of therapy There is little evidence on which to base decisions about the duration of bone protective therapy in GIO. Optimisation of calcium and vitamin D status should continue for the duration of glucocorticoid therapy. Some specialists also advise continuing bisphosphonates throughout glucocorticoid therapy. However, there are already concerns about adverse effects n Glucocorticoid-induced osteoporosis is the most prevalent form of secondary osteoporosis. Glucocorticoids are associated with loss of bone mineral density and are independently associated with increased fracture risk n The most rapid bone loss occurs early after glucocorticoid initiation and therefore all patients should undergo a fracture risk assessment at the commencement of treatment. n Clinicians should be aware of the limitations of fracture risk assessment tools, which do t fully account for glucocorticoid dosage, duration or mode of delivery. Lumbar spine bone mineral density, a common site for fractures in glucocorticoid-induced osteoporosis, is t assessed with the FRAX tool. Bone mineral density is t accounted for at all with QFracture n Alendronate, risedronate, zoledronic acid and teriparatide are all licensed for the prevention and treatment of glucocorticoid-induced osteoporosis in the UK n For patients over 65 years and/or those with a history of fragility fracture, bone protective treatment (calcium, vitamin D and an antiresorptive agent) can be considered without the need for a DXA scan of long-term bisphosphonates particularly with regard to osteonecrosis of the jaw and atypical femoral fractures. It is also recognised that glucocorticoid therapy itself is a risk factor for both of these adverse effects. We suggest that the role of ongoing bisphosphonate therapy should be reassessed after five years, as has been advocated in postmepausal osteoporosis. 21 In those patients who discontinue glucocorticoids before five years have elapsed, a reappraisal of fracture risk should be undertaken before making decisions about discontinuation of bone protective treatment. The GP s role in management Primary care teams play a central role in the assessment and management of bone health. Glucocorticoids are often initiated in primary care and patients on medium- to long-term glucocorticoid therapy can be readily identified. Initial risk assessment and commencement of bone protective therapy can be carried out in primary care settings. Oral bisphosphonates are well understood, including the benefits and risks of treatment, and GPs are good at identifying which patients may need to be referred to secondary care for consideration of other therapies. However, despite this, many patients are still missing out on fracture risk assessments and are t offered any bone protection therapy. 22 It is vital that good lines of communication and treatment pathways are established between primary and secondary care if we are to reduce the impact of GIO. Finally, adherence to bone protective therapy must be monitored at regular intervals in order to ensure optimal outcomes. References 1. Jehle PM. Steroid-induced osteoporosis: how can it be avoided? Nephrol Dial Transplant 2003;18: Weinstein RS. Clinical practice: Glucocorticoid-induced bone disease. N Engl J Med 2011;364: van Staa TP, et al. Use of oral corticosteroids in the United Kingdom. Q J Med 2000; 93(2); LoCascio V, et al. Bone loss in response to long-term glucocorticoid therapy. Bone Miner 34 z Prescriber 19 November 2015

5 Glucocorticoid osteoporosis l PRESCRIBING IN PRACTICE n 1990;8: Saito JK, et al. Users of low-dose glucocorticoids have increased bone loss rates: a longitudinal study. Calcif Tissue Int 1995; 57: Canalis E, et al. Perspectives on glucocorticoid-induced osteoporosis. Bone 2004; 34: Weinstein RS. Glucocorticoid-induced bone disease. In Rosen CJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism, 8th edn. John Wiley & Sons, 2013; Jia D, et al. Glucocorticoids act directly on osteoclasts to increase their lifespan and reduce bone density. Endocrilogy 2006;147: Angeli A, et al. High prevalence of asymptomatic vertebral fractures in post-mepausal women receiving chronic glucocorticoid therapy: A cross-sectional outpatient study. Bone 2006;39: Steinbuch M, et al. Oral glucocorticoid use is associated with an increased risk of fracture. Osteoporosis Int 2004;15: van Staa TP, et al. Use of oral corticosteroids and risk of fractures. J Bone Miner Res 2000;15(6): Bone and Tooth Society, National Osteoporosis Society, Royal College of Physicians. Glucocorticoid-induced osteoporosis: guidelines for prevention and treatment. London: RCP, Homik J, et al. Calcium and vitamin D for corticosteroid-induced osteoporosis. Cochrane Database Syst Rev 2000;Issue 2:CD Saag KG, et al, and the Glucocorticoid- Induced Osteoporosis Intervention Study Group. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. N Engl J Med 1998;339: Reid DM, et al. Efficacy and safety of daily risedronate in the treatment of corticosteroidinduced osteoporosis in men and women: a randomized trial. European Corticosteroid- Induced Osteoporosis Treatment Study. J Bone Miner Res 2000;15: Reid DM, et al. Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet 2009;373(9671): Saag KG, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 2007;357(20): Kung AW, et al. Osteopenia in young hypogonadal women with systemic lupus erythematosus receiving chronic steroid therapy: A randomized controlled trial comparing calcitriol and hormonal replacement therapy. Rheumatology 1999;38: Mok CC, et al. Raloxifene for prevention of glucocorticoid-induced bone loss: a 12-month randomised double-blinded placebo-controlled trial. Ann Rheum Dis 2011;70(5): Mok CC, et al. Switching of oral bisphosphonates to desumab in chronic glucocorticoid users: A 12-month randomized controlled trial. Bone 2015;75: National Osteoporosis Guidelines Group. Osteoporosis: Clinical guideline for prevention and treatment. November Guzman-Clark JR, et al. Barriers in the management of glucocorticoid-induced osteoporosis. Arthritis Rheum 2007;57(1); Further reading Grossman JM, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res 2010;62(11): Declaration of interests None to declare. Dr Tracey is a specialist registrar in rheumatology and Dr Ahmed is a consultant rheumatologist at the Royal National Hospital for Rheumatic Diseases, Royal United Hospitals Bath NHS Foundation Trust Visit Prescriber online at Prescriber.co.uk The Prescriber website provides an easy-to-use search function and visitors have free access to all articles published since In addition there are up-to-date news items, CPD, blogs, Ask Prescriber and diary dates. Visit us at Prescriber.co.uk www. Prescriber 19 November 2015 z 35