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The prevention of glucocorticoid‐induced osteoporosis in patients with immune thrombocytopenia receiving steroids: a British Society for Haematology Good Practice Paper

2019; Wiley; Volume: 185; Issue: 3 Linguagem: Inglês

10.1111/bjh.15735

1365-2141

Quentin A. Hill, John D. Grainger, Jecko Thachil, Drew Provan, Gillian Evans, Mamta Garg, Charlotte Bradbury, Catherine Bagot, John А. Kanis, Juliet Compston,

Bone health and treatments

This Good Practice Paper was compiled according to the British Society for Haematology (BSH) process at http://www.b-s-h.org.uk/guidelines/proposing-and-writing-a-new-bsh-guideline/. The BSH produces Good Practice Papers to recommend good practice in areas where there is a limited evidence base but for which a degree of consensus or uniformity is likely to be beneficial to patient care. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. A search for English language literature on glucocorticoid-induced osteoporosis in patients with immune thrombocytopenia (ITP) from 1960 to 2017 was carried out on 21 November 2017. Ovid Medline, Embase and the Cochrane database of systematic reviews were searched. Details of the search and a summary table of the main findings can be found in Appendix S1 and Table SI. Review of the manuscript was performed by members of the UK ITP Forum, the Committee of Scientific Advisors of the International Osteoporosis Foundation, the BSH Guidelines Committee General Haematology Task Force, the BSH Guidelines Committee and the General Haematology Sounding Board of BSH. It was also placed on the members section of the BSH website for comment. The manuscript has also been reviewed by The ITP Support Association, although this organisation does not necessarily approve or endorse the contents. Glucocorticoids are a standard first line treatment for immune thrombocytopenia (ITP) and are an important risk factor for osteoporosis. Glucocorticoids act directly to suppress bone formation by inhibiting osteoblast function and triggering osteoblast (and osteocyte) apoptosis. They also act indirectly by inhibiting intestinal calcium absorption and reducing gonadal hormones. Despite this, current ITP guidelines (Provan et al, 2010; Neunert et al, 2011) have not addressed the need to identify patients at high risk of fragility fracture, who would benefit from bone-protective treatment. However, recent guidelines for the prevention and treatment of osteoporosis give recommendations for patients receiving glucocorticoids, irrespective of the underlying diagnosis (Buckley et al, 2017; Compston et al, 2017) and have been based on systematic review of the literature. In this Good Practice Paper, we conduct a systematic review of the literature on osteoporosis in patients with ITP receiving glucocorticoids, assess the applicability of current guidelines on the prevention of glucocorticoid-induced osteoporosis (GIOP) to the treatment regimens used for patients with ITP and make treatment recommendations. Fragility fractures, particularly vertebral fractures, occur in up to 30–50% of adults receiving long term glucocorticoids (Rizzoli et al, 2012). Loss of bone mineral density (BMD) is most rapid in the first 3–6 months but continues to decline at a slower rate with continued use (Buckley et al, 2017). This is associated with an increased fracture risk. A meta-regression analysis of randomised controlled trials found that the annual incidence of vertebral fracture was 5·1% in patients who had commenced oral glucocorticoids ≤6 months previously vs. 3·2% if commenced >6 months ago (Amiche et al, 2016). Loss of BMD appears partially reversible after withdrawal of glucocorticoids and withdrawal leads to a reduction in fracture risk (Rizzoli et al, 2012) although a residual increased risk persists (Kanis et al, 2004). Fracture in patients receiving glucocorticoids is not solely dependent on bone loss (Kanis et al, 2004) and fractures occur at higher BMD compared to postmenopausal osteoporosis (Canalis et al, 2007). Fracture risk rises with age, and with higher cumulative and daily dose of glucocorticoids. Additional clinical risk factors for fracture that are independent of BMD are listed in Table 1 (Compston et al, 2017). A UK evidence-based guideline for osteoporosis prevention has recently been published by the National Osteoporosis Guideline Group (NOGG) (Compston et al, 2017). The guideline includes the management of patients receiving oral glucocorticoids with an anticipated duration of ≥3 months and some key conclusions are summarised in Table 2, although clinicians should refer to the original guideline for full details. The input of a specialist in the care of osteoporosis may be helpful for complex cases. The management of children and adults aged <40 years was not addressed in detail in the UK NOGG osteoporosis guideline (Compston et al, 2017). Although fracture risk is lower in pre-menopausal women and men aged <50 years, this risk can still be significant in some individuals, for example, the 10-year fracture risk has been estimated at 5–20% in pre-menopausal women aged ≥30 years receiving very high doses of glucocorticoids (Buckley et al, 2017). Other risk factors identified in pre-menopausal women include prior fragility fracture, low BMD, family history of osteoporosis, low body mass index or low weight, age, age at menarche, major depression and alcohol intake (Horowitz et al, 1988; Honkanen et al, 1997; Blum et al, 2001; Cohen et al, 2009; Sugiyama et al, 2010; Lekamwasam et al, 2012). Recent American guidelines concluded that BMD testing should be considered in adults aged <40 years at treatment onset if there were additional risk factors, and bone protective therapy considered in adults aged <40 years if: (1) prior fragility fracture, (2) receiving ≥7·5 mg prednisolone daily with a Z-score <−3 at hip or spine, or 10% or more BMD loss/year at hip or spine, or (3) aged ≥30 years receiving ≥30 mg prednisolone daily with a cumulative dose >5 g in the last year (Buckley et al, 2017). For patients aged 40–90 years, clinical risk factors (with or without a BMD measurement) can be entered into a validated algorithm (FRAX®), available on-line at www.sheffield.ac.uk/FRAX/tool.jsp, that calculates the 10-year probability of hip fracture or major osteoporotic fracture (i.e. clinical fracture at the spine, distal forearm, humerus or hip). Having calculated the fracture risk on-line, a link is provided to guidance from the NOGG, based on UK intervention thresholds for treatment, that is adjusted for glucocorticoid dose (see Table SII). High risk patients should be considered for bone-protective treatment. Patients at low risk can be reassured and provided with lifestyle advice. BMD assessment is recommended for those with intermediate risk and the result entered into the FRAX tool to determine the need for treatment. Because the intervention threshold is generally exceeded, bone protective treatment can be considered in (1) men or women aged ≥70 years and (2) men aged ≥50 years or post-menopausal women with a prior fragility fracture or taking a high dose of glucocorticoids (≥7·5 mg prednisolone), without further risk assessment (Compston et al, 2017). Interventions for patients at risk of GIOP include lifestyle measures, optimizing calcium and vitamin D intake, and bone protective therapy. The evidence base for lifestyle measures in adults (Table 2) is based on smoking and greater alcohol intake being risk factors for osteoporosis (Kanis et al, 2005a,b) and weight-bearing exercise having a beneficial effect on BMD (Howe et al, 2011), rather than evidence that these measures will prevent fractures. Two meta-analyses demonstrated that, for patients receiving glucocorticoids, the combination of calcium and vitamin D supplements was more effective in preserving BMD than calcium alone or no therapy (Amin et al, 1999; Homik et al, 2000). Bisphosphonates (e.g. alendronate, risedronate or zoledronic acid), denosumab and teriparatide (recombinant human parathyroid hormone) have been shown to reduce fractures in post-menopausal women with osteoporosis (Black et al, 1996, 2007; Reginster et al, 2000; Neer et al, 2001; Saag et al, 2018) and are licenced for the prevention of GIOP in adults, based on evidence of effectiveness in BMD bridging studies (Saag et al, 1998, 2009; Wallach et al, 2000; Reid et al, 2009) and, in the case of bisphosphonates and teriparatide, prevention of vertebral ± non-vertebral fractures (Thomas et al, 2013; Overman et al, 2015; Amiche et al, 2017). Treatment with bisphosphonates has also been shown to preserve bone density in pre-menopausal women whilst data in men aged 1000 mg/kg vs. 0/19 receiving a cumulative dose <1000 mg/kg (Yildirim et al, 2008). Different regimens appeared to vary in their impact on BMD, but data were insufficient to draw conclusions. In the adult study the average total (prednisolone equivalent) dose received was 5233 ± 3541 mg, 7/18 (39%) patients had osteoporosis, and a significant negative correlation was found between BMD and both total and mean daily steroid dose (Nomura et al, 2010). The same study reported on BMD in 32 patients with low bone mass, before and after treatment with the bisphosphonate alendronate, and demonstrated a significant increase after 6 and 12 months. There is no mechanistic reason why the impact of glucocorticoids on BMD should be different in patients with ITP, as compared to patients with other disorders. The studies reviewed support this. General guidelines for osteoporosis prevention are applicable to patients with ITP (1C). Although an arbitrary cut-off, some studies have found that fracture risk is not significantly elevated in patients receiving oral glucocorticoids for 1 g. The highest vertebral fracture risk (relative risk 14·4) was with a daily dose ≥30 mg and cumulative dose >5 g (De Vries et al, 2007). A second population-based study also found that in patients aged ≥18 years receiving a cumulative dose <1 g, the risk of major osteoporotic fracture was not increased (Oshagbemi et al, 2017). Glucocorticoids are currently a first line treatment for ITP but relapsing patients may receive repeated courses, either as rescue therapy, in combination with other treatments, or as low dose maintenance therapy in selected refractory cases (Provan et al, 2010; Neunert et al, 2011; Cuker & Neunert, 2016; Cooper, 2017). Newer therapeutic agents for ITP, such as thrombopoietin receptor agonists (TPO-RA), have reduced, but not eliminated, the need for longer term glucocorticoids and in an open label extension study of the TPO-RA romiplostim, glucocorticoids were required in 35% of patients during weeks 1–24, and 20% during weeks 121–144 (Michel et al, 2011). Initial treatment is with oral prednisolone 1 mg/kg for between 4 days and 4 weeks followed by a taper over 4–6 weeks (Provan et al, 2010; Neunert et al, 2011; Wei et al, 2016; Cooper, 2017), or with dexamethasone 40 mg daily for 4 days every 2–4 weeks for 1–4 cycles (Provan et al, 2010; Wei et al, 2016). The cumulative dose for typical first line adult regimens is therefore approximately 1–2 g (Table 3). Hence the daily and cumulative doses are high, but the duration is slightly shorter than that covered by standard guidelines for glucocorticoid-induced osteoporosis. In children requiring treatment for ITP, glucocorticoids are often used first line. However paediatric regimens are usually shorter, for example, prednisolone 3–4 mg/kg/day for 4 days, or prednisolone 2 mg/kg for 14 days then stopped or tapered over a further 21 days (Provan et al, 2010; Neunert et al, 2011) (Table 3). As shown above, some children subsequently receive multiple glucocorticoid courses that result in reduced BMD. The recommendations below are based on recent UK NOGG guidelines for the prevention and treatment of osteoporosis (Compston et al, 2017), which are accredited by the National Institute of Health and Care Excellence (NICE). However, they have been further adapted to consider the typical dose and duration of steroids used for ITP patients. All authors were involved in the formulation and writing of the manuscript, as well as approval of its final version. The BSH general task force members at the time of writing this good practice paper were Charlotte Bradbury and Mamta Garg. The authors would like to thank them, the BSH sounding board and the BSH guidelines committee for their support in preparing this Good Practice Paper. We would also like to thank Mrs Shirley Watson for her review and comments on behalf of the UK ITP Support Association. Finally, we would like to thank the Committee of Scientific Advisors of the International Osteoporosis Foundation for their review and endorsement of this Good Practice Paper. No expenses were incurred during the writing of this Good Practice Paper. All authors have made a declaration of interests to the BSH and Task Force Chairs which may be viewed on request. QAH is secretary of the UK ITP Forum and has received honoraria from Novartis and Shire. JDG has received honoraria from Novartis, Amgen, Ono Pharmaceuticals and Biotest. JT has received honoraria from Novartis and Amgen. CaB has received speaker fees from Novartis and Amgen. DP has received honoraria from Novartis and Amgen, and research support from Novartis, Amgen and the UK ITP Support Association. JAK reports grants from Amgen, Lilly, Radius Health and UCB. JAK is a member of the National Osteoporosis Guideline Group (NOGG) and the principal architect of FRAX® but derives no financial benefit. JC is chair of the NOGG. The following members of the writing group have no conflicts of interest to declare: ChB, MG, GE. Members of the writing group will inform the writing group Chair if any new pertinent evidence becomes available that would alter the strength of the recommendations made in this document or render it obsolete. The document will be archived and removed from the BSH current guidelines website if it becomes obsolete. If new recommendations are made an addendum will be published on the BSH guidelines website ( www.b-s-h.org.uk/guidelines/). While the advice and information in this guidance is believed to be true and accurate at the time of going to press, neither the authors, the BSH nor the publishers accept any legal responsibility for the content of this guidance. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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