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      Optimising both disease control and glucocorticoid dosing is essential for bone protection in patients with rheumatic disease

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          Abstract

          Objectives

          Inflammatory rheumatic and musculoskeletal diseases (iRMDs) are associated with increased systemic bone loss that is mediated by chronic inflammation, treatment with glucocorticoids (GCs) and other factors. Our objective was to analyse the impact of variables that influence osteoporosis (OP) in patients with iRMD treated with GC.

          Methods

          Rh-GIOP (acronyme) is a prospective observational cohort study investigating bone health in consecutive patients with iRMD and current or prior GC treatment. We present an analysis of the patients’ baseline data here. Bone mineral density (BMD) measured by dual X-ray absorptiometry was the primary outcome. Multivariable linear regression models were performed to identify variables associated with BMD.

          Results

          Data from 1066 patients with iRMD were analysed. GC doses of <5 mg prednisone equivalent per day, cumulative dose and duration of GC therapy were not associated with negative effects on BMD. Dosages of ≥5 mg/day lost their negative association with BMD after adjustment for confounders. When subanalysing patients with exactly 5 mg/day, no negative effect was seen. For patients with rheumatoid arthritis (RA), GC doses of >7.5 mg/day showed a negative association with BMD overall, but this effect seemed to be specific only to patients with moderate or high disease activity (Disease Activity Score 28–C reactive protein >3.2).

          Conclusions

          GCs of ≤5 mg/day did not seem to be associated with a reduction of BMD in patients with iRMD and current or prior exposure to GC. This is most likely due to the dampening of inflammation by GC, which exerts a mitigating effect on the risk of OP. In RA, current GC doses of >7.5 mg/day were negatively associated with BMD, but only in patients with moderate to high disease activity.

          Trial registration number

          NCT02719314.

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          Most cited references44

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          Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies.

          Anticitrullinated protein antibodies (ACPA) are a major risk factor for bone loss in rheumatoid arthritis (RA). We have recently shown that ACPA directly induce bone loss by stimulating osteoclast differentiation. As ACPA precede the clinical onset of RA by years, we hypothesised that ACPA positive healthy individuals may already show skeletal changes.
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            The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis.

            Studies of oral corticosteroid dose and loss of bone mineral density have reported inconsistent results. In this meta-analysis, we used information from 66 papers on bone density and 23 papers on fractures to examine the effects of oral corticosteroids on bone mineral density and risk of fracture. Strong correlations were found between cumulative dose and loss of bone mineral density and between daily dose and risk of fracture. The risk of fracture was found to increase rapidly after the start of oral corticosteroid therapy (within 3 to 6 months) and decrease after stopping therapy. The risk remained independent of underlying disease, age and gender. We conclude that oral corticosteroid treatment using more than 5 mg (of prednisolone or equivalent) daily leads to a reduction in bone mineral density and a rapid increase in the risk of fracture during the treatment period. Early use of preventive measures against corticosteroid-induced osteoporosis is recommended.
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              A Meta-Analysis of Trabecular Bone Score in Fracture Risk Prediction and Its Relationship to FRAX

              Trabecular bone score (TBS) is a gray-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a bone mineral density (BMD)-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual-level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables, and outcomes during follow-up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities, and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% confidence interval [CI] 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR = 1.32, 95% CI 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65-1.87 versus 1.70, 95% CI 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. © 2015 American Society for Bone and Mineral Research.
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                Author and article information

                Journal
                Ann Rheum Dis
                Ann Rheum Dis
                annrheumdis
                ard
                Annals of the Rheumatic Diseases
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0003-4967
                1468-2060
                September 2022
                9 June 2022
                : 81
                : 9
                : 1313-1322
                Affiliations
                [1 ] departmentDepartment of Rheumatology and Clinical Immunology , Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health , Berlin, Germany
                [2 ] departmentInstitute of Biometry and Clinical Epidemiology , Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health , Berlin, Germany
                [3 ] departmentDepartment of Dermatology, Venerology and Allergology , Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health , Berlin, Berlin, Germany
                [4 ] departmentInstitute of Allergology, Charité , Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health , Berlin, Berlin, Germany
                [5 ] departmentCenter for Musculoskeletal Surgery , Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health , Berlin, Germany
                [6 ] departmentEpidemiology and Data Science , Amsterdam UMC, Vrije Universiteit , Amsterdam, Netherlands
                [7 ] departmentVasculitis and Glomerulonephritis Center, Rheumatology, Immunology and Allergy Division , Massachusetts General Hospital, Harvard Medical School , Boston, Massachusetts, USA
                [8 ] departmentRheumatology , Medical University of Graz , Graz, Austria
                [9 ] departmentRheumatology , Brunico Hospital (SABES-ASDAA) , Brunico, Italy
                Author notes
                [Correspondence to ] Professor Frank Buttgereit, Department of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; frank.buttgereit@ 123456charite.de
                Author information
                http://orcid.org/0000-0002-0434-7832
                http://orcid.org/0000-0001-7518-1131
                http://orcid.org/0000-0002-6969-283X
                http://orcid.org/0000-0001-6588-9435
                http://orcid.org/0000-0002-0173-0668
                http://orcid.org/0000-0003-2534-550X
                Article
                annrheumdis-2022-222339
                10.1136/annrheumdis-2022-222339
                9380479
                35680387
                42e34406-d326-4480-a158-aac9d4cb7360
                © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 11 February 2022
                : 08 May 2022
                Funding
                Funded by: Glaxo SmithKline;
                Award ID: n/a
                Funded by: FundRef http://dx.doi.org/10.13039/100002491, Bristol-Myers Squibb;
                Award ID: n/a
                Funded by: Mundipharma Germany;
                Award ID: n/a
                Funded by: FundRef http://dx.doi.org/10.13039/100002429, Amgen;
                Award ID: n/a
                Funded by: FundRef http://dx.doi.org/10.13039/501100014756, Hexal AG;
                Award ID: n/a
                Funded by: Horizon Therapeutics, Lilly, Medac;
                Award ID: n/a
                Funded by: FundRef http://dx.doi.org/10.13039/100004337, Roche;
                Award ID: n/a
                Funded by: Generic Assays;
                Award ID: n/a
                Funded by: FundRef http://dx.doi.org/10.13039/100004319, Pfizer;
                Award ID: n/a
                Funded by: Chugai;
                Award ID: n/a
                Funded by: FundRef http://dx.doi.org/10.13039/100004336, Novartis;
                Award ID: n/a
                Funded by: Sanofi-Genzyme;
                Award ID: n/a
                Funded by: FundRef http://dx.doi.org/10.13039/100005614, Biogen;
                Award ID: n/a
                Categories
                Osteoporosis
                2311
                2498

                Immunology
                glucocorticoids,osteoporosis,outcome assessment, health care,arthritis, rheumatoid
                Immunology
                glucocorticoids, osteoporosis, outcome assessment, health care, arthritis, rheumatoid

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