Risk from low-dose steroids challenged

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Surprising results from a large study into glucocorticoid-induced osteoporosis have got rheumos talking.

A research team in Germany looking into glucocorticoid-induced osteoporosis in rheumatic disease patients has found that current use of low-dose glucocorticoids did not appear to be associated with a loss of bone mass density (BMD).

Higher doses were also not associated with BMD after adjustment, nor was cumulative dose and duration of glucocorticoid therapy.

The findings, published in the Annals of the Rheumatic Diseases, are based on an ongoing single-centre cohort study investigating disease-related and bone-related data in patients with inflammatory rheumatic and musculoskeletal diseases with current or prior use of glucocorticoids.

Data collection started in 2015 and the current analysis covers five years of data. Just over 1000 patients were included, comprising RA, connective tissue diseases, vasculitides and spondyloarthritides.

Almost half the patients (49%) had osteopenia at baseline, 22% had osteoporosis and 31% had fragility fractures. The authors noted in the study limitations that BMD alone might not account for the increased rate of fractures seen in patients treated with glucocorticoids. Bone quality wasn’t measured.

Age, male sex, menopause and health assessment question score were negatively associated with BMD T-scores. Conventional, biological or targeted synthetic DMARD use was not associated with BMD.

There were no differences between T-scores of patients on glucocorticoid doses of <5mg/day and zero. They also found that higher doses of glucocorticoids (≥ 5mg per day) lost their effect on BMD after adjusting to include only significant variables for the respective score.

In a sub-analysis of RA patients taking >7.5mg per day, a negative effect was found only in patients with moderate or high disease activity (DAS 28-CRP >3.2).

Meanwhile, a sub-analysis of patients from the cohort with polymyalgia rheumatica, giant cell arteritis and other vasculitides, presented in poster 1139 at EULAR 2022, also reported no association between glucocorticoid use and BMD minimum T-scores.


Results interesting, but “need to be interpreted with caution”

While the findings have surprised some in the rheumatology community, the opportunity to open the conversation about low dose steroids in the treatment of rheumatic diseases has been welcomed.

Dr Queenie Luu, a Sydney rheumatologist with special interest and expertise in osteoporosis, found the study interesting but cautioned that causal relationships can’t be drawn from a cross-sectional study.

Dr Luu also pointed out that the primary outcome was bone mineral density, which is a surrogate for fracture risk.

“Risk of fracture is what we, as clinicians, and patients are most interested in. In my opinion, the results will need to be interpreted with caution as fractures occur in patients on corticosteroids in the presence of higher bone density than in patients with involutional osteoporosis.”

Rheumatologist Dr John Van Der Kallen told Rheumatology Republic he was surprised that the higher doses of glucocorticoids were not associated with worse bone density scores, as measured by DEXA in the spine and femur, unless it was also associated with moderate or high disease activity.

“It appears that it is the disease activity rather than the glucocorticoids per se that is the problem. Obviously, there are confounders: RA patients with high disease activity are also likely to have glucocorticoids, and high disease activity is known to effect bone density as well,” said Dr Van Der Kallen.

“However,” he added, “it is interesting to see that RA patients on prednisone 5 mg daily, with any level of disease activity, did not have a significant change in bone density.”

Dr Van Der Kallen said it was reassuring that low-dose prednisone, biologics or other DMARDs were not associated with a decline in BMD.

“The study highlights the importance of controlling disease activity for maintaining bone health and is re-assuring regarding the use of disease modifying therapy and its impact on bone health.”

Bone effects of GCs offset by reduced inflammation

The University of Sydney’s Professor Mark Cooper, an expert on the effects of endogenous and therapeutic glucocorticoids on bone, wasn’t surprised by the findings. He pointed to the role of glucocorticoids in better controlling disease, leading to reduced inflammation – which itself is associated with negative effects on bone health.

“It has long been debated whether bone damage in patients with systemic disease that need steroids is due to the inflammation or the steroids needed,” Professor Cooper told Rheumatology Republic.

“Uncontrolled inflammation is very destructive to bone health and if inflammation can be effectively switched off with steroids this might prevent these adverse effects.”

He pointed out that it wasn’t so long ago that the choice of anti-inflammatory medications was limited, and glucocorticoids were used in higher doses to try to suppress inflammation.

“This approach had limited effectiveness in suppressing inflammation and so there was the dangerous combination of persistent inflammation and high doses of glucocorticoids, and this was clearly bad for bones.”

However, he says, the situation today is very different.

“The current study was done at a highly regarded academic centre and patients were treated with a range of other powerful anti-inflammatory medications and/or DMARDs, and thus glucocorticoids are used in a different way – for example, to provide some short-term bridging therapy or to amplify the effects of other medications,” said Professor Cooper.

Practice implications

The authors concluded that glucocorticoids in doses optimised for disease control, in conjunction with appropriate anti-osteoporosis measures, are likely to be safe for bone health. They also suggested glucocorticoid-associated osteoporosis might be a better term than glucocorticoid-induced osteoporosis.

Dr Luu supported the broader practice implications of the study.

“I agree with the authors that frequent review of the corticosteroid dose is important to optimise the dose of corticosteroids so that it is the lowest dose needed to control the inflammatory disease for that patient at that point in time,” said Dr Luu.

Ann Rheum Dis 2022, online 8 June

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