Opinions on the value of glucocorticoids (GCs) have fluctuated between euphoric acceptance and outright rejection. This ambivalence of opinion arose because of their important clinical effects on one hand, and the potential risks of these substances on the other hand. It seems, however, that these important drugs have now found their correct place in rheumatology (and other special areas in medicine). The current view on these drugs is: They are indispensable; however when they are used, they should be administered as much as necessary, but as little as possible.
Without any doubt, GCs at higher dosages are needed to terminate flares and/or to reduce the activity of rheumatic diseases. But this “emergency” usage represents only one option for successfully administering these drugs since many patients are more or less continuously treated with what is called “maintenance therapy”. However, the crucial current question is: how long should we aim at using concomitant GC therapy in RA? There are virtually three scenarios: (1) GCs could/should be used as bridging therapy only, i.e. as an initial short term treatment followed by tapering off as rapidly as clinically feasible. This procedure represents the current recommendation; (2) GCs at low dosages could/should be used for at least two years (a “long-bridge” therapy) because of their beneficial effects; (3) The third scenario would be to administer GCs at very low dosages in many RA patients concomitantly as a maintenance therapy, assuming that this approach improves the overall benefit risk ratio. The answer to this question is open since for the time being we do not have enough scientifically sound data.
Also with regard to glucocorticoid effects on bone, we need to understand better the full picture describing the benefit risk ratio. What we actually know is the existence of a “magical triangle” or the “Janus-head-like behaviour of glucocorticoids”: Accelerated bone loss in RA includes radiological periarticular osteoporosis and joint erosions. GCs at low dosages have been shown to reduce the rate of radiographic progression of the disease and the extent of disease-related periarticular osteoporosis. However, prolonged GC therapy per se does result in rapid and profound reductions in bone mineral density (especially within the first months of treatment).
In greater detail: GC excess decreases osteoclastogenesis, but does also lead to early, transient increases in osteoclast survival, cancellous osteoclasts and bone resorption. At the same time, GC decrease osteoblastogenesis, increase apoptosis of osteoblasts, and lead to both early and continual decreases in osteoblast numbers, synthetic ability of osteoblasts and, consequently, bone formation. Glucocorticoids also increase apoptosis of osteocytes which results in compromised canalicular circulation and, therefore, decreased bone quality. Together with unwanted effects on calcium and phosphate uptake (reduced), PTH secretion (increased) and calcitonin levels (reduced), this finally leads to osteoporosis.
The other side of the coin, however, is that in rheumatoid arthritis (among other mechanisms) proinflammatory cytokines such as TNFalpha and IL-1 induce T cells and osteoblasts to secrete RANKL. RANKL ligand binds to RANK receptors sitting both on osteoclast precursor cells and on mature osteoclasts. This interaction leads to facilitated maturation of osteoclast precursor cells into mature osteoblasts, more aggressive osteoblasts, and, finally, to induced bone resorption. Clinical signs of these underlying mechanisms comprise joint erosions and periarticular osteoporosis. Glucocorticoids interfere with these mechanisms by reducing the synthesis of both proinflammatory cytokines and inflammation. As a consequence, it has been convincingly shown that glucocorticoids are capable of reducing the radiographic progression of the disease and that they can diminish inflammatory periarticular demineralisation.
In conclusion, it is still a matter of debate how to disentangle unwanted consequences of the disease RA itself and/or its treatment with GC. This is true for bon, but also for glucose metabolism and the cardiovascular system. Nevertheless, the question how harmful long-term GCs are with regard to their capability to induce osteoporosis in RA patients needs further assessment in well-designed, longitudinal, randomised trials.
Disclosure of Interest F. Buttgereit Grant/Research support from: Horizon, Consultant for: Horizon, Mundipharma, Pfizer, Conflict with: Horizon, Mundipharma