RA & Bone Loss

m.ard.bmj.com

While RA patients are at higher risk for Osteoporosis due to prolonged uncontrolled inflammation and steroid medication, there is also more pronounced bone loss around the inflamed joints. This, it seems, is autoimmune in pathogenesis, involving ACPA (anti-CCP) autoantibodies activating osteoclasts (bone resorption) though IL8.


Sclerostin, an inhibitor of the Wnt/β-catenin pathway, negatively regulates osteoblast differentiation and has anti-anabolic effects on bone…
rheumnow.com

Romosozumab, an anti-Sclerostin biologic, is poised to be the next big thing in Osteoporosis treatment, demonstrated in trials to match if not better Teriparatide as a bone former.
Unfortunately, and for reasons yet unclear, it appears to worsen joint inflammation and damage in animal models of RA.
A possible mechanism is as follows:
Sclerostin is produced by Osteocytes residing deep in bone matter, to dampen bone surface residing Osteoblasts from overproducing new bone unnecessarily. It is thus an anti-growth factor inhibiting through a cell's Wnt signaling pathway.
Apparently, inflamed synovial cells also produce Sclerostin to limit its own growth and joint destruction (a normal functioning immune system is very into "balance", like The Force).
So, when you administer an anti-Sclerostin antibody, you not only unleash the Osteoblasts to form new bone, you also take the brakes off the marauding RA pannus (inflammatory Synoviocytes) to destroy the joint.

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