Do RANKL inhibitors (denosumab) affect inflammation and immunity?

Abstract

Receptor activator of nuclear factor kappa B ligand (RANKL) and its natural antagonist, osteoprotegerin (OPG), are, respectively, an indispensable factor and a potent inhibitor for osteoclast differentiation, activity, and survival. The development of a human monoclonal antibody to RANKL, denosumab, constitutes a novel approach to prevent fragility fractures in osteoporosis, skeletal complications of malignancy, and potentially bone erosions in rheumatoid arthritis (RA). In addition to being expressed by osteoblasts, RANKL is abundantly produced by activated T cells, and synoviocytes in RA, whereas its receptor, RANK, is also expressed by monocytes/macrophages and dendritic cells. However, in preclinical and clinical studies of RA-including patients with some degree of immunosuppression-RANKL inhibitors did not significantly alter inflammatory processes. RANKL, RANK, and OPG deficiency in murine models highlights the important role of this pathway in the development and maturation of the immune system in rodents, including functions of T and/or B cells, whereas OPG overexpression in mice and rats seems innocuous with regard to immunity. In contrast, loss-of-function mutations in humans have more limited effects on immune cells. In clinical studies, the overall rate of infections, cancer, and death was similar with denosumab and placebo. Nevertheless, the risk of severe infections and cancer in some specific tissues remains to be carefully scrutinized.

A High-grade Sarcoma Arising in a Patient With Recurrent Benign Giant Cell Tumor of the Proximal Tibia While Receiving Treatment With Denosumab

“…Additionally although five patients had serious adverse events, none were deemed to be treatmentrelated. It has been questioned if RANKL inhibitors affect inflammation and immunity, as RANKL is expressed by endothelial cells, T lymphocytes, synovial fibroblasts, and various tumor cells [5]. Nevertheless, no meaningful clinical extraskeletal effects have been reported after denosumab administration for osteoporosis, and the overall rate of infections, cancer, and patient mortality have been similar with denosumab use compared with placebo at doses used for the treatment of patients with osteoporosis [5,20].…”

“…It has been questioned if RANKL inhibitors affect inflammation and immunity, as RANKL is expressed by endothelial cells, T lymphocytes, synovial fibroblasts, and various tumor cells [5]. Nevertheless, no meaningful clinical extraskeletal effects have been reported after denosumab administration for osteoporosis, and the overall rate of infections, cancer, and patient mortality have been similar with denosumab use compared with placebo at doses used for the treatment of patients with osteoporosis [5,20]. High-dose denosumab therapy, similar to that used in patients with an unresectable giant cell tumor of bone, was recommended for prevention of skeletal-related events in patients with bone metastasis from a solid tumor [21].…”

OPG/RANKL/RANK axis is a critical inflammatory signaling system in ischemic brain in mice

“…It binds to a receptor activator of nuclear factor-кB ligand (RANKL) (4,5), whose receptor is the receptor activator of NF-κB (RANK), and inhibits RANKL/RANK signaling. The OPG/RANKL/RANK system in bone (6) and vasculature (7) is well known to work on bone metabolism (8) and vascular calcification (7). In addition, immune cells (6,(9)(10)(11)(12) express these molecules, and this system is believed to be associated with the regulation of inflammatory and immune responses (13,14).…”

“…+ T cells (6) and macrophages (9,10), whereas OPG is expressed in mature B cells (6) and macrophages (11,12). RANK is expressed in macrophage and dendritic cells (6).…”

Molecular target therapy for bone metastasis: starting a new era with denosumab, a RANKL inhibitor

“…RANKL is expressed not only by osteoblasts but also by activated T cells and synoviocytes [37]. RANK is a receptor expressed by monocytes, macrophages and dendritic cells.…”