Reply.

We thank Dr. Ana Lleo and colleagues for having interest in our paper showing that long‐term administration of denosumab safely increased bone mineral density in osteoporotic patients with primary biliary cholangitis (PBC) and autoimmune hepatitis.1

The beneficial effect of denosumab on bone metabolism is achieved by suppressing RANK signaling in osteoclastogenesis. The influence of inhibiting RANK‐RANKL axis is now explored in other areas. A recent phase 3 trial demonstrated that adjuvant denosumab in postmenopausal patients with hormone receptor–positive breast cancer significantly improved disease‐free survival compared with placebo (hazard ratio 0.82 [0.69‐0.98]).2 RANK and RANKL are expressed in immune cells and possibly in tumor and stroma cells, and these interactions in the tumor microenvironment could lead to immunosuppression.3 Remarkable response was documented following concurrent treatment with denosumab and immune‐checkpoint inhibitors in several case reports.4 Therefore, denosumab might be used as an adjuvant in anticancer therapy.

In PBC, the RANK‐RANKL axis might also have implications beyond osteoclastogenesis. A previous study demonstrated that the expression of RANK in cholangiocytes and RANKL in CD4, CD8, and CD19 cells around bile ducts was significantly greater in patients with PBC than those with other liver diseases,5 suggesting the involvement of RANK‐RANKL axis in the mechanism of bile duct injury in PBC. Therefore, denosumab might improve not only bone metabolism but also liver function in this intractable disease.

We analyzed the change in serum alkaline phosphatase (ALP) and gamma‐glutamyltransferase (GGT) levels in 6 patients with PBC who received 3‐year denosumab therapy.1 The ALP levels decreased, although it was largely attributable to the decline in bone‐related isozyme. Serum GGT levels were not improved by denosumab therapy. As our patients had been receiving ursodeoxycholic acid for a long time when denosumab therapy initiated, there might be no room for further decrease in ALP and GGT. Nevertheless, a hypothesis that the RANK‐RANKL axis plays a role in bile duct injury in PBC is worth further investigation. A prospective trial comparing the efficacy of denosumab with bisphosphonate in the treatment of osteoporotic patients with PBC is ongoing. Analysis from the viewpoint of improving bile duct injury might prove this hypothesis.