Combating Myeloma-Induced Bone Disease: The Dual Approach of DKK1 and LRP6 Targeting

Multiple myeloma is a malignant condition characterized by the proliferation of abnormal plasma cells in bone marrow, leading to systemic bone deterioration and osteolytic lesions. Over 90% of patients suffer from these bone lesions, which can cause pain and a heightened risk of fractures, negatively affecting their quality of life. While current bone-targeted therapies can mitigate lesion progression and decrease the risk of fractures, they do not restore bone loss, leaving patients susceptible to further fractures.

To address this, there is a need for treatments that promote bone formation to enhance skeletal integrity and prevent fractures in myeloma patients. Agents targeting the Wnt signaling pathway, known for its role in bone formation, could be instrumental in rebuilding bone and strengthening it. A new anti-LRP6 agent has been found to enhance Wnt signaling by binding to the LRP6 receptor, which can prevent bone loss caused by myeloma by inhibiting bone resorption.

Given that myeloma patients exhibit both increased bone resorption and decreased bone formation, a combination therapy of anti-LRP6 with anti-DKK1 was hypothesized to yield more significant improvements in bone structure than single treatments. MicroCT analysis showed that the combination treatment led to a substantial increase in bone volume in mice without tumors, and significantly improved bone volume in myeloma-bearing mice, providing greater resistance to fractures.

This combination therapy resulted in a significant reduction in osteoclast numbers and osteoclast surface area in myeloma-bearing mice, indicating a primary effect on bone resorption. Notably, the tumor activity remained unchanged with both single and combination treatments. This research presents a novel therapeutic approach that could potentially reduce fractures and improve the quality of life for myeloma patients when used alongside treatments targeting the tumor.