Recent Advances in Patient Treatment and Care (Track)



The role of antiresorptive agents in the management of multiple myeloma-related bone disease

Evangelos Terpos
Department of Clinical Therapeutics University of Athens School of Medicine Athens, Greece

Abstract:

Osteolytic bone disease is a frequent complication of multiple myeloma (MM) which results in significant skeletal morbidity, including pathological fractures, hypercalcemia, spinal cord compression, pain requiring surgery, or radiotherapy. Lytic lesions are due to increased osteoclastic activity, which is not accompanied by a comparable increase in bone formation. Targeting osteoclastic bone resorption represents to-date the most important approach to treating patients with myeloma-related bone disease.

Bisphosphonates (BPs) are potent inhibitors of osteoclast activity and function. BPs are effective in preventing the development of osteolytic bone disease in patients with myeloma and have become key agents in treating MM patients. Intravenous pamidronate and intravenous zoledronic acid are the most common BPs used for the management of myeloma-related bone disease. A recent report from the MRC Myeloma IX trial, a phase III, randomized, prospective study comparing zoledronic acid versus clodronate in patients with newly diagnosed MM (N = 1,960) showed that zoledronic acid significantly reduced the risk for SREs by 24% compared to clodronate. Furthermore, zoledronic acid improved overall survival (p=0.011) and progression-free survival (p=0.017) versus clodronate: zoledronic acid reduced the relative risk of death by 16% compared to clodronate. The survival benefit associated with zoledronic acid was maintained in analyses adjusting for the potential effects of SREs on survival (p=0.017 vs. clodronate), again supporting anticancer mechanisms for zoledronic acid, which may involve positive effects on anticancer immune responses.

Denosumab is a fully human immunoglobulin (Ig)G2 monoclonal antibody that binds to RANKL with high affinity and specificity, thereby inhibiting osteoclastogenesis. A number of recent studies also demonstrated that denosumab improved SREs among patients with bone metastases from breast or other solid tumors, or MM and regarding MM this effects seems to be at least equal to zoledronic acid.

Novel anti-myeloma agents, such as IMiDs and bortezomib alter abnormal bone metabolism in myeloma patients. Lenalidomide, thalidomide and bortezomib reduce bone resorption. However, in terms of the restoration of osteoblast function, only bortezomib is able to directly stimulate osteoblast differentiation and function and leads to increased bone formation at least in responders, leading to increased bone volume.