From the Guidelines
Osteoclast activation in multiple myeloma occurs primarily due to the overproduction of RANKL and the decreased production of OPG, leading to an increased RANKL/OPG ratio, which favors osteoclastogenesis and osteoclast function, as evidenced by the study published in the Annals of Oncology in 2009 1. The interaction between myeloma cells and bone marrow stromal cells (BMSCs) plays a crucial role in this process, resulting in the overproduction of cytokines with osteoclast activation function, including IL-6, IL-11, IL-1b, M-CSF, and TNF-a. Some key points to consider include:
- The production of RANKL, a potent activator of osteoclasts, is increased in the bone marrow microenvironment of multiple myeloma patients 1.
- The production of OPG, the soluble decoy receptor for RANKL, is reduced in BMSCs inhabiting the myeloma marrow setting, further contributing to the increased RANKL/OPG ratio 1.
- Myeloma cells internalize and degrade OPG via CD138 (syndecan-1), which also contributes to the increased RANKL/OPG ratio and subsequent osteoclast activation 1.
- The increased osteoclast activity leads to excessive bone resorption, resulting in characteristic osteolytic lesions, bone pain, hypercalcemia, and pathological fractures seen in multiple myeloma patients.
- Simultaneously, myeloma cells inhibit osteoblast function, preventing new bone formation and repair, which creates a vicious cycle where bone destruction releases growth factors from the bone matrix that further promote myeloma cell growth and survival.
From the Research
Osteoclast Activation in Multiple Myeloma
- Osteoclast activation is a key factor in the development of osteolytic bone lesions in multiple myeloma patients 2.
- The receptor activator of NF-kappaB ligand (RANKL) plays a critical role in the activation of osteoclastic cells in multiple myeloma 2.
- Myeloma cells induce an imbalance in the bone marrow environment of the RANKL/OPG ratio in favor of RANKL, triggering osteoclast formation and activation leading to bone destruction 2.
- The direct production of the chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha) by myeloma cells, in combination with the RANKL induction in BM stromal cells in response to myeloma cells, are critical in osteoclast activation and osteoclastogenesis 2.
Mechanisms of Osteoclast Activation
- Myeloma-osteoclast interactions result in stimulation of myeloma cell growth and osteoclastic activity through activation of major signalling pathways and upregulation of proteases 3.
- Signals from osteoclasts activate the p44/p42 MAPK, STAT3 and PI3K/Akt pathways in myeloma cells, while myeloma cells trigger p38 MAPK and NF-kappaB signalling in osteoclasts 3.
- Myeloma-osteoclast interactions stimulate the production of TRAP, cathepsin K, matrix metalloproteinase (MMP)-1, -9, and urokinase plasminogen activator (uPA) 3.
Treatment of Multiple Myeloma Bone Disease
- Bisphosphonates, such as zoledronic acid and pamidronate, are the mainstay of myeloma bone disease treatment 4.
- Denosumab, a monoclonal antibody targeting RANKL, has been shown to be non-inferior to zoledronic acid in preventing skeletal-related events in patients with newly diagnosed multiple myeloma 5.
- Zoledronic acid has been associated with increased overall survival and decreased skeletal-related events compared to pamidronate in patients with multiple myeloma 6.