Skeletal Complications

The skeletal complications of MM are the most distressing of all the end-organ complications encountered in this disease. Osteopenia and lytic bone lesions are a cause of disabling pain and pathologic fractures. Spinal cord compression may result as well. Thirty percent of patients will present with nonvertebral fractures and more than 50% will present with back pain or vertebral fractures.44,45 Approximately 80% of patients will have radiographic evidence of osteoporosis, lytic lesions, or fractures at the time of diagnosis.2 Osteoporosis, focal lysis, and hypercalcemia all result from increased osteoclastic activity. The molecular mechanism causing this enhanced activity is incompletely understood, but continues to be an area of intense investigation. The current paradigm proposes that an imbalance in osteoprotegerin (OPG) and osteoprotegerin ligand (OPGL) are central to bone resorption.46 OPGL is known to activate osteoclastic cells via the receptor activator of NF-kB (RANK).46 Ex vivo coculture studies suggest that plasma cells derived from patients with MM modulate osteoblast and bone marrow stromal cell production of OPGL and its decoy receptor OPG in such a way that OPG is downregu-lated while OPGL itself is upregulated.46 Recombinant OPG is currently in clinical development and the results of a phase I trial have been published.47

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