Management Of Skeletal Disease

Bone disease in the form of lytic lesions, pathological fractures, or osteoporosis are present at diagnosis over three-quarters of the time,130 ultimately leading to significant morbidity in many patients with MM. While external beam radiation therapy is remarkably effective palliation for pain relief from existing lesions, it is the localized therapy without the potential to reduce the risk of skeletal complications outside of the radiation port.

Bone resorption in MM results occurs due to stimulation of osteoclasts, which in turn results predominantly from receptor activator of NF-kB (RANK) signaling by RANK-ligand.131' 132 Bisphosphonates are synthetic pyrophosphate analogues that inhibit osteo-clast function directly though disruption of intracellu-lar biochemical pathways133, 134 or induction of apopto-sis,135 or indirectly by stimulating production of the inhibitory RANK decoy molecule, osteoprotegerin.136 The two bisphosphonates currently approved for use in treating MM-related bone disease are pamidronate (Aredia) and zoledronic acid (Zometa). Pamidronate, 90 mg intravenously over 4 hours every 4 weeks, has been shown in randomized trials to significantly reduce the rate of skeletal complications associated with MM compared to placebo, 28% versus 44% at 12 months, as well as delaying the median time to first skeletal complication from 12 months to 21 months.137 This effect persisted with treatment extended out to almost 2 years.138 It should be noted that this dose of pamidronate can be given safely over 60-90 minutes. Zoledronic acid is a newer bisphosphonate with 1000 times the potency of pamidronate and an even shorter infusional time of 15 minutes. In a randomized trial with extended follow-up, comparing zoledronic acid 4 mg every 3-4 weeks to pamidronate 90 mg, comparable efficacy in preventing skeletal complications was observed.139, 140 As a result of these trials, the American Society of Clinical Oncology has released clinical guidelines recommending the routine use of either pamidronate or zoledronic acid for MM patients with lytic bone lesions or myeloma-related osteopenia.13 There is no consensus on the optimal duration of bis-phosphonate therapy, but the widespread practice of indefinite monthly administration of these agents has recently come under scrutiny with the recognition of ONJ as an uncommon toxicity associated with prolonged bisphosphonate use.14 Patients with ONJ develop exposed areas of chronic, nonhealing necrotic bone in their mouths, in many cases after tooth extraction. While much work remains to be done in terms of fully characterizing this problem, some groups have developed treatment guidelines which reflect the currently available information on ONJ and bisphosphonates.15 Newer approaches to treating myeloma-related bone disease include percutaneous kyphoplasty or verte-broplasty of vertebral compression fractures related to lytic lesions141, 142 or osteoporosis143; utilization of radioactive Strontium-89144; and recombinant osteoprotegerin or the soluble RANK-ligand receptor, RANK-Fc, to block the osteoclast-activating effects of endogenous RANK-ligand in the marrow microenvironment.145, 146

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