The rate of normalizing calcium and duration of action were greater with OPG administration than with pamidronate or zoledronic acid. dosage . The iv. BPs approved for use in treatment of malignancy-associated hypercalcemia include pamidronate (approved in 1991) and zoledronic acid (approved in 2001). Results pooled from Phase III trials have shown zoledronic acid to be more potent than pamidronate with faster normalization of calcium levels, longer duration of calcium control and a higher response rate . Although iv. BPs have a slow onset of action (24C72 h), the duration of therapeutic action is long (?30 days for zoledronic acid and 20 days for pamidronate) . Though usually well tolerated, side effects from iv. infusion of BPs include flu-like symptoms, impaired renal function, hypocalcemia and hypophosphatemia, especially in patients with vitamin D deficiency. The use of iv. BPs is limited in patients with compromised renal function, due to drug-induced nephrotoxicity; thus, dose reduction is required in patients with glomerular filtration rate less than 60 ml/min. Prolonged dosing with potent iv. BPs increases the risk of rare complications such as osteonecrosis of the jaw and atypical femoral fractures . Corticosteroids are useful in HCM mediated by ectopic production of calcitriol seen in some lymphoma patients. By inhibiting 1-alpha-hydroxylase, steroids (hydrocortisone, prednisone) will prevent the conversion of precursor 25-hydroxyvitamin D into calcitriol . Additionally, in such cases of vitamin D-mediated hypercalcemia, restriction of dietary calcium is needed. For patients with severe renal insufficiency and oliguria, aggressive hydration and diuresis may not be possible and hemodialysis with a low calcium bath may be necessary. Denosumab: the new kid on the block for HCM Denosumab is usually a fully human monoclonal antibody that binds to RANKL to prevent ligand conversation with RANK receptors on precursor osteoclasts, thus, interfering with osteoclast maturation, function and survival . Consequently, bone resorption is usually reduced. This agent is usually approved by the Guanosine 5′-diphosphate disodium salt FDA for the treatment of postmenopausal women and men with osteoporosis, and cancer treatment-related bone loss (dosing regimen C 60 mg sc. every 6 months). It is also FDA approved for the prevention of skeletal-related events in patients with metastatic bone disease from solid tumors and patients with unresectable giant cell tumor of bone (dosing regimen C 120 mg sc. every 4 weeks). In clinical trials, denosumab decreased the incidence of skeletal-related events or HCM in patients with advanced solid-organ cancers with bone metastases [23C26]. In a preclinical study investigating OPG in murine models of PTH-rP-mediated HHM, RANKL inhibition with a single injection of OPG caused a rapid reversal of hypercalcemia . The rate of normalizing calcium and duration of action were greater with OPG administration than with pamidronate or zoledronic acid. Since 2012, there have been numerous case reports reporting the effectiveness of denosumab in patients with cancer-associated hypercalcemia in tumors including multiple myeloma, renal cell carcinoma and ovarian cancer and parathyroid carcinoma [28C35]. Given these findings and recognizing that some patients with HCM either do not respond to or do not have sustainable responses to iv. BP therapy, denosumab was evaluated in a single-arm multicenter, international Phase II study for the treatment of patients with BP-refractory HCM, as defined by hypercalcemia (albumin-corrected serum calcium [CSC] 12.5 mg/dl) despite receiving iv. BP treatment 7 Guanosine 5′-diphosphate disodium salt and 30 days prior to screening [10,36]. The primary endpoint was the Guanosine 5′-diphosphate disodium salt proportion of patients with a response of CSC 11.5 mg/dl (Common Terminology Criteria for Adverse Events grade 1) by day 10. A complete response was defined as a CSC 10.8 mg/dl. The study group of 33 patients with solid (breast [n = 6], neuroendocrine Rabbit Polyclonal to 4E-BP1 (phospho-Thr69) [n = 4], non-small-cell lung (n = 3), renal cell (n = 3), head and neck (n = 2) and one each for bladder/liver/ovarian/small-cell lung/sarcoma/adenocarcinoma of unknown primary) or hematologic malignancies received denosumab 120 mg sc. on day 1 and every 4 weeks afterward, with two additional doses on days 8 and 15 to reach steady-state.
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