Moderate doses of furosemide (20–40 mg every 12 hours) increase saline-induced urinary calcium excretion and are useful in preventing or managing fluid overload in adequately rehydrated patients. Aggressive treatment with furosemide (80–100 mg every 2–4 hours) is problematic because it requires concurrent administration of large volumes of saline to prevent intravascular dehydration.[Level of evidence: III] This, in turn, requires intensive hemodynamic monitoring (to avoid volume overload and cardiac decompensation) and frequent serial measurements of urinary volume and electrolytes (to prevent life-threatening hypophosphatemia, hypokalemia, and hypomagnesemia).[6,8][Level of evidence: IV]
Pharmacologic Inhibition of Osteoclastic Bone Resorption
Described below are therapies that can inhibit osteoclastic bone resorption. The most widely used modality for this purpose is a bisphosphonate (such as pamidronate). The use of other agents such as calcitonin, mithramycin, or gallium nitrate is less common.
Bisphosphonates are one of the most effective pharmacologic alternatives for controlling hypercalcemia. They bind to hydroxyapatite in calcified bone, rendering it resistant to hydrolytic dissolution by phosphatases, thereby inhibiting both normal and abnormal bone resorption. Bisphosphonate treatment reduces the number of osteoclasts in sites undergoing active bone resorption and may prevent osteoclast expansion by inhibiting differentiation from their monocyte-macrophage precursors.[Level of evidence: IV] Bisphosphonates have variable effects on other aspects of bone remodeling, such as new bone formation and mineralization. For example, etidronate at clinically relevant dosages (300–1,600 mg/day) inhibits new bone formation and mineralization.[Level of evidence: II] With prolonged etidronate use, osteomalacia and pathologic fractures may occur.[Level of evidence: III] In contrast, clodronate, pamidronate, and alendronate are 10, 100, and 1,000 times more potent inhibitors of bone resorption than etidronate and are clinically useful at dosages that are less likely to adversely affect new bone formation and mineralization.[Level of evidence: IV];[14,15,16][Level of evidence: II] Many bisphosphonates may be useful in treating hypercalcemia of malignancy. In the United States, etidronate and pamidronate are the only bisphosphonates approved for treating hypercalcemia.
In a randomized double-blind study comparing pamidronate with etidronate for the treatment of cancer-related hypercalcemia, pamidronate (60 mg intravenous [IV] single dose over 24 hours) has been demonstrated to be more effective with respect to serum calcium reduction and duration of hypocalcemic response than etidronate (7.5 mg/kg of body weight per day administered over 2 hours as a daily IV infusion for 3 consecutive days).[Level of evidence: I] This finding has led to the diminished use of etidronate.
In treating moderate hypercalcemia (corrected serum calcium <13.5 mg/dL, <6.75 mEq/L, or <3.37 mmol/L), pamidronate 60 to 90 mg IV is administered over 2 to 24 hours. Onset of pamidronate's effect is apparent within 3 to 4 days, with maximal effect within 7 to 10 days after commencing treatment. The effect may persist for 7 to 30 days.[Level of evidence: I] It is recommended that a minimum of 7 days elapse before re-treatment with pamidronate to assess full response to the initial dose. Adverse effects include transient low-grade temperature elevations (1°C–2°C) that typically occur within 24 to 36 hours after administration and persist for up to 2 days in up to 20% of patients. Pamidronate has also been used successfully in children, with similar side effects.[Level of evidence: III] Other bisphosphonates (except clodronate) may also produce transient temperature elevations; the incidence of temperature elevation, nausea, anorexia, dyspepsia, and vomiting may be increased by rapid administration.[Level of evidence: I];[Level of evidence: III] New-onset hypophosphatemia and hypomagnesemia may occur; pre-existing abnormalities in the same electrolytes may be exacerbated by treatment. Serum calcium may fall below the normal range, and hypocalcemia (typically asymptomatic) may result. Renal failure has only been reported after rapid etidronate and clodronate injection, but rapid administration should be avoided with all bisphosphonates.[Level of evidence: III] Intravenous pamidronate administration has been associated with acute-phase responses, including transiently decreased peripheral lymphocyte counts. Local reactions (thrombophlebitis, erythema, and pain) at the infusion site have been reported.