Table 3.

Adverse Event Recommendations

Recommendation Category	2003 Recommendations	2011 Recommendations	Change
Renal safety concerns	In patients with pre-existing renal disease and a serum creatinine less than 3.0 mg/dL (265 μmol/L), no change in dosage, infusion time, or interval of pamidronate or zoledronic acid is required. Use of these bisphosphonates among patients with worse function has been minimally assessed. Infusion times less than 2 h with pamidronate or less than 15 min with zoledronic acid should be avoided. The Panel recommends that serum creatinine should be monitored prior to each dose of pamidronate or zoledronic acid, in accordance with FDA-approved labeling. Serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin should also be monitored regularly but there is no evidence upon which to base a recommendation for time intervals. In contrast to multiple myeloma patients, there currently is no data to support routine assessments for albuminuria in breast cancer patients.	In patients with a calculated serum creatinine clearance > 60 mL/min, no change in dosage, infusion time, or interval of pamidronate or zoledronic acid administration is required. Use of bone-modifying agents among patients with reduced renal function has been incompletely assessed. The packet insert of zoledronic acid provides guidance for dosing when baseline serum creatinine clearance is ≥ 30 and < 60 mL/min. Infusion times less than 2 h with pamidronate or less than 15 min with zoledronic acid should be avoided. The Panel recommends that serum creatinine should be monitored prior to each dose of pamidronate or zoledronic acid, in accordance with FDA-approved labeling. Serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin should also be monitored regularly. The risk of hypocalcemia with denosumab dosed at 120 mg every 4 wk has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis. Monitor for hypocalcemia in patients with impaired creatinine clearance.There is no evidence to guide the interval for monitoring serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin with denosumab, pamidronate, or zoledronic acid.	Addition regarding denosumab. A change in serum creatinine clearance threshold. Last sentence of 2003 recommendation taken out. Term changed from bisphosphonates to bone-modifying agents.
Osteonecrosis of the jaw	N/A	Osteonecrosis of the jaw (ONJ) is an uncommon but potentially serious condition associated with the use of bone-modifying agents. The Update Committee concurs with the revised FDA label for zoledronic acid and pamidronate and the FDA label for denosumab and recommends that all patients with cancer receive a dental examination and necessary preventive dentistry prior to initiating therapy with inhibitors of osteoclast function unless there are mitigating factors that preclude the dental assessment. These recommendations should be observed whenever possible. While receiving inhibitors of osteoclast function, patients should maintain optimal oral hygiene and, if possible, avoid invasive dental procedures that involve manipulation of the jaw bone or periosteum. Although most cases of ONJ have occurred in patients treated with IV bisphosphonates and bone-modifying agents who underwent an invasive dental procedure, cases have occurred spontaneously and have been reported in patients treated with other bone-modifying agents, including oral bisphosphonates and direct osteoclast inhibitors.	New recommendation
The role of biochemical markers	The use of the biochemical markers to monitor bisphosphonate use is not suggested for routine care.	The use of the biochemical markers to monitor bone-modifying agent use is not recommended for routine care.	(Unchanged in substance from 2003) Term changed from bisphosphonates to bone-modifying agents.

Note: Bolded text indicates substantive changes. Italicized text indicates minor changes.

Abbreviations: IV, intravenous; h, hours; min, minutes; wk, weeks.