Pamidronic Acid

Atypical femur fractures (after minimal or no trauma) have been reported. The fractures include subtrochanteric femur (bone just below the hip joint) and diaphyseal femur (long segment of the thigh bone). Some patients experience prodromal pain weeks or months before the fracture occurs. It is unclear if bisphosphonate therapy is the cause for these fractures. Patients receiving long-term (>3 to 5 years) bisphosphonate therapy may be at an increased risk. Consider discontinuing pamidronate in patients with a suspected femoral shaft fracture. Patients who present with thigh or groin pain in the absence of trauma should be evaluated.

Infrequently, severe (and occasionally debilitating) bone, joint, and/or muscle pain have been reported during bisphosphonate treatment. The onset of pain ranged from a single day to several months. Consider discontinuing therapy in patients who experience severe symptoms; symptoms usually resolve upon discontinuation. Some patients experienced recurrence when rechallenged with same drug or another bisphosphonate; avoid use in patients with a history of these symptoms in association with bisphosphonate therapy.

Use has been associated with asymptomatic electrolyte abnormalities (including hypophosphatemia, hypokalemia, hypomagnesemia, and hypocalcemia). Rare cases of symptomatic hypocalcemia, including tetany, have been reported.

Patients with preexisting anemia, leukopenia, or thrombocytopenia should be closely monitored during the first 2 weeks of treatment.

Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving bisphosphonates. Known risk factors for MRONJ include invasive dental procedures (eg, tooth extraction, dental implants, boney surgery), cancer diagnosis, concomitant therapy (eg, chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, ill-fitting dentures, and comorbid disorders (anemia, coagulopathy, infection, preexisting dental or periodontal disease). Risk may increase with increased duration of bisphosphonate use and/or may be reported at a greater frequency based on tumor type (eg, advanced breast cancer, multiple myeloma). According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), MRONJ has been associated with bisphosphonates and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy; risk is significantly higher in cancer patients receiving antiresorptive therapy compared to patients receiving osteoporosis treatment (regardless of medication used or dosing schedule). MRONJ risk is also increased with monthly IV antiresorptive therapy compared to the minimal risk associated with oral bisphosphonate use, although risk appears to increase with oral bisphosphonates when duration of therapy exceeds 4 years. The AAOMS suggests that if medically permissible, initiation of IV bisphospho

Single pamidronate doses should not exceed 90 mg. Initial or single doses have been associated with renal deterioration, progressing to renal failure and dialysis. Glomerulosclerosis (focal segmental) with or without nephrotic syndrome has also been reported. Longer infusion times (>2 hours) may reduce the risk for renal toxicity, especially in patients with pre-existing renal insufficiency. Withhold pamidronate treatment (until renal function returns to baseline) in patients with evidence of renal deterioration. Disease-related concerns:

The American Society of Clinical Oncology (ASCO) updated guidelines on the role of bone-modifying agents (BMAs) in the prevention and treatment of skeletal-related events for metastatic breast cancer patients (Van Poznak, 2011). The guidelines recommend initiating a BMA (denosumab, pamidronate, zoledronic acid) in patients with metastatic breast cancer to the bone. There is currently no literature indicating the superiority of one particular BMA. Optimal duration is not yet defined; however, the guidelines recommend continuing therapy until substantial decline in patient’s performance status. The ASCO guidelines are in alignment with prescribing information for dosing, renal dose adjustments, infusion times, prevention and management of osteonecrosis of the jaw, and monitoring of laboratory parameter recommendations. BMAs are not the first-line therapy for pain. BMAs are to be used as adjunctive therapy for cancer-related bone pain associated with bone metastasis, demonstrating a modest pain control benefit. BMAs should be used in conjunction with agents such as NSAIDS, opioid and nonopioid analgesics, corticosteroids, radiation/surgery, and interventional procedures.

Adequate hydration is required during treatment (urine output ~2 L/day); avoid overhydration, especially in patients with heart failure.

Use caution with a history of thyroid surgery; patients may have relative hypoparathyroidism, predisposing them to pamidronate-related hypocalcemia.

Patients with Bence-Jones proteinuria and dehydration should be adequately hydrated prior to therapy. The American Society of Clinical Oncology (ASCO) has also published guidelines on bisphosphonates use for prevention and treatment of bone disease in multiple myeloma (Kyle, 2007). Bisphosphonate (pamidronate or zoledronic acid) use is recommended in multiple myeloma patients with lytic bone destruction or compression spine fracture from osteopenia. Bisphosphonates may also be considered in patients with pain secondary to osteolytic disease, adjunct therapy to stabilize fractures or impending fractures, and for multiple myeloma patients with osteopenia but no radiographic evidence of lytic bone disease. Bisphosphonates are not recommended in patients with solitary plasmacytoma, smoldering (asymptomatic) or indolent myeloma, or monoclonal gammopathy of undetermined significance. The guidelines recommend monthly treatment for a period of 2 years. At that time, consider discontinuing in responsive and stable patients, and reinitiate if a new-onset skeletal-related event occurs. The ASCO guidelines are in alignment with the prescribing information for dosing, renal dose adjustments, infusion times, prevention and management of osteonecrosis of the jaw, and monitoring of laboratory parameter recommendations. According to the guidelines, in patients with extensive bone disease with existing severe renal disease (a serum creatinine >3 mg/dL or CrCl 500 mg/24 hours, withhold the dose

Patients with serum creatinine >3 mg/dL were not studied in clinical trials; limited data are available in patients with CrCl