Zoledronic Acid

Atypical femur fractures (AFF) have been reported in patients receiving bisphosphonates. 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; atypical femur fractures have also been reported in patients not taking bisphosphonates, and in patients receiving glucocorticoids. Patients receiving long-term (>3 to 5 years) bisphosphonate therapy may be at an increased risk (Adler 2016; NOF [Cosman 2014]); however, benefits of therapy (when used for osteoporosis) generally outweigh absolute risk of AFF within the first 5 years of treatment (Adler 2016). Patients presenting with thigh or groin pain with a history of receiving bisphosphonates should be evaluated for femur fracture. Consider interrupting bisphosphonate therapy in patients who develop a femoral shaft fracture; assess for fracture in the contralateral limb.

Rare cases of urticaria and angioedema and very rare cases of anaphylactic reactions/shock have been reported.

Hypocalcemia (including severe and life-threatening cases) has been reported with use; patients with Paget disease may be at significant risk for hypocalcemia after treatment with zoledronic acid (because pretreatment rate of bone turnover may be elevated); severe and life-threatening hypocalcemia has also been reported with oncology-related uses. Measure serum calcium prior to treatment initiation. Correct preexisting hypocalcemia before initiation of therapy in patients with Paget disease, osteoporosis, or oncology indications. Use with caution with other medications known to cause hypocalcemia (severe hypocalcemia may develop). Ensure adequate calcium and vitamin D supplementation during therapy. Use caution in patients with disturbances of calcium and mineral metabolism (eg, hypoparathyroidism, thyroid/parathyroid surgery, malabsorption syndromes, excision of small intestine). QTc prolongation, cardiac arrhythmias, and neurologic events (eg, tetany, tonic-clonic seizures, numbness) secondary to severe hypocalcemia have been reported 1 day to several months after initiation of therapy.

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.

Conjunctivitis, uveitis, episcleritis, iritis, scleritis, and orbital inflammation have been reported (infrequently) with use; further ophthalmic evaluation (and possibly therapy discontinuation) may be necessary in patients with complicated infection.

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, bony surgery), cancer diagnosis, concomitant therapy (eg, chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, ill-fitting dentures, and comorbid disorders (anemia, coagulopathy, infection, preexisting dental disease). Risk may increase with duration of bisphosphonate use and/or may be reported at a greater frequency based on tumor type (eg, advanced breast cancer or 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 manufacturer’s labeling states that there are no data to suggest whether discontinuing bisphospho

Use with caution in patients with aspirin-sensitive asthma; may cause bronchoconstriction.

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.

The American Society of Clinical Oncology (ASCO) has published guidelines on bisphosphonate 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 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 a serum creatinine >3 mg/dL or CrCl 500 mg/24 hours, withhold the dose until level returns to baseline, then recheck every 3 to 4 weeks. Upon reinitiation, the guidelines recommend considering increasing the zoledronic acid infusion time to

Use with caution in mild to moderate renal impairment. Single and multiple infusions in patients with both normal and impaired renal function have been associated with renal deterioration, resulting in renal failure and dialysis (rare). Preexisting renal compromise, severe dehydration, and concurrent use with diuretics or other nephrotoxic drugs may increase the risk for renal impairment. Adequate hydration is required during treatment (urine output ~2 L/day); avoid overhydration, especially in patients with heart failure. Nononcology indications: Use is contraindicated in patients with CrCl 5 mg and do not infuse over less than 15 minutes. Patients with underlying moderate to severe renal impairment, increased age, concurrent use of nephrotoxic or diuretic medications, or severe dehydration prior to or after zoledronic acid administration may have an increased risk of acute renal impairment or renal failure. Others with increased risk include patients with renal impairment or dehydration secondary to fever, sepsis, gastrointestinal losses, or diuretic use. If history or physical exam suggests dehydration, treatment should not be given until the patient is normovolemic. Obtain serum creatinine and calculate creatinine clearance (using actual body weight) with the Cockcroft-Gault formula prior to each administration. Transient increases in serum creatinine may be more pronounced in patients with impaired renal function; monitoring creatinine clearance in at-risk patients takin

Because decreased renal function occurs more commonly in elderly patients, take special care to monitor renal function. Other warnings/precautions:

Do not administer Zometa and Reclast (Aclasta [Canadian product]) to the same patient for different indications.