Bone pain is one of the most common causes of morbidity in multiple myeloma (MM) and metastatic prostate cancer (CaP). This pain originates with the underlying pathologic processes of the cancer and with downstream skeletal-related events (SREs). SREs—fractures, spinal cord compression, and irradiation or surgery performed in ≥ 1 bone sites—represent a significant health care burden, particularly given the incidence of the underlying malignancies. According to American Cancer Society statistics, CaP is the second most common cancer in American men, and MM the second most common hematologic malignancy, despite its relatively low overall lifetime risk.1,2 Regardless of the underlying malignancy, bisphosphonates are the cornerstone of SRE prevention, though the optimal dosing strategy is the subject of clinical debate.
Although similar in SRE incidence, MM and CaP have distinct pathophysiologic processes in the dysregulation of bone resorption. MM is a hematologic malignancy that increases the risk of SREs by osteoclast up-regulation, primarily through the RANK (receptor activator of nuclear factor α-B) signaling pathway.3 CaP is a solid tumor malignancy that metastasizes to bone. Dysregulation of the bone resorption or formation cycle and net bone loss are a result of endogenous osteoclast up-regulation in response to abnormal bone formation in osteoblastic bone metastases.4 Androgen-deprivation therapy, the cornerstone of CaP treatment, further predisposes CaP patients to osteoporosis and SREs.
Prevention of SREs is pharmacologically driven by bisphosphonates, which have antiresorptive effects on bone through promotion of osteoclast apoptosis.5 Two IV formulations, pamidronate and zoledronic acid (ZA), are US Food and Drug Administration approved for use in bone metastases from MM or solid tumors.6-10 Although generally well tolerated, bisphosphonates can cause osteonecrosis of the jaw (ONJ), an avascular death of bone tissue, particularly with prolonged use.11 With its documented incidence of 5% to 6.7% in bone metastasis, ONJ represents a significant morbidity risk in patients with MM and CaP who are treated with IV bisphosphonates.12
Investigators are exploring bisphosphonate dosing intervals to determine which is most appropriate in mitigating the risk of ONJ. Before 2006, bisphosphonates were consistently dosed once monthly in patients with MM or metastatic bone disease—a standard derived empirically rather than from comparative studies or compelling pharmacodynamic data.13-15 In a 2006 consensus statement, the Mayo Clinic issued an expert opinion recommendation for increasing the bisphosphonate dosing interval to every 3 months in patients with MM.16 The first objective evidence for the clinical applicability of extending the ZA dosing interval was reported by Himelstein and colleagues in 2017.17 The randomized clinical trial found no differences in SRE rates when ZA was dosed every 12 weeks,17 prompting a conditional recommendation for dosing interval extension in the American Society of Clinical Oncology MM treatment guidelines (2018).13 Because of the age and racial demographics of the patients in these studies, many questions remain unanswered.
For the US Department of Veterans Affairs (VA) population, the pharmacokinetic and dynamic differences imposed by age and race limit the applicability of the available data. However, in veterans with MM or CaP, extending the bisphosphonate dosing interval may help decrease medication-related morbidity (eg, ONJ, nephrotoxicity) without compromising therapeutic benefit. To this end at the Memphis VA Medical Center (VAMC), we assessed for differences in SRE rates by comparing outcomes of patients who received ZA in standard- vs extended-interval dosing.