Bone is the most common site of metastatic disease in patients with solid tumors. Approximately 30%–40% of patients with lung cancer and 20%–25% of patients with advanced renal cell carcinoma are found to have bone metastasis on autopsy.1
In patients with metastatic breast and prostate cancer, 65%–80% will develop bone metastasis, and bone is the most common site of first recurrence in breast cancer patients.1
In addition, pain from bone metastasis is the most frequent form of pain reported in patients with cancer.3
Patients with metastatic disease of the bone are at risk for skeletal-related events, which are defined as: radiation therapy to alleviate pain or prevent fracture, surgery to prevent or treat fracture, pathologic fracture (excluding major trauma), spinal cord compression, and other complications related to skeletal involvement, including hypercalcemia of malignancy. Skeletal-related events are thus a major source of morbidity for cancer patients.
Cancer patients often experience multiple skeletal-related events over the course of their disease. Patients with metastatic breast cancer experience an average of four skeletal-related events, lung cancer patients approximately 2.7 skeletal-related events, and prostate cancer patients an average 1.5 skeletal-related events over the course of their disease if untreated.4
Skeletal-related events also add considerable costs to the management of patients with bone metastases and can be a major cause of hospitalization. Fractures are the most commonly reported skeletal-related events and occur in up to 60% of untreated breast cancer patients with bone metastasis.7
Bone metastases cause pain, limited mobility, fears of future fracture, and loss of function, significantly decreasing quality of life. Thus, the prevention of skeletal-related events in patients with metastatic solid tumors is a vital component of their oncologic care.
Since the 1990s, bisphosphonates have been the mainstay of treatment to prevent skeletal-related events in patients with cancer metastases to bone. Bisphosphonates are rapidly incorporated into bone and are released during osteoclast-mediated bone resorption, where they impair the ability of osteoclasts to adhere to the bony surface and inhibit continued bone resorption. Bisphosphonates also decrease osteoclast progenitor development and recruitment, and induce osteoclast apoptosis. The most commonly used intravenous bisphosphonates are zoledronic acid (Zometa®, Novartis Pharmaceuticals East Hanover, NJ) and pamidronate (Aredia®, Novartis Pharmaceuticals East Hanover, NJ).
Zoledronic acid is the most potent bisphosphonate currently available, 500–1000 times more potent than pamidronate, and is the first drug in this class approved for use in all solid tumor patients with bone metastases as well as in multiple myeloma. Its use has been studied most extensively in breast cancer, prostate cancer, multiple myeloma, and lung cancer.4
Despite optimal bisphosphonate therapy, 30%–50% of cancer patients with bone metastases still develop skeletal-related events while on bisphosphonate therapy.5
In addition, there are concerning treatment-related side effects associated with bisphosphonates, including gastrointestinal irritation, nephrotoxicity, osteonecrosis of the jaw, and hypocalcemia. Intravenous infusion of zoledronic acid can be associated with an acute-phase reaction, including bone pain, fever, and chills in up to 30% of patients following their first infusion. In addition, intravenous bisphosphonates, and in particular zoledronic acid carry the risk of renal toxicity that is dose-dependent and infusion time-dependent. Zoledronic acid is currently not recommended for use in patients with a creatinine clearance lower than 30 mL/minute and must be dose-reduced if creatinine clearance is less than 60 mL/minute.12
Consequently, monthly monitoring of renal function is required prior to each dose of intravenous bisphosphonate. The use of bisphosphonates in patients with solid tumors and renal dysfunction is thus limited and the concomitant use of zoledronic acid with other nephrotoxic drugs or chemotherapeutic agents can be problematic.
Receptor activator of NF-κB ligand (RANKL)-mediated osteoclast activity is a key regulator of bone metabolism. RANKL is produced by osteoblasts, bone mar row stromal cells, and other cells under the control of various proresorptive growth factors, hormones, and cytokines. Osteoblasts and stromal cells produce osteoprotegerin, a decoy receptor, which binds to and inactivates RANKL. In the absence of osteoprotegerin, RANKL activates the RANK receptor, which is found on osteoclasts and preosteoclast precursors. RANK-RANKL interactions lead to preosteoclast recruitment, fusion into multinucleated osteoclasts, osteoclast activation, and osteoclast survival. The pivotal role of this pathway in bone metabolism make it a prime target for the treatment of bone disease. The first commercially available drug to target the RANK-RANKL pathway is denosumab, a fully human monoclonal antibody that specifically binds and neutralizes RANKL, thereby inhibiting osteoclast function. The initial Phase I trials demonstrated that osteoclastic activity is almost completely eradicated while denosumab is in circulation.13
However, the effect is reversible, as indicated by a rise in markers of bone turnover when the drug is cleared.13
Initial trials with denosumab were in the treatment of women with primary osteoporosis. In the Phase III FREEDOM trial, 7868 postmenopausal women (aged 60–90 years) with osteoporosis were randomly assigned to subcutaneous denosumab (60 mg every 6 months) or placebo. 14
After 3 years, denosumab improved bone mineral density compared with placebo. In addition, biochemical markers of bone turnover and fractures were significantly reduced in patients taking denosumab.14
When compared with bisphosphonates in the treatment of primary osteoporosis, denosumab has shown improvements in both bone mineral density and markers of bone loss.15
Denosumab has also been studied in bone loss associated with hormonal therapy in both breast and prostate cancer. In postmenopausal patients with hormone receptor-positive breast cancer, aromatase inhibitor use is associated with bone loss and increased fracture risk.16
Guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network recommend bone mineral density testing with a dual-emission x-ray absorptiometry scan for postmenopausal women taking aromatase inhibitors and drug therapy for those with documented osteoporosis.17
In a randomized, double-blind, placebo-controlled trial, 252 women with hormone receptor-positive, early-stage breast cancer treated with adjuvant aromatase inhibitor therapy were randomly assigned to receive placebo or subcutaneous denosumab 60 mg every 6 months.19
At enrollment, all patients were required to have evidence of low bone mass (excluding osteoporosis). At 12 and 24 months, lumbar spine bone mineral density increased by 5.5% and 7.6%, respectively, in the denosumab group compared with the placebo group (P
= 0.0001). In the HALT (Hormone Ablation Bone Loss) trial, 1468 men receiving androgen deprivation therapy for nonmetastatic prostate cancer were randomly assigned to denosumab (60 mg subcutaneously every 6 months) or placebo.20
Eligibility included male gender, age ≥70 years or <70 years with baseline low bone mineral density (T score at the lumbar spine, total hip, or femoral neck of less than −1.0). At 24 months, denosumab was associated with increased bone mineral density at all measured sites, including the total hip, femoral neck, distal third of the radius, and whole body (absolute difference versus placebo of 4.8%, 3.9%, 5.5%, and 4.0%, respectively, P
< 0.001 for all comparisons). Because of the increased power of this larger study, a statistically significant decrease in new vertebral fractures at 36 months was also observed in the denosumab arm (1.5% versus 3.9% with placebo, relative risk, 0.38; 95% confidence interval, 0.19–0.78; P
= 0.006). The promising outcomes in the initial trials with denosumab in treatment-related osteoporosis associated with breast and prostate cancer led to exploration of its use for the prevention of skeletal-related events in patients with solid tumors and bone metastasis, which is the focus of this review.