Advances in
Bone Cancer Treatment:
Preventing Metastasis and Bone Loss
New Approaches to Treating Metastatic Bone Cancer
Assessment
The skeleton is the preferred site of metastasis for many solid tumors. At diagnosis, bone metastases are often found in multiple sites, most often including the vertebrae, pelvis, femur, ribs, humerus, and skull. In patients with a diagnosed primary cancer, bone pain is highly indicative of bone metastases, though not all patients report pain. A bone fracture in a patient with primary disease should also be investigated for possible metastases.28 A radionuclide bone scan is usually the first method of checking for bone metastases, as it is the most available and cost-effective whole-body screening test. Radiography (plain film or computerized tomography [CT]) is required for characterizing lesions once they have been identified. Combined analysis improves diagnosis and assessment of response to therapy. The use of magnetic resonance imaging or position emission tomography scans, which have improved diagnostic sensitivity, depends on their availability, patient throughput, and cost.
Current Approaches
Bisphosphonate Therapy
Bisphosphonates inhibit osteoclast-mediated bone resorption and are currently the mainstay for long-term treatment of bone metastases and SREs associated with solid tumors and multiple myeloma. Over the past decade, several generations of increasingly potent bisphosphonates with higher therapeutic indices have been developed. Five bisphosphonates (ibandronic acid, zoledronic acid, pamidronate, risedonate, and clodronate) have now received international regulatory approval for use in the oncology setting, although currently only pamidronate and zoledronic acid are approved for oncologic use in the United States. Zoledronic acid is the most potent bisphosphonate currently available. In several large phase III trials, intravenous (IV) zoledronic acid delayed the onset and decreased the proportion of patients experiencing an SRE.29-32 Consensus guidelines recommend that all patients with multiple myeloma or radiologically confirmed bone metastases from breast cancer should start on bisphosphonate therapy at the time of diagnosis and continue for at least 2 years. The 2003 American Society of Clinical Oncology (ASCO) Guidelines on the Role of Bisphosphonates and Bone Health Issues in Women with Breast Cancer can be accessed at http://jco.ascopubs.org/cgi/content/full/18/6/1378.33-34
Bisphosphonate Safety
The safety profile of zoledronic acid is well defined, with the most common adverse events including bone pain, myalgia, nausea, fatigue, pyrexia, and emesis. Approximately one third of patients receiving an IV bisphosphonate experience an infusion reaction.35 Acute-phase reactions are typically self-limiting, resolve within 24-48 hours, and occur less frequently after subsequent infusions. Supportive care, such as nonsteroidal anti-inflammatory drugs, acetaminophen, and adequate hydration, are usually sufficient management of the acute-phase reaction. Intravenous bisphosphonates are excreted primarily by the kidneys and are associated with dose and infusion rate-dependent effects on renal function. Package inserts for both pamidronate and zoledronic acid require testing of patients for renal sufficiency before dosing.
Osteonecrosis of the jaw (ONJ), the presence of exposed bone in the mandible or maxilla for a period of 8 weeks or longer in the absence of infection, has been reported in patients receiving bisphosphonate therapy. The overall frequency of ONJ in patients with metastatic bone disease receiving cancer therapies, including bisphosphonates, has been estimated to be 0.73%, though the incidence appears to be higher in patients with multiple myeloma.36,37 Before starting bisphosphonate therapy, patients should be encouraged to have a routine dental examination. If the patient requires a surgical dental procedure, it is recommended that it be completed before initiation of bisphosphonate therapy when possible. While on therapy, patients should maintain excellent oral hygiene and avoid invasive dental procedures if possible. If a dental procedure is necessary in a patient that has previously initiated bisphosphonate therapy, holding the drug immediately prior to and following the procedure should be considered, and the patient should inform their dentist of bisphosphonate use. A conservative approach is recommended to treat ONJ, including antibiotics, oral rinses, pain control, and limited debridement.
While bisphosphonates currently represent the only bone-targeted and approved therapy to treat skeletal complications of cancer and cancer treatment, they only prevent a proportion of SREs, and it is clear that newer therapies are needed. Several novel agents are in development for the treatment and prevention of bone metastasis and bone loss.
Denosumab RANK-RANKL Inhibitor
As discussed above, RANK, RANKL, and osteoprotegrin (OPG) are a triad of molecules that regulate the maturation, differentiation, and survival of osteoclasts. RANKL is a key mediator in the perpetuating cycle of bone destruction in metastatic cancer. Denosumab, a monoclonal antibody that binds to and neutralizes RANKL, is being studied across a range of conditions, including osteoporosis, treatment-induced bone loss, bone metastases, multiple myeloma, and rheumatoid arthritis.
A randomized, active-controlled phase II study in patients with breast cancer-related metastases showed that denosumab, administered subcutaneously every 4 or 12 weeks, was as effective as IV bisphosphonates in suppressing bone turnover as measured by levels of urinary N-telopeptide (NTx) at 13 weeks. This trial was not designed to compare SREs in the treatment groups, but the time to first SRE was similar for patients in the denosumab and bisphosphonate cohorts, with SREs occurring in 9% and 16% of patients treated with denosumab and bisphosphonates, respectively.38 In addition, in patients with elevated NTx despite bisphosphonate treatment, denosumab was more effective than continued bisphosphonate treatment in decreasing NTx.39
Several phase III trials are evaluating the efficacy of denosumab in metastatic bone disease. Trials in hormone-refractory prostate cancer, advanced breast cancer, and other solid tumors or multiple myeloma are comparing the efficacy of denosumab with that of zoledronic acid in reducing SREs. Results of a phase III trial comparing denosumab to zoledronic acid in 2046 women with breast cancer metastatic to bone were reported in December 2009 at the San Antonio Breast Cancer Symposium.40 Patients were randomly assigned to subcutaneous denosumab or IV zoledronic acid on a monthly schedule. Denosumab significantly delayed the time to first and subsequent on-study SRE (P=0.001). Adverse events due to toxicity were similar in the two groups. Notably, although overall toxicities were similar in the two arms, the incidence of ONJ was numerically but not statistically higher in denosumab-treated patients (2% vs. 1.4%). In a second phase III trial of denosmub versus zoledronic acid in patients with solid tumors (not including breast or prostate) or multiple myeloma,41 the median time to first SRE was 20.6 months for patients receiving denosumab and 16.3 months for patients receiving zoledronic acid (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.71–0.98). This result was statistically significant for non-inferiority (P=0.0007). A trial of zoledronic acid versus denosumab in metastatic prostate cancer has yet to be reported.
Cathepsin K Inhibitors
Cathepsin K is a cysteine protease that is selectively expressed in and secreted by osteoclasts. It breaks down collagen, leading to resorption of bone matrix. Inhibitors of cathepsin K suppress bone resorption in animal models.42 When administered weekly for 2 years to postmenopausal women with low BMD, a 50-mg dose of the cathepsin K inhibitor odanacatib increased spinal and hip BMD by 5.5% and 3.2%, respectively, whereas BMD remained relatively unchanged in placebo-treated subjects. Levels of urinary NTx and bone-specific alkaline phosphatase also decreased by 52% and 13%, respectively, with odanacatib, whereas with placebo urinary NTx decreased by only 5% and bone-specific alkaline phosphatase increased by 3%.43 A recent double-blind study showed that daily administration of odanacatib 5 mg or a single IV dose of zoledronic acid 4 mg to women with breast cancer metastatic to bone reduced markers of bone remodeling after 4 weeks. Odanacatib and zoledronic acid suppressed urinary NTx by 77% and 73%, respectively. Odanacatib increased serum cross-linked C-terminal peptide of type I collagen (ICTP) by 93%, indicating specific inhibition of cathepsin K.4444
Endothelin Receptor Antagonists
Endothelin-1 (ET-1) binds to its receptor ET-A and initiates signaling pathways that play a central role in the osteoblastic response in metastatic prostate cancer. Atrasentan is an inhibitor of the ET-A receptor that has been shown to block formation of osteoblastic metastases in mice. In a placebo-controlled phase II trial in men with asymptomatic hormone-refractory prostate cancer and evidence of metastasis, atrasentan significantly delayed the time to disease progression compared with placebo in the evaluable but not the intent-to-treat population.45 However, in a subsequent placebo-controlled phase III trial in 809 men with metastatic prostate cancer, atrasentan 10 mg/day did not reduce the risk of disease progression relative to placebo, although levels of bone alkaline phosphatase and prostate-specific antigen (PSA) were significantly reduced.46 A similar placebo-controlled phase III study of atrasentan conducted in men with nonmetastatic prostate cancer but with increasing PSA levels also showed that time to progression did not differ significantly between atrasentan and placebo treatment.47 The combination of atrasentan with zoledronic acid in men with metastatic prostate cancer did not induce any additive or synergistic effects on levels of alkaline phosphatase.48 Results of trials of other endothelin receptor antagonists in metastatic prostate cancer are expected shortly.
Other Therapeutic Approaches
c-Src is a nonreceptor tyrosine kinase that may be required for the formation of the ruffled border in osteoclasts and is therefore important for the resorptive activity of these cells. Preclinical studies have demonstrated that reduction of c-Src expression not only inhibited bone resorption but also stimulated osteoblast proliferation and bone formation.49 AZD0530 is an orally active small-molecular-weight inhibitor of c-Src and BCR-Abl. Its efficacy in bone resorption has been demonstrated in two phase I clinical trials of healthy male volunteers.50
TGF-beta is a cytokine that promotes the invasion and metastasis of human cancers through inactivation or mutations affecting various components of its signaling pathway. The TGF-β signal is transduced through two transmembrane receptors, TGFβR-1 and TGFβR-2. Several small molecules that inhibit TGFβR-1 activity in vitro have been developed. In an experimental model of breast cancer-induced bone metastasis in mice, an inhibitor of this receptor reduced the incidence of widespread skeletal metastases and decreased the tumor burden, demonstrating that abrogation of TGF-β signaling in vivo could inhibit bone metastasis.12
Another strategy for treating bone disease is to target integrins, which are receptors that anchor osteoclasts to the bone matrix and provide the physical juxtaposition needed for resorption. The αVβ3 integrin is essential to the resorptive process. In a preclinical study in rats, blockade of this receptor with a small-molecule inhibitor attenuated osteoclast activity and prevented loss of trabecular bone after oophorectomy, demonstrating the bone-sparing efficacy of this approach.
In some cancers, such as in multiple myeloma, osteoblastic bone formation becomes inhibited and therefore tips the balance in bone metastases toward osteolysis. Multiple myeloma cells secrete DKK1, an inhibitor of Wnt signaling that prevents osteoblast differentiation and suppresses bone formation. Therapies that neutralize DKK1 activity may thus help rebuild bone. To test this concept, neutralizing anti-DKK1 antibody was injected daily in mice bearing a human myeloma xenograft.18 This treatment increased BMD, increased osteoblast activity, reduced the number of osteoclasts, and lowered the myeloma burden.
Bortezomib is a first-in-class proteasome inhibitor that is currently clinically available, and has demonstrated antineoplastic activity in multiple myeloma. In addition to its antitumor effects, bortezomib may also have a beneficial effect on bone disease. Bortezomib induces the differentiation of mesenchymal cells into osteoblasts, resulting in new bone formation. Bortezomib can increase the expression of bone-formation markers and the number of osteoblasts in biopsy specimens, but it does not affect osteoclastic activity or lytic bone disease. It has potential utility in combination with agents that target the osteolytic process.51,52
Conclusion
Over the past two decades bisphosphonate therapy has changed the natural history of metastatic bone disease. Early promising trials have suggested that adjuvant therapy with bisphosphonates may prevent metastatic disease in both skeletal and extraskeletal sites; confirmatory studies are in progress. In addition, data comparing inhibition of RANKL using denosumab with standard bisphosphonate therapy are expected in 2010.