Novel Bone-Targeted Therapies
Although management of tumor-induced bone loss can potentially include therapies to inhibit bone resorption or stimulate bone formation, the most advanced approaches currently are focused on blocking bone resorption. Table 4, below, lists novel bone-targeted agents in development.
Inhibiting Osteoclast Differentiation: Denosumab
As discussed above, activated osteoclasts are found in proximity to tumor cells and play a key role in patients with multiple myeloma and solid tumor-related bone metastases. A triad of molecules has been shown to regulate the maturation, differentiation, and survival of osteoclasts: RANK, RANK Ligand (RANK L) and osteoprotegerin. RANK L, a member of the tumor necrosis family, binds to RANK on preosteoclasts and mature osteoclasts and mediates the differentiation, function and survival of osteoclasts. Osteoprotegerin, a natural soluble decoy receptor of RANK L, modulates the effect of RANK L and is able to prevent excessive bone resorption.38,39 An excessive production of RANK L by osteoblasts plays a key role in the pathogenesis of tumor-induced osteolysis. Inhibition of RANK L in animal models prevents tumorinduced bone destruction.
Denosumab (AMG-162) is an investigational, fully human monoclonal antibody that specifically binds RANK L, thereby inhibiting osteoclast-mediated bone destruction and blocking the vicious cycle typical of cancer-mediated bone disease. As a human immunoglobulin G2 molecule, it has a long circulatory residence time and results in a rapid and sustained decrease of bone resorption in both healthy postmenopausal women and patients with bone metastases. Denosumab does not cause renal toxicity and results in fewer acute phase reactions than bisphosphonates. Denosumab is in phase IIl trials in patients with postmenopausal osteoporosis and metastatic cancer.40,41
Two phase II randomized trials are now being conducted to assess the safety and efficacy of denosumab as compared to intravenous (IV) bisphosphonates (BP) in reducing urinary markers of bone resorption in metastatic bone cancer. Interim analysis from one of these trials was reported by Lipton et al. in bisphosphonate-na’ve breast cancer patients with bone metastases showed that denosumab suppressed levels of bone turnover markers to an extent similar to that seen with intravenous bisphosphonates.41 This study enrolled 255 women who were stratified by type of antineoplastic therapy received and randomly assigned to one of six cohorts: five denosumab and one open-label IV BP. The primary endpoint for the study was median percent change in the bone turnover marker urine N-telopeptide corrected for urine creatinine (uNTx/Cr) from baseline to study week 13. Secondary endpoints included percentage of patients achieving >65% uNTx/Cr reduction, time to >65% uNTx/Cr reduction, patients experiencing one or more on-study skeletal related events (SRE), and safety. Suppression of uNTx/Cr was seen in all treatment groups. In the denosumab groups this reduction was seen at the first study visit after initial dosing and through week 13 (Figure 3).
Study Week
Source for data: Lipton A, et al. J Clin Oncol. 2006; 24(18S):6S abstract #512
Median (Q1, Q3) percentage reduction in urine N-telopeptide (uNTx) corrected for urine creatine level (INTx/Cr) from baseline through study week 25. All denosumab (subcutaneous) versus intravenous bisphosphnate (IV BP) and denosumab dose groups versus IV BP. Study week 1= baseline. Q4W= every 4 weeks; Q12W= every 12 weeks.
At 13 weeks on study the median percent reduction in uNTx/Cr was 71% for the pooled denosumab treatment groups and 79% for the IV BP group. Greater than 65% reduction in uNTx/Cr occurred in 74% of the denosumabtreated patients and 63% in the IV BP-treated patients (91% received zoledronic acid). The median time to >65% reduction in uNTx/Cr reduction was 13 and 29 days for all denosumab and IV BP treatment groups respectively.The time to the first on-study SRE appeared to be similar for patients in the denosumab and IV BP cohorts. On study SREs were experienced by 9% (20 of 211) and 16% of the denosumab and IV BP cohorts, respectively. The incidences of adverse events (AEs) were similar among the denosumab and IV BP cohorts and the pattern of the AEs were consistent with advanced cancer patients receiving systemic therapy. These early data suggest that denosumab may be similar to IV BPs in suppressing bone turnover and reducing SRE risk.
Three phase III trials are now ongoing, comparing the safety and efficacy of denosumab to zoledronic acid for the treatment of bone metastases in breast cancer, hormone-refractory prostate cancer, advanced cancer (excluding breast and prostate) and myeloma patients. A fourth phase III study being conducted is a randomized, double-blind, placebo-controlled study of denosumab on prolonging bone metastasis-free survival in men with hormone refractory prostate cancer.42 There are also two phase III clinical trials in patients with nonmetastatic cancer. The purpose of these studies is to evaluate denosumab for the treatment of bone loss in subjects undergoing aromatase inhibitor therapy for breast cancer and androgen deprivation therapy for prostate cancer.
Inhibiting Osteoclast Signaling: Inhibitors of Cathepsin K and Src
Cathepsin K is a lysosomal protease that is highly expressed in osteoclasts and plays a key role in the degradation of bone collagen. Inhibitors of cathepsin K effectively suppress bone resorption in animal tumor models.43,44 Odanacatib (formerly MK-0822, Merck & Co, Whitehouse Station) is a highly selective cathepsin K inhibitor. In a recently completed phase II trial in women with breast cancer and bone metastasis, odanacatib suppressed markers of bone resorption uNTx and UDPD after 4 weeks of treatment. 45 Another novel cathepsin K inhibitor, Balicatib (formerly AAE581, Novartis Oncology, East Hanover), has been shown to reduce breast cancer induced osteolysis and skeletal tumor burden in an animal model. Several Phase II studies have recently completed accrual in postmenopausal women with osteopenia/ osteoporosis. The primary endpoints of these trials are changes in bone mineral density.46
Src is a tyrosine kinase that is required for the formation of the ruffled border in osteoclasts. The importance of Src in osteoclast activity is revealed by Src null mice that develop osteopetrosis because of the lack of bone resorption. Inhibition of Src activity decreases skeletal destruction in animal tumor model systems.47 Dasatinib (BMS-354825, Bristol-Myers Squibb, New York), an inhibitor of multiple tyrosine kinases, is currently on the market place for the treatment of adults with resistant CML and Philadelphia chromosome positive ALL. Two phase II trials are now ongoing to assess the efficacy of dasatinib alone or in combination with zoledronic acid in patients with breast cancer and bone metastasis. In these trials changes in bone turnover markers, tumor response, progression free survival and overall survival will be evaluated.49,50 AZD0530 (AstraZeneca,Wilmington), a dual inhibitor of Src/Abl kinase inhibitor, is also being evaluated in metastatic bone cancer. 51
Chemokine Antagonists 
Stromal cell derived factor 1 (SDF-1) is a chemokine that regulates stem cell activity, and its action on cancer cells is thought to promote their migration to SDF-1-rich areas such as the bone marrow, liver, and lungs, with subsequent angiogenesis and metastasis. CTCE-9908, an analog of SDF-1 now in Phase I/II clinical testing, acts as a competitive antagonist at CXCR4 receptors commonly found on the surfaces of stem cells and various common cancers.