Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2014 Apr 24.
Published in final edited form as: Anticancer Res. 2012 Jul;32(7):2391–2398.

Novel Concepts in Pharmacotherapy of Skeletal-Related Events in Metastatic Castrate Resistant Prostate Cancer: A Focused Review

Shawn Spencer 2, Bernard L Marini 1, William D Figg 3,*
PMCID: PMC3997992  NIHMSID: NIHMS573830  PMID: 22753695

Abstract

Biphosphonates have long been the standard of care for anti-resorptive treatment of bone metastases from castrate-resistant prostate cancer (mCRPC). Although the indication has historically been mostly palliative, response rates in skeletal-related events (SRE) remain low. Denosumab has been shown to be effective in prolonging time to first SRE in clinical settings however critical questions remain on its ability to affect bone metastases in mCRPC. The landscape for research progress in reducing SREs using novel pharmacotherapies is growing rapidly with several agents in clinical trials. This focused review outlines the most promising investigational drugs for treating bone metastases in mCRPC.

Introduction

Prostate cancer is the most common malignancy among men and is associated with substantial morbidity and mortality [1]. Although localized prostate cancer (PCa) is largely curable, a significant proportion of patients will go on to develop advanced, castrate-resistant disease. The skeleton is a preferred site for metastasis of prostate cancer cells and is the primary cause of morbidity and mortality in metastatic castrate-resistant prostate cancer (mCRPC). Current data suggests approximately 33-46% of men with progressive castration-resistant nonmetastatic PCa will develop bone metastases at 2 years [2-3]. Outcomes in prostate cancer patients with metastatic bone disease (MBD) is poor, with an approximate 1-year survival rate of only 40-47%[4] and a median survival of approximately 12-24 months [5].

Our current understanding of the mechanisms of prostate cancer cells metastasizing to bone has lead to bone-targeted therapies in prostate cancer patients. The bone microenvironment represents a highly favorable site for tumor growth and invasion, involving a complex cellular interaction of osteoclasts, osteoblasts, endothelial cells, immunologic cells and tumor cells. The steps leading to prostate cell metastasis are decreased local cell adhesion and detachment of cells from the primary tumor, invasion of the stroma, angiogenesis and intravasation into the vasculature, homing of cells to the vascular endothelium, and extravasation to bone marrow endothelial cells. Tumor growth in the bone microenvironment is fueled by growth factors released during osteoclastic bone resorption, such as insulin-like growth factor (IGF), transforming growth factor beta (TGFβ). This supports proliferation of tumor cells their release of growth factors that stimulate osteoblast growth and differentiation, including endothelin-1 (ET-1), bone morphogenetic proteins (BMPs), fibroblast growth factors, platelet-derived growth factor (PDGF) and interleukin-6 (IL-6). Additionally, both osteoblasts and prostate cancer cells secrete factors that stimulate osteoclast activity, including RANKL, parathyroid hormone-related protein (PTHrP), and TGFβ [6-11]. This multifaceted cross-talk between prostate cancer cells, osteoblasts, and osteoclasts is considered a “vicious cycle” of bone metastasis in prostate cancer (see figure 1) [9].

Figure 1.

Figure 1

Open in a new tab

Tumor cells secrete factors which contribute both to osteoblastic bone formation and osteoclastic bone resorption, which releases factors stimulating tumor growth causing a “vicious cycle” of osteolytic metastases

Bone metastases decrease health-related quality of life in patients with prostate cancer leading to skeletal-related events (SRE) such as pathological bone fractures, hypercalcemia of malignancy, spinal cord compression, and the use of surgery or radiation to relieve significant bone pain [12]. NCCN clinical practice guidelines recommend either zoledronic acid or denosumab for prevention of SREs in metastatic castrate-resistant prostate cancer (mCRPC), but the preferred agent is unclear [13-14]. Furthermore, the rate of SRE remains unacceptably high with the use of these agents, creating a need for continued development of novel therapies. A considerable amount of research is ongoing regarding bisphosphonates and novel targeted therapies for prevention of SRE. This focused review will provide the investigative clinician with an update on the pharmacotherapy of bone metastases in mCRPC.

Current Use and Development of FDA and EU-Approved Agents

Bisphosphonates: Teaching an old dog new tricks

The affinity and selectivity of bisphosphonates towards hydroxyapatite in the mineralized bone matrix makes them particularly attractive agents for managing skeletal metastases. Second generation, nitrogen-containing bisphosphonates (e.g. pamidronate, zoledronate) are internalized by osteoclasts whereupon they inhibit the key enzyme farnesyl pyrophosphatase, upregulate pro-apoptotic molecules, and ultimately arrest osteoclastic bone resorption [15]. Additionally, it has been posited that bisphosphonates may have direct antitumor properties through a variety of mechanisms including inhibition of angiogenesis, immunomodulation, and induction of apoptosis [16-20]. Zoledronate, the most potent bisphosphonate currently available, has demonstrated the greatest response in decreasing the incidence of SRE in mCRPC. In a pivotal randomized controlled trial, zoledronate was associated with a significant reduction in SRE compared to placebo (44.2 vs. 33.2%, p=0.021) [21]. However, a modest absolute decrease of 11% in the frequency of SRE has led researchers to explore new ways of utilizing these agents.

Recently, several novel bisphosphonate conjugates have been synthesized in order to couple the bone-selectivity of bisphosphonates with the antitumor properties of more traditional chemotherapy. Many of these agents have shown potential in several pre-clinical models of bone metastases. A gemcitabine/bisphosphonate conjugate was utilized in a mouse model of human breast cancer bone metastases and demonstrated a reduction in the number and size of bone metastases compared to a gemcitabine alone and an untreated control group [22]. Several other bisphosphonate/chemotherapy conjugates have been synthesized that successfully inhibit a wide variety of human tumor cell lines as well as osteoclasts in vitro [23-24]. Bisphosphonates have also been successfully incorporated into nanoparticles to facilitate cytotoxic drug delivery to bone metastases. In a murine breast cancer bone metastasis model, a nanoparticle (consisting of a polymer and the bisphosphonate alendronate) loaded with doxorubicin significantly decreased the incidence and size of skeletal metastases [25]. Theoretically, this use of bone-targeted drug delivery of doxorubicin with bisphosphonates may also circumvent the considerable cardiotoxicity of this agent, although this has yet to be demonstrated in clinical trials.

Bisphosphonate-containing polymers have also been synthesized that incorporate angiogenesis inhibitors. A conjugate comprised of a copolymer backbone, alendronate, and the angiogenesis inhibitor TNP-470 produced significant anti-angiogenic effects, high localization to the bone, and a significant decrease in tumor growth in a murine osteosarcoma model. Furthermore, mice treated with the TNP-470-copolymer-alendronate conjugate demonstrated superior overall survival and decreased neurototoxicity (a well-characterized toxicity of TNP-470) compared with TNP-470 and alendronate given together, but as separate agents [26]. Considering the importance of angiogenesis in the metastasis of prostate cancer, further research of these conjugates is warranted.

Denosumab: Where does the RANK-L inhibitor rank?

Receptor activator of nuclear factor-kappa B (RANK) expressed on the surface of preosteoclasts is activated by its ligand (RANK-L) which is expressed by osteoblasts and released by activated T-cells. The binding of RANK-L to RANK triggers osteoclast formation, activation, adherence, survival, and ultimately, bone resorption. Osteoprotegerin (OPG), a decoy receptor produced by numerous cell types (including osteoblasts), binds to RANK-L and prevents the RANK:RANK-L interaction, leading to a reduction in bone resorption. In prostate cancer, metastatic tumor cells in the bone express RANK-L and also upregulate its expression in osteoblasts [27]. Thus, the critical interplay between RANK, RANK-L, and OPG in bone metabolism has become a desirable target for preventing SRE in mCRPC.

The human monoclonal antibody directed against RANKL, denosumab (AMG-162), was developed after recombinant Fc-OPG was not pursued due to concerns of possible inhibition of the TNF-related apoptosis-inducing ligand (TRAIL) antitumor pathway, as well as the generation of anti-Fc-OPG antibodies. Compared to Fc-OPG, denosumab displayed greater potency in decreasing markers of bone turnover, as well as a longer duration of antiresorptive activity [28]. A multicenter, international phase III trial conducted from 2006 to 2009 compared denosumab and zoledronic acid in the prevention of SRE in men with bone metastases in mCRPC. Results of the study, published in 2011, showed that denosumab was superior to zoledronate in delaying the time to first SRE (20.7 months vs. 17.1 months, p=0.008) and the time to first and subsequent on-study SRE (494 vs. 584 events). Adverse effects were similar between the two groups, although hypocalcemia was more common in patients receiving denosumab (13% vs 6%, p<0.0001). Overall survival and disease progression were not different between the two treatment arms [29].

Denosumab was approved by the FDA in 2010, and received approval in the EU in 2011 for the prevention of SRE in mCRPC. The cost-effectiveness of denosumab in the prevention of SRE been questioned considering the relatively modest absolute reduction in the time to first SRE of only 18% (3.6 months) compared to the less-expensive zoledronate. A recent pharmacoeconomic analysis estimated that the 1-year and 3-year estimated total direct costs per SRE avoided with denosumab compared to zoledronic acid were $71,027 and $51,319, respectively. This corresponded to a total incremental cost of $3.91 million per quality-adjusted life year (QALY) gained with denosumab at 1 year and $2.77 million per QALY gained with denosumab at 3 years, indicating that the use of denosumab may not be cost-effective in the setting of mCRPC [30]. The improvement in quality of life has also been questioned [31].

Denosumab is the first agent to show significant benefit in the reduction of SRE compared to zoledronate. However, the modest efficacy and great expense of this agent may limit its clinical utilization. Moreover, in vitro data indicate that osteoclastogenesis can occur through RANK-L independent pathways, which may explain the incomplete effect of denosumab in the prevention SRE [32]. Further research is necessary to characterize and target these alternative osteoclastogenesis pathways, as well as to elucidate the effectiveness of combinations of denosumab and other antiresorptive agents in the prevention of SRE in mCRPC.

Radiopharmaceuticals: Bone-seeking targeted therapy

The clinical efficacy of bone-targeted radiopharmaceuticals has proven beneficial in palliative relief of bone pain. A recent Cochrane systematic review revealed that radiopharmaceuticals significantly increased the frequency of complete pain relief of skeletal metastases relative to placebo (RR = 2.1) [33]. The most commonly used agents for a number of years are beta-emitting samarium-153 (sm153) and strontium-89 (sr89), and may also provide a survival advantage in mCRPC [34-35]. A recent study evaluating the effect of sr89 with docetaxel compared to zolendronate revealed that 73/101 mCRPC patients receiving docetaxel and sr89 successfully reached 6 months of chemotherapy [36], however the trial is ongoing. A phase II trial combining docetaxel with sm153 has shown a median progression-free survival (PFS) of 6.4 months reporting long-term pain relief [37], whereas another trial reports mean PFS of 7.5 months in taxane naïve patients [38]. Similar combination studies are also ongoing [39-41].

Bisphosphonates have been successfully utilized to enhance targeted radiotherapy of bone metastases. In an effort to improve the distribution and specificity of these agents to metastatic bone lesions, several radiopharmaceutical-bisphosphonate conjugates have been synthesized and have demonstrated superior biodistribution to bone compared to nonbisphosphonate-conjugated radioisotopes [42-44]. Utilizing bisphosphonates as an innovative drug delivery mechanism for radiopharmaceuticals show promise in the prevention of SRE in mCRPC, although studies in humans are needed to assess the true clinical efficacy and safety of these complexes.

Investigational Agents in Clinical Trials

Cathepsin K Inhibitors

Cathepsin K is a cysteine protease expressed by osteoclasts that cleaves collagen I, the most abundant collagen in bone, and osteoclast adherence to the bone extracellular matrix is dependent on cathepsin K activity [45]. Cathepsin K has also been shown known to cleave the glycoprotein osteonectin, resulting in high-affinity peptides that stimulate tumor angiogenesis and invasion by cancer cells. Furthermore, prostate bone tumors have been shown to upregulate both osteonectin and cathepsin K [46]. Thus, inhibition of cathepsin K represents a logical treatment modality for the prevention of SRE in mCRPC.

Odanacatib, an orally bioavailable selective cathepsin K inhibitor, has shown the most promise in clinical trials to date. Compared to other cathepsin K inhibitors (e.g. relacatib and balicatib), odanacatib is characterized by greater selectivity for cathepsin K, more potent cathepsin K inhibition, and the absence of the morphea-like skin rash that has been reported in clinical trials with balicatib [45,47]. In a double-blind, randomized controlled trial in women with breast cancer and bone metastases, odanacatib is non-inferior to zoledronic acid in the suppression of urinary N-telopeptide of type I collagen (uNTx; a marker of bone resorption) over a 4-week period (−77% vs. −73%) and was well tolerated [48]. Further studies are required to determine if this biomarker reduction corresponds to a reduction in SRE, and unfortunately, clinical trials of odanacatib in the setting of mCRPC are currently lacking. Thus, although odanacatib remains a promising agent based on its efficacy in decreasing biomarkers of bone resorption, the effectiveness of this agent for reducing SRE in mCRPC is unknown.

Inhibitors of the Endothelin Pathway

The endothelin (ET) pathway has emerged as a promising target for preventing SRE in mCRPC. ETs are a family of vasoactive peptides with varying patterns of distribution throughout the body. ET-1, the most abundant ET, is expressed primarily by endothelial cells and exerts its effect by binding to one of two target receptors, ETA or ETB. Binding of ET-1 to ETA triggers several signal transduction pathways, resulting in a broad range of physiologic effects, while ETB acts as a decoy receptor. In the setting of mCRPC, activation of ETA contributes to angiogenesis, prostate cancer proliferation and escape from apoptosis, and facilitation of the favorable skeletal microenvironment for tumor metastases [49]. Additionally, ET-1 concentrations are significantly elevated in men with mCRPC, and the endothelin pathway has been shown to enhance the pain response in models of prostate cancer-related pain [50]. Atrasentan, an ET receptor inhibitor with preferential affinity for the ETA receptor, shows promising activity in phase I and II trials in mCRPC, demonstrating decreases in cancer-related pain, a reduction in prostate-specific antigen (PSA) levels, and decreased time to disease progression compared to placebo [51-52]. However, a multinational phase III trial of 809 men with mCRPC found that although atrasentan resulted in a significant decrease in bone alkaline phosphatase (BAP) and PSA, atrasentan did not delay time to disease progression compared to placebo. Disease progression in this study was defined as any evidence of radiographic or clinical progression, and SRE were one component of the definition of clinical progression in this study. Interestingly, researchers reported that the majority of disease progression events resulted from radiographic progression, and 87% of radiographic progression events occurred in the absence of any study-defined clinical progression [53]. Thus, although atrasentan did not meet the primary outcome of time to any disease progression, this study does not rule out the potential efficacy of this agent in the prevention of SRE.

In contrast to atrasentan, zibotentan, another ETA inhibitor in clinical development, does not bind to the ETB decoy receptor [54]. Phase I studies of this agent alone and in combination with docetaxel for mCRPC have revealed that the agent is well-tolerated, with headache, peripheral edema, fatigue, nasal congestion and nausea as the most frequent adverse effects [54-55]. A phase II trial of 312 patients with mCRPC and bone metastases who were pain-free or mildly symptomatic for pain failed to demonstrate an advantage of zibotentan in the primary outcome of time to progression. However, patients treated with either dose of zibotentan experienced a significant improvement in median overall survival compared to placebo (24.5 months (10 mg) and 23.5 months (15 mg) vs 17.3 months) [56]. An extended follow up of patients enrolled in the phase II trial confirmed the benefit of zibotentan on median overall survival. Zibotentan 15 mg and 10 mg were associated with a non-significant 24% (HR, 0.76; 80% CI, 0.61–0.94; P= 0.103) and 17% (HR, 0.83; 80% CI, 0.67–1.02; P= 0.254) reduction in the risk of death compared to placebo, respectively [57]. Loss of significance in the follow-up analysis could be due to the early time-to-progression observed in the study, causing patients to stop treatment. Kaplan-Meier curves support this hypothesis, as the divergence in placebo and zibotentan curves become parallel at cessation of treatment for most patients [57]. Of particular interest in the prevention of SRE, treatment with zibotentan 10 mg resulted in a significant reduction in bone metastases at study discontinuation compared to placebo. The 15 mg dose was no different from placebo in this regard, although the number of bone metastases at baseline was higher at 15 mg doses, compared to 10 mg and placebo [57]. Phase III trials of zibotentan in mCRPC, both alone (ENTHUSE M1) and in combination with docetaxel (ENTHUSE M1c) have been completed, which will likely shed further light into the clinical utility of this agent in preventing SRE (clinicaltrials.gov).

MMP Inhibitors

Matrix metalloproteinases (MMPs) are proteases that degrade the extracellular matrix, facilitating tumor metastasis and angiogenesis. MMPs are overexpressed in the setting of mCRPC, and there is evidence that prostate cancer cells themselves secrete MMPs which aid in the degradation of the mineralized bone matrix [58]. Early-generation MMPs were associated with significant musculoskeletal toxicity, limiting their clinical usefulness. This toxicity has been attributed to inhibition of non-MMP proteases (including those of the ADAM and ADAMTS families) and their associated “sheddase” activity [59].

Rebimastat (BMS-275291) is a broad-spectrum MMP inhibitor devoid of toxicity-related inhibition of “sheddases.” A phase I trial of rebimastat in patients with advanced or metastatic cancer found the drug to be well-tolerated; arthralgia, myalgia, rash, fatigue, headache, nausea, and dysgeusia were the most common adverse reactions, all of which were grade 1 or 2 [59]. Unfortunately, a phase II trial comparing two different doses of rebimastat in 80 patients with mCRPC demonstrated a disappointing lack of efficacy, with a median progression free survival time of only 1.8 months [60]. Investigators were therefore unable to obtain serial measurements of bone resorption markers, and it remains to be seen whether rebimastat can prevent SRE in mCRPC.

Tyrosine Kinase Inhibitors

Although metastatic tumor growth is supported through induction of angiogenesis, inhibition of receptor tyrosine kinase pathways have not been extensively evaluated in clinical trials of mCRPC. This is likely due to only moderate responses [61-64] or negative effects in the mCRPC setting [65]. Inhibition of nonreceptor tyrosine kinase SRC with dasatinib however has proven to be an effective approach for inhibiting bone osteolysis due to prostate cancer metastases [66]. In a phase II study of dasatinib monotherapy in mCRPC, responses were encouraging with significant reductions in bone resorption marker urinary N-telopeptide (uNTx) and serum BAP in the majority of patients [67]. Combination studies of dasatinib with docetaxel has shown to be a promising regimen in mCRPC, with 14 of 46 patients with a disappearance of a lesion on bone scan, and 87% of patients with decreases in uNTx [68]. In a Phase I study of the SRC inhibitor saracatinib in healthy men, markers of bone resorption decreased significantly in a dose-dependent manner [69]. Another SRC inhibitor, bosutinib, causes dramatic reductions in bone lesions in preclinical models [70], but saracatinib and bosutinib have yet to be evaluated in mCRPC [71-72].

Bone metastases are associated with increased expression of tyrosine kinase MET, and cabozantinib is a dual-targeted agent that blocks both MET kinase and vascular endothelial growth factor receptor-2 (VEGFR-2) receptor. In preliminary data from phase II studies, high rates of objective response with complete or partial regression of bone metastases in 75- 85% of patients have been reported [73-74]. Moreover, median PFS in docetaxel-prereated and docetaxel-naive patients was 24 and 29 weeks respectively, with improved pain in 67% patients with painful bone metastases. The majority of patients had reductions in bone turnover markers, however was not consistent with objective responses [75]. Overall, cabozantinib appears to be clinically active in mCRPC.

Alpha-emitting Radiopharmaceuticals

Changing the landscape of radionuclide therapy are ongoing investigations with the alpha-emitter, radium-223 (223Ra) which irradiates tumors over a limited range compared to beta-particle emitters. 223Ra has a tumor to bone marrow absorbed dose ratio of 30:1 expected to result in reduced myelosuppression [76]. In a phase II trial of 223Ra in symptomatic patients with mCRPC, 223Ra was exceptionally well tolerated with median time to progression of 26 weeks accompanied by significant reductions in BAP [77]. In the phase III placebo-controlled ALSYMPCA trial, 223Ra was discontinued early due to clear evidence of a significant treatment benefit. 223Ra delayed the time to SRE from 8.4 to 13.6 months, and also significantly prolonged overall survival in symptomatic mCRPC patients [78]. It was also reported that dose-dependent normalization of BAP is associated with the survival benefit [79].

Conclusion

SRE in mCRPC are a significant clinical problem, resulting in considerable patient morbidity and mortality. FDA-approved agents for the prevention of SRE – the bisphosphonate zoledronate and the RANK-L inhibitor denosumab – have only resulted in modest reductions in incidence. The relative efficacy and safety of the cathepsin K inhibitor odanacatib and the ETA inhibitor zibotentan in phase I and II trials has underscored the need for further investigation of these agents, either alone or in combination with other proven therapies for mCRPC. Despite the paucity of robust, phase III clinical trial data with these investigational agents, much progress has been made towards developing novel therapeutic strategies aimed at reducing SRE in mCRPC.

REFERENCES

  • 1.Horner M, Ries L, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2006. National Cancer Institute; Bethesda, MD: 2009. [Google Scholar]
  • 2.Smith MR, Cook R, Lee KA, Nelson JB. Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer. 2011;117(10):2077–2085. doi: 10.1002/cncr.25762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Smith MR, Kabbinavar F, Saad F, et al. Natural history of rising serum prostatespecific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005;23(13):2918–2925. doi: 10.1200/JCO.2005.01.529. [DOI] [PubMed] [Google Scholar]
  • 4.Norgaard M, Jensen AO, Jacobsen JB, Cetin K, Fryzek JP, Sorensen HT. Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007) J Urol. 2010;184(1):162–167. doi: 10.1016/j.juro.2010.03.034. [DOI] [PubMed] [Google Scholar]
  • 5.Armstrong AJ, Tannock IF, de Wit R, George DJ, Eisenberger M, Halabi S. The development of risk groups in men with metastatic castration-resistant prostate cancer based on risk factors for PSA decline and survival. Eur J Cancer. 2010;46(3):517–525. doi: 10.1016/j.ejca.2009.11.007. [DOI] [PubMed] [Google Scholar]
  • 6.Thobe MN, Clark RJ, Bainer RO, Prasad SM, Rinker-Schaeffer CW. From Prostate to Bone: Key Players in Prostate Cancer Bone Metastasis. Cancers (Basel) 2011;3(1):478–493. doi: 10.3390/cancers3010478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Msaouel P, Pissimissis N, Halapas A, Koutsilieris M. Mechanisms of bone metastasis in prostate cancer: clinical implications. Best Pract Res Clin Endocrinol Metab. 2008;22(2):341–355. doi: 10.1016/j.beem.2008.01.011. [DOI] [PubMed] [Google Scholar]
  • 8.Clarke NW, Hart CA, Brown MD. Molecular mechanisms of metastasis in prostate cancer. Asian J Androl. 2009;11(1):57–67. doi: 10.1038/aja.2008.29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Jin JK, Dayyani F, Gallick GE. Steps in prostate cancer progression that lead to bone metastasis. Int J Cancer. 2011;128(11):2545–2561. doi: 10.1002/ijc.26024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Ye L, Kynaston HG, Jiang WG. Bone metastasis in prostate cancer: molecular and cellular mechanisms (Review) Int J Mol Med. 2007;20(1):103–111. [PubMed] [Google Scholar]
  • 11.Arya M, Bott SR, Shergill IS, Ahmed HU, Williamson M, Patel HR. The metastatic cascade in prostate cancer. Surg Oncol. 2006;15(3):117–128. doi: 10.1016/j.suronc.2006.10.002. [DOI] [PubMed] [Google Scholar]
  • 12.Weinfurt KP, Li Y, Castel LD, et al. The significance of skeletal-related events for the health-related quality of life of patients with metastatic prostate cancer. Ann Oncol. 2005;16(4):579–584. doi: 10.1093/annonc/mdi122. [DOI] [PubMed] [Google Scholar]
  • 13.Mohler J, Bahnson RR, Boston B, et al. NCCN clinical practice guidelines in oncology: prostate cancer. J Natl Compr Canc Netw. 2010;8(2):162–200. doi: 10.6004/jnccn.2010.0012. [DOI] [PubMed] [Google Scholar]
  • 14.Mottet N, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2011;59(4):572–583. doi: 10.1016/j.eururo.2011.01.025. [DOI] [PubMed] [Google Scholar]
  • 15.Green JR. Bisphosphonates: preclinical review. Oncologist. 2004;9(Suppl 4):3–13. doi: 10.1634/theoncologist.9-90004-3. [DOI] [PubMed] [Google Scholar]
  • 16.Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther. 2002;302(3):1055–1061. doi: 10.1124/jpet.102.035295. [DOI] [PubMed] [Google Scholar]
  • 17.Santini D, Vincenzi B, Avvisati G, et al. Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res. 2002;8(5):1080–1084. [PubMed] [Google Scholar]
  • 18.Castella B, Riganti C, Fiore F, et al. Immune modulation by zoledronic acid in human myeloma: an advantageous cross-talk between Vgamma9Vdelta2 T cells, alphabeta CD8+ T cells, regulatory T cells, and dendritic cells. J Immunol. 2011;187(4):1578–1590. doi: 10.4049/jimmunol.1002514. [DOI] [PubMed] [Google Scholar]
  • 19.Dumon JC, Journe F, Kheddoumi N, Lagneaux L, Body JJ. Cytostatic and apoptotic effects of bisphosphonates on prostate cancer cells. Eur Urol. 2004;45(4):521–528. doi: 10.1016/j.eururo.2003.12.012. discussion 528-529. [DOI] [PubMed] [Google Scholar]
  • 20.Nakajima H, Magae J, Tsuruga M, et al. Induction of mitochondria-dependent apoptosis through the inhibition of mevalonate pathway in human breast cancer cells by YM529, a new third generation bisphosphonate. Cancer Lett. 2007;253(1):89–96. doi: 10.1016/j.canlet.2007.01.008. [DOI] [PubMed] [Google Scholar]
  • 21.Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94(19):1458–1468. doi: 10.1093/jnci/94.19.1458. [DOI] [PubMed] [Google Scholar]
  • 22.El-Mabhouh AA, Nation PN, Abele JT, et al. A conjugate of gemcitabine with bisphosphonate (Gem/BP) shows potential as a targeted bone-specific therapeutic agent in an animal model of human breast cancer bone metastases. Oncol Res. 2011;19(6):287–295. doi: 10.3727/096504011x13021877989874. [DOI] [PubMed] [Google Scholar]
  • 23.Nakatake H, Ekimoto H, Aso M, Ogawa A, Yamaguchi A, Suemune H. Dialkyl bisphosphonate platinum(II) complex as a potential drug for metastatic bone tumor. Chem Pharm Bull (Tokyo) 2011;59(6):710–713. doi: 10.1248/cpb.59.710. [DOI] [PubMed] [Google Scholar]
  • 24.Schott H, Goltz D, Schott TC, Jauch C, Schwendener RA. N-[Alkyl-(hydroxyphosphono)phosphonate]-cytidine-new drugs covalently linking antimetabolites (5-FdU, araU or AZT) with bone-targeting bisphosphonates (alendronate or pamidronate) Bioorg Med Chem. 2011;19(11):3520–3526. doi: 10.1016/j.bmc.2011.04.015. [DOI] [PubMed] [Google Scholar]
  • 25.Salerno M, Cenni E, Fotia C, et al. Bone-targeted doxorubicin-loaded nanoparticles as a tool for the treatment of skeletal metastases. Curr Cancer Drug Targets. 2010;10(7):649–659. doi: 10.2174/156800910793605767. [DOI] [PubMed] [Google Scholar]
  • 26.Segal E, Pan H, Benayoun L, et al. Enhanced anti-tumor activity and safety profile of targeted nano-scaled HPMA copolymer-alendronate-TNP-470 conjugate in the treatment of bone malignances. Biomaterials. 2011;32(19):4450–4463. doi: 10.1016/j.biomaterials.2011.02.059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Castellano D, Sepulveda JM, Garcia-Escobar I, Rodriguez-Antolin A, Sundlov A, Cortes-Funes H. The role of RANK-ligand inhibition in cancer: the story of denosumab. Oncologist. 2011;16(2):136–145. doi: 10.1634/theoncologist.2010-0154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Schwarz EM, Ritchlin CT. Clinical development of anti-RANKL therapy. Arthritis Res Ther. 2007;9(Suppl 1):S7. doi: 10.1186/ar2171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813–822. doi: 10.1016/S0140-6736(10)62344-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Xie J, Namjoshi M, Wu EQ, et al. Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases. J Manag Care Pharm. 2011;17(8):621–643. doi: 10.18553/jmcp.2011.17.8.621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Sartor O. Denosumab in bone-metastatic prostate cancer: known effects on skeletal-related events but unknown effects on quality of life. Asian J Androl. 2011;13(4):612–613. doi: 10.1038/aja.2011.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Hemingway F, Taylor R, Knowles HJ, Athanasou NA. RANKL-independent human osteoclast formation with APRIL, BAFF, NGF, IGF I and IGF II. Bone. 2011;48(4):938–944. doi: 10.1016/j.bone.2010.12.023. [DOI] [PubMed] [Google Scholar]
  • 33.Roque IFM, Martinez-Zapata MJ, Scott-Brown M, Alonso-Coello P. Radioisotopes for metastatic bone pain. Cochrane Database Syst Rev. 2011;(7):CD003347. doi: 10.1002/14651858.CD003347.pub2. [DOI] [PubMed] [Google Scholar]
  • 34.Buchali K, Correns HJ, Schuerer M, Schnorr D, Lips H, Sydow K. Results of a double blind study of 89-strontium therapy of skeletal metastases of prostatic carcinoma. Eur J Nucl Med. 1988;14(7-8):349–351. doi: 10.1007/BF00254382. [DOI] [PubMed] [Google Scholar]
  • 35.Quilty PM, Kirk D, Bolger JJ, et al. A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol. 1994;31(1):33–40. doi: 10.1016/0167-8140(94)90411-1. [DOI] [PubMed] [Google Scholar]
  • 36.Porfiri E, Collins S, Barton D, et al. Initial feasibility and safety results from a phase II/III clinical trial to evaluate docetaxel (D) therapy in combination with zoledronic acid (ZA){±} strontium-89 (Sr89) in hormone-refractory prostate cancer patients: ISRCTN12808747. 2010. p. 4677.
  • 37.Fizazi K, Beuzeboc P, Lumbroso J, et al. Phase II trial of consolidation docetaxel and samarium-153 in patients with bone metastases from castration-resistant prostate cancer. Journal of Clinical Oncology. 2009;27(15):2429. doi: 10.1200/JCO.2008.18.9811. [DOI] [PubMed] [Google Scholar]
  • 38.Morris M, Pandit-Taskar N, Stephenson R, et al. Phase I/II study of docetaxel and 153Sm for castrate metastatic prostate cancer (CMPC): summary of dose-escalation dohorts and first report on the expansion cohort. J Clin Oncol. 2009;27(15):5057. [Google Scholar]
  • 39.Eisenberger M, Lin J, Sinibaldi V, et al. Phase I trial with a combination of docetaxel and 153 Sm-EDTMP in patients (pts) with castration-resistant metastatic prostate cancer (mCRPC) 2009. p. 5155. [DOI] [PMC free article] [PubMed]
  • 40.Tu S, Jones D, Mathew P, Logothetis C. Phase I study of concurrent weekly docetaxel (Tax) and repeated 153 Sm-lexidronam (Sam) in androgen-independent prostate cancer (AIPC) J Clin Oncol. 2008;26:5132. doi: 10.1200/JCO.2008.20.5393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Lin J, Sinibaldi V, Carducci M, et al. Phase I trial with a combination of docetaxel and (153) Sm-lexidronam in patients with castration-resistant metastatic prostate cancer. Urologic oncology. 2009 doi: 10.1016/j.urolonc.2009.10.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.El-Mabhouh A, Mercer JR. 188Re-labeled bisphosphonates as potential bifunctional agents for therapy in patients with bone metastases. Appl Radiat Isot. 2005;62(4):541–549. doi: 10.1016/j.apradiso.2004.10.004. [DOI] [PubMed] [Google Scholar]
  • 43.Ogawa K, Kawashima H, Shiba K, et al. Development of [(90)Y]DOTA-conjugated bisphosphonate for treatment of painful bone metastases. Nucl Med Biol. 2009;36(2):129–135. doi: 10.1016/j.nucmedbio.2008.11.007. [DOI] [PubMed] [Google Scholar]
  • 44.Torres Martin de Rosales R, Finucane C, Foster J, Mather SJ, Blower PJ. 188Re(CO)3-dipicolylamine-alendronate: a new bisphosphonate conjugate for the radiotherapy of bone metastases. Bioconjug Chem. 2010;21(5):811–815. doi: 10.1021/bc100071k. [DOI] [PubMed] [Google Scholar]
  • 45.Gauthier JY, Chauret N, Cromlish W, et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett. 2008;18(3):923–928. doi: 10.1016/j.bmcl.2007.12.047. [DOI] [PubMed] [Google Scholar]
  • 46.Podgorski I, Linebaugh BE, Koblinski JE, et al. Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis. Am J Pathol. 2009;175(3):1255–1269. doi: 10.2353/ajpath.2009.080906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Runger TM, Adami S, Benhamou CL, et al. Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib. J Am Acad Dermatol. 2011 doi: 10.1016/j.jaad.2010.11.033. [DOI] [PubMed] [Google Scholar]
  • 48.Jensen AB, Wynne C, Ramirez G, et al. The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial. Clin Breast Cancer. 2010;10(6):452–458. doi: 10.3816/CBC.2010.n.059. [DOI] [PubMed] [Google Scholar]
  • 49.Carducci MA, Jimeno A. Targeting bone metastasis in prostate cancer with endothelin receptor antagonists. Clin Cancer Res. 2006;12(20 Pt 2):6296s–6300s. doi: 10.1158/1078-0432.CCR-06-0929. [DOI] [PubMed] [Google Scholar]
  • 50.Yuyama H, Koakutsu A, Fujiyasu N, et al. Inhibitory effects of a selective endothelin-A receptor antagonist YM598 on endothelin-1-induced potentiation of nociception in formalin-induced and prostate cancer-induced pain models in mice. J Cardiovasc Pharmacol. 2004;44(Suppl 1):S479–482. doi: 10.1097/01.fjc.0000166309.63808.5f. [DOI] [PubMed] [Google Scholar]
  • 51.Carducci MA, Nelson JB, Bowling MK, et al. Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics. J Clin Oncol. 2002;20(8):2171–2180. doi: 10.1200/JCO.2002.08.028. [DOI] [PubMed] [Google Scholar]
  • 52.Carducci MA, Padley RJ, Breul J, et al. Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J Clin Oncol. 2003;21(4):679–689. doi: 10.1200/JCO.2003.04.176. [DOI] [PubMed] [Google Scholar]
  • 53.Carducci MA, Saad F, Abrahamsson PA, et al. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer. 2007;110(9):1959–1966. doi: 10.1002/cncr.22996. [DOI] [PubMed] [Google Scholar]
  • 54.Schelman WR, Liu G, Wilding G, Morris T, Phung D, Dreicer R. A phase I study of zibotentan (ZD4054) in patients with metastatic, castrate-resistant prostate cancer. Invest New Drugs. 2011;29(1):118–125. doi: 10.1007/s10637-009-9318-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Trump DL, Payne H, Miller K, et al. Preliminary study of the specific endothelin a receptor antagonist zibotentan in combination with docetaxel in patients with metastatic castration-resistant prostate cancer. Prostate. 2011;71(12):1264–1275. doi: 10.1002/pros.21342. [DOI] [PubMed] [Google Scholar]
  • 56.James ND, Caty A, Borre M, et al. Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial. Eur Urol. 2009;55(5):1112–1123. doi: 10.1016/j.eururo.2008.11.002. [DOI] [PubMed] [Google Scholar]
  • 57.James ND, Caty A, Payne H, et al. Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic for pain: a double-blind, placebo-controlled, randomized Phase II trial. BJU Int. 2010;106(7):966–973. doi: 10.1111/j.1464-410X.2010.09638.x. [DOI] [PubMed] [Google Scholar]
  • 58.Nemeth JA, Yousif R, Herzog M, et al. Matrix metalloproteinase activity, bone matrix turnover, and tumor cell proliferation in prostate cancer bone metastasis. J Natl Cancer Inst. 2002;94(1):17–25. doi: 10.1093/jnci/94.1.17. [DOI] [PubMed] [Google Scholar]
  • 59.Rizvi NA, Humphrey JS, Ness EA, et al. A phase I study of oral BMS-275291, a novel nonhydroxamate sheddase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer. Clin Cancer Res. 2004;10(6):1963–1970. doi: 10.1158/1078-0432.ccr-1183-02. [DOI] [PubMed] [Google Scholar]
  • 60.Lara PN, Jr., Stadler WM, Longmate J, et al. A randomized phase II trial of the matrix metalloproteinase inhibitor BMS-275291 in hormone-refractory prostate cancer patients with bone metastases. Clin Cancer Res. 2006;12(5):1556–1563. doi: 10.1158/1078-0432.CCR-05-2074. [DOI] [PubMed] [Google Scholar]
  • 61.Pezaro C, Rosenthal MA, Gurney H, et al. An open-label, single-arm phase two trial of gefitinib in patients with advanced or metastatic castration-resistant prostate cancer. Am J Clin Oncol. 2009;32(4):338–341. doi: 10.1097/COC.0b013e31818b946b. [DOI] [PubMed] [Google Scholar]
  • 62.Dror Michaelson M, Regan MM, Oh WK, et al. Phase II study of sunitinib in men with advanced prostate cancer. Ann Oncol. 2009;20(5):913–920. doi: 10.1093/annonc/mdp111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Whang YE, Armstrong AJ, Rathmell WK, et al. A phase II study of lapatinib, a dual EGFR and HER-2 tyrosine kinase inhibitor, in patients with castration-resistant prostate cancer. Urol Oncol. 2011 doi: 10.1016/j.urolonc.2010.09.018. [DOI] [PubMed] [Google Scholar]
  • 64.Dahut WL, Scripture C, Posadas E, et al. A phase II clinical trial of sorafenib in androgen-independent prostate cancer. Clin Cancer Res. 2008;14(1):209–214. doi: 10.1158/1078-0432.CCR-07-1355. [DOI] [PubMed] [Google Scholar]
  • 65.Mathew P, Tannir N, Tu SM, et al. Accelerated disease progression in prostate cancer and bone metastases with platelet-derived growth factor receptor inhibition: observations with tandutinib. Cancer Chemother Pharmacol. 2011;68(4):889–896. doi: 10.1007/s00280-011-1567-2. [DOI] [PubMed] [Google Scholar]
  • 66.Koreckij T, Nguyen H, Brown LG, Yu EY, Vessella RL, Corey E. Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis. Br J Cancer. 2009;101(2):263–268. doi: 10.1038/sj.bjc.6605178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Yu EY, Wilding G, Posadas E, et al. Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res. 2009;15(23):7421–7428. doi: 10.1158/1078-0432.CCR-09-1691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Araujo JC, Mathew P, Armstrong AJ, et al. Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study. Cancer. 2012;118(1):63–71. doi: 10.1002/cncr.26204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Hannon RA, Clack G, Rimmer M, et al. Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: a randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial. J Bone Miner Res. 2010;25(3):463–471. doi: 10.1359/jbmr.090830. [DOI] [PubMed] [Google Scholar]
  • 70.Rabbani SA, Valentino ML, Arakelian A, Ali S, Boschelli F. SKI-606 (Bosutinib) blocks prostate cancer invasion, growth, and metastasis in vitro and in vivo through regulation of genes involved in cancer growth and skeletal metastasis. Mol Cancer Ther. 2010;9(5):1147–1157. doi: 10.1158/1535-7163.MCT-09-0962. [DOI] [PubMed] [Google Scholar]
  • 71.Campone M, Bondarenko I, Brincat S, et al. Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy. Annals of Oncology. 2011 doi: 10.1093/annonc/mdr261. [DOI] [PubMed] [Google Scholar]
  • 72.Hussain A, Evans C, Hannon R, et al. A phase II, randomized, open-label, pilot study to evaluate the safety and the effects on bone resorption of saracatinib (AZD0530) in patients with prostate cancer or breast cancer with metastatic bone disease. Bone. 2011;48(1):S17–S17. [Google Scholar]
  • 73.Stockwell S. Dual-Targeted Agent Cabozantinib Shows Early Activity in Common Solid Tumors & Bone Metastases. Oncology Times. 2011 [Google Scholar]
  • 74.Laino C. Prostate cancer: promising results with cabozantinib, abiraterone, and degarelix. Oncology Times UK. 2011;8(4):9. [Google Scholar]
  • 75.Hussain M, Smith M, Sweeney C, et al. Cabozantinib (XL184) in Metastatic Castration Resistant Prostate Cancer (mCRPC): Results From a Phase 2 Randomized Discontinuation Trial. J Clin Oncol. 2011;29(Suppl) (293s), (Abstr 4516) [Google Scholar]
  • 76.Nilsson S, Larsen RH, Fossa SD, et al. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res. 2005;11(12):4451–4459. doi: 10.1158/1078-0432.CCR-04-2244. [DOI] [PubMed] [Google Scholar]
  • 77.Nilsson S, Franzen L, Parker C, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8(7):587–594. doi: 10.1016/S1470-2045(07)70147-X. [DOI] [PubMed] [Google Scholar]
  • 78.Parker C, Heinrich D, O’Sullivan J, et al. Overall Survival Benefit of Radium-223 Chloride (Alpharadin™) in the Treatment of Patients with Symptomatic Bone Metastases in Castration-resistant Prostate Cancer (CRPC): a Phase III Randomized Trial (ALSYMPCA) European Journal of Cancer. 2011;47:3. [Google Scholar]
  • 79.Nilsson S, O’Bryan-Tear C, Bolstad B, Lokna A, Parker C. Alkaline phosphatase (ALP) normalization and overall survival in patients with bone metastases from castration-resistant prostate cancer (CRPC) treated with radium-223. J Clin Oncol. 2011;29(Suppl):a4620. (318s) [Google Scholar]

RESOURCES