Efficacy of Bisphosphonates and Other Bone-Targeted Agents in Metastatic Bone Disease From Solid Tumors Other Than Breast and Prostate Cancers

Syed Mustafa Karim, MD, Janet Brown, MD, and Jamal Zekri, MD

Clinical Advances in Hematology & Oncology

May 2013, Volume 11, Issue 5


Syed Mustafa Karim, MD, Janet Brown, MD, and Jamal Zekri, MD

Dr. Karim is a Consultant in Medical Oncology at King Faisal Specialist Hospital and Research Center in Jeddah, Saudi Arabia. Dr. Brown is a Senior Clinical Lecturer/Consultant in Medical Oncology at the University of Leeds, St James’s Hospital, Cancer Research UK Clinical Centre in Leeds, United Kingdom. Dr. Zekri is a Consultant in Medical Oncology at King Faisal Specialist Hospital and Research Center in Jeddah, Saudi Arabia.

Address correspondence to: Syed Mustafa Karim, MD, MBC-J64, PO Box 40047, King Faisal Specialist Hospital and Research Center, Jeddah 21499, Saudi Arabia; Phone: 966-2-667-7777; E-mail: skarim@kfshrc.edu.sa


Bone is the most common site for metastases in cancer patients and has been intensively studied in breast and prostate cancers, largely because of the prevalence of these diseases and the particularly high rates of skeletal metastasis.1 However, bone metastases are more common than often realized in a wide range of malignancies. For example, clinically and at the time of autopsy, 20–50% of patients with lung, thyroid, and kidney cancers have bone metastases (Table 1).2-9 The lung is the most common site of metastasis in renal cell carcinoma (RCC), but bone metastases occur in 20–35% of patients with advanced disease.4 Similarly, while malignant melanoma is known to metastasize mostly to visceral organs, a recent study reported that 18% of patients with stage IV malignant melanoma had bone metastases.9

Increased bone resorption is the hallmark of metastatic bone disease (MBD) leading to skeletal-related events (SREs), which include bone pain requiring radiotherapy or surgery, pathological fracture, spinal cord compression, and hypercalcemia. Without treatment to reduce bone resorption, it is estimated that patients with bone metastases from advanced cancer will experience, on average, 2–4 SREs per year.10 Bisphosphonates are a class of bone-targeting agents that primarily inhibit osteoclast function and therefore decrease bone resorption; other functions of bisphosphonates include anti-tumor effects.11 Several bisphosphonates, which may be given orally or intravenously, have been developed for the treatment of bone loss and MBD. One of the most potent agents is the nitrogen-containing bisphosphonate zoledronic acid (ZA), which is now widely used as a standard of care in reducing the incidence of SREs in MBD.

This review highlights the clinical data underpinning the role of bisphosphonates, with special reference to ZA in the management of MBD from solid tumors other than breast and prostate. It also discusses a wider adoption of newer agents, such as denosumab (Xgeva, Amgen), and other bone-targeting drugs in development.

Studies Assessing Clodronate and Ibandronate

Only a few trials have assessed bisphosphonates for the treatment of MBD from solid tumors other than breast and prostate cancers. An early trial investigated the relatively less potent bisphosphonate clodronate in 66 patients with poorly responsive tumors, such as non–small cell lung cancer (NSCLC), bladder cancer, gastrointestinal cancers, kidney cancer, melanoma, and metastatic carcinoma of unknown origin. Only 50 patients were followed for more than 2 months and were able to be adequately evaluated. At 3 months, clodronate did not significantly reduce the pain score, but analgesic consumption was considerably reduced.12

Ibandronate, the more potent nitrogen bisphosphonate, was investigated in a randomized placebo-controlled trial in 77 patients with bone metastases from colorectal cancer. Ibandronate significantly reduced the proportion of patients with SREs (39% vs 78%; P=.019), prolonged the time to first event by at least 6 months (median, >279 days vs 93 days; P=.009), and significantly reduced the skeletal morbidity rate (mean, 2.36 vs 3.14; P=.018).13

Studies of Zoledronic Acid in Multiple Tumor Types

ZA is a highly potent nitrogen bisphosphonate that has been shown to be effective in the treatment of skeletal complications in 3 large registration trials. These studies included patients with bone metastases secondary to breast and prostate carcinomas.14,15 Also, in a randomized phase III trial, ZA was compared to placebo in 773 patients with bone metastases from solid tumors other than breast and prostate.16 Patients had advanced-stage malignancies, with more than 20 tumor types represented. Among enrolled patients, 378 had NSCLC (50%), 74 patients (10%) had RCC, 58 patients (8%) had small cell lung carcinoma, 17 patients had carcinoma of the head and neck (2%), and 11 patients had thyroid carcinoma (1%). Unknown and other types of primary tumors accounted for approximately 7% and 23%, respectively, of the remaining diagnoses. Intravenous ZA (4 mg or 8 mg) was administered every 3 weeks for 9 months, with concomitant antineoplastic therapy. The 8-mg dose was reduced to 4 mg (8/4-mg group) for renal safety reasons. The primary efficacy analysis was the proportion of patients with at least 1 SRE. ZA reduced the proportion of patients with an SRE and increased the time to first SRE.

Overall, ZA was well tolerated, and the treatment duration was extended to 21 months. An updated publication in 2004 reported the results after the extension phase of treatment.17 Efficacy conclusions were not drawn from the 8/4-mg dose group because of the heterogeneity of the dose. The report confirmed the efficacy of ZA (4 mg) in decreasing the proportion of SREs, the annual incidence of SREs, and time to development of first SRE. A multiple-event analysis was carried out to account for the absolute number of SREs and for the timing between them in order to provide a more sensitive assessment of the risk of skeletal complications between the 2 treatment groups. Using this multiple-event analysis, a hazard ratio (HR) of 0.693 indicated a 31% reduction in the risk of developing SREs in patients treated with ZA (Table 2).

There was also a trend toward a small decrease in Eastern Cooperative Group Performance Status (ECOG PS) scores at the end of the study for patients who received ZA 4 mg versus patients who received placebo (with a lower number denoting better performance status). At 21 months, the mean increase in ECOG PS was 0.99 +/- 1.20 for the ZA 4 mg group and 1.20 +/- 1.22 for the placebo group (P=.080). Biochemical markers of bone resorption tended to remain stable or increase slightly from baseline in patients treated with placebo. However, in patients treated with 4 mg of ZA, urinary levels of N-telopeptide and deoxypyridinoline decreased significantly from baseline. Long-term administration of ZA at a dose of 4 mg was found to be safe and well tolerated. The percentage of patients with increased serum creatinine was 10.9% for the 4-mg dose and 12.7% for the 8/4-mg group, versus 6.7% with placebo. Adjusting the treatment dose of ZA from 8 mg to 4 mg and the infusion time from 5 minutes to 15 minutes reduced grade 3 or 4 serum creatinine increases to 1.8% for the 4-mg dose, 1.1% for the 8/4-mg dose, and 1.8% for the placebo group.

Unlike earlier bisphosphonate trials, where there was no benefit demonstrated in solid tumors other than breast and prostate, this large, positive, registration trial led to ZA being licensed to prevent SREs in this patient population, and has become the standard of care in many countries.

Studies of Zoledronic Acid in Individual Solid Tumor Types

Few trials have investigated ZA in patients with 1 particular solid tumor. However, a retrospective subset analysis of patients with RCC who were enrolled in the above ZA registration study was performed, and results were published separately.18 In this subset of 74 patients, ZA (4 mg) was found to significantly reduce the proportion of patients with an SRE (37% vs 74% for placebo; P=.015). Similarly, ZA significantly reduced the mean skeletal morbidity rate (2.68 vs 3.38 for placebo; P=.014), extended the time to the first event (median not reached vs 72 days for placebo; P=.006), and extended time to first pathological fracture (median not reached vs 168 days for placebo; P=.003). A multiple-event analysis demonstrated that the risk of developing an SRE was reduced by 61% compared with placebo (HR, 0.394; P=.008). The median time to progression of bone lesions was significantly longer for patients who were treated with ZA (P=.014). The median overall survival showed a trend favoring ZA (295 days for ZA vs 216 days for placebo), but did not achieve statistical significance (P=.179).

The efficacy of ZA was investigated in a small, prospective, randomized, placebo-controlled trial that involved patients with bone metastases from urinary bladder cancer who were receiving palliative radiotherapy.19 Forty patients were randomized to placebo or ZA for 6 months. Patients receiving ZA had a lower mean incidence of SREs (2.05 +/- 1.0 vs 0.95 +/- 0.9, respectively), and fewer patients experienced an on-study SRE (2 vs 8 patients, respectively). ZA also prolonged the median time to first SRE compared with placebo (16 weeks vs 8 weeks, respectively). Multiple-event analysis of SREs revealed that ZA decreased the risk of SRE development by 59% (HR, 0.413). ZA also increased the 1-year survival rate compared with placebo (36.3 +/- 11.2 vs 0%, respectively).

In a retrospective study of 803 patients with renal cancer who were treated at a single center, 32% (N=254) presented with or later developed bone metastases, and 83% of these patients also developed metastases elsewhere.20 The mean number of SREs experienced by the bone metastatic patients was 2.4; only 37 patients experienced no SREs. The skeletal morbidity rate (number of SREs per patient-years at risk) for patients who received or did not receive bisphosphonates was 1.0 and 1.4, respectively.

In a study of 144 patients with bone metastases from lung cancer (non-randomized), 87 patients experienced bone pain and received ZA 4 mg, and 57 patients received no ZA.21 All patients received the same chemotherapy (docetaxel and carboplatin). Patients who received ZA had a statistically significant longer survival (P<.01). A statistically significant positive correlation was found between the number of cycles of therapy with ZA and overall survival (P<.01, Pearson correlation), as well as time to tumor progression (P<.01). These findings suggest that ZA may have an anti-tumor effect. In another study of 150 patients with stage III and IV lung cancer who were receiving chemotherapy, patients were randomized 2:1 to receive monthly ZA (maximum, 12 months) or no ZA. However, treatment with ZA failed to demonstrate an advantage in progression-free survival or overall survival.22

Comparison of Zoledronic Acid With Other Bisphosphonates

In breast cancer patients with at least 1 osteolytic lesion, ZA has shown superiority to pamidronate in delaying time to first SRE.23 However, such comparisons are less well-documented in patients with solid tumors other than breast or prostate. In a Chinese study, 228 patients with bone pain induced by MBD from solid tumors and multiple myeloma were randomized to receive ZA or pamidronate. Both treatments reduced pain and bone resorption markers and were comparable in efficacy and tolerability.24

Another study compared the pain-relieving efficacy of ZA with ibandronate and pamidronate. Of the 280 patients accrued in the study, 187 were eligible for final analysis. Forty-five of these patients had breast or prostate cancer, 78 patients had lung cancer, 22 patients had gastrointestinal malignancy, 21 patients had bone and soft tissue cancer, and 21 patients had other primary malignancies. Patients were randomized to receive ZA, pamidronate, or ibandronate. There was no difference in pain scores among the 3 treatment arms assessed at 3 months. However, the pain scores at 6 months were significantly reduced in the ZA arm as compared to the other 2 arms. Also, the rate of hypercalcemia was significantly reduced among patients treated with ZA (28.3%) compared to patients who received ibandronate (44.6%) and pamidronate (50%) treatment (P=.041).25

Comparison of Zoledronic Acid With Denosumab

Denosumab is a fully humanized monoclonal antibody that binds to the receptor activator of nuclear factor kappa-B ligand (RANKL), inhibiting osteoclast activity in the bone, which results in decreased bone resorption. A recent study compared denosumab with ZA in terms of delaying or preventing SREs in patients with advanced cancer (excluding breast and prostate cancers) and bone metastases.26 Of note, this study included patients with multiple myeloma (180 out of 1,776 patients). The results of this study showed non-inferiority of denosumab to ZA in delaying time to first SRE as its primary endpoint. There was no difference in overall survival or disease progression between the 2 arms. However, a subgroup analysis of the largest group showed a survival advantage in the denosumab arm among the lung cancer group (including NSCLC). Future studies powered to further investigate this potential benefit are currently planned. The adverse effect profiles of the 2 agents were similar, though with lower (non-significant) incidence of renal adverse events and no acute-phase reaction in the denosumab arm. Another advantage of denosumab is that it is administered subcutaneously rather than by intravenous infusion, as is the case for ZA.

The Use of Bone Markers in Metastatic Bone Disease

Many biomarkers of the pathways occurring in bone metabolism have now been described, including those which have special relevance to metastatic bone disease. A detailed account of such bone markers is beyond the scope of this article, and there are already more detailed reviews on this topic.27,28 However, the use of bone markers in monitoring the effects of bisphosphonates and other bone-targeted therapies is worthy of mention.

An analysis of bone markers measured prospectively in the placebo arm of a registration trial for ZA examining patients with NSCLC and other solid tumors showed that high levels of the bone resorption marker N-telopeptide of type I collagen (NTX) were a strong prognostic indicator of negative outcomes.29 For patients with NSCLC and solid tumors other than breast and prostate, those with high N-telopeptide levels had an increased relative risk (RR) of SREs (RR, 1.79; 95% CI, 1.15–2.79; P=.010), disease progression (RR, 1.91; 95% CI, 1.16–3.15; P=.011), and death (RR, 2.67; 95% CI, 1.85–3.85; P<.001) compared with patients with low N-telopeptide levels. Corresponding analyses in the ZA arm of this trial showed that, when compared with low NTX levels, high NTX levels were associated with a fourfold to sixfold increase in the risk of death on study, and moderate NTX levels were associated with a twofold to fourfold increase in the risk of death on study (P<.001).30

In further analyses of all 3 ZA registration trials, normalization of NTX after 3 months of bisphosphonate treatment was associated with improvement in overall survival.  Among the 291 patients with NSCLC and solid tumors other than breast and prostate who were treated with ZA, results showed that in patients with abnormal elevated baseline pretreatment levels of NTX, normalization of NTX occurred in 81% of patients treated with ZA and in 17% of patients treated with placebo. Risk of death was reduced in patients who were treated with ZA and had normalized NTX (RR of death, 0.43; 95% CI, 0.22–0.83; P=.0116) versus patients whose NTX remained elevated.31

A further illustration of the value of bone markers in trials of MBD is demonstrated by a phase II study of denosumab versus ZA (N=111), which included patients with solid tumors other than breast and prostate (n=15), who had elevated NTX despite ongoing bisphosphonate therapy.32 Bone resorption was further suppressed in a higher percentage of patients who were treated with denosumab compared with those treated with ZA, as demonstrated by the number of patients with urinary NTX levels less than 50 nM (64% vs 37%, respectively) at week 13 of the study.

New and Emerging Bone-Targeted Therapies

In recent years, a greater understanding of the biology of the bone metastatic process has led to a number of promising targets for novel agents. Elucidation of the RANK/RANK-L/osteoprotegerin axis led directly to denosumab, and other agents that target molecules in the bone metastasis pathway are in development. These include Src kinase inhibitors (such as dasatinib [Sprycel, Bristol-Myers Squibb], saracatinib, bosutinib [Bosulif, Pfizer], and cathepsin K inhibitors.33,34 Alpharadin (223RaCl2), an α‑particle–emitting agent that localizes in bone, is very promising and has shown a survival benefit in a phase III study of patients with castration-resistant prostate cancer.35 An especially interesting recent development concerns the potential use of skeletal anabolic agents. Sclerostin is a protein that is a potent inhibitor of osteoblastogenesis. Monoclonal antibodies to sclerostin, while still in the early stages of development, present new opportunities and may be especially valuable in diseases such as renal cancer, where the lesions are predominantly lytic.36 As expected, the first groups to be assessed with such new agents are patients with breast and prostate cancer. However, there is every reason to believe that these treatments could be utilized in other solid tumors.

Survival and Possible Anti-Tumor Effect of Zoledronic Acid and Denosumab

Intriguingly, there is growing evidence suggesting that ZA improves progression-free survival and overall survival in patients with advanced cancer,13-15 possibly due to direct and indirect anti-tumor effects.11,37 Large adjuvant trials with ZA are ongoing or have recently been completed. The 3,360-patient AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) study in breast cancer38 compared adjuvant ZA given for 5 years with no adjuvant therapy. At a median follow-up of 59 months, there was no difference between groups in the primary endpoint, with a disease-free survival rate of 77% in each group (adjusted HR in the ZA group, 0.98; 95% CI, 0.85–1.13; P=.79). However, among postmenopausal patients, the rates of invasive-disease–free survival were 78.2% in the ZA group and 71.0% in the control group (adjusted HR with ZA, 0.75; 95% CI, 0.59–0.96; P=.02) In addition, among patients who had undergone menopause more than 5 years earlier, the 5-year overall survival rate was 84.6% in the ZA group and 78.7% in the control group (adjusted HR, 0.74; 95% CI, 0.55–0.98; P=.04).

In a randomized, placebo-controlled trial of 1,432 men with castration-resistant prostate cancer and no bone metastases, denosumab significantly increased bone-metastasis–free survival by a median of 4.2 months compared with placebo (median, 29.5 months vs 25.2 months; HR, 0.85; 95% CI, 0.73–0.98; P=.028). Denosumab also significantly delayed time to first bone metastasis (33.2 months vs 29.5 months; HR, 0.84; 95% CI, 0.71–0.98; P=.032). However, overall survival did not differ between the 2 groups.39

Further studies of adjuvant use of bisphosphonates are being conducted in patients with breast, prostate, and lung cancer. Because of a subgroup analysis40 of the phase III denosumab study33 (mentioned earlier) showing a survival advantage for denosumab over ZA in lung cancer patients, a study is planned to look at this patient subgroup in more detail. However, no data are currently available regarding the efficacy of bisphosphonates or other bone-targeted therapies in the adjuvant setting for other solid tumors.

Safety and Toxicity of Bone-Targeted Agents

Bisphosphonates have been administered for many years, both in the postmenopausal osteoporosis setting and in the MBD setting. During this time, the potency of the bisphosphonates commonly used has progressively increased, culminating in the nitrogen-containing bisphosphonates, ZA and ibandronate. The higher and more intensive dosing regimens used in treating MBD as compared with osteoporosis can result in significant toxicity and side effects. For example, intravenous bisphosphonates such as ZA are associated with an acute, flu-like reaction on first use, and may have adverse effects on renal function, sometimes necessitating dose reduction.41 Although relatively rare, the most serious associated toxicity is osteonecrosis of the jaw (ONJ). This is a severe condition that is strongly linked to poor dental health, especially that leading to tooth extraction.42 ONJ is also associated with denosumab treatment, at approximately the same incidence as with ZA. The incidence and management of ONJ has become much more understood in recent years, and preventative measures, such as avoidance of tooth extraction and good dental health, are now emphasized. In recent trials, the cumulative incidence of ONJ has been approximately 1–2% per year.42


Relatively fewer clinical trial data are available regarding the use of bisphosphonates and other bone-targeted agents in patients with metastatic bone disease from primary tumors other than breast and prostate cancer. The available studies strongly suggest a benefit with bisphosphonates, particularly ZA, in terms of improvement in symptoms and a decrease in SREs. Denosumab has been shown to have a similar efficacy to ZA in this patient population, but has a relatively convenient mode of administration (subcutaneous) and is not associated with renal toxicity. However, despite these advances, SREs still occur. There is clear evidence for the use of ZA and denosumab in patients with bone metastases arising from solid tumors other than breast and prostate, and it is important to consider treatment with a bone-targeted therapy in such patients. There is reason to be optimistic that agents currently in development, either alone or in combinations with currently licensed bone-targeted therapy, will further improve prospects for these patients.


1. Galasko C. The anatomy and pathways of skeletal metastases. In: Weiss L, Gilbert A, eds. Bone Metastases. Boston, MA: GK Hall; 1981:49-63.

2. Toloza EM, Harpole L, McCrory DC. Noninvasive staging of non-small cell lung cancer: a review of the current evidence. Chest. 2003;123(1 suppl):137S.

3. Sugiura H, Yamada K, Sugiura T, Hida T, Mitsudomi T. Predictors of survival in patients with bone metastasis of lung cancer. Clin Orthop Relat Res. 2008;466:729-736.

4. Zekri J, Ahmed N, Coleman RE, Hancock BW. The skeletal metastatic complications of renal cell carcinoma. Int J Oncol. 2001;19:379-382.

5. Wood SL, Brown JE. Skeletal metastasis in renal cell carcinoma: current and future management options. Cancer Treat Rev. 2012;38:284-291.

6. Pittas AG, Adler M, Fazzari M, et al. Bone metastases from thyroid carcinoma: clinical characteristics and prognostic variables in one hundred forty-six patients. Thyroid. 2000;10:261-268.

7. Tickoo SK, Pittas AG, Adler M, et al. Bone metastases from thyroid carcinoma: a histopathologic study with clinical correlates. Arch Pathol Lab Med. 2000;124:1440-1447.

8. Bernier M, Leenhardt L, Hoang C, et al. Survival and therapeutic modalities in patients with bone metastases of differentiated thyroid carcinomas. J Clin Endocrinol Metabol. 2001;86:1568-1573.

9. Kandukurti K, Zekri J, Marples M, Brown J. Skeletal metastases in malignant melanoma. Cancer Treat Rev. 2008;34:18.

10. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12:6243s-6249s.

11. Ottewell PD, Mönkkönen H, Jones M, Lefley DV, Coleman RE, Holen I. Antitumor effects of doxorubicin followed by zoledronic acid in a mouse model of breast cancer. J Natl Cancer Inst. 2008;100:1167-1178.

12. Piga A, Bracci R, Ferretti B, et al. A double blind randomized study of oral clodronate in the treatment of bone metastases from tumors poorly responsive to chemotherapy. J Exp Clin Cancer Res. 1998;17:213-217.

13. Heras P, Karagiannis S, Kritikos K, Hatzopoulos A, Mitsibounas D. Ibandronate is effective in preventing skeletal events in patients with bone metastases from colorectal cancer. Eur J Cancer Care. 2007;16:539-542.

14. Berenson JR, Rosen LS, Howell A, et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer. 2001;91:1191.

15. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96:879.

16. Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial-the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol. 2003;21:3150-3157.

17. Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial. Cancer. 2004;100:2613-2621.

18. Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer. 2003;98:962-969.

19. Zaghloul MS, Boutrus R, El-Hossieny H, Kader YA, El-Attar I, Nazmy M. A prospective, randomized, placebo-controlled trial of zoledronic acid in bony metastatic bladder cancer. Int J Clin Oncol. 2010;15:382-389.

20. Woodward E, Jagdev S, McParland L, et al. Skeletal complications and survival in renal cancer patients with bone metastases. Bone. 2011;48:160-166.

21. Zarogoulidis K, Boutsikou E, Zarogoulidis P, et al. The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis. Int J Cancer. 2009;125:1705-1709.

22. Pandya KJ, Gajra A, Warsi GM, et al. Multicenter, randomized, phase 2 study of zoledronic acid in combination with docetaxel and carboplatin in patients with unresectable stage IIIB or stage IV non-small cell lung cancer. Lung Cancer. 2010;67:330-338.

23. Rosen LS, Gordon DH, Dugan W Jr, et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer. 2004;100:36-43.

24. Dong M, Feng FY, Zhang Y, et al. Phase III clinical study of zoledronic acid in the treatment of pain induced by bone metastasis from solid tumor or multiple myeloma. Zhonghua Zhong Liu Za Zhi. 2008;30:215-220.

25. Choudhury KB, Mallik C, Sharma S, Choudhury DB, Maiti S, Roy C. A randomized controlled trial to compare the efficacy of bisphosphonates in the management of painful bone metastasis. Indian J Palliat Care. 2011;17:210-218.

26. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29:1125-1132.

27. Brown JE, Sim S. Evolving role of bone biomarkers in castration-resistant prostate cancer. Neoplasia. 2010;12:685-696.

28. Coleman R, Costa L, Saad F, et al. Consensus on the utility of bone markers in the malignant bone disease setting. Crit Rev Oncol Hematol. 2011;80:411-432.

29. Brown JE, Cook RJ, Major P, et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst. 2005;97:59-69.

30. Coleman RE, Major P, Lipton A, et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol. 2005;23:4925-4935.

31. Lipton A, Cook R, Saad F, et al. Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid. Cancer. 2008;113:193-201.

32. Fizazi A, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol. 2009;27:1564-1571.

33. 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;15:7421-7428.

34. Gucalp A, Sparano JA, Caravelli J, et al. Phase II trial of saracatinib (AZD0530), an oral SRC-inhibitor for the treatment of patients with hormone receptor-negative metastatic breast cancer. Clin Breast Cancer. 2011;11:306-311.

35. Parker C, Heinrich D, O’Sullivan JM, 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). Eur J Cancer. 2011;47(S2):3.

36. van Lierop AH, Hamdy NA, Hamersma H, et al. Patients with sclerosteosis and disease carriers: human models of the effect of sclerostin on bone turnover. J Bone Miner Res. 2011;26:2804-2811.

37. Almubarak H, Jones A, Chaisuparat R, Zhang M, Meiller TF, Scheper MA. Zoledronic acid directly suppresses cell proliferation and induces apoptosis in highly tumorigenic prostate and breast cancers. J Carcinog. 2011;10:2.

38. Coleman R, Marshall H, Cameron D, et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med. 2011;365:1396-1405.

39. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012;379:39-46.

40. Scagliotti GV, Hirsh V, Siena S, et al. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol. 2012;7:1823-1829.

41. Lipton A. The safety of zoledronic acid. Expert Opin Drug Saf. 2007;6:305-313.

42. Saad F, Brown JE, Van Poznak C, et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol. 2012;23:1341-1347.

43. Lipton A, Uzzo R, Amato RJ, et al. The science and practice of bone health in oncology: managing bone loss and metastasis in patients with solid tumors. J Natl Compr Canc Netw. 2009;7(suppl 7):S1-S30.

44. Kuru B, Camlibel M, Dinc S, Gulcelik MA, Gonullu D, Alagol H. Prognostic factors for survival in breast cancer patients who developed distant metastasis subsequent to definitive surgery. Singapore Med J. 2008;49:904.

45. Yavas O, Hayran M, Ozisik Y. Factors affecting survival in breast cancer patients following bone metastasis. Tumori. 2007;93:580-586.

46. Solomayer EF, Diel IJ, Meyberg GC, Gollan C, Bastert G. Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat. 2000;59:271-278.

47. Huang CY, Hsu H, Chang C, Tseng KF, Fong Y. Prostate cancer with bone metastases: a clinical profile. Mid Taiwan J Med. 2006;11:82-89.