Purpose of Review
The purpose of this review is to highlight novel and impactful discoveries in systemic treatment of bone metastatic disease in solid tumors published within the past 5 years.
Major developments in systemic treatment of bone metastatic disease in solid tumors include evidence that decreasing frequency of dosing zoledronic acid in metastatic breast and prostate cancer maintains efficacy in preventing skeletal-related events while decreasing costs. The landmark findings on the use of Radium-223 to treat metastatic prostate cancer were reported in 2013. Recently, it has been found that not all systemic therapy combinations with Radium-223 are necessarily safe or effective unless bone-targeted therapy is also included in the regimen.
More cost-effective dosing intervals of zoledronic acid and efficacy and safety nuances of combination radiopharmaceutical and chemotherapy treatment have been better delineated.
This is a preview of subscription content,to check access.
Access this article
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Sousa S, Clézardin P. Bone-targeted therapies in cancer-induced bone disease. Calcif Tissue Int. 2018;102:227–50.
Macedo F, Ladeira K, Pinho F, Saraiva N, Bonito N, Pinto L, et al. Bone metastases: an overview. Oncol Rev. 2017;11(1):321.
Kan C, Vargas G, Pape FL, Clézardin P. Cancer Cell colonisation in the bone microenvironment. Int J Mol Sci. 2016;17(1):1–16.
Hussain A, Lee RJ, Graff JN, Halabi S. The evolution and understanding of skeletal complication endpoints in clinical trials of tumors with metastasis to the bone. Crit Rev Onc/Hem. 2019;139:108–16.
Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27(3):165–76.
Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350(16):1655–64.
Weinfurt KP, Castel LD, Li Y, Timbie JW, Glendenning GA, Schulman KA. Health-related quality of life among patients with breast cancer receiving zoledronic acid or pamidronate disodium for metastatic bone lesions. Med Care. 2004;42(2):164–75.
Costa L, Major PP. Effect of bisphosphonates on pain and quality of life in patients with bone metastases. Nat Clin Pract Oncol. 2009;6(3):163–74.
Van Poznak C, Somerfield MR, Barlow WE, Biermann JS, Bosserman LD, Clemons MJ, et al. Role of bone-modifying agents in metastatic breast cancer: an American Society of Clinical Oncology-Cancer Care Ontario focused guideline update. J Clin Oncol. 2017;35:3978–86.
Parker C, Castro E, Fizazi K, Heidenreich A, Ost P, Procopio G, et al. Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(9):1119–34.
Alibhai SMH, Zukotynski K, Walker-Dilks C, Emmenegger U, Finelli A, Morgan SC, et al. Bone health and bone-targeted therapies for prostate cancer: a programme in evidence-based care - Cancer Care Ontario Clinical Practice Guideline. Clin Oncol (R Coll Radiol). 2017;29(6):348–55.
Novello S, Barlesi F, Califano R, et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 5):v1–v27.
National Comprehensive Cancer Network. Breast Cancer (Version 1.2021). https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed February 2, 2021.
National Comprehensive Cancer Network. Prostate Cancer (Version 1.2021). https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed February 2, 2021.
Amadori D, Aglietta M, Alessi B, Gianni L, Ibrahim T, Farina G, et al. Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial. Lancet Oncol. 2013;14(7):663–70.
Himelstein AL, Foster JC, Khatcheressian JL, Roberts JD, Seisler DK, Novotny PJ, et al. Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases: a randomized clinical trial. JAMA. 2017;317(1):48–58 This phase III study demonstrates dosing zoledronic acid every 12 weeks is non-inferior to dosing every 4 weeks in patients with new bone metastases from breast cancer or prostate cancer. This data is practice changing.
Hortobagyi GN, Van Poznak C, Harker WG, Gradishar WJ, Chew H, Dakhil SR, et al. Continued treatment effect of zoledronic acid dosing every 12 vs 4 weeks in women with breast cancer metastatic to bone: the OPTIMIZE-2 randomized clinical trial. JAMA Oncol. 2017;3(7):906–12.
Clemons MJ, Ong M, Stober C, Ernst DS, Booth CM, Canil CM, et al. A randomized trial comparing 4-weekly versus 12-weekly administration of bone-targeted agents (denosumab, zoledronate, or pamidronate) in patients with bone metastases from either breast or castration-resistant prostate cancer. J Clin Oncol. 2019;37:11501. https://doi.org/10.1200/JCO.2019.37.15_suppl.11501.
Luo Q, Men P, Liu Z, Zhai S, Jiang M. Is de-escalated bisphosphonate therapy a suitable alternative to standard dosing in malignant tumor patients with bone-metastases: a systematic review and meta-analysis. Front Oncol. 2019;9:774.
Awan AA, Hutton B, Hilton J, Mazzarello S, Van Poznak C, Vandermeer L, et al. De-escalation of bone-modifying agents in patients with bone metastases from breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat. 2019;176(3):507–17.
Shapiro CL, Moriarty JP, Dusetzina S, Himelstein AL, Foster JC, Grubbs SS, et al. Cost-effectiveness analysis of monthly zoledronic acid, zoledronic acid every 3 months, and monthly denosumab in women with breast cancer and skeletal setastases: CALGB 70604 (Alliance). J Clin Oncol. 2017;35(35):3949–55 The cost effectiveness of bone-modifying agents is evaluated here.
James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387:1163–77.
James N, Pirrie S, Pope A, Barton D, Andronis L, Goranitis I, et al. TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer. Health Technol Assess. 2016;20(53):1–288.
Al Zahrani M, Clemons M, Vandermeer L, Sienkiewicz M, Awan AA, Hutton B, et al. Ng TL, Real-world practice patterns and attitudes towards de-escalation of bone-modifying agents in patients with bone metastases from breast and prostate cancer: a physician survey. J Bone Oncol. 2021. https://doi.org/10.1016/j.jbo.2020.100339.
Campagnaro E, Reimers MA, Qin A, Alva AS, Schneider BJ, Van Poznak CH. Use of bone-modifying agents in myeloma and bone metastases: how recent dosing interval studies have affected our practice. J Oncol Pract. 2018;14(8):457–64.
Udagawa H, Niho S, Kirita K, Umemura S, Matsumoto S, Yoh K, et al. Impact of denosumab use on the survival of untreated non- squamous non-small cell lung cancer patients with bone metastases. J Cancer Res Clin Oncol. 2017;143:1075–82.
Peters S, Danson S, Hasan B, Dafni U, Reinmuth N, Majem M, et al. A randomized open-label phase III trial evaluating the addition of denosumab to standard first-line treatment in advanced NSCLC: the European Thoracic Oncology Platform (ETOP) and European Organisation for Research and Treatment of Cancer (EORTC) SPLENDOUR Trial. J Thorac Oncol. 2020;15(10):1647–56.
Lamy O, Stoll D, Aubry-Rozier B, Rodriguez EG. Stopping denosumab. Curr Osteoporos Rep. 2019;17(1):8–15.
Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213–23.
Parker CC, Coleman RE, Sartor O, Vogelzang NJ, Bottomley D, Heinrich D, et al. Three-year safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases from phase 3 randomized alpharadin in symptomatic prostate cancer trial. Eur Urol. 2018;73(3):427–35.
Vogelzang NJ, Coleman RE, Michalski JM, Nilsson S, O’Sullivan JM, Parker C, et al. Hematologic safety of radium-223 dichloride: baseline prognostic ractors associated with myelosuppression in the ALSYMPCA trial. Clin Genitourin Cancer. 2017;15(1):42–52.
Sartor O, Heinrich D, Mariados N, Méndez Vidal MJ, Keizman D, Thellenberg Karlsson C, et al. Re-treatment with radium-223: first experience from an international, open-label, phase I/II study in patients with castration-resistant prostate cancer and bone metastases. Ann Oncol. 2017;28(10):2464–71 This phase I/II study demonstrates safety and efficacy of repeat dosing of Radium 223.
Smith M, Parker C, Saad F, Miller K, Tombal B, Ng QS, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(3):408–19.
Matsubara N, Kimura G, Uemura H, Uemura H, Nakamura M, Nagamori S, et al. A randomized, double-blind, comparison of radium-223 and placebo, in combination with abiraterone acetate and prednisolone, in castration-resistant metastatic prostate cancer: subgroup analysis of Japanese patients in the ERA 223 study. Int J Clin Oncol. 2020;25(4):720–31.
Tombal BF, Loriot Y, Saad F, McDermott RS, Elliott T, Rodriguez-Vida A, et al. Decreased fracture rate by mandating bone-protecting agents in the EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone: an interim safety analysis. J Clin Oncol. 2019;37:5007 The addition of zoledronic acid decreases the risk of cancer therapy associated fractures.
Sternberg CN, Saad F, Graff JN, Peer A, Vaishampayan UN, Leung E, et al. A randomised phase II trial of three dosing regimens of radium-223 in patients with bone metastatic castration-resistant prostate cancer. Ann Oncol. 2020;31(2):257–65.
Geva R, Lopez J, Danson S, Joensuu H, Peer A, Harris SJ, et al. Radium-223 in combination with paclitaxel in cancer patients with bone metastases: safety results from an open-label, multicenter phase Ib study. Eur J Nucl Med Mol Imaging. 2019;46(5):1092–101.
Ye X, Sun D, Lou C. Comparison of the efficacy of strontium-89 chloride in treating bone metastasis of lung, breast, and prostate cancers. J Cancer Res Ther. 2018;14(Supplement):S36–40.
Seider MJ, Pugh SL, Langer C, Wyatt G, Demas W, Rashtian A, et al. Randomized phase III trial to evaluate radiopharmaceuticals and zoledronic acid in the palliation of osteoblastic metastases from lung, breast, and prostate cancer: report of the NRG Oncology RTOG 0517 trial. Ann Nucl Med. 2018;32(8):553–60.
Mazziotti G, Formenti AM, Panarotto MB, Arvat E, Chiti A, Cuocolo A, et al. Real-life management and outcome of thyroid carcinoma-related bone metastases: results from a nationwide multicenter experience. Endocrine. 2018;59(1):90–101.
Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, et al. METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917–27.
Escudier B, Powles T, Motzer RJ, Olencki T, Arén Frontera O, Oudard S, et al. Cabozantinib, a new standard of care for patients with advanced renal cell carcinoma and bone metastases? Subgroup analysis of the METEOR trial. J Clin Oncol. 2018;36(8):765–72.
Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016;34(25):3005–13.
Schott AF, Barlow WE, Van Poznak CH, Hayes DF, Moinpour CM, Lew DL, et al. Phase II studies of two different schedules of dasatinib in bone metastasis predominant metastatic breast cancer: SWOG S0622. Breast Cancer Res Treat. 2016;159(1):87–95.
Mitri Z, Nanda R, Blackwell K, Costelloe CM, Hood I, Wei C, et al. Translational breast cancer research consortium. TBCRC-010: phase I/II study of dasatinib in combination with zoledronic acid for the treatment of breast cancer bone metastasis. Clin Cancer Res. 2016;22(23):5706–12.
Prevention of symptomatic skeletal events with denosumab administered every 4 weeks versus every 12 weeks. NCT02051218. https://clinicaltrials.gov/ct2/show/NCT02051218. Accessed February 2, 2021.
Study to test the safety and how Radium-223 Dichloride an alpha particle-emitting radioactive agent works in combination with pembrolizumab an immune checkpoint Inhibitor in patients with stage IV non-small cell lung cancer with bone metastases. NCT03996473. https://clinicaltrials.gov/ct2/show/NCT03996473. Accessed February 2, 2021.
Coleman R, Brown J, Rathbone E, Flanagan L, Reid A, Kendall J, et al. CApecitabine plus Radium-223 (Xofigo™) in breast cancer patients with BONe metastases (CARBON): study protocol for a phase IB/IIA randomised controlled trial. Trials. 2020;21(1):89.
Testing the addition of radium therapy (Radium-223 Dichloride) to the usual chemotherapy treatment (Paclitaxel) for advanced breast cancer that has spread to the bones. NCT04090398. https://clinicaltrials.gov/ct2/show/NCT04090398. Accessed February 2, 2021.
We are grateful for the writing contributions made to this manuscript by Mounia Amzerin MD, Ahmad Bin Zayed Al Nahyan Of Cancer Treatment, Tangier, Morocco.
Conflict of Interest
Dr Falvello has no conflicts of interest. Dr Van Poznak has received research support from Bayer that was provided to her institution
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Cancer-Induced Musculoskeletal Diseases
About this article
Cite this article
Falvello, V., Van Poznak, C. Updates in Management of Bone Metastatic Disease in Primary Solid Tumors with Systemic Therapies. Curr Osteoporos Rep 19, 452–461 (2021). https://doi.org/10.1007/s11914-021-00689-5