The Role of Bisphosphonates In The Management of Bone Metastasis

International Journal of Medical Science
© 2020 by SSRG - IJMS Journal
Volume 7 Issue 10
Year of Publication : 2020
Authors : Ngwobia Peter Agwu, Ahmed Mohammed Umar
How to Cite?

Ngwobia Peter Agwu, Ahmed Mohammed Umar, "The Role of Bisphosphonates In The Management of Bone Metastasis," SSRG International Journal of Medical Science, vol. 7,  no. 10, pp. 5-11, 2020. Crossref,


Metastasis to the bone indicates late and mostly incurable stage of cancer with an associated reduction in the quality of life of the subjects. Bone is a frequent site for distant metastasis, most especially from cancers of the prostate, breast, thyroid, and kidneys. It is associated with increased morbidity resulting from bone pain, spinal cord compression, and pathological fracture. Bisphosphonates are stable analogs of pyrophosphates, and they have been shown to effectively inhibit bone resorption, thereby improving mineral bone density and minimizing the risk of pathological fracture and other skeletal-related events while providing relief of pain in patients with bone metastasis and patients with prostate cancer on androgen deprivation therapy. There are better pain control and less requirement of analgesics in patients treated with bisphosphonates. Severe toxicity to bisphosphonates is uncommon but can arise with osteonecrosis of the jaw been one of the most serious complications. In this article, we review the Mechanism of bone metastasis, the pharmacology and Mechanism of action of bisphosphonates, and their role in the management of patients with bone metastasis supporting it with clinical studies that support their efficacy. We finally review the literature for their possible toxicity


Bisphosphonates, breast cancer, osteonecrosis of the jaw, prostate cancer.


[1] Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2020. CA Cancer J Clin 2020;0:1-24.
[2] Park JH, Lee KS, Choi KS. The burden of cancer in Korea during 2000–2020. Cancer Epidemiology 2013;37:353-359.
[3] Price AJ, Ndom P, Atenguena E, Nouemssi JPM. Cancer care challenges in developing countries. Cancer 2012;118:3627-3635.
[4] Oladeji A, Atalabi O, Jimoh M, Ntekim IT, T. E. Delay in the presentation of cancer patients for diagnosis and management: An institutional report. The Internet Journal of Oncology 2016;13.
[5] Weidle UH, Birzele F, Kollmorgen G, Ruger R. Molecular Mechanisms of Bone Metastasis. Cancer Genomics and Proteomics 2016;13:1-12.
[6] Macedo F, Ladeira K, Pinho F, Saraiva N, Bonito N, Pinto L, et al. Bone Metastases: An Overview. Oncol Rev 2017;11:321-321.
[7] Robert EC. Bisphosphonates: Clinical Experience. The Oncologist 2004;9:14-27.
[8] Wilkinson AN, Viola R, Brundage MD. Managing skeletal-related events resulting from bone metastases. BMJ 2008;337:a2041.
[9] Lipton A, Fizazi K, Stopeck AT, Henry DH, Smith MR, Shore N, et al. Effect of denosumab versus zoledronic acid in preventing skeletal related events in patients with bone metastases by baseline characteristics. European Journal of Cancer 2016;53:75-83.
[10] Waning DL, Guise TA. Molecular Mechanisms of Bone Metastasis and Associated Muscle Weakness. Clin Cancer Res 2014;20:3071–3077.
[11] Quiroz-Munoz M, Izadmehr S, Arumugam D, Wong B, Kirschenbaum A, Levine AC. Mechanisms of Osteoblastic Bone Metastasis in Prostate Cancer: Role of Prostatic Acid Phosphatase. Journal of the Endocrine Society 2019;3:655-664.
[12] Wu MY, Li CJ, Yiang GT, Cheng YL, Tsai APY, Hou YT, et al. Molecular Regulation of Bone Metastasis Pathogenesis. Cellular Physiology and Biochemistry 2018;46:1423-1438.
[13] Suva LJ, Washam C, Nicholas RW, Griffin RJ. Bone metastasis: mechanisms and therapeutic opportunities. Nat Rev Endocrinol 2011;7:208-218.
[14] Garnered P, Buchs N, Zekri J, Rizzoli R, Coleman RE, Delmas PD. Markers of bone turnover for the management of patients with bone metastases from prostate cancer. British Journal of Cancer 2000;82:858-864.
[15] Ottanelli S. Prevention and treatment of bone fragility in a cancer patient. Clinical Cases in Mineral and Bone Metabolism 2015;12:116-129.
[16] Jayasekera J, Onukwugha E, Bikov K, Mullins CD, Seal B, Hussain A. The economic burden of skeletal-related events among elderly men with metastatic prostate cancer. PharmacoEconomics 2014;32:173-191.
[17] Israeli RS, Ryan CW, Jung LL. Managing bone loss in men with locally advanced prostate cancer receiving androgen deprivation therapy. J Urol 2008:414-423.
[18] Jensen AO, Jacobsen JB, Nørgaard M, Yong M, Fryzek JP, Sørensen HT. Incidence of bone metastases and skeletal-related events in breast cancer patients: A population-based cohort study in Denmark. BMC Cancer 2011;11:29.
[19] Adler RA. Cancer treatment-induced bone loss. Current Opinion in Endocrinology, Diabetes & Obesity 2007;14:442-445.
[20] Cathomas R, Bajory Z, Bouzid M, El Ghoneimy A, Gillessen S, Goncalves F, et al. Management of Bone metastasis in patients with castrate-resistant prostate cancer. Urologia Internationalis 2014;92:377-386.
[21] Gdowski AS, Ranjan A, Vishwanatha JK. Current concepts in bone metastasis, contemporary therapeutic strategies, and ongoing clinical trials. Journal of Experimental & Clinical Cancer Research 2017;36:108.
[22] Wu S, Dahut WL, Gulley JL. The use of bisphosphonates in cancer patients. Acta Oncol 2007;46:581-591.
[23] Paget S. Distribution of secondary growths in cancer of the breast. The Lancet 1889;133:571-573.
[24] Liu Q, Zhang H, Jiang X, Qian C, Liu Z, Luo D. Factors involved in cancer metastasis: a better understanding of to “seed and soil” hypothesis. Molecular Cancer, 2017;16:176.
[25] Faraji F, Eissenberg JC. Seed and Soil: A conceptual framework of metastasis for clinicians. Missouri Medicine 2013;110:302-308.
[26] Talmadge JE, Fidler IJ. AACR centennial series: The biology of cancer metastasis: a historical perspective. Cancer Res 2010;70:5647-5669.
[27] Ganguly KKP, S, Moulik SC, A. Integrins, and metastasis. Cell Adh Migr 2013;7:251-261.
[28] Esposito M, Guise T, Kang Y. The Biology of Bone Metastasis. Cold Spring Harbor Perspectives in Medicine 2017.
[29] Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. Journal of Clinical Investigation, 2003;112:1776–1784.
[30] Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009;119:1420-1428.
[31] Futakuchi M, Fukamachi K, Suzui M. Heterogeneity of tumor cells in the bone microenvironment: Mechanisms and therapeutic targets for bone metastasis of prostate or breast cancer. Advanced Drug Delivery Reviews 2016;99:206-211.
[32] Buenrostro D, Park SI, Sterling JA. Dissecting the role of bone marrow stromal cells on bone metastases. BioMed Research International, 2014.
[33] Brown JE, Webbe HN, Coleman RE. The role of bisphosphonates in breast and prostate cancers. Endocrine-Related Cancer 2004;11:207-224.
[34] Drake MT, Clarke BL, Khosla S. Bisphosphonates: Mechanism of Action and Role in Clinical Practice. Mayo Clin Proc 2008;83:1032-1045.
[35] Oades GM, Coxon J, Colston KW. The potential role of bisphosphonates in prostate cancer. Prostate Cancer and Prostatic Diseases 2002;5:264-272.
[36] Rogers MJ, Watts DJ, Russell RGG. Overview of Bisphosphonates. Cancer Supplement 1997;80:1652-1660.
[37] Smith MR. Osteoclast targeted therapy for prostate cancer: Bisphosphonates and beyond. Urol Oncol 2008;26:420-425.
[38] Lee RJ, Saylor PJ, Smith MR. Treatment and prevention of bone complications from prostate cancer. Bone 2011;48:88-95.
[39] Ross JR, Saunders Y, Edmonds PM, Patel S, Wonderling D, Normand C, et al. A systematic review of the role of bisphosphonates in metastatic disease. Health Technol Assess 2004;8:1-176.
[40] Perazella, MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney International 2008;74:1385-1393.
[41] Corey E, Brown LG, Quinn JE, Poot M, Roudier MP, Higano CS, et al. Zoledronic Acid Exhibits Inhibitory Effects on Osteoblastic and Osteolytic Metastases of Prostate Cancer. Clinical Cancer Research 2003;9:295-306.
[42] Bubendorf L, Schopfer A, Wagner U, Sauter G, Moch H, Willi N, et al. Metastatic patterns of prostate cancer: An autopsy study of 1,589
patients Human Pathology 2000;31:578-583.
[43] Bruder JM, Ma JZ, Wing N, Basler J, Katselnik D. Effects of alendronate on bone mineral density in men with prostate cancer treated with androgen deprivation therapy. J Clin Densitom 2006;9:431-437.
[44] Planas J, Trilla E, Raventós C, Cecchini L, Orsola A, Salvador C, et al. alendronate decreases the fracture risk in patients with prostate cancer on androgen-deprivation therapy and with severe osteopenia or osteoporosis. BJU Int 2009;104:1 6 3 7 – 1 6 4 0.
[45] Smith MR, McGovern FJ, Zietman AL, Fallon MA, Hayden DL, Schoenfeld DA, et al. Pamidronate to prevent bone loss during
androgen deprivation therapy for prostate cancer. N Engl J Med 2001;345.
[46] Doeff TB, Agarwal N. Bisphosphonates Bone targeted therapy in prostate cancer. Asian J Androl 2018;20:215-220. Ngwobia Peter Agwu et al. / IJMS, 7(10), 5-11, 2020
[47] Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. A randomized placebo-controlled trial of Zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. Journal of the National Cancer Institute 2002;94:1458-1468.
[48] Hong SJ, Cho KS, Choi HY, Ahn H, Kim CS, Chung BH. A prospective multicenter open-label trial of Zoledronic acid in patients with hormone-refractory prostate cancer. Yonsei Medical Journal 2007;46.
[49] Kirby RS. Zoledronic acid: a new advance in managing skeletal events in prostate cancer. BJU Int 2003;91:464-465.
[50] Coleman RE. Risks and Benefits of Biphosphonates. British Journal of Cancer 2008;98:1736-1740.
[51] Coleman RE, Lipton A, Costa L, Cook RJ, Lee K, Saad F, et al. Possible survival benefits from zoledronic acid treatment in patients with bone metastases from solid tumors and poor prognostic features—An exploratory analysis of placebo-controlled trials. Journal of Bone Oncology 2013;2:70-76.
[52] Heidenreich A, Elert A, Hofmann R. Ibandronate in the treatment of prostate cancer-associated painful osseous metastases. Prostate Cancer and Prostatic Diseases 2002;5:231-235.
[53] Blanchette PS, Pritchard KI. The role of bisphosphonates in earlyand advanced-stage breast cancer: Have we finally optimized Care? Available at: Accessed 27th May 2020.
[54] McKay RR, Lin X, Perkins JJ, Heng DY, Simantov R, Choueiri TK. Prognostic significance of bone metastases and bisphosphonate therapy in patients with renal cell carcinoma. Eur Urol 2014;66:502-509.
[55] Vrdoljak E, Gore M, Leyman S, Szczylik C, Kharkevich G, Schöffski P, et al. Bisphosphonates in patients with renal cell carcinoma and bone metastases: a sunitinib global expanded-access trial subanalysis. Future Oncol 2015;11:2831-2840.
[56] Kennel KA, Drake MT. Adverse Effects of Bisphosphonates: Implications for Osteoporosis Management. Mayo Clin Proc 2009;84:632-638.
[57] Morgan C, Wagstaff J. Is there a role for ibandronate in the treatment of prostate cancer patients with bony metastases? Acta Oncol 2009;48:882-889.
[58] Watts NB, Diab DL. Long-Term Use of Bisphosphonates in Osteoporosis. J Clin Endocrinol Metab 2010;95:1555-1565.
[59] Badayan I, Cudkowicz ME. ProfoundMuscleWeakness and Pain after One Dose of Actonel. Case Reports in Medicine 2009:1-3.
[60] Woo S, Hellstein JW, Kalmar JR. Systematic Review: Biphosphonates and Osteonecrosis of the Jaws. Ann Intern Med 2006;144:753-761.