CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2021; 42(03): 240-246
DOI: 10.1055/s-0041-1732851
Review Article

Cancer Treatment–Induced Bone Loss and Role of Denosumab in Nonmetastatic Prostate Cancer: A Narrative Review

Deepak Dabkara
1   Department of Medical Oncology, Tata Medical Center, Kolkata, West Bengal, India
› Author Affiliations
Funding None.

Abstract

Bone loss is an important complication of prostate cancer and its associated treatments, especially androgen-deprivation therapy (ADT). There is a 5 to 10 times increased loss of bone mineral density (BMD) in men receiving ADT with yearly 4 to 13% BMD loss. The risk of fracture increases yearly by 5 to 8% with ADT. ADT associated bone loss of 10 to 15% of BMD doubles the risk of fractures. Hence, BMD evaluation through dual-energy X-ray absorptiometry and evaluation of individual fracture risk assessed before initiating ADT. The use of vitamin D, calcium, bisphosphonates, and denosumab has shown improved bone health in men with prostate cancer receiving ADT. Denosumab 60 mg is approved to increase bone mass in men at high risk for fractures receiving ADT for nonmetastatic prostate cancer. Denosumab has shown improvement of 5.6% BMD at 2 years in nonmetastatic prostate cancer patients, with significant improvements seen at the total hip, femoral neck, and distal third of the radius. Denosumab has shown a 62% decreased incidence of new vertebral fractures at 36 months. Furthermore, denosumab delays the onset of bone metastases in high-risk nonmetastatic prostate cancer patients. Denosumab can be preferred over other bone modifying agents owing to several advantages, such as subcutaneous administration and no requirement of hospitalization, no dose modifications in renal impairment and less incidence of acute phase anaphylactic reactions. We review the available evidence of denosumab for managing bone loss in nonmetastatic prostate cancer patients. The relevant articles used in this narrative review were obtained through general search on google and PubMed using the key terms “non-metastatic prostate cancer,” “denosumab,” “bone loss,” “bone mineral density,” “fracture,” “CTIBL,” and “chemotherapy induced bone loss.”



Publication History

Article published online:
20 September 2021

© 2021. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

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  • References

  • 1 Bray F, Ferlay J, Soerjomataram I. et al Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (06) 394-424
  • 2 Palmbos PL, Hussain M. Non-castrate metastatic prostate cancer: have the treatment options changed?. Semin Oncol 2013; 40 (03) 337-346
  • 3 Gilbert SM, Kuo YF, Shahinian VB. Prevalent and incident use of androgen deprivation therapy among men with prostate cancer in the United States. Urol Oncol 2011; 29 (06) 647-653
  • 4 Meng MV, Grossfeld GD, Sadetsky N, et al. Contemporary patterns of androgen deprivation therapy use for newly diagnosed prostate cancer. Urology 2002;60(3, suppl 1):7–11, discussion 11–12
  • 5 Lee CE, Leslie WD, Czaykowski P. et al A comprehensive bone-health management approach for men with prostate cancer receiving androgen deprivation therapy. Curr Oncol 2011; 18 (04) e163-e172
  • 6 Matsushima H. Prostate cancer and cancer treatment-induced bone loss (CTIBL) [in Japanese]. Clin Calcium 2016; 26 (12) 1039-1045
  • 7 Saad F, Adachi JD, Brown JP. et al Cancer treatment-induced bone loss in breast and prostate cancer. J Clin Oncol 2008; 26 (33) 5465-5476
  • 8 Maxwell C, Viale PH. Cancer treatment-induced bone loss in patients with breast or prostate cancer. Oncol Nurs Forum 2005; 32 (03) 589-603
  • 9 Charles JF, Aliprantis AO. Osteoclasts: more than ‘bone eaters’. Trends Mol Med 2014; 20 (08) 449-459
  • 10 Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 2008; 473 (02) 139-146
  • 11 Planas Morin J, Morote Robles J. Skeletal complications of ADT: disease burden and treatment options. Asian J Androl 2012; 14 (05) 670-675
  • 12 Jones DH, Kong Y-Y, Penninger JM. Role of RANKL and RANK in bone loss and arthritis. Ann Rheum Dis 2002; 61 (suppl, 2) ii32-ii39
  • 13 Gholz RC, Conde F, Rutledge DN. Osteoporosis in men treated with androgen suppression therapy for prostate cancer. Clin J Oncol Nurs 2002; 6 (05) 88-93
  • 14 Leder BZ, LeBlanc KM, Schoenfeld DA, Eastell R, Finkelstein JS. Differential effects of androgens and estrogens on bone turnover in normal men. J Clin Endocrinol Metab 2003; 88 (01) 204-210
  • 15 Chen Z, Maricic M, Nguyen P. et al Low bone density and high percentage of body fat among men who were treated with androgen deprivation therapy for prostate carcinoma. Cancer 2002; 95 (10) 2136-2144
  • 16 James ND, Sydes MR, Clarke NW. 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 (10024) 1163-1177
  • 17 Buehring B, Viswanathan R, Binkley N, Busse W. Glucocorticoid-induced osteoporosis: an update on effects and management. J Allergy Clin Immunol 2013; 132 (05) 1019-1030
  • 18 Handforth C, D’Oronzo S, Coleman R, Brown J. Cancer treatment and bone health. Calcif Tissue Int 2018; 102 (02) 251-264
  • 19 Rachner TD, Coleman R, Hadji P, Hofbauer LC. Bone health during endocrine therapy for cancer. Lancet Diabetes Endocrinol 2018; 6 (11) 901-910
  • 20 Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005; 352 (02) 154-164
  • 21 Greenspan SL, Coates P, Sereika SM. et al Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer. J Clin Endocrinol Metab 2005; 90 (12) 6410-6417
  • 22 Morote J, Orsola A, Abascal JM. et al Bone mineral density changes in patients with prostate cancer during the first 2 years of androgen suppression. J Urol 2006; 175 (05) 1679-1683 discussion 1683
  • 23 Wadhwa VK, Weston R, Mistry R, Parr NJ. Long-term changes in bone mineral density and predicted fracture risk in patients receiving androgen-deprivation therapy for prostate cancer, with stratification of treatment based on presenting values. BJU Int 2009; 104 (06) 800-805
  • 24 Maillefert JF, Sibilia J, Michel F. et al Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. J Urol 1999; 161 (04) 1219-1222
  • 25 Gralow JR, Biermann JS, Farooki A. et al NCCN task force report: bone health in cancer care. J Natl Compr Canc Netw 2013; 11 (suppl 3) S1-S50, quiz S51
  • 26 Mitsuzuka K, Arai Y. Metabolic changes in patients with prostate cancer during androgen deprivation therapy. Int J Urol 2018; 25 (01) 45-53
  • 27 Oefelein MG, Ricchuiti V, Conrad W. et al Skeletal fracture associated with androgen suppression induced osteoporosis: the clinical incidence and risk factors for patients with prostate cancer. J Urol 2001; 166 (05) 1724-1728
  • 28 Guise TA, Oefelein MG, Eastham JA. et al Estrogenic side effects of androgen deprivation therapy. Rev Urol 2007; 9 (04) 163-180
  • 29 Morote J, Morin JP, Orsola A. et al Prevalence of osteoporosis during long-term androgen deprivation therapy in patients with prostate cancer. Urology 2007; 69 (03) 500-504
  • 30 Wu CT, Yang YH, Chen PC, Chen MF, Chen WC. Androgen deprivation increases the risk of fracture in prostate cancer patients: a population-based study in Chinese patients. Osteoporos Int 2015; 26 (09) 2281-2290
  • 31 Lassemillante AC, Doi SA, Hooper JD, Prins JB, Wright OR. Prevalence of osteoporosis in prostate cancer survivors: a meta-analysis. Endocrine 2014; 45 (03) 370-381
  • 32 Smith MR, Lee WC, Brandman J. et al Gonadotropin-releasing hormone agonists and fracture risk: a claims-based cohort study of men with nonmetastatic prostate cancer. J Clin Oncol 2005; 23 (31) 7897-7903
  • 33 Mottet N, Bellmunt J, Bolla M. et al EAU-ESTRO-SIOG guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol 2017; 71 (04) 618-629
  • 34 Jackson RD, LaCroix AZ, Gass M. et al Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006; 354 (07) 669-683
  • 35 Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC. et al Effect of vitamin D on falls: a meta-analysis. JAMA 2004; 291 (16) 1999-2006
  • 36 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
  • 37 Poon Y, Pechlivanoglou P, Alibhai SMH. et al Systematic review and network meta-analysis on the relative efficacy of osteoporotic medications: men with prostate cancer on continuous androgen-deprivation therapy to reduce risk of fragility fractures. BJU Int 2018; 121 (01) 17-28
  • 38 Khan AA, Morrison A, Hanley DA. et al Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 2015; 30 (01) 3-23
  • 39 Doria C, Leali PT, Solla F. et al Denosumab is really effective in the treatment of osteoporosis secondary to hypogonadism in prostate carcinoma patients? A prospective randomized multicenter international study. Clin Cases Miner Bone Metab 2016; 13 (03) 195-199
  • 40 Hadji P, Kyvernitakis I, Kann PH. et al GRAND-4: the German retrospective analysis of long-term persistence in women with osteoporosis treated with bisphosphonates or denosumab. Osteoporos Int 2016; 27 (10) 2967-2978
  • 41 Razaq A, Khan S, Hassan J, Malik BH, Razaq M. Comparing the efficacy and safety of denosumab with bisphosphonates in increasing bone mineral density in patients with prostate cancer and breast cancer on antihormonal treatment. Cureus 2019; 11 (12) e6401-e6401
  • 42 Alibhai SMH, Zukotynski K, Walker-Dilks C. et al Bone health and bone-targeted therapies for nonmetastatic prostate cancer: a systematic review and meta-analysis. Ann Intern Med 2017; 167 (05) 341-350
  • 43 Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003; 423 (6937) 337-342
  • NCCN Clinical Practice Guidelines in Oncology. NCCN guidelines for patients. Available at: https://www.nccn.org/patients/guidelines/content/PDF/prostate-advanced-patient.pdf. Accessed June 30, 2021
  • 45 Cosman F, de Beur SJ, LeBoff MS. et al National Osteoporosis Foundation. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int 2014; 25 (10) 2359-2381
  • 46 Ross AC. The 2011 report on dietary reference intakes for calcium and vitamin D. Public Health Nutr 2011; 14: 938-939
  • 47 Smith MR, Egerdie B, Hernández Toriz N. et al Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009; 361 (08) 745-755
  • 48 Smith MR, Saad F, Egerdie B. et al Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer. J Urol 2009; 182 (06) 2670-2675
  • 49 Hayes AR, Brungs D, Pavlakis N. Osteoclast inhibitors to prevent bone metastases in men with high-risk, non-metastatic prostate cancer: A systematic review and meta-analysis. PLoS One 2018; 13 (01) e0191455
  • 50 Pond GR, Armstrong AJ, Wood BA. et al Evaluating the value of number of cycles of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer. Eur Urol 2012; 61 (02) 363-369
  • 51 Foncubierta A, Gutierrez D, Medina F. et al Hypersensitivity reaction to denosumab in patient with osteoporosis: desensitization methodology. J Allergy Clin Immunol 2014; 133 (2, suppl) AB272
  • Prolia (denosumab). Highlights of prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125320s205lbl.pdf. Accessed July 21, 2020
  • 53 Saad F, Ivanescu C, Phung D. et al Skeletal-related events significantly impact health-related quality of life in metastatic castration-resistant prostate cancer: data from PREVAIL and AFFIRM trials. Prostate Cancer Prostatic Dis 2017; 20 (01) 110-116
  • 54 Boquete-Castro A, Gómez-Moreno G, Calvo-Guirado JL, Aguilar-Salvatierra A, Delgado-Ruiz RA. Denosumab and osteonecrosis of the jaw. A systematic analysis of events reported in clinical trials. Clin Oral Implants Res 2016; 27 (03) 367-375
  • 55 Body J-J, von Moos R, Niepel D, Tombal B. Hypocalcaemia in patients with prostate cancer treated with a bisphosphonate or denosumab: prevention supports treatment completion. BMC Urol 2018; 18 (01) 81-81
  • 56 Chang JT, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med 2003; 349 (17) 1676-1679
  • 57 Stopeck AT, Lipton A, Body JJ. et al Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010; 28 (35) 5132-5139
  • 58 Cummings SR, Ferrari S, Eastell R. et al Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res 2018; 33 (02) 190-198
  • 59 Tsourdi E, Langdahl B, Cohen-Solal M. et al Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS. Bone 2017; 105: 11-17
  • 60 Cristino J, Finek J, Jandova P. et al Cost-effectiveness of denosumab versus zoledronic acid for preventing skeletal-related events in the Czech Republic. J Med Econ 2017; 20 (08) 799-812
  • 61 Stopeck A, Brufsky A, Kennedy L. et al Cost-effectiveness of denosumab for the prevention of skeletal-related events in patients with solid tumors and bone metastases in the United States. J Med Econ 2020; 23 (01) 37-47