Bone health is a critical area of unmet need among men with advanced prostate cancer. Age increases the risk for fragility fractures among both men and women, and older men with fragility fractures are at higher risk of subsequent death than are women.1-3 Systemic anti-androgen therapies for prostate cancer, while life-prolonging, accelerate bone loss by tipping the balance of bone homeostasis toward bone resorption, which further increases patients’ risk of fragility fractures.4
Unfortunately, this adverse effect is characteristic of both conventional androgen deprivation therapy (ADT)5 and the newer and more potent androgen receptor (AR) pathway inhibitors, including abiraterone acetate, apalutamide, and enzalutamide.6-8
For this reason, clinicians should educate all patients with advanced prostate cancer about core strategies to protect and improve their bone health. These include regular exercise, calcium (at least 1,200 mg per day from dietary sources and supplements), vitamin D supplementation (800-2,000 IU per day), smoking cessation, limiting alcohol to no more than two drinks per day, and interventions to reduce the risk for falls and fractures, including balance exercises, posture awareness, and the use of spine-sparing strategies (sitting down when tying shoes, bending the knees when lifting, and turning with the whole body, rather than only the spine).9
As experts at the Advanced Prostate Cancer Consensus Conference (APCCC) 2019 noted, it is important not only to measure baseline bone mineral density when patients are starting on long-term ADT, but also to evaluate other significant risk factors for osteoporotic (fragility) fractures, such as long-term glucocorticoid exposure, current smoking, heavy alcohol use (>3 drinks per day), and a family history of fracture.2 Although low bone mineral density is a risk factor for fragility fractures, most men with fragility (osteoporotic) fractures have normal bone mineral density.10 The online FRAX® fracture risk assessment tool uses both bone mineral density and other risk factors to calculate patients’ estimated fracture risk over time. Bone mineral density of the femoral neck is optional but not required, and in most cases, FRAX® will provide a comparable result without it.11
Oral bisphosphonate therapy helps protect against treatment-induced bone loss when administered to men receiving ADT for prostate cancer.12-15 Guidelines from the National Institute for Health and Care Excellence recommend oral bisphosphonates as an option for patients whose 10-year probability of osteoporotic fracture is 1% or higher.16 Note that for a 60-year-old man with no risk factors (including no exposure to exogenous glucocorticoids or anti-androgen therapies) the 10-year probability of osteoporotic fracture is 3.8% when calculated by FRAX®.
For men with bone-metastatic castration-resistant prostate cancer (mCRPC), clinicians should consider antiresorptive therapy administered at the more intensive dose and schedule used to prevent skeletal-related events (SREs).17 As experts discussed at APCCC 2019, the less intensive dose and schedule of antiresorptives used for osteoporosis are not adequate to prevent pathologic fracture and other SREs in men with mCRPC.18 The American Urological Association recommends choosing between either the monoclonal antibody denosumab or the bisphosphonate zoledronic acid, while the National Comprehensive Cancer Network (NCCN) recommends denosumab as the preferred therapy, with zoledronic acid as the alternative.17,19 This is based on limited evidence that denosumab may be more effective than zoledronic acid for the prevention of SREs in bone-metastatic prostate cancer. In a randomized international study of 1,904 men with mCRPC, denosumab therapy was associated with an approximately 18% decrease in hazard of fracture compared with zoledronic acid therapy, a statistically significant difference (hazard ratio [HR] for SRE, 0.82; 95% confidence interval [CI], 0.71 to 0.95).20 Note that both groups of patients in this study received the more intensive dose and schedule of antiresorptive therapy used for SRE prevention (120 mg denosumab or 4 mg zoledronic acid, administered every 4 weeks).
Osteonecrosis of the jaw is an uncommon but serious side effect of antiresorptive therapy. In the previously described randomized international trial, a median of approximately 12 months of denosumab therapy and 11 months of zoledronic acid therapy was associated with incident (new-onset) osteonecrosis of the jaw among 2% and 1% of patients, respectively.20 In another prospective study of 942 patients with bone-metastatic prostate cancer, the incidence of osteonecrosis of the jaw was 0.7% per 100 patient-years of exposure to zoledronic acid and 1.1% per patient-years of exposure to denosumab.21 Among men in the study who continued to receive denosumab during follow-up, the incidence of osteonecrosis of the jaw increased from 1.1% to 4.1% per 100 person-years of exposure. Thus, the risk for jaw osteonecrosis increases with longer durations of antiresorptive therapy but remains low for most patients. To reduce the risk for osteoporosis of the jaw, I recommend that patients should receive a baseline dental examination and receive treatment for any dental health concerns prior to starting on denosumab or zoledronic acid.
At APCCC 2019, some experts recommended reserving antiresorptive therapy for those individuals with CRPC who are at the highest risk for fracture.18 They described a lack of conclusive evidence that anti-resorptive therapy significantly improves key outcomes, such as quality of life and overall survival, in the contemporary era of prostate cancer management. In fact, recent studies have produced mixed results. In the randomized controlled TRAPEZE trial, zoledronic acid therapy was associated with a statistically significant improvement in SRE-free survival but not overall survival among patients receiving docetaxel plus prednisolone for the management of bone-metastatic CRPC.22 In contrast, in a posthoc analysis of the COU-AA-302 trial of abiraterone-prednisone versus placebo-prednisone for the treatment of CRPC, prior bisphosphonate therapy was associated with statistically significant prolongations in time to opiate use (a proxy for cancer-related pain) and time to deterioration of ECOG performance status.23 Additionally, in a posthoc analysis of the ERA 223 study, rates of fracture in the combination-treatment arm (abiraterone-prednisone plus radium-223) were 15% among patients who were on antiresorptive therapy at baseline versus 37% among those who were not.24 Notably, in the control (abiraterone-prednisone plus placebo) arm, rates of fracture were 7% among those on antiresorptive therapy at baseline and 15% among those who were not.
In my view, more studies are needed to further evaluate the efficacy of comprehensive nonpharmacologic bone health management strategies and antiresorptive treatment. However, we cannot wait for the results of those studies to increase our emphasis on bone health for our patients with prostate cancer. This emphasis will become ever more critical as patients exposed to more potent anti-androgen therapies, and for longer durations of time. Given the current trend toward upfront treatment intensification, it is essential that we consistently educate and reinforce bone health management strategies with our patients, evaluate their fracture risk at baseline and over time, and based on these results, carefully consider whether antiresorptive therapy should be initiated.
Written by: Fred Saad, MD, FRCS, Full Professor and Chief of Urologic Oncology, Medical Director of Interdisciplinary Urologic Oncology Group, Department of Surgery/Faculty of Medicine, Institut du cancer de Montréal/CRCHUM, Montréal, Quebec, Canada
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2. Papaioannou A., Morin S., Cheung A.M., Atkinson S., Brown J.P., Feldman S., et al. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in canada: Summary. Cmaj. 2010;182:1864-1873.
3. Kannegaard P.N., van der Mark S., Eiken P., Abrahamsen B. Excess mortality in men compared with women following a hip fracture. National analysis of comedications, comorbidity and survival. Age Ageing. 2010;39:203-209.
4. Michaelson M.D., Marujo R.M., Smith M.R. Contribution of androgen deprivation therapy to elevated osteoclast activity in men with metastatic prostate cancer. Clin Cancer Res. 2004;10:2705-2708.
5. Saylor P.J., Smith M.R. Adverse effects of androgen deprivation therapy: Defining the problem and promoting health among men with prostate cancer. J Natl Compr Canc Netw. 2010;8:211-223.
6. Fizazi K., Tran N., Fein L., Matsubara N., Rodriguez-Antolin A., Alekseev B.Y., et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352-360.
8. Shore N.D., Chowdhury S., Villers A., Klotz L., Siemens D.R., Phung, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (terrain): A randomised, double-blind, phase 2 study. Lancet Oncol. 2016;17:153-163.
9. Too fit to fall or fracture. Osteoporosis Canada.
10. Binkley N., Adler R., Bilezikian J.P. Osteoporosis diagnosis in men: The t-score controversy revisited. Current osteoporosis reports. 2014;12:403-409.
11. Gadam R.K., Schlauch K., Izuora K.E. Frax prediction without bmd for assessment of osteoporotic fracture risk. Endocr Pract. 2013;19:780-784.
12. Smith M.R., McGovern F.J., Zietman A.L., Fallon M.A., Hayden D.L., Schoenfeld D.A., et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med. 2001;345:948-955.
13. Michaelson M.D., Kaufman D.S., Lee H., McGovern F.J., Kantoff P.W., Fallon M.A., et al. Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol. 2007;25:1038-1042.
14. Greenspan S.L., Nelson J.B., Trump D.L., Resnick N.M. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: A randomized trial. Ann Intern Med. 2007;146:416-424.
15. Smith M.R., Eastham J., Gleason D.M., Shasha D., Tchekmedyian S., Zinner N. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol. 2003;169:2008-2012.
16. Bisphosphonates for treating osteoporosis. National Institute for Health and Care Excellence.
18. Parker C. Anti-resorptive therapy to reduce sre risk in men with bone-metastatic crpc: Only for very select men with crpc and bone metastases Advanced Prostate Cancer Consensus Conference 2019. Basel, Switzerland.
19. National comprehensive cancer network. NCCN clinical practice guidelines in oncology. Prostate cancer version 4.2019—august 19, 2019. 2019.
20. Fizazi K., Carducci M., Smith M., Damiao R., Brown J., Karsh L., 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;377:813-822.
21. Stopeck A.T., Fizazi K., Body J.J., Brown J.E., Carducci M., Diel I., et al. Safety of long-term denosumab therapy: Results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer. Support Care Cancer. 2016;24:447-455.
22. 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;20:1-288.
23. Saad F., Shore N., Van Poppel H., Rathkopf D.E., Smith M.R., de Bono J.S., et al. Impact of bone-targeted therapies in chemotherapy-naive metastatic castration-resistant prostate cancer patients treated with abiraterone acetate: Post hoc analysis of study cou-aa-302. Eur Urol. 2015;68:570-577.
24. Smith M., Parker C., Saad F., Miller K., Tombal B., Ng Q.S., 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;20:408-419.
Further Related Content: Prevention and Treatment of Osteoporosis Presentation (Fred Saad's Presentation at APCCC 2019)
Published Date: December 2019