With Shabbir Alibhai, MD, MSc
Bone health and bone mineral density (BMD) are important clinical concerns for men with prostate cancer. In men who underwent androgen-deprivation therapy (ADT) for prostate cancer, and who received bisphosphonates and denosumab benefited from an increased BMD.1 In addition, denosumab decreased the risk of radiographic vertebral fractures in based on findings from a meta-analysis in the Annals of Internal Medicine .1
While necessary, ADT may introduce a variety of adverse events, including decreased BMD and increased risk of fragility fractures, particularly within the first year of use for prostate cancer treatment.2, 3
Denosumab (Prolia) is a human monoclonal antibody that inhibits the tumor necrosis factor, Receptor activator of nuclear factor kappa-B ligand (RANKL). Its effect is to inhibit the formation of osteoclasts, thereby decreasing the rate at which bone is broken down. Bisphosphonates, the most frequently prescribed treatment for osteoporosis reduces bone loss by inducing apoptosis of osteoclasts.
Researchers assessed the efficacy of medications, dietary supplements, and lifestyle interventions designed to prevent bone fracture, improve BMD, and prevent or postpone the onset of osteoporosis in men with non-metastatic prostate cancer.1 Data meeting the criteria from Ovid MEDLINE from 1946 to January 2017, EMBASE from 1980 to January 2017, and the Cochrane Database of Systematic Reviews in January 2017 were reviewed.
This metaanalysis1 examined randomized trials and systematic reviews comparing bone-targeted treatments with placebo, the standard of care, and additional active treatments involving men with nonmetastatic prostate cancer. The risk of bias was determined for each outcome. In total, this research evaluated two systematic reviews and 28 reports, encompassing 27 trials.
Though bisphosphonates effectively increased BMD, trials of the drugs in non-metastatic patients have been too small and underpowered to detect differences in outcomes for fractures.1 However, when denosumab was given at 60 mg once every six months also improved BMD but also achieved a decrease in the rate of new radiographic vertebral fractures based on one high-quality trial.1
Toremifene, a selective estrogen receptor modulator, decreased all fractures and radiographic vertebral fractures, though the agent is not yet approved in the United States or Canada for this indication. Another selective estrogen receptor modulator, raloxifene (Evista), had results indicating improvements in BMD, but these results were limited to a single trial. Additionally, raloxifene showed a potential to increase the risk of venous thromboembolism.1
“No trial involving bisphosphonates was adequately powered to assess changes in fracture rate. Two large phase III trials were adequately powered to look at the impact on fractures, one using denosumab and one using toremifene. Toremifene is not approved currently by either the FDA or Health Canada, which leaves us with only one drug with strong evidence for fracture reduction,” said first author Dr. Shabbir Alibhai, MD, MSc, assistant professor of medicine at the Institute of Health Policy, Management, and Evaluation at the University of Toronto, Canada.
None of the trials compared supplementation with calcium or vitamin D to placebo. None of the three trials evaluating lifestyle interventions reflected any significant differences in BMD between groups that exercised and groups that underwent standard-of-care without the intervention of exercise.1
“We were a little disappointed by the lack of high-quality data on calcium and vitamin D effects, but most disappointed by the limited data on the efficacy of bisphosphonates in reducing fractures,” Dr. Alibhai told EndocrineWeb.
For now, clinicians will have to continue to work with individual patients can to determine the best treatment based on risk of fractures.
“I recommend that men who are starting, continuing, or have been on ADT have their bone mineral density checked at a minimum to understand their fracture risk. For men at low fracture risk (which can be determined using one of several tools that incorporate age, bone mineral density results, and other risk factors), they should take supplemental calcium and vitamin D, and be encouraged to exercise based on [osteoporosis] guidelines,” said Dr. Alibhai, “For men at high risk of fracture, they should be advised to strongly consider starting denosumab or, if this agent is not available, then an oral or intravenous bisphosphonate.”
Clearer strategies will come when more participants are studied to increase the power of these trials to detect risk of fracture. Additionally, “two other things can be done. Increase the length of follow-up , which allows for more outcomes to be observed. Second, enroll a higher-risk population (eg, only men at high risk of fracture), which would again increase the number of outcomes,” said Dr. Alibhai.
Though prostate cancer, and ADT for its treatment, is fairly common, clinicians typically face several obstacles in treating these patients. There is a dearth of data from trials features clinically relevant endpoints, such as fracture. Yet, no trials assessed additional outcomes that could affect patients, such as pain, disability, and quality of life.
To date, no high-quality results exist for the prescription of calcium and vitamin D, and the evidence for the use of bisphosphonates in this setting only indicates improved BMD, suggesting a need for more information and likely better options.
To summarize, Dr. Alibhai told EndocrineWeb, “there are three key main messages for clinicians:
This review was supported by grants from the Program in Evidence-Based Care, the provincial guidelines initiative of Cancer Care Ontario, which receives funding from the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario.
None of the authors indicated a conflict of interest with regard to this paper.