Benefits and Harms of Antiresorptive Therapy in Men with Non-metastatic Prostate Cancer on Androgen Deprivation Therapy: A Systematic Review and Meta- analysis of Randomized Controlled Trials and a Critical Appraisal of Guidelines

Abstract

Background: Androgen deprivation therapy (ADT) is widely used as an adjuvant therapy in men with prostate cancer. However, with the use of ADT, estrogen and androgen levels decrease substantially, leading to a disruption in bone hemostasis. ADT is therefore associated with bone loss and increased fractures risk especially within the first year of treatment. Objectives: The aim of this systematic review is to evaluate the effects of antiresorptive therapy on bone health in men with early prostate cancer on ADT. We also conducted a clinical appraisal of all available guidelines to evaluate the available recommendations and their development process. Methods: We searched four databases (Medline, CINAHL, Embase and the Cochrane Library) up to November 23rd, 2020. We screened records, and abstracted data independently and in duplicate. For our systematic review we included randomized controlled trials (RCTs) conducted in men with non-metastatic prostate cancer receiving ADT. Our outcomes of interest included fracture risk, %change in bone mineral density (BMD) at the lumbar spine (LS), total hip (TH) and femoral neck (FN), bone turnover markers (BTM), mortality and adverse events. We stratified the meta-analyses by the type of antiresorptive therapy compared to control (no treatment) or placebo. We assessed the risk of bias of each RCT using the Version 1 of the Cochrane risk-of-bias tool independently and in duplicate. We also used the GRADE methodology to assess the certainty of the evidence. For the guideline’s appraisal, we included guidance documents with recommendations regarding screening, prevention and treatment of ADT induced bone loss. We assessed the quality of these documents using the Appraisal of Guidelines for Research and Evaluation II (AGREE-II) tool independently and in duplicate. Results: We included 26 RCTs. The intervention was intravenous (IV) Zoledronic acid in 14 RCTs, IV pamidronate in 1 RCT, oral bisphosphonates (BP) in 5 RCTs, intramuscular (IM) BP in 2 RCTs and denosumab in 2 RCTs. 2 RCTs had two interventions including oral BP and denosumab. The most common types of ADT used were GnRH and LHRH agonists. The participants had a mean age range of 65-80 years, and a mean BMI range of 23-32 kg/m2. The risk of bias was high in 23 and unclear in 3 RCTs. Treatment with oral BP (N=347) revealed a non-significant decrease of 43% (RR=0.57; 95%CI [0.10, 3.23]; I2 0%; very low certainty) in fracture incidence at 12 months in men with prostate cancer on ADT compared to control. Treatment with IV BP revealed a non-significant increase in the risk of morphometric vertebral fractures at 36 months compared to control (RR=1.06; 95%CI[0.57,1.98]; I272%; very low certainty). The incidence of other types of fractures (clinical, traumatic, fragility) captured as adverse events in most of the IV BP trials varied by number of events and definition across trials. One of the Denosumab trials reported on the incidence of fractures, as a secondary outcome and suggested a significant decrease in the risk of new morphometric fracture at 12 (RR=0.15; p-value=0.004), 24 (RR=0.31; p- value=0.004) and 36 months (RR=0.38; 95%CI [0.19-0.78]) in the treatment group compared to the control group. However, a non-significant decrease in the incidence of clinical fractures at any site at 36 months was reported (RR=0.72; 95% CI [0.48 to 1.07]). Treatment with oral BP for 12 months in addition to ADT causes a significant increase in LS (+4%), TH (+2%) and FN (+3%) BMD compared to control. Increased bone mass was also present after 24 months at the LS and FN. Furthermore, studies suggest that treatment with IM bisphosphonates in addition to ADT for 12 revealed mild increments in LS, TH and FN BMD compared to loss in BMD with ADT alone. In addition, treatment with IV BP in addition to ADT causes a significant increase in BMD compared to ADT alone reaching a MD of +11% at the LS, +9% at the TH, and +12% at the FN after 36 months of treatment. Similarly, denosumab in addition to ADT compared to ADT alone leads to a significant increase in BMD reaching +8% at the LS, +6% at the TH and +5% at the FN at 36 months. Our analyses also showed a significant decrease in bone turnover markers across anti-resorptive agents. The % changed reached a range of -24% to -71% with oral BPs compared to ADT alone at 12 months; - 37% to -87% with IV BPs compared to ADT control at 12 months, and -30% to -44% with denosumab treatment in addition to ADT at 12 months compared to ADT alone. These changes were consistent for both bone formation and resorption markers. Mortality data was scarce across trials, we were able to perform a meta-analysis for IV BPs which showed a non-statistically significant difference between the treatment and the control groups. The most commonly reported adverse events were gastrointestinal side effects across all types of antiresorptives. Acute phase reactions and flu-like symptoms were common with IV and IM BP while ONJ and hypocalcemia were reported with IV BP and denosumab. We identified 15 guidelines, position statements or expert opinions regarding the screening, prevention and treatment of ADT induced bone loss. 12 out of the 15 guidelines were developed by national or international organizations. Several guidelines recommend the assessment of risk factors for fracture or osteoporosis smoking, alcohol use, vitamin D deficiency, inadequate calcium intake, history of previous fragility fractures, family history of osteoporosis, steroid use, and low BMI in men with prostate cancer starting ADT therapy. 10 out of the 15 guidelines recommend screening with BMD measurement using DEXA scan in men with non-metastatic prostate cancer at the start of ADT. Recommendations for lifestyle modifications to improve bone health include smoking cessation, moderate alcohol, and optimizing vitamin D and Calcium intake. Different indications are available for the initiation of anti-resorptive therapy in men with non-metastatic prostate cancer on ADT and several treatment options are available including oral BP, IV BP and denosumab. Guidelines assessment revealed low scores (<40%) in most of the included guidelines specially in the following domains: stakeholder agreement (11-61%), rigor of development (10-68%), applicability (2- 69%), and editorial independence (0-63%). Conclusion: Our systematic review suggests a protective role of antiresorptive therapy on BMD and BTMs in men with non-metastatic prostate cancer receiving ADT. However, data on fracture rate reduction is scarce and inconsistent across trials. Although future well designed and powered RCTs with longer follow-up are still needed to assess the effect of antiresorptive therapies on fracture risk in men with non- metastatic prostate cancer on ADT; our results from BMD and BTM, surrogates for fracture rates, highlight the importance of considering antiresorptive therapy as an imperative treatment option for men receiving ADT. Several guidance documents have been published regarding screening, preventing, and treating ADT induced bone loss. However, these recommendations suffer a lot of variability and intrinsic limitations especially due to lack of resources and implementation strategies.