The Clinical Significance of Bone Mineral Density Changes Following Long Term Androgen Deprivation Therapy in Prostate Cancer Patients Enrolled in the PCS V Trial

Abstract

Treatment for advanced prostate cancer includes long term androgen deprivation therapy (ADT), which has been associated with decreased bone mineral density (BMD). It is unclear whether this translates to a clinically significant change in bone density status. Some evidence suggests that there is no impact on fracture risk despite a decrease in BMD. We quantified changes in BMD when all patients on ADT were mandated to take Calcium and Vitamin D (CaVitD) in the setting of a phase III randomized clinical trial and compared the findings to historical data. BMD analysis was conducted for high-risk prostate cancer patients enrolled in the PCS V study (NCT01444820), a randomized phase III trial comparing conventional and hypofractionated radiotherapy regimens. Patients received 24 months of ADT and were prescribed CaVitD supplementation (Carbocal D 1 tablet twice daily; 500mg of Calcium + 400 IU of Vitamin D3). Long-course ADT consisted of luteinizing hormone-releasing hormone agonist therapy, with 14 days of bicalutamide (50 mg per day) with the first injection only. BMD reports at baseline and at 30 months of follow-up had the areal density and T-scores (spine, femoral neck, and total femur) extracted and the absolute change calculated. The results were then compared to the BMD decline of CaVitD control groups in bisphosphonate trials. Clinical bone density status (normal, osteopenia, versus osteoporosis) was monitored. In total, BMD reports were obtained from 329 patients. Patient data was further analyzed if a 24-month follow-up BMD data was present for a given site - 226 (spine), 231 (femoral neck), and 173 (total femur). The mean change (standard deviation) in the areal density was -2.65% (5.78), -2.76% (5.59), -4.27% (4.41), respectively. The difference was statistically significant for all three sites (p<0.001). The average decrease in BMD across all three sites was -3.2% after 24 months of ADT, compared to a historical figure of -2.1% following 12 months of ADT. For most patients (n=140, 83%), there was no clinically significant decline in bone density status. Eight patients (5%) with osteopenia prior to ADT became osteoporotic, 18 patients (11%) who had normal BMD became osteopenic, and no patients with normal BMD developed osteoporosis. In comparison to historical data for one year of ADT, our analysis of the prospectively collected BMD data showed minimal further deterioration with two years of ADT. Despite the drop in BMD, the change in bone density status remains low. This is in accordance with data from bisphosphonate trials using CaVitD as a control group, which showed that there is no clinically significant difference in fracture risk despite changes in BMD. As such, mandating patients to take CaVitD alone while on prolonged ADT may suffice, and we propose that steps should be taken to standardize dosing and encourage patient compliance.