Vitamin D Metabolites in Nonmetastatic High-Risk Prostate Cancer Patients with and without Zoledronic Acid Treatment after Prostatectomy

Abstract

There are limited and discrepant data on prostate cancer (PCa) and vitamin D. We investigated changes in three vitamin D₃ metabolites in PCa patients after prostatectomy with zoledronic acid (ZA) treatment regarding their metastasis statuses over four years. In 32 patients from the ZEUS trial, 25(OH)D₃, 24,25(OH)₂D₃, and 1,25(OH)₂D₃ were measured with liquid chromatography coupled with tandem mass spectrometry at four time points. All the patients received daily calcium and vitamin D₃. Bone metastases were detected in 7 of the 17 ZA-treated patients and in 5 of the 15 controls (without ZA), without differences between the groups (p = 0.725). While 25(OH)D₃ and 24,25(OH)₂D₃ increased significantly after the study's start, with following constant values, the 1,25(OH)₂D₃ concentrations remained unchanged. ZA treatment did not change the levels of the three metabolites. 25(OH)D₃ and 24,25(OH)₂D₃ were not associated with the development of bone metastases. In contrast, 1,25(OH)₂D₃ was also higher in patients with bone metastasis before the study's start. Thus, in high-risk PCa patients after prostatectomy, 25(OH)D₃, 24,25(OH)₂D₃, and 1,25(OH)₂D₃ were not affected by supportive ZA treatment or by the development of metastasis over four years, with the exception of 1,25(OH)₂D₃, which was constantly higher in metastatic patients. There might be potential prognostic value if the results can be confirmed.

Keywords: 1,25(OH)2D3; 24,25(OH)2D3; 25(OH)D3; circulating vitamin D metabolites; prostate cancer; prostatectomy; vitamin D; zoledronic acid treatment.

Figure 1

Overview of the study design and patient characteristics depending on the season of the study’s start in winter/spring (a) and summer/autumn (b). Abbreviation: ZA = zoledronic acid.

Figure 2

Levels of (a,b) 25(OH)D₃, (c,d) 24,25(OH)₂D₃, and (e,f) 1,25(OH)₂D₃ at different time intervals of the study in the total cohort, and dependence on the season of the start of the study. Subfigures (a,c,e) present the results of the repeated-measures ANOVA for a single-factor study after treatment in the total cohort (n = 32). The corresponding subfigures (b,d,f) show the results of the two-factor study with repeated-measures ANOVA on the factor “study start” (winter/spring, n = 16, and summer/autumn, n = 16). Repeated measures were performed before the treatment (time point = 0) and 3 and 9 months after the treatment start. The last time point was 39 months (mean value) after the treatment start. Data at the time points are mean values with their 95% confidence intervals. At the error bars, the letters a, b, c, and d indicate statistically significant differences in the vitamin D₃ levels between the different measuring points (at least p < 0.05; corrected values according to Holm–Sidak test): a, compared to “before study”; b, compared to 3 months; c, compared to 9 months; d, compared to ~39 months. Statistically significant differences between the metabolite levels of the two study subgroups at the respective time points are characterized by asterisks: **, p < 0.01; ***, p < 0.001. Abbreviations: ANOVA = analysis of variance; MP factor = related to the time intervals of the measuring points.

Figure 3

Levels of (a) 25(OH)D₃, (b) 24,25(OH)₂D₃, and (c) 1,25(OH)₂D₃ before and during the ZA treatment at different time intervals of the study. Repeated measures were performed before the treatment (time point = 0) and 3 and 9 months after the treatment start. The last measuring points were 36 and 42 months (mean values) for patients without and with ZA treatment, respectively. Results of the repeated-measures two-factor ANOVA classified according to the factor ZA treatment (without ZA, n = 15; with ZA, n = 17) are shown as mean values with their 95% confidence intervals. At the error bars, the letters a, b, c, and d indicate statistically significant differences in the vitamin D₃ levels between the different measuring points (at least p < 0.05; corrected values according to Holm–Sidak test): a, compared to “before study”; b, compared to 3 months; c, compared to 9 months; d, compared to ~36–42 months. No statistically significant differences for all three metabolite levels were found between the two ZA groups at the respective measuring points. Abbreviations: ANOVA = analysis of variance; ZA = zoledronic acid; MP factor = related to the time intervals of the measuring points.

Figure 4

Levels of (a) 25(OH)D₃, (b) 24,25(OH)₂D₃, and (c) 1,25(OH)₂D₃ in patients with and without developed bone metastases during the study. Repeated measures were performed before the treatment (time point = 0) and 3 and 9 months after the treatment start. The last measuring points were 27 and 42 months (mean values) for the patients with (n = 12) and without (n = 20) bone metastasis, respectively. Results of the repeated-measures two-factor ANOVA classified according to the factor metastasis are shown as mean values with their 95% confidence intervals. At the error bars, the letters a, b, c, and d indicate statistically significant differences in the vitamin D₃ levels between the different measuring points (at least p < 0.05; corrected values according to Holm–Sidak test): a, compared to “before study”; b, compared to 3 months; c, compared to 9 months; d, compared to ~27–42 months. Statistically significant differences between the metabolite levels for the two study subgroups at the respective time points are characterized by asterisks: **, p < 0.01; *** p < 0.001. Abbreviations: ANOVA = analysis of variance; Meta factor = related to the developed bone metastasis; MP factor = related to the time intervals of the measuring points.

Figure 5

Change in the vitamin D₃ metabolite ratio (VMR) in the total cohort during the study. The ratio [24,25(OH)₂D₃ to 25(OH)D₃ × 100] defined as vitamin D₃ metabolite ratio increased during the study. Data at the time points are mean values with their 95% confidence intervals. At the error bars, the letters a, b, c, and d indicate statistically significant differences between the levels at the different measuring points (at least p < 0.05; corrected values according to Holm–Sidak test): a, compared to “before study”; b, compared to 3 months; c, compared to 9 months; d, compared to ~39 months. Further explanations are provided in the legend of Figure 2.