Effects of high-dose vitamin D supplementation on phase angle and physical function in patients with prostate cancer on ADT

Abstract

Purpose:

Androgen deprivation therapy (ADT) is commonly used to treat patients with advanced prostate cancer but is associated with functional decline. Bioelectrical impedance analysis (BIA)-derived phase angle may reflect frailty and functional decline in cancer patients. High-dose vitamin D supplementation may improve phase angle values and physical function.

Methods:

We conducted an exploratory analysis from a phase II randomized controlled trial investigating the efficacy of high-dose vitamin D supplementation in prostate cancer patients (age ≥ 60 yrs). Fifty-nine patients were randomized to high-dose vitamin D (600 IU/day plus 50,000 IU/week) or low-dose: RDA for vitamin D (600 IU/day plus placebo weekly) for 24 weeks. Phase angle was measured by BIA. Physical function measures included handgrip strength, 6-minute walk test, Short Performance Physical Battery and leg extension. All testing was completed at baseline, week 12 and week 24.

Results:

Phase angle values were wider over the entire study in the high-dose vitamin D arm indicating healthier muscle cells. The low-dose vitamin D arm had phase angle values consistent with frailty cutoffs in older men (< 5.7°).

Conclusion:

Patients in the high-dose vitamin D arm experienced wider phase angle values over the course of the study which may indicate less frailty. ClinicalTrials.gov ID: NCT02064946.

Introduction

Androgen deprivation therapy (ADT) is standard treatment for patients with advanced prostate cancer and ADT use is becoming more common (1–4). Patients on ADT are at risk for loss of functionality in part due to changes in body composition, further aggravated by the effects of aging (5). Side effects resulting from ADT include muscle loss, loss of strength and increased adiposity (1, 2), which may lead to sarcopenic obesity, functional decline and long-term frailty (6). Furthermore, men with prostate cancer often present with less lean mass before ADT administration (7).

Low vitamin D status is associated with poorer outcomes in prostate cancer (8, 9). Vitamin D deficiency is believed to lead to decreased lean body mass and muscle quality and may accelerate functional decline with aging and disease (10–13). Muscle cells contain the vitamin D receptor (VDR), which decreases with age, even as physical strength and functionality also decline (14–16). Vitamin D may further impact muscle by its relationship to calcium metabolism, as reduced calcium concentrations lead to atrophy of type II muscle fibers (12, 14).

Research findings on vitamin D supplementation evaluating frailty and musculoskeletal function are inconclusive. In a recent randomized controlled trial (RCT) by Liberman et al., a supplement containing vitamin D combined with whey protein reduced inflammatory markers associated with sarcopenia in older adults (17). Another RCT in elderly women by Zhu et al. found that daily intake of 1,000 IU vitamin D and 1000 mg calcium increased muscle function and strength over one year in the subjects who were weakest at baseline (18). However, more recent findings such as a longitudinal study by Bolzetta et al., showed that vitamin D supplementation did not improve any symptoms or measures of frailty in older adults over an eight-year period (19). When considering how this differs from previous research, Bolzetta et al. noted that previous studies used a higher dose of vitamin D and enrolled subjects with lower vitamin D levels at baseline (19). For example, in a recent RCT, older adults administered 10,000 IU vitamin D (oral gel cap supplements) daily for five days per week, higher vitamin D supplementation combined with exercise improved muscle quality and aerobic fitness more than aerobic training alone (20). Higher doses of vitamin D supplementation may be more effective; doses as high as 50,000 IU/week have been shown to increase serum 25-OH vitamin D levels in patients with cancer (21–23). Previous research shows that taking high-dose vitamin D supplementation is generally safe, however, the question remains as to whether vitamin D supplementation reduces ADT-induced side effects in older patients with prostate cancer (19).

In addition to physical function, preliminary impairments in cellular membrane function and fluid imbalance that eventually lead to functional decline can be detected before changes in body composition by bioelectrical impedance analysis (BIA) (24). Phase angle is a non-invasive technique measured from BIA to assess functionality and frailty (25–27). Phase angle may indicate nutrition and hydration status in various populations including diseases of aging, sarcopenia and cancer, and lower phase angle values signal the onset of functional decline (24, 27, 28). In patients with cancer, nutrition and hydration, as measured by phase angle, are indicators for overall well-being and are used in the decision process for treatment (27). Phase angle in patients with cancer serves as a predictor of poor health status and lower survival (27).

The aim of this study was to investigate the impact of vitamin D supplementation in a dose-dependent manner on phase angle and physical function in prostate cancer patients on ADT. The dosage of vitamin D supplementation may be crucial to effectively improve health outcomes in this population (29, 30). Patients with suboptimal vitamin D levels at baseline may benefit more from vitamin D supplementation.

Patients and Methods

Study Design

This study is an exploratory analysis of data from a phase II randomized, double-blind clinical trial examining the effect of high-dose vitamin D supplementation on bone health in patients with prostate cancer receiving ADT (31). Recruitment for the original study occurred over 26 months at the Wilmot Cancer Center, Highland Hospital Radiation Oncology, and outpatient Urology offices following approval by the University of Rochester Research Subjects Review Board. This phase II RCT investigated the feasibility and preliminary efficacy of high-dose vitamin D supplementation for 24 weeks in prostate cancer patients receiving ADT. Participants were randomized to: 1) low-dose vitamin D₃ (placebo vitamin D weekly + daily multivitamin containing the RDA for vitamin D: 600 IU/day + 210 mg/day calcium and calcium supplements (800 mg/day)); or to 2) high-dose vitamin D₃ (50,000 IU/ week + daily multivitamin containing the RDA for vitamin D: 600 IU/day + 210 mg/day calcium and calcium supplements (800 mg/day)) over 24 weeks. There were safety checks every six weeks. All study investigators, study coordinators, and subjects were blinded; only the research pharmacist had access to group assignment.

Prostate cancer patients were recruited by clinical research coordinators through the use of direct contact during regularly scheduled oncology visits. Eligibility criteria included 1) a confirmed diagnosis of prostate cancer (stage I-IV) with no bone metastases; 2) being within six months of starting ADT with an additional six more months planned; 3) suboptimal vitamin D levels (<32 ng/ml); 4) total serum calcium ≤10.5 mg/dl; 4) no contraindications for fitness testing and 5) ≥ 60 years old. Potentially eligible patients were administered a serum 25-OH vitamin D test and those with adequate vitamin D levels were excluded. Exclusion criteria also included hypercalcemia, osteoporosis, stage IV kidney disease or myocardial infarction within the past year.

Outcome Measures

For this current analysis, measures of phase angle, physical function and lean mass were assessed between arms in 59 prostate cancer patients providing evaluable data. Outcomes were identified at the final 24-week assessment. A trial period of 24 weeks was chosen because that time period is long enough to observe changes in body composition as a result of supplementation. Clinical data were collected by clinical research coordinators from medical charts, and demographic information was collected using study-specific forms completed by subjects.

For BIA (RJL Systems Quantum II Desktop BIA, Clinton Township, MI) testing, participants lay supine on a flat surface to ensure a resting metabolic state, while electrodes were placed on the right hand (proximal phalanx of the 3^rd finger and the radiocarpal joint) and right foot (distal end of the 3rd and 4th metatarsal and distal end of the tibia and fibula). Phase angle values were calculated from the arc of the tangent of the reactance and resistance ratio (measured in ohms from BIA) (25, 26). Lean mass was also assessed from BIA testing.

Handgrip test using a hand dynamometer (Hand Dynamometer, Jamar; Bolingbrook, IL) measured the maximal voluntary contraction generated by the arm muscles. The test was administered with the patient standing in anatomical position, the elbow joint angle held constant at 180° with the medial distal humeral epicondyle two inches from the torso. The knee extension test (leg extension machine, Life Fitness; Schiller Park, IL) measured lower body strength and was performed with both legs, extending the legs at the knee, and progressing towards the maximum weight that the participant could lift for 7–10 repetitions (32). The short physical performance battery (SPPB) summary score was derived from the sum of three main tasks: 1) standing balance test 2) walking speed (timed 4-meter walk) 3) and the repeated sit-to-stand or chair stand test (33–35). For standing balance the score was based on the side-by-side stand, semi-tandem stand and tandem stand tests where the tandem stand test contributed two out of the four points. The chair test was scored based on the speed that a participant can complete five chair stands with a higher score given to those who completed the task in less time. Each domain is scored from 0–4 with 0 being “unable to complete the task” and 4 being “at the highest level of performance (36)”. Impairment was defined as a total SPPB score of 9 or less out of 12 (37). All physical assessment measures were potentially modified based on the subject’s risk, as outlined by ACSM fitness testing guidelines (32). All physical function testing occurred at baseline, week 12 and week 24. Compliance to study intervention was measured by a pill count at weeks 12 and 24. Scheduled blood draws every six weeks served as safety checks and a means to assess serum calcium and vitamin D levels by study arm assignment.

Statistical Considerations

Clinical and sociodemographic variables were evaluated with analysis of variance (ANOVA) models for continuous variables and χ² for categorical variables to assess differences between treatment arms in bivariate analysis. The multivariate linear model with arm as the main factor and baseline levels for age, baseline lean mass, time on ADT and exercise as covariates was used to evaluate treatment effects. Adjusted mean between arm difference was calculated using marginal means that were estimated by the multivariate model. A p-value <0.05 was considered statistically significant in this analysis. All calculations were conducted in SAS 9.4 (SAS Institute, Cary, NC).

Results

A total of 59 prostate cancer patients on ADT provided evaluable data for this analysis. They were 67.6 ± 5.4 years old and 85% were Caucasian. There was no difference in age, race, BMI, lean mass, time on ADT, exercise (hours per week), previous treatment or Karnofsky Performance Status (KPS) scores between arms (see Table 1).

Table 1.

Baseline descriptive characteristics of participants (N=59)

Variables	Low-Dose(n=30)	High-Dose(n=29)	P-value
Age (mean, SD)	67.8±4.4	67.5±6.4	.842
Body Mass Index,	29.4±4.6	29.9±4.9	.712
Lean Mass (lbs)	140.9±22.4	145.1±23.8	.500
Race (n, %)			.210
Caucasian	27 (90%)	22 (76%)
other	3 (10%)	7 (24%)
ADT (weeks)	47.9±37.2	39.7±37.6	.405
Radiation (y/n)	10 (33%)	7 (24%)	.442
Exercise (hrs/week)	2.9±1.6	2.7±1.4	.599
KPS (mean, SD)	74.3±37.4	75.6±34.2	.892

P-value was based on ANOVA for continuous variables and Chi-square for all categorical variables.

Phase Angle & Lean Mass

Phase angle values between arms were no different at baseline. The high-dose vitamin D arm had significantly wider phase angle values in the high-dose group at week 12 (p=0.014; 95% C.I. −0.824, −0.098) and at week 24 (p=0.018; 95% C.I. −0.922, −0.090). Lean mass was significantly higher in the high-dose arm at week 12 (p=0.036; 95% C.I. 0.229, 6.556) but was not different between arms at any other time point (see Table 2).

Table 2.

Phase angle values and lean mass obtained from the BIA, adjusted mean ± standard error.

Variables	Low-Dose	High-Dose	P-value	Mean Difference§	95% C.I.
Phase Angle, adj. mean±SE
Baseline	5.62±0.12	5.84±0.12	0.210	−0.223	(−0.575, 0.130)
Week 12	5.34±0.12	5.80±0.13	0.014	−0.461	(−0.824, −0.098)
Week 24	5.40±0.14	5.90±0.15	0.018	−0.506	(−0.922, −0.090)
Lean Mass, adj. mean±SE
Baseline	142.7±4.42	145.17±4.51	0.700	−2.466	(−15.253, 10.322)
Week 12	142.2±1.12	145.6±1.08	0.036	3.393	(0.229, 6.556)
Week 24	144.0±1.15	145.47±1.13	0.373	1.465	(−1.821, 4.750)

Adjusted for age, baseline lean mass, time on ADT and baseline exercise using multivariate model.

^§The mean difference is calculated from the average of 95% confidence intervals.

Physical Function

At baseline, the high-dose arm showed a trend towards lower standing balance (p=0.057). Other measures of physical function: handgrip strength, standing balance, walking speed, chair stand, SPPB, total and leg extension were not different between arms at any time point. Baseline and week 24 are presented, although there is no difference between arms (see Table 3).

Table 3.

Physical function measures between arms at baseline and week 24, adjusted mean ± standard error.

Variable	Low-Dose	High-Dose	P-value	Mean Difference§	95% C.I.
Handgrip, adj. mean±SE
Baseline	38.4±1.2	36.7±1.3	0.329	1.735	(−1.803, 5.274)
Week 24	37.3±1.4	36.8±1.5	0.819	0.486	(−3.781, 4.753)
Standing Balance
Baseline	4.0±0.1	3.8±0.1	0.057	0.194	(−0.006, 0.394)
Week 24	3.9±0.1	3.8±0.1	0.263	0.118	(−0.092, 0.327)
Walking Speed
Baseline	3.9±0.1	3.9±0.1	0.591	0.058	(−0.157, 0.272)
Week 24	4.0±0.0	3.9±0.0	0.820	0.015	(−0.114, 0.143)
Chair Stand Test
Baseline	3.6±0.2	3.7±0.2	0.715	−0.092	(−0.594, 0.410)
Week 24	3.8±0.1	3.8±0.1	0.939	−0.011	(−0.304, 0.282)
SPPB Total
Baseline	11.5±0.2	11.3±0.2	0.613	0.160	(−0.474, 0.795)
Week 24	11.7±0.2	11.4±0.2	0.252	0.0.362	(−0.267, 0.992)
Leg Extension
Baseline	59.2±3.13	63.8±3.3	0.325	−4.522	(−13.674, 4.631)
Week 24	61.8±4.8	61.0±5.1	0.907	0.835	(−13.555, 15.225)

Adjusted for age, baseline lean mass, time on ADT and baseline exercise.

^§The mean difference is calculated from the average of 95% confidence intervals.

Discussion

To our knowledge, this study is one of the first to compare the impact of high-dose versus low-dose vitamin D supplementation on phase angle and physical function in patients with prostate cancer on ADT. Phase angle values improved over time in the high-dose vitamin D supplementation arm and the value declined and remained below the cutoff for frailty in older men in the low-dose vitamin D supplementation arm. Phase angle values in the high-dose arm were wider at week 12 and 24 than the low-dose arm. For the low-dose arm, phase angle values declined from baseline to week 24. In previous studies evaluating patients with cancer, lower phase angle scores were associated with sarcopenia, impaired functionality and weight loss (38, 39). A phase angle value <5.7 in older men is a cutoff value for frailty (26). Throughout this study, the low-dose arm had phase angle values consistently <5.7 that declined significantly from baseline to week 24 (see Figure 1). Other study measures were not associated with phase angle values in this study. Lean mass was higher in the high-dose arm at week 12. Measures of physical function stayed the same over the course of the study.

Figure 1.

Change in phase angle values from baseline at week 12 and week 24, low-dose and high dose arms. Red line indicates frailty cutoff in older men (5.7°).

In this analysis, no other differences were observed between arms across study measures over time. Physical function measures did not differ at any time point between arms and stayed the same over the course of the study without further decline. Taking into consideration that patients on ADT experience a loss of lean mass and physical function over time (40, 41), participants in this study may have benefitted from the vitamin D supplementation and might have experienced further decline without the supplement.

Results from previous studies that examined vitamin D supplementation and physical function are mixed (42). A recent study looking at the effect of 4000 IU of vitamin D₃ on 40 older adults with frailty, showed an improvement in SPPB scores and vitamin D levels in this population, but only in those who were vitamin D insufficient at baseline (43). In another recent RCT from the Netherlands examining older adults with vitamin D deficiency, however, 1200 IU/day supplementation failed to lead to improvement in physical function measures (44). In most previous literature, there was either no improvement in physical function with vitamin D supplementation or vitamin D supplementation improved measures of physical function only in those with baseline vitamin D insufficiency (<20 ng/mL) (42–44). This may be due in part to participants with low serum vitamin D receiving higher levels of the supplement. In the current analysis, enrollment criteria included low vitamin D levels (<32 ng/ml) for all participants including those who received high-dose vitamin D supplementation. Currently, there are few studies strictly investigating prostate cancer patients on ADT and vitamin D supplementation to compare our findings to (45).

Men with prostate cancer on ADT often develop sarcopenia. Maintaining lean mass may potentially be indicative of a possible role the vitamin D supplementation exerted (46). The high-dose vitamin D arm had higher levels of lean mass at week 12. Our data also showed that both high-dose and low-dose vitamin D supplementation arms maintained lean body mass levels from baseline until week 24. When studying the impact of vitamin D on muscle, researchers look at vitamin D receptor (VDR). VDR is a cognate nuclear receptor to which the active hormone 1,25-dihydroxy vitamin D binds, exerting both genomic and non-genomic effects in cells (47). The VDR is the primary operating unit for vitamin D throughout the body and there are VDRs located in skeletal muscle (47). In recent years, the impact of VDR on skeletal muscle mass has become a topic of debate (48). In a recent study, Roh et al. found that sarcopenic (low muscle mass and strength) adults had significantly lower vitamin D receptor expression than healthy controls (49). Similarly, a relationship has been identified between vitamin D deficiency and atrophy of type II muscle fibers that resembles the decline seen in aging muscle (21). The vitamin D supplementation may have exerted a positive effect on muscle or lean mass in all participants in this study, especially the high-dose arm, since none experienced further decline. By utilizing phase ange measurements, our findings add to the body of literature and show that the mechanism by which vitamin D may improve skeletal muscle health and physical function could be in part via cellular membrane integrity.

Some research has found that vitamin D supplementation combined with resistance exercise training increases lean mass, but it cannot be determined whether or not resistance exercise alone exerted the effect (50). A RCT in daily vitamin D supplementation and postmenopausal women actually found a negative relationship of vitamin D supplementation to lean mass (51). More longitudinal studies in patients with cancer are needed to determine the impact of vitamin D and exercise on lean mass and phase angle values.

Strengths for this study include the random assignment of vitamin D doses, monitoring adherence to study intervention during the study period and the use of objective physical function testing. Blood tests at five time points from baseline until the final assessment confirmed that participants were compliant with vitamin D supplemental intake, had suboptimal vitamin D levels at baseline and that the treatment arm had higher vitamin D levels corresponding to their higher supplement regimen.

Limitations include a small sample size and missing data for factors such as cancer stage which may have further influenced the impact of the intervention.

Conclusion

Patients with prostate cancer on ADT who received high-dose vitamin D supplementation had greater phase angle values after 24 weeks. Phase angle values in the low-dose vitamin D supplementation arm gradually declined and were all below the cutoff for frailty for older men throughout the study. Physical function and lean mass did not differ between arms and did not decline further over the course of the study. More research in larger populations is needed to evaluate the benefit of high-dose vitamin D supplementation on measures of phase angle and physical function in prostate cancer patients on ADT.