Effect of Calcitriol Supplementation on Blood Pressure in Older Adults

Jaime Alberto Bricio‐Barrios RD, Alín Jael Palacios-Fonseca MSc, Mario del Toro-Equihua PhD & Carmen Alicia Sanchez-Ramirez PhD

To cite this article: Jaime Alberto Bricio‐Barrios RD, Alín Jael Palacios-Fonseca MSc, Mario del Toro-Equihua PhD & Carmen Alicia Sanchez-Ramirez PhD (2016) Effect of Calcitriol Supplementation on Blood Pressure in Older Adults, Journal of Nutrition in Gerontology and Geriatrics, 35:4, 243-252, DOI: 10.1080/21551197.2016.1206499
To link to this article: http://dx.doi.org/10.1080/21551197.2016.1206499

Published online: 29 Nov 2016.

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JOURNAL OF NUTRITION IN GERONTOLOGY AND GERIATRICS 2016, VOL. 35, NO. 4, 243–252

http://dx.doi.org/10.1080/21551197.2016.1206499

Effect of Calcitriol Supplementation on Blood Pressure in Older Adults
Jaime Alberto Bricio‐Barrios, RD, Alín Jael Palacios-Fonseca, MSc,
Mario del Toro-Equihua, PhD, and Carmen Alicia Sanchez-Ramirez, PhD
Facultad de Medicina, Universidad de Colima, Colima, Mexico

KEYWORDS
Blood pressure; calcitriol; hypertension; older adults; vitamin D

Introduction
The prevalence and incidence of cardiovascular disease increases exponentially with age (1). These diseases account for 30% of global mortality, and more than 80% of cardiovascular disease deaths that take place in the developing countries (2).
Although there is considerable variability, almost all nations worldwide are currently experiencing growth in the number of residents 65 years and older. It is estimated that by the year 2035, nearly one out of every four individuals will be 65 years of age or older (3). Most developed countries have relatively high proportions of individuals 65 years and older, but the most rapid increase in older populations is in developing countries, including Mexico (4–5). This phenomenon is accompanied by an increasing prevalence of chronic diseases such as high blood pressure (HBP) (6).
Vitamin D (VD) deficiency and insufficiency are prevalent in much of the world (7). Older adults are especially at risk for developing VD deficiency due

CONTACT Carmen Alicia Sanchez-Ramirez [email protected] Facultad de Medicina, Universidad de Colima, Av. Universidad 333, Colonia Las Víboras, Colima, Col. CP 28010.
© 2016 Taylor & Francis

to low exposure to sunlight (8), a decreased capacity of aging skin to synthesize VD, and a lower consumption of VD food sources (9, 10).
The major and best-known function of VD is to maintain calcium and phosphorus homeostasis and to promote bone mineralization. However, recent studies suggest that VD plays an important role in cardiovascular disease, including atherosclerosis and endothelial dysfunction (11), and this may explain why VD supplementation substantially reduces mortality (12). Moreover, VD insufficiency seems to be implicated in blood pressure (BP) control through activation of the renin-angiotensin system (13). Published studies have shown that adequate VD levels can prevent vascular smooth muscle contraction and increase arterial compliance, acting on blood vessels as a possible vasodilator; in addition, improved endothelial function has also been reported (14). These protective or beneficial mechanisms can thus be potentially compromised in individuals with deficient or insufficient VD levels (15). These findings may support the recommendation for VD supple- mentation in older adults as HBP prophylaxis or treatment. However, the role of this supplementation for HBP is controversial. Some intervention studies have demonstrated that it decreases BP (16–18), whereas others have shown no effect (19–21). The purpose of our study was to investigate whether calcitriol supplementation reduced BP levels in older adults.

Methods
Study population
Adults aged 60 years and older with essential HBP (≥140/90 mmHg) were recruited through nursing homes and recreation centers in the state of Colima in Mexico. At the screening visit prior to randomization, 312 subjects had a routine clinical examination and medical history interview. Forty-nine subjects were assessed for eligibility at our outpatient clinic. None of the subjects were undergoing hormone replacement therapy, including VD within the past 3 months, or had impaired renal or hepatic function. All were receiving antihypertensive treatment, and doses did not change during the study. Before randomization, two subjects withdrew their written informed consent for per- sonal reasons, and two subjects were excluded due to severe HBP diagnosis.

Design
During a 6-week, double-blind, controlled trial, subjects were randomly assigned to either the calcitriol group or placebo group. Twenty-two participants were enrolled in the calcitriol group for 6 weeks of treatment with a daily dose of 1,000 IU of calcitriol (administered as one capsule of 1,000 IU each), and 23 participants were enrolled in the placebo group (the control group) that received a similar placebo capsule, also for 6 weeks. The subjects

enrolled were recruited from nursing homes (n = 11) and recreation centers (n = 34). The participants were randomly assigned to one of the two arms using a computer-generated randomization code. The dependent variable was BP, and we analyzed the difference in BP, expressed in mmHg, before and after the intervention. During treatment, 9 participants (20%) were excluded, leaving a total of 36 (80%) patients available for follow-up measurements. All patients provided written informed consent and the study was conducted in accordance with the Declaration of Helsinki II and the Good Clinical Practice guidelines. Approval was obtained from the Bioethics Committee of the Faculty of Medicine at the Universidad de Colima (FM014/2012) and the study was registered at ClinicalTrial.gov (no. NCT02047799).

Measurement
BP was measured consecutively 3 times at each time point using an integrated aneroid sphygmomanometer kit with stethoscope (Medimetrics 5769); the patient was seated, in a rested state for at least 5 minutes. Those subjects with BP ≥ 140/90 mmHg were included in the study.
Once enrolled in the study, the basal and final measurements of the BP were obtained each week, at the same hour of the day, and in the same conditions; anthropometric measurements were also collected. Body mass index (kg/m2) was calculated from weight and height measurements. For these measurements, participants wore light clothing and removed their shoes. For the determination of serum 25(OH)D, two blood samples were collected in the morning after a minimum 8-hour overnight fast on the day of randomization and at the end of the study. The cut-off value of optimal serum 25(OH)D was >75 nmol/L (22–23) and VD insufficiency, defined as serum 25(OH)D levels <75 nmol/L (24).

Safety and Adherence
The participants attended follow-up visits every week for safety measures, adverse event registration, and assessment of compliance. Returned pills were counted at each visit and compliance was calculated as the percentage of used pills compared with the expected number.

Biochemistry
Serum 25(OH)D concentration was measured by means of the competitive enzyme-linked immunosorbent assay (ELISA: Immundiagnostik, Bensheim, Germany) after solid-phase extraction in pairs, pre-/postintervention. The coefficients of variation for inter-assay analyses were 9.2% and intra-assay was 6.9%.

Statistical analysis
The data were analyzed with the SPSS version 21 program. The variables studied were described as frequencies, percentages, and medians (interquartile range); inferential statistics were performed with the Mann-Whitney U test to compare the two groups and the Wilcoxon test was used when comparing related samples. Statistical significance was set at a p-value <0.05.

Results
Baseline characteristics
Forty-five older adults were included in the trial (77.7% of the subjects were women), during April to June 2013. Randomization was balanced with no significant differences in demographic, anthropometric, or clinical variables between the two groups at the baseline (Table 1). Thirty-six subjects (80%) completed the trial, and compliance was above 95% for all participants, the rest of the participants (n = 9) were removed from the study for noncompliance for treatment or for personal reasons. The baseline character- istics among those who completed treatment and those who dropout are shown in Table 2.

Levels of 25(OH)D
At the beginning of the study, all participants had serum levels of 25(OH)D below the optimal value. Baseline [54.06 nmol/L (46.4–71.5)] and final [54.8 nmol/L (39.8–64.1)] serum levels of 25(OH)D were similar, with no statistical difference in the calcitriol group (p = 0.215). There were significantly lower serum levels in the control group at the end of the study 36.7 nmol/L

Table 1. Demographic, baseline. anthropometric, and clinical variables between the two groups at
Placebo (n = 18) Calcitriol (n = 18) p*
Age (yrs.) 69.5 (63.5–77.2) 71.0 (63.0–82.2) 0.7
Nursing Home (n) 6 (33.3%) 5 (27.7%) 0.9
Community-dwelling (n) 12 (66.6%) 13 (72.2%) 0.9
Women (n) 14 (77.7%) 14 (77.7%) 1.0
Weight (kg) 69.0 (54.9–76.8) 63.1 (52.8–71.4) 0.3
Height (cm) 1.5 (1.5–1.6) 1.5 (1.5–1.6) 0.7
BMI (kg/m2) 27.1 (23.6–33.1) 25.7 (23.2–28.8) 0.3
SBP (mmHg) 147.7 (140.7–153.0) 146.7 (140.3–155.0) 0.7
DBP (mmHg) 80.0 (73.6–85.6) 80.0 (75.7–90.0) 0.3
Plasma 25(OH)D (nmol/L) 54.0 (30.6–65.7) 54.0 (46.4–71.5) 0.5
Values are presented as median and interquartile ranges (the 25th–75th percentile) [Reference range].
*The differences between the two groups were compared using the Mann–Whitney U-test or χ2-test, as appropriate.
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Table 2. Comparison of baseline characteristics between completed treatment group and those who dropout.
Completed Treatment (n = 36) Dropout Treatment (n = 9) p*
Age (yrs.) 69.0 (63.5–78.5) 71 (69.2–78.0) 0.61
SBP (mmHg) 147.5 (140.7–153.5) 140.0 (140.0–146.8) 0.07
DBP (mmHg) 80.0 (75.0–86.0) 80.0 (72.5–89.1) 0.84
Plasma 25(OH)D (nmol/L) 55.60 (44.14–69.12) 66.48 (60.36–69.32) 0.06
Values are presented as median and interquartile ranges (the 25th–75th percentile) [Reference range].
*The differences between the two groups were compared using the Mann–Whitney U-test or χ2-test, as appropriate.
SBP, systolic blood pressure; DBP, diastolic blood pressure.

(14.9–45.7), compared with the baseline levels 54 nmol/L (30.6–65.7)
(p = 0.001).

Blood pressure
The baseline and final values of systolic blood pressure (SBP) and diastolic blood pressure (DBP) are shown in Table 3. In the calcitriol group, SBP and DBP decreased significantly after the intervention (p < 0.001). However, in the control group, SBP was lower, without being significant and DBP remained the same.

Adverse events
No subjects reported any adverse events during the study.

Discussion
To the best of our knowledge, this is the first double-blind, randomized, placebo-controlled trial that investigated the effects of calcitriol supplementa- tion (1,000 IU daily for 6 weeks) in older Mexican subjects with HBP (≥140/90 mmHg). The main finding were that the group that received calcitriol had a significant reduction in SBP and DBP compared with the placebo group; these results support the findings of Kimura and colleagues (25) in which calcitriol

Table 3. Baseline and Final Values of Systolic Blood Pressure and diastolic blood pressure, according to the Groups Studied.
Group SBP/DBP Initial Value Final Value Difference P
Calcitriol SBP (mmHg) 146.7 (140.3–155.0) 125.0 (120.0–130.0) 20.25 (10.0–30.5) 0.001*
DBP (mmHg) 80.0 (73.6–85.6) 70.0 (67.2–75.0) 7.0 (2.0–16.2) 0.01*
Placebo SBP (mmHg) 147.7 (140.7–153.0) 143.5 (141.5–148.1) 1.5 (−1.0–7.2) 0.06
DBP (mmHg) 80.0 (75.7–90.0) 80.0 (76.1–90.0) 1.0 (−6.2–10.0) 0.70
Values are presented as median and interquartile ranges (the 25th–75th percentile) [Reference range].
*p was determined by the Mann-Whitney test.
SBP, systolic blood pressure; DBP, diastolic blood pressure.

lowered BP from 145/96 mmHg to 128/85 mmHg after two weeks of calcitriol therapy. In addition, Bernini and associates (26), in 18 hypertensive patients who received a single oral dose of 300,000 IU of cholecalciferol, reduced BP from 147/93 mmHg to 132/79 mmHg after 8 weeks. A pilot study (n = 9) carried out by Judd and coauthors (27) reported a reduction of 9% in the SBP in the group receiving calcitriol compared with the placebo group (p < 0.001), and no significant reductions in DBP. These results differ from other published studies that have demonstrated a lower decrease in SBP and no effects on DBP. Wu and colleagues (28) conducted a meta-analysis that included four double-blind, randomized, controlled trials involving 429 normo- tensive and hypertensive individuals. The main findings indicated that VD supplementation reduced SBP by 2.44 mmHg, but there was no reduction in DBP compared with calcium or placebo. Pfeifer and coauthors (16) studied the effects of 8 weeks of supplementation with 200 mg of calcium and 800 IU/ d of VD on BP in 148 elderly women and compared with calcium alone, supplementation with VD plus calcium resulted in a decrease in SBP of 9.3% (p = 0.02). A total of 81% of the subjects in the VD plus calcium group compared with 47% of the subjects in the calcium group showed a decrease in the SBP of 5 mmHg or more (p = 0.04). No statistically significant difference was observed for DBP.
Moreover, there are studies who have not found significant relationships
between VD supplementation and BP after 7 years of treatment with 400 IU of VD (29) and dosages that range from 2,700 to 5,700 IU/d for 1 year (19). It is important to mention that various intervention studies involving the impact of VD therapy on BP have been heterogeneous in relation to daily dose of VD (800 IU ≥ 4,000 IU) administered and the duration of the therapy, which are factors that may contribute to BP changes and outcome.
Other meta-analyses exhibit different results: Witham and colleagues (17) conducted a meta-analysis that included 11 randomized, controlled trials in which the mean BP was higher than 140/90 mmHg, showing a small, but stat- istically significant reduction in DBP (−3.1 mmHg, 95% CI −5.5 to −0.6) and a nonsignificant reduction in SBP in the VD group compared with placebo. In 14 randomized trials (n = 751) receiving VD supplementation, compared with placebo (n = 767), Elamin and coauthors (21) found no significant changes in the surrogate outcomes of SBP (0.95 [95% CI − 1.98, 1.87]) and DBP (0.33 [95% CI − 1.03, 0.35]). In a meta-analysis of 3 cohorts with a 7- to 10-year follow-up, Pittas and researchers (20) identified a statistically significant association, comparing the lowest 25(OH)D concentration versus the highest category of 25(OH)D and incident of hypertension (RR = 1.76;95% CI 1.27, 2.44). The meta-analyses also conducted by Pittas and colleagues (20) included 9 randomized trials (n = 37,162) of different quality, in which VD was given alone or with calcium at doses of 400 to 8571 IU/d; they found no statistically

significant effect of VD supplementation versus placebo on SBP or DBP. Burgaz and coauthors (18) carried out a meta-analysis that included 18 studies (4 prospective and 14 cross-sectional) involving 17,028 subjects. In 14 of the studies there was an inverse association between 25(OH)D concentrations and HBP and a statistically significant association was observed in only 10 of them. The odds ratio for HBP decreased by 16% for every 16 ng/mL increase in 25(OH)D blood concentrations. They explained that the observed heterogeneity of the 25(OH)D blood concentrations and HBP among the studies was due to ethnic differences.
It is also important to mention that at the beginning of the study, the baseline 25(OH)D serum levels of all the participants were below the optimal amount; this phenomenon has been published by several authors among older participants from the United States and Spain (30–33). According to a multinational study involving 18 countries at various latitudes, a high preva- lence of VD insufficiency, defined as serum 25(OH)D levels <75 nmol/L, was identified in Korea (92.1%), Japan (90.4%), Lebanon (84.9%), Turkey (76.7%), the United Kingdom (74.5%), Germany (68.0%), Mexico (67.1%),
and Spain (64.7%) (24).
When comparing the 25(OH)D serum levels between the two study groups, we identified a decreasing trend in the calcitriol group, without being signi- ficant; however, in the placebo group, this decrease was significant. The first finding could be explained by our dosing protocol. The calcitriol group received 1,000 IU, which is within the suggested daily intake range (800–2,000 IU) of VD (34). No doses above 3,000 IU were administered in other published reports in which they identified significant increases in the serum levels of 25(OH)D (26–35, 36). It is important to note that we admini- strated 1,25(OH)D (active VD) and we measured 25(OH)D (pre-VD). Probably the biochemical changes were identified in 1,25(OH)D, but for the purpose of research purpose it is recommended to measure 25(OH)D. Bernini and coauthors (26) performed a similar study in patients with essen- tial hypertension in which the calcitriol group (n = 10) received 1,000 IU of VD daily for 7 days and the control group (n = 10) had no supplementation and were normotensive subjects. Eight weeks later, the blood pressure in the calcitriol group decreased from 145/90 mmHg to 133/81.6 mmHg (p < 0.05). The biochemical changes in the intervention group had a slight increase of 25(OH)D from 12.6 to 14.5 ng/mL without being significant: while the levels in the control group changed from 20.1 to 20.4 ng/mL. The levels of 1,25(OH)D in the intervention group increased from 28 to 38.9 pg/mL and in the control group decreased from 35.4 to 24.0 pg/mL. The results of the Bernini and coauthors are similar to our results, in which we identified a significantly decrease of blood pressure without a significant increase of 25(OH)D in the calcitriol group.

Limitations
The main limitations of our study are a small sample size, a dropout of 20%, the short duration of the supplementation (lasting only 6 weeks) and the fact that the calcitriol dose did not increase 25(OH)D. We administrated 1,25 (OH)D (active VD), which likely accounted for the biochemical changes we identified. However, we measured 25(OH)D (pre-VD) because of its standard clinical use as an indicator of Vitamin D status. Bernini et al. (26) performed a similar study in patients with essential hypertension in which the calcitriol group (n = 10) received 1,000 IU of VD daily for seven days and the control group (n = 10) had no supplementation and were normotensive subjects. Eight weeks later, the blood pressure in the calcitriol group decreased from 145/90 mmHg to 133/81.6 mmHg (p < 0.05). The biochemical changes in the intervention group had a non-significant increase of 25(OH) D from
12.6 to 14.5 ng/mL; likewise, the levels in the control group were also unchanged (20.1 to 20.4 ng/mL). The levels of 1,25(OH)D in the intervention group increased from 28 to 38.9 pg/mL and in the control group decreased from 35.4 to 24.0 pg/mL. Thus, the results of the Bernini et al. are similar to our results, in which we also identified a significantly decrease of blood pressure without a significant increase of 25(OH)D in the calcitriol group.
Take away points
. The data reported in the present study demonstrated that calcitriol supplementation significantly decreased both SBP and DBP values in older hypertensive participants under antihypertensive treatment.
. All participants had serum levels of 25-hydroxyvitamin-D under the desired value.
. Considering the prevalence of vitamin D insufficiency identified in our population, the reported effects on BP could be of considerable clinical importance, supporting the recommendation of calcitriol supplementation in older populations alongside the conventional therapy indicated.
Acknowledgments
The authors wish to thank the privately owned welfare institutions “La Armonía,” “San Vicente de Paul,” and “El poder de tu amor sana al prójimo,” and the state-run “Instituto para la atención al adulto en plenitud” and “Grupos de la Tercera edad Parque Regional.”

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