A Pilot Study of Paricalcitol plus Nanoliposomal Irinotecan and 5-FU/LV in Advanced Pancreatic Cancer Patients after Progression on Gemcitabine-Based Therapy.

PURPOSE: Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models. PATIENTS AND METHODS: We conducted a pilot study to evaluate the safety and preliminary efficacy of the vitamin D analogue paricalcitol in combination with nanoliposomal irinotecan (Nal-iri) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with advanced pancreatic cancer who had progressed on gemcitabine-based therapy. Two dose levels (DL) of paricalcitol were tested: fixed dose weekly (75 mcg, DL1) and weight-based weekly (7 mcg/kg, /DL2). The primary endpoint was safety, and secondary endpoints included overall response rate, progression-free survival (PFS), and overall survival (OS). Correlative objectives aimed to identify molecular predictors of response and alterations in the tumor stroma. RESULTS: Twenty patients (10 each in DL1 and DL2) enrolled between March 2019 and May 2021. No grade 3/4 adverse events related to paricalcitol were observed. The most common toxicities were nausea, diarrhea and fatigue, which were similar in both cohorts. Three patients discontinued study after one cycle and were not radiographically evaluable. Of the remaining 17 evaluable patients, 2 had partial response and 12 had stable disease. The median PFS for response-evaluable patients in DL1 was 4.14 months, for DL2 was 4.83 months. Intent-to-treat median OS was 6.15 and 6.66 months for DL1 and DL2, respectively. Correlative studies showed increased tumor vascularity in posttreatment samples in patients receiving the higher dose of paricalcitol (DL2). CONCLUSIONS: Paricalcitol at 7 mcg/kg/week in combination with Nal-iri/ 5-FU/LV is safely tolerated, may increase tumor vascularity and warrants further investigation.

The Effect of Vitamin D Supplementation on Treatment-Induced Pain in Cancer Patients: A Systematic Review.

OBJECTIVES: Despite the widespread use of complementary and alternative medicine by patients and physicians alike, there is no accurate evidence regarding the effects of vitamin D supplementation on treatment-induced pain in cancer patients. Thus, the aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the impact of vitamin D administration on therapy-related pain in subjects diagnosed with malignant disorders. REVIEW ANALYSIS METHODS: We searched the Web of Science, Scopus, PubMed/Medline, Embase, and Google Scholar databases up to October 2020 to identify published RCTs that investigated the use of vitamin D in the management of treatment-induced pain in individuals with cancer. RESULTS: Nine RCTs were detected. The median duration of the intervention was of 24 weeks (range 12-52 weeks) and dose of vitamin D employed was 2000-50000 IU of vitamin D3 weekly orally each day. Six RCTs reported a significant reduction in pain, whereas three did not detect a notable decrease of this variable. Of the six studies that reported an alleviation of pain, an RCT which recruited 60 participants and lasted for 24 weeks consisted of supplementation with high doses of vitamin D2 weekly for 8 weeks in women receiving anastrozole as adjuvant therapy, then supplementation with vitamin D2 monthly for 4 months, effectively alleviated the aromatase inhibitor-associated musculoskeletal syndrome (AIMSS). The results of the same RCT also suggested a beneficial effect of vitamin D on musculoskeletal pain. CONCLUSIONS: Our results suggest that the supplementation with high doses of vitamin D in cancer patients with low serum levels of vitamin D, can be effective in reducing treatment-related pain.

A systematic review of the pharmacotherapy of secondary hyperparathyroidism (SHPT) in grades 3-5 Chronic Kidney Disease (CKD).

OBJECTIVE: The data on the treatment of secondary hyperparathyroidism (SHPT) provided in scientific publications are divergent and contradictory. Therefore, the aim of our systematic review was to evaluate the efficacy of SHPT treatment in (chronic kidney disease) CKD. MATERIALS AND METHODS: The Cochrane, PubMed, and Scopus databases were searched independently by two authors. The search strategy included controlled vocabulary and keywords. The effectiveness and side effects of calcifediol, ergocaliferol, calcitriol, paricalcitol, and cinacalcet were compared and analyzed. RESULTS: Extended-release (ER) calcifediol raised the total serum 25-hydroxyvitamin D level over the threshold of 30 ng/mL in 80% of the patients analyzed in the study. It is the level required for intact PTH (iPTH) suppression. ER calcifediol reduced the iPTH level by 30% in about 30% of the patients, whereas only 2.1% of them had hypercalcemia. Calcitriol significantly decreased the iPTH values. It was the cause of hypercalcemia in 1.7% of the patients. The reduction of the iPTH level by more than 30% was observed in 85.7% of the patients in the paracalcitol group after 48-week supplementation. Paricalcitol was the cause of hypercalcemia in 1.9% of the patients. The cinacalcet therapy resulted in the highest percentage of patients with the iPTH level within the limits recommended by the KDOQI (70-110 ng/L for stage 4 CKD and 150-300 ng/L for stage 5 CKD). 92% of the patients met the KDOQI guidelines and the mean decrease in the serum iPTH level was 68%. CONCLUSIONS: Calcifediol ER, paricalcitol, and cinacalcet significantly decreased the iPTH level in the patients under study. Paricalcitol increased the serum calcium concentration the most of all the drugs under analysis. It is noteworthy that only cinacalcet does not carry the risk of hypercalcemia.

Adjunctive host-directed therapies for pulmonary tuberculosis: a prospective, open-label, phase 2, randomised controlled trial.

BACKGROUND: Current tuberculosis treatments leave patients with clinically significant lung injury and increased all-cause mortality post-cure. Adjunctive host-directed therapies could protect the lungs, improve long-term survival, and shorten treatment duration; however, few have been tested clinically. Therefore, we aimed to assess the safety and preliminary efficacy of four host-directed therapies for tuberculosis. METHODS: In this prospective, open-label, phase 2, randomised controlled trial, patients with pulmonary tuberculosis were recruited at three clinical sites in South Africa. Eligible patients were aged 18-65 years, HIV-1-negative, and had rifampicin-susceptible Mycobacterium tuberculosis, a sputum Xpert cycle threshold of less than 20, and moderately advanced or far advanced disease on chest radiography. By use of numbers generated in blocks of ten and stratification by site, eligible patients were randomly assigned (1:1:1:1:1) to receive one of the four oral host-directed treatments plus standard tuberculosis treatment or standard treatment alone (the control group). Host-directed treatments were: CC-11050 (200 mg twice daily, taken with food; day 1-112); everolimus (0·5 mg/day; day 1-112); auranofin (3 mg/day for seven doses, then 6 mg/day; day 1-112); and ergocalciferol (5 mg on day 1, then 2·5 mg on day 28 and day 56). All study participants received oral rifabutin-substituted standard tuberculosis treatment for 180 days. Patients and clinicians were not masked to treatment assignment. Spirometry and sputum culture with solid and liquid media were done at baseline and up to 180 days at specified intervals throughout treatment. The primary endpoint was safety and tolerability up to day 210. Secondary preliminary efficacy endpoints were treatment effects on sputum microbiology (culture status at day 56 and the hazard ratio for stable culture conversion up to day 180) and lung function (FEV1 and forced vital capacity [FVC]) measured by spirometry at day 56, day 180, and day 540. Safety was analysed in the intention-to-treat population and preliminary efficacy primarily in the per-protocol population. The trial is registered at ClinicalTrials.gov, NCT02968927. Post-treatment follow-up was completed in 2020. FINDINGS: Between Nov 18, 2016, and Sept 27, 2018, 200 patients were screened and randomly assigned to different treatment groups (n=40 per group, apart from n=39 in the everolimus group after one patient withdrew consent). 11 treatment-emergent serious adverse events occurred either during treatment or within 30 days after treatment discontinuation, of which three were attributable to a host-directed treatment. Life-threatening thrombocytopenia occurred in an auranofin recipient; apparent intra-abdominal sepsis leading to death occurred in another auranofin recipient and was classified as a suspected unexpected serious adverse reaction. Tuberculous spondylitis occurred as an apparent paradoxical reaction in a patient receiving ergocalciferol. Two patients in the control group had life-threatening, treatment-attributable liver injury. No treatment-emergent, treatment-attributable serious adverse events occurred in patients receiving CC-11050 or everolimus. Mean FEV1 in the control group was 61·7% of predicted (95% CI 56·3-67·1) at baseline and 69·1% (62·3-75·8) at day 180. Patients treated with CC-11050 and everolimus had increased recovery of FEV1 at day 180 relative to the control group (mean difference from control group 6·30%, 95% CI 0·06-12·54; p=0·048; and 6·56%, 0·18-12·95; p=0·044, respectively), whereas auranofin and ergocalciferol recipients did not. None of the treatments had an effect on FVC during 180 days of follow-up or on measures of sputum culture status over the course of the study. INTERPRETATION: CC-11050 and everolimus were safe and reasonably well tolerated as adjunctive therapies for tuberculosis, and analysis of preliminary efficacy suggests they might also enhance the recovery of FEV1, a key measure of lung function and predictor of all-cause mortality. Further studies of these candidates are warranted. FUNDING: The Bill & Melinda Gates Foundation and the South African Medical Research Council.

High-dose versus low-dose ergocalciferol for correcting hypovitaminosis D after fragility hip fracture: a randomized controlled trial.

BACKGROUND: Hypovitaminosis D can be observed in most fragility hip fracture patients. However, measurement of 25-hydroxyvitamin D (25(OH)D) level is costly and may not be available in some centers. Without the baseline serum 25(OH)D level, the appropriate dose of vitamin D supplementation is not known. The aim of this study was to evaluate the effectiveness and safety of vitamin D supplementation in fragility hip fracture patients compared between high- and low-dose vitamin D supplementation. METHODS: A total of 140 patients diagnosed with fragility hip fracture were randomly allocated to either the high-dose (60,000 IU/week) or low-dose (20,000 IU/week) vitamin D2 supplementation group for 12 weeks. The number of patients who achieved optimal vitamin D level (serum 25(OH)D > 30 ng/mL), the proportion of patients who developed hypercalcemia, and the functional outcome were compared between groups. RESULTS: Of the 140 patients who were enrolled, 21 patients were lost to follow-up during the study period. The remaining 119 patients (58 and 61 in the high- and low-dose groups, respectively) were included in the final analysis. The high-dose group had a higher rate of serum 25(OH)D restoration to optimal level than the low-dose group (82.8% vs 52.5%, respectively; p < 0.001). Approximately 3.4 and 1.6% of patients in the high- and low-dose groups, respectively, had mild transient hypercalcemia, but none developed moderate, severe, or symptomatic hypercalcemia. There were no differences in functional outcome scores between groups. CONCLUSIONS: In treatment settings where baseline serum 25(OH)D level can't be evaluated in older adults with fragility hip fracture, we recommend high-dose vitamin D2 of approximately 60,000 IU/week for 12 weeks, with subsequent switch to a maintenance dose. This regimen effectively restored serum vitamin D to an optimal level in 82.8% of patients without causing symptomatic hypercalcemia. TRIAL REGISTRATION: The protocol of this study was retrospectively registered in the Thai Clinical Trials Registry database no. TCTR20180302007 on 20 February 2018.

A comparative analysis of the efficacy and safety of paricalcitol versus other vitamin D receptor activators in patients undergoing hemodialysis: A systematic review and meta-analysis of 15 randomized controlled trials.

Paricalcitol, a new vitamin D receptor activator (VDRA), is reported to be more effective than other VDRAs in reducing calcium and phosphorus levels in patients undergoing hemodialysis. However, the efficacy and safety of paricalcitol remain controversial. This analysis compares paricalcitol with other VDRAs in patients undergoing hemodialysis. We searched the Cochrane Library, PubMed, EMBASE, Web of Science, and CNKI up to April 22, 2019. Standardized mean difference (SMD), risk ratio (RR) and 95% confidence interval (CI) values were estimated to compare the outcomes of the groups. Two reviewers extracted data and assessed trial quality independently. All statistical analyses were performed using the standard statistical procedures of RevMan 5.2 and Stata 12.0. Fifteen studies (N = 110,544) were included in this meta-analysis. Of these studies, 11 were randomized controlled trials (RCTs) and 4 were non-randomized studies of interventions (NRSIs). Patients receiving paricalcitol experienced better overall survival (OS) than patients receiving other VDRAs, with a pooled hazard ratio of 0.86 (95% CI 0.80-0.91; P < 0.00001). Intact parathyroid hormone (iPTH) levels were significantly reduced in the paricalcitol group compared to the group receiving other VDRAs, with a pooled SMD of -0.53 (95% CI -0.89- -0.16; P = 0.004). There was a significant increase in serum calcium levels from baseline in the paricalcitol group compared to the other VDRAs group when limiting the analysis to RCTs, with a pooled SMD of 2.14 (95% CI 0.90-3.38; P = 0.0007). Changes in serum calcium levels were significantly lower in the paricalcitol group when the analysis was limited to NRSIs, with a pooled SMD of -0.85 (95% CI -1.34--0.35; P = 0.0008). The NSRI analysis also showed a significant reduction in serum phosphorus levels in the paricalcitol group, with a pooled SMD of -0.57 (95% CI -1.00--0.13; P = 0.01). No significant differences were observed in the incidence of hypercalcemia, hyperphosphatemia, or adverse events. Generally, paricalcitol seems superior to other VDRAs in reducing mortality and iPTH levels in patients undergoing hemodialysis. However, the comparative effectiveness of paricalcitol in reducing serum calcium and phosphorus levels needs further exploration. No significant difference was found in the rate of adverse events.

Treatment of secondary hyperparathyroidism with paricalcitol in patients with end-stage renal disease undergoing hemodialysis in Turkey: an observational study.

OBJECTIVE: To evaluate monthly percentage changes of intact parathyroid hormone (iPTH) and other major bone marker levels in patients with secondary hyperparathyroidism (SHPT) undergoing hemodialysis (HD) and receiving paricalcitol. METHODS: A total of 493 (F/M 244/249) adult patients with SHPT who were undergoing HD in 22 HD units and receiving paricalcitol treatment, with iPTH > 300 mg/mL, adjusted serum levels of calcium (Ca) < 10.2 mg/dL, and serum levels of inorganic phosphorus (iP) < 6 mg/dL were included in this multi-center, national, prospective, observational study. Data regarding efficacy, safety, and adverse events of paricalcitol treatment were collected during a 12-month follow-up period through monthly visits along with serum iPTH, Ca, iP, alkaline phosphatase (ALP) and other required biochemistry tests as necessary. Mortality data until 6 months after the end of the study were also investigated. RESULTS: The mean age was 58.3 ± 15.8 years and the mean duration of HD was 6.2 ± 5.5 years, respectively. As of 12th month, mean iPTH values decreased from 646 ± 424 pg/mL to 473 ± 387 pg/mL (p < 0.001); no statistically significant changes were observed in Ca levels (p > 0.05). Serum ALP levels also significantly decreased (p = 0.001) and serum phosphorus levels significantly increased (p < 0.001) during the study observation period. Reasons for early terminations were being lost to follow-up (n = 119, 24.1%), hyperphosphatemia (iP > 6 mg/dL, n = 108, 21.9%), low iPTH levels (iPTH < 150 mg/dL, n = 97, 19.7%), and withdrawal of consent (n = 41, 8.3%). In total 32 patients (6.5%) were prematurely terminated the study with hypercalcemia (Ca > 10.2 mg/dL). 46.9% of those hypercalcemic patients had other anomalies with iP and iPTH levels along with hypercalcemia. CONCLUSION: Paricalcitol treatment, resulted in successful iPTH control. In approximately 6.5% of the patients paricalcitol treatment was discontinued since Ca levels reached > 10.2 mg/dL in those patients. No unfavorable effects on serum phosphorus and Ca-phosphorus (Ca × P) product were observed.

Questioning the Safety of Calcidiol in Hemodialysis Patients.

BACKGROUND: Epidemiological studies have suggested a survival benefit for hemodialysis patients on paricalcitol or calcitriol, but nutritional vitamin D supplementation of patients already on vitamin D receptor (VDR) activators is controversial. METHODS: This observational retrospective cohort study was conducted with prospectively collected data from all consecutive patients with chronic kidney disease (CKD) who underwent hemodialysis under routine clinical practice conditions for two years. RESULTS: Of the 129 patients, 89 were treated with calcidiol, paricalcitol, and/or calcitriol. The patients with any vitamin D formulation had higher serum concentrations of 25-hydroxy vitamin D and fibroblast growth factor-23 and tended to have higher mortality rates (42% vs. 25%, p = 0.07). On subgroup analysis, any calcidiol treatment or calcidiol combined with paricalcitol associated with significantly higher mortality rates than no treatment (47% and 62.5%, p = 0.043 and 0.008, respectively). The association between calcidiol/paricalcitol treatment and elevated mortality remained significant after adjusting for age, sex, diabetes, C-reactive protein, and hemodialysis vintage. Any calcidiol and calcidiol/paricalcitol treatment exhibited a dose-response relationship with mortality (p for trend: 0.002 and 0.005, respectively). CONCLUSIONS: These data draw attention to the hitherto unexplored safety of calcidiol supplementation in patients on hemodialysis, especially in those already on vitamin D. Until clinical trials demonstrate the safety and efficacy of this approach, caution should be exercised when prescribing these patients ≥0.5 calcidiol mg/month.

Efficacy and safety of paricalcitol in patients undergoing hemodialysis: a meta-analysis.

BACKGROUND: The elevated calcium and phosphorus levels in patients undergoing hemodialysis may increase the risk of all-cause mortality. Paricalcitol, as a new vitamin D receptor activator (VDRA), seemed to be effective in reducing the calcium and phosphorus levels. OBJECTIVES: The aim of this study was to compare the efficacy and safety of paricalcitol with other VDRAs in patients undergoing hemodialysis. METHODS: PubMed, Embase, and Web of Science database were systematically reviewed. SELECTION CRITERIA: Studies that focused on the use of paricalcitol for hemodialysis patients were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two independent investigators performed the literature search, data extraction, and assessment of methodological quality. The outcomes were expressed with standard mean difference (SMD), HR, or risk ratio (RR) with 95% CI. RESULTS: Thirteen studies involving 112,695 patients were included in this meta-analysis. Among these studies, four studies were cohort studies and nine studies were randomized controlled trials (RCTs). For cohort studies, they were regarded as being of high quality; for RCTs, only one was classified as being at low risk of bias; and the remaining eight studies were at being unclear risk of bias. Compared with other VDRAs, paricalcitol significantly improved the overall survival (HR =0.86, 95% CI: 0.80, 0.92; P<0.001) and reduced the intact parathyroid hormone (iPTH) (SMD =-0.53, 95% CI: -0.90, -0.17; P=0.004). Paricalcitol offered similar effect with other VDRAs in the control of calcium (SMD =0.32, 95% CI: -0.04, 0.67; P=0.078) and phosphorus (SMD =0.06, 95% CI: -0.26, 0.37; P=0.727) levels. However, the serum change in calcium phosphate product was greater in the paricalcitol group than in the other VDRA group (SMD =2.13, 95% CI: 0.19, 4.07; P=0.031). There was no significant difference in the incidence of adverse events between the two groups (RR =1.02, 95% CI: 0.93, 1.12; P=0.674). CONCLUSION: Paricalcitol was crucial in reducing the mortality in patients undergoing hemodialysis. Moreover, both paricalcitol and other VDRAs were effective in control of the serum iPTH, calcium, and phosphorus levels. Given the potential limitations in this study, more prospective large-scale, well-conducted RCTs are needed to confirm these findings.

A phase 1, open-label, dose escalation study of intravenous paricalcitol in combination with gemcitabine in patients with advanced malignancies.

BACKGROUND: Calcitriol, the active analogue of vitamin D, is antiproliferative and enhances the cytotoxicity of several anticancer agents, including gemcitabine. The vitamin D receptor (VDR) is expressed in the tumor stroma and treatment with VDR ligands results in stromal remodeling and increased intratumoral gemcitabine delivery. Furthermore, calcitriol can decrease the activity of the gemcitabine deactivating enzyme cytidine deaminase (CDD). Because hypercalcemia has been the most worrisome calcitriol-related adverse event, the less hypercalcemic agent paricalcitol may be preferred for further investigation. METHODS: The authors undertook a phase 1 study of gemcitabine in combination with escalating doses of paricalcitol administered weekly intravenously in patients with advanced cancers. A standard 3+3 dose escalation schema was used. Pharmacokinetic assessment of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) was performed. Pharmacodynamic assessment of paricalcitol was performed by measurement of CDD activity in peripheral blood mononuclear cells. RESULTS: A total of 44 patients were enrolled. Somnolence was the main dose-limiting toxicity. The highest dose of paricalcitol administered was 10.5 µg/kg. Hypercalcemia was infrequent and mild in severity. Paricalcitol did not appear to affect the pharmacokinetics of gemcitabine and dFdU. Evaluation of CDD activity was available for 9 patients; no clear trend for CDD activity after treatment with paricalcitol was established. The overall response rate was 4%; the rate of disease control was 67% in patients who were pretreated with gemcitabine. Progression-free and overall survival were 3.4 months and 6.5 months, respectively. CONCLUSIONS: Paricalcitol can be administered safely in doses up to 7 µg/kg weekly with fixed dose rate gemcitabine without dose-limiting hypercalcemia. To the best of the authors' knowledge, the maximum tolerated dose has not been formally established to date. Preliminary clinical activity deserves further exploration.

Paricalcitol supplementation during the first year after kidney transplantation does not affect calcification propensity score.

BACKGROUND: Cardiovascular complications are common in kidney transplant patients and calcification propensity of blood, measured as T50, is associated with cardiovascular outcomes. Paricalcitol supplementation affects calcium/phosphate homeostasis and may affect calcification propensity. To assess this hypothesis we measured T50 in kidney transplant recipients participating in a randomized study comparing paricalcitol versus no treatment during the first year after kidney transplantation. METHODS: Stored serum samples from 76 kidney transplant recipients (paricalcitol n = 37, no treatment n = 39) were analyzed. Analyses were performed at inclusion (8 weeks after transplantation) and repeated one year after transplantation. RESULTS: There were no statistically significant differences in T50 between the paricalcitol and placebo groups, neither at baseline (p = 0.56) nor at 1 year (p = 0.61). Also, there were no significant changes in T50 over time in either group or when pooling all data (p <  0.20). In multivariate regression analysis, out of 16 potentially relevant covariates, comprising clinical and biochemical parameters, only plasma PTH and T50 at baseline were significantly correlated to T50 after one year. (p <  0.03 and p < 0.01, respectively). CONCLUSIONS: Calcium propensity measured as T50 score remained unchanged with paricalcitol treatment in kidney transplant recipients, and was not changed over time during the study period of one year. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01694160 , registered 23 September 2012.

Vitamin D receptor activation by paricalcitol and insulin resistance in CKD.

BACKGROUND AND AIMS: The nature of the link (causal vs non-causal) between low 1,25-OH vitamin D and insulin resistance (IR) in patients with chronic kidney disease (CKD) remains elusive. We have now made a post hoc analysis of the effect of vitamin D receptor activation by paricalcitol on IR in the complete dataset of a double-blind, randomized, placebo controlled trial, the Paricalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY). METHODS AND RESULTS: Eighty-eight patients with stage 3-4 CKD were randomized (1:1) to receive 2 µg/day paricalcitol or matching placebo for 12 weeks. IR was measured by five IR indices: the homeostasis model assessment of insulin resistance (HOMA-IR), the quantitative insulin sensitivity check index (QUICKI), the McAuley index, the HOMA corrected for adiponectin (HOMA-AD) and the Leptin-adiponectin ratio (LAR). As compared to placebo, paricalcitol produced the expected small rise in serum calcium (+0.07 mmol/L, P = 0.01) and phosphate (+0.08 mmol/L, P = 0.034) and the expected parathyroid hormone suppression (-96 pg/ml, P < 0.001). However, the drug largely failed to affect the five indices of IR which remained unchanged both in the active and the placebo arm (paricalcitol vs placebo, P ranging from 0.25 to 0.62) and no effect modification of paricalcitol on IR by vitamin D or other parameters was registered. CONCLUSION: Paricalcitol treatment for 12 weeks does not improve IR in patients with stage 3-4 CKD. Low vitamin D receptor activation is not a causal factor for IR in the CKD population.

Noncalcemic adverse effects and withdrawals in randomized controlled trials of long-term vitamin D2 or D3 supplementation: a systematic review and meta-analysis.

CONTEXT: Recent randomized controlled trials (RCTs) provide evidence for a possible beneficial impact of vitamin D supplementation on health outcomes beyond bone health, but there are few reviews of noncalcemic adverse effects from long-term supplementation. OBJECTIVE: The aims of this systematic review of vitamin D supplementation in RCTs were as follows: to determine whether all adverse effects, when combined, are reported equally between treatment arms; to identify the most common noncalcemic adverse effects reported; and to ascertain whether withdrawal rates, as a marker of clinical adverse effects, differ between treatment arms. DATA SOURCES: The MEDLINE Ovid, Embase, and Cochrane Library databases were searched systematically up to May 2016. STUDY SELECTION: Randomized controlled trials that met the following criteria were selected: administered vitamin D2 or D3 supplements for a minimum supplementation or follow-up period of 24 weeks, had a placebo/control group, and were conducted among adults (≥ 18 y). DATA EXTRACTION: Two researchers independently screened studies for eligibility, extracted data, and carried out quality assessment of selected studies. A total of 128 studies with 52 297 participants were identified. A random-effects model was used to calculate risk ratios in a meta-analysis. RESULTS: Long-term vitamin D2 or D3 supplementation, compared with placebo, did not increase all adverse effects, when combined, as reported in 62 studies with 19 389 participants (relative risk [RR] = 0.97; 95%CI, 0.92-1.02). Vitamin D also did not increase the risk of the most common noncalcemic adverse effects: gastrointestinal symptoms were reported in 27 studies with 9189 participants (RR = 1.01; 95%CI, 0.87-1.17), and dermatological symptoms were reported in 8 studies with 1695 participants (RR = 1.33; 95%CI, 0.82-2.15). Vitamin D did not increase withdrawals from 123 studies with 41 861 participants (RR = 1.03; 95%CI, 0.96-1.09). However, participants given vitamin D were more likely to report withdrawals than those given placebo in studies in which calcium was given in both arms (RR = 1.16; 95%CI, 1.02-1.33) when compared with participants in studies in which calcium was not given in either arm (RR = 1.00; 95%CI, 0.95-1.06; P for interaction = 0.009). CONCLUSIONS: Overall, these findings suggest that vitamin D, by itself, does not increase the risk of noncalcemic adverse effects.

Effect of Paricalcitol on Bone Density After Kidney Transplantation: Analysis of 2 Transplant Centers.

INTRODUCTION: The Kidney Disease: Improving Global Outcomes Clinical Practice Guidelines on the management of bone disease in patients with chronic kidney disease recommend periodic measurement of serum calcium, phosphorus, vitamin D, and parathyroid hormone levels after kidney transplantation, with the frequencies that will vary according to the severity of bone disease and graft function. Paricalcitol, a selective vitamin D receptor activator, is indicated in the prevention and treatment of secondary hyperparathyroidism. MATERIALS AND METHODS: We retrospectively evaluated the effect of treatment with paricalcitol among our kidney transplant recipients. We monitored the effect of paricalcitol on bone density; the plasma levels of parathyroid hormone, calcium, and phosphorus; and proteinuria and calciuria. Comparisons were made between these parameters before treatment and 12 months after treatment. RESULTS: Eighty-eight kidney transplant recipients with a mean age at the time of transplantation of 47.1 ± 10.5 years were receiving paricalcitol. On average, paricalcitol was included into the treatment for 48 months from transplantation (median, 27 months). The patients had significantly improved bone density (P < .001), significantly lower parathyroid hormone levels (P < .001), and significantly decreased proteinuria (P = .02) after 12 months of treatment. During the treatment with paricalcitol, the immunosuppressive therapy, dose of prednisone, body mass index, and vitamin D levels had not significantly changed. Nor had any significant change occurred to graft function. CONCLUSIONS: Paricalcitol is an effective therapy for secondary hyperparathyroidism in kidney transplant recipients.

Effects of Vitamin D2 Supplementation on Vitamin D3 Metabolism in Health and CKD.

BACKGROUND AND OBJECTIVES: Vitamin D supplements are prescribed to correct low circulating concentrations of 25-hydroxyvitamin D. In CKD, vitamin D metabolism is complicated by decreased conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by CYP27B1 and possibly decreased conversion of 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D by CYP24A1. The aim of this study was to determine the effects of vitamin D2 supplementation on vitamin D metabolism in health and CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a treatment-only intervention study of 25 individuals with CKD (eGFR<60 ml/min per 1.73 m2) and 44 individuals without CKD from three academic centers, all with screening 25-hydroxyvitamin D <30 ng/ml. Each participant was prescribed vitamin D2 (ergocalciferol) 50,000 IU orally twice weekly for 5 weeks. We tested whether changes in plasma concentrations of vitamin D metabolites and vitamin D metabolic ratios differed by CKD status. Plasma 1,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio and 24,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio were calculated as estimates of CYP27B1 and CYP24A1 function, respectively. RESULTS: With treatment, plasma 25-hydroxyvitamin D2 and total 25-hydroxyvitamin D concentrations increased similarly for participants with and without CKD. For participants without CKD, 1,25-dihydroxyvitamin D2 increased (2.8±1.3-32.9±1.4 pg/ml), whereas 1,25-dihydroxyvitamin D3 decreased (45.6±1.9-14.6±1.9 pg/ml), resulting in no significant change in total 1,25-dihydroxyvitamin D; 1,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio decreased (3.0±0.2-1.7±0.2 pg/ng), and 24,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio increased (115.7±7.8-195.2±7.9 pg/ng). Individuals with CKD had lower baseline levels and smaller changes in magnitude for 1,25-dihydroxyvitamin D2 (2.1±1.6-24.4±1.6 pg/ml; P interaction =0.01), 1,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio (1.8±0.2-1.1±0.2 pg/ng; P interaction =0.05), and 24,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio (72.0±9.1-110.3±9.3 pg/ng; P interaction <0.001). Fibroblast growth factor-23 and parathyroid hormone were not significantly changed in either group. CONCLUSIONS: Vitamin D2 supplementation decreases conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 and induces vitamin D3 catabolism as evidenced by changes in D3 metabolites and vitamin D metabolic ratios. These effects occur without significant changes in fibroblast growth factor-23 or parathyroid hormone and are blunted in CKD. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_08_02_CJASNPodcast_17_09.mp3.

Paricalcitol as an Antiproteinuric Agent Can Result in the Deterioration of Renal and Heart Function in a Patient with Fabry Disease.

BACKGROUND Fabry disease is a rare and progressive X-linked inherited disorder of glycosphingolipid metabolism that is due to deficient or absent lysosomal a-galactosidase A activity. Among its other associated signs and symptoms, patients present with renal failure and proteinuria, which are markers of disease progression. Renin-angiotensin-aldosterone system (RAAS) blockers can slow the progression of chronic renal failure and proteinuria. In fact, some studies have shown the beneficial effects of paricalcitol on proteinuria. CASE REPORT We present a case of a female patient with the classic variant of Fabry disease. She was treated with a high dose of paricalcitol as an antiproteinuric agent due to unsatisfactory double-RAAS blockage, which resulted in transient worsening of cardiac and renal function. CONCLUSIONS Despite the positive effects of paricalcitol as an antiproteinuric agent, as previously shown by some authors, our case highlights the possible serious adverse effects associated with the use of high doses of this drug.

Early introduction of oral paricalcitol in renal transplant recipients. An open-label randomized study.

In stable renal transplant recipients with hyperparathyroidism, previous studies have indicated that vitamin D agonist treatment might have anti-proteinuric effects. Animal studies indicate possible anti-fibrotic and anti-inflammatory effects. Early introduction of paricalcitol in de novo renal transplant recipients might reduce proteinuria and prevent progressive allograft fibrosis. We performed a single-center, prospective, randomized, open-label trial investigating effects of paricalcitol 2 µg/day added to standard care. Participants were included 8 weeks after engraftment and followed for 44 weeks. Primary end point was change in spot urine albumin/creatinine ratio. Exploratory microarray analyses of kidney biopsies at study end investigated potential effects on gene expression. Secondary end points included change in glomerular filtration rate (GFR), pulse wave velocity (PWV), and endothelial function measured by peripheral arterial tonometry as reactive hyperemia index (RHI). Seventy-seven de novo transplanted kidney allograft recipients were included, 37 receiving paricalcitol. Paricalcitol treatment lowered PTH levels (P = 0.01) but did not significantly reduce albuminuria (P = 0.76), change vascular parameters (PWV; P = 0.98, RHI; P = 0.33), or influence GFR (P = 0.57). Allograft gene expression was not influenced. To summarize, in newly transplanted renal allograft recipients, paricalcitol reduced PTH and was well tolerated without negatively affecting kidney function. Paricalcitol did not significantly reduce/prevent albuminuria, improve parameters of vascular health, or influence allograft gene expression.

Vitamin D supplementation for the management of knee osteoarthritis: a systematic review of randomized controlled trials.

Conflicting evidence exists concerning the supplementation of vitamin D in knee osteoarthritis condition. This systematic literature review was done to explore the effects of vitamin D supplementation in the management of knee osteoarthritis. Electronic literature search was done in databases like PubMed®, Embase®, and Cochrane CENTRAL from inception to 6th July 2016. The quality of included Randomized Controlled Trials (RCTs) was assessed using Cochrane risk of bias tool. We considered change in Western Ontario and McMaster Universities (WOMAC) index, Visual Analog Scale (VAS) and Functional Pain Score (FPS) as the primary outcome measure. Change in tibial cartilage thickness, joint space width and safety profile was considered as secondary outcomes. Participants were randomized either to treatment or placebo group. Participants received cholecalciferol as an intervention through oral route in the dose range of 800-60,000 IU except in the one study where participants received ergocalciferol. All included RCTs showed a significant increase in serum vitamin D level in the treatment group compared to the placebo group at the end point. No significant reduction in pain and function was reported on WOMAC scale except in one study. No significant difference was reported for WOMAC stiffness in any study. VAS was assessed in three studies in which two showed statistically significant improvement in knee pain. Three of the RCTs reported safety data with one incidence of calculus ureteric and hip fracture found to be related to the drug. The study found evidence from RCTs to be insufficient to support the use of vitamin D supplementation for patients with knee osteoarthritis.