Calcifediol (25OHD) Deficiency and Its Treatment in Women's Health and Fertility.

Currently, there is abundant scientific evidence showing that the vitamin D endocrine system (VDES) is a highly complex endocrine system with multiple actions in different regions of the body. The unequivocal presence of vitamin D receptors in different tissues related to fertility, and to specific aspects of women's health such as pregnancy, undoubtedly implies functions of this steroid hormone in both male and female fertility and establishes relationships with different outcomes of human gestation. In order to review the role of the VDES in human fertility, we evaluated the relationships established between 25-hydroxyvitamin D (calcifediol) deficiency and in vitro fertilization, as well as aspects related to ovarian reserve and fertility, and commonly diagnosed endocrinopathies such as polycystic ovary disease. Likewise, we briefly reviewed the relationships between calcifediol deficiency and uterine fibroids, as well as the role that treatment may have in improving human fertility. Finally, the best scientific evidence available on the consequences of calcifediol deficiency during pregnancy is reviewed in relation to those aspects that have accumulated the most scientific literature to date, such as the relationship with the weight of the newborn at the time of delivery, the appearance of preeclampsia, and the risk of developing gestational diabetes and its final consequences for the pregnancy. To date, there is no definitive consensus on the necessary dose for treatment of calcifediol deficiency in the therapeutic management of infertility or during pregnancy. Large prospective clinical intervention studies are needed to clarify the benefits associated with this supplementation and the optimal dose to use in each situation. Although most intervention studies to date have been conducted with cholecalciferol, due to its much longer history of use in daily care, the use of calcifediol to alleviate 25-hydroxyvitamin D deficiency seems safe, even during pregnancy. The unequivocal presence of vitamin D receptors in very different tissues related to human fertility, both male and female, as well as in structures typical of pregnancy, allows us to investigate the crucial role that this steroid hormone has in specific aspects of women's health, such as pregnancy and the ability to conceive. Well-designed clinical studies are needed to elucidate the necessary dose and the best form of treatment to resolve the very common calcifediol deficiency in women of reproductive age.

Calcifediol (25OH Vitamin D3) Deficiency: A Risk Factor from Early to Old Age.

Vitamin D deficiency is the main cause of nutritional rickets in children and osteomalacia in adults. There is consensus that nutritional access to vitamin D can be estimated by measuring serum concentrations of 25OHD and vitamin D deficiency can thus be considered as calcifediol deficiency. However, the threshold for vitamin D/calcifediol sufficiency remains a matter of debate. Vitamin D/calcifediol deficiency has been associated with musculoskeletal effects but also multiple adverse extra-skeletal consequences. If these consequences improve or if they can be treated with vitamin D supplementation is still unclear. Observational studies suggest a higher infection risk in people with low calcifediol levels. There is also a consistent association between serum calcifediol and cardiovascular events and deaths, but large-scale, long-term intervention studies did not show any benefit on cardiovascular outcomes from supplementation, at least not in subjects without clear vitamin D deficiency. Cancer risk also did not change with vitamin D treatment, although there are some data that higher serum calcifediol is associated with longer survival in cancer patients. In pregnant women, vitamin D supplementation decreases the risk of pre-eclampsia, gestational diabetes mellitus, and low birth weight. Although preclinical studies showed that the vitamin D endocrine system plays a role in certain neural cells as well as brain structure and function, there is no evidence to support a beneficial effect of vitamin D in neurodegenerative diseases. Vitamin D supplementation may marginally affect overall mortality risk especially in elderly subjects with low serum calcifediol concentrations.

An investigation on the relevance of prolactin, insulin-like growth factor-1 and 25-hydroxyvitamin D3 (25-OHD3 ) in canine benign prostatic hyperplasia in a predisposed breed model.

Serum concentrations of prolactin (PRL), insulin-like growth factor-1 (IGF-1) and 25 hydroxyvitamin D3 (25-OHD3 ) were analysed to investigate their possible involvement in the pathogenesis of benign prostatic hyperplasia (BPH). For this, dogs of the Rhodesian Ridgeback (RR) breed were used because of a verified breed disposition for the development of BPH. Labrador Retrievers (LR) served as controls. The prostate gland status was characterised by the prostate gland volume, clinical signs of BPH (haemospermia and sonographic findings) and the plasma concentration of canine prostate-specific arginine esterase (CPSE). Breed specificity in the RR was expressed by a correlation of PRL with breed (p < 0.05). Similar relationships existed in the dogs with normal CPSE (CPSEn) with respect to the IGF-1 concentrations (LR: p < 0.05). The latter were negatively correlated with prostatic volume and age (both p < 0.05). Concentrations of 25-OHD3 were tendentially (p = 0.18) lower in the RR with increased CPSE (CPSEi) compared with the CPSEn LR and RR showing clinical signs of BPH. A negative correlation between serum 25-OHD3 and age (p < 0.05) existed in the CPSEi RR. Proof of 25-OHD3 in prostatic secretion proved to be a breed specific feature in the RR (p < 0.0001). For all RR dogs showing clinical signs of BPH, a close to significant (p = 0.06) positive correlation with prostate gland volume was found. The results of the present study reveal no clear hints towards the significance of PRL and IGF-1 in the pathogenesis of canine BPH. In the RR breed there were indications of a causal relationship with age-dependent changes in the vitamin D metabolism. The data suggest the possibility of preventing or treating canine BPH by administering vitamin D or substances involved in the intraprostatic vitamin D metabolism.

Evaluation of the potential anticancer activity of different vitamin D metabolites on colorectal and breast cancer cell lines.

OBJECTIVES: Vitamin D is very important for calcium and mineral metabolism, and many hypotheses appear to link sunlight exposure with cancer risk and prognosis. As many studies supported the antitumor effect of vitamin D we wanted to investigate the potential effect of multiple vitamin D metabolites. METHODS: This study compared the anticancer effect of three inactive forms of vitamin D3 which are; cholecalciferol, alfacalcidol, and calcifediol on two human cancer cell lines colorectal cancer (CaCo II) and breast cancer (MCF-7). All were examined after 24, 48, and 72 h continuous exposure using a colorimetric assay (MTT) seeded in 96-multiwell plates. Doxorubicin anticancer used as a standard agent for comparison, while normal skin fibroblast cells (HDFa) was used as our negative control. IC50 values were calculated as indication of antitumor effect. RESULTS: Broad-spectrum of cytotoxicity with IC50 values ranging from 4 to 200 µM were found. Alfacalcidol was the most potent cytotoxic agents on colorectal cancer (CaCo II) and breast cancer (MCF-7) compared to cholecalciferol, and calcifediol. Both, alfacalcidol and calcifediol were more cytotoxic than cholecalciferol on the tested cell lines as they are partially active metabolites. Breast cancer (MCF-7) was the most sensitive to all metabolites at all-time intervals with the best IC50 values of 4.35 µM ± 1.06 after 72 h continuous exposure of alfacalcidol. CONCLUSIONS: Vitamin D metabolites are a potential option for cancer treatment along with or an alternative to chemo-therapeutics although extensive preclinical studies are required to prove this effect.

Vitamin D ameliorates adipose browning in chronic kidney disease cachexia.

Patients with chronic kidney disease (CKD) are often 25(OH)D3 and 1,25(OH)2D3 insufficient. We studied whether vitamin D repletion could correct aberrant adipose tissue and muscle metabolism in a mouse model of CKD-associated cachexia. Intraperitoneal administration of 25(OH)D3 and 1,25(OH)2D3 (75 µg/kg/day and 60 ng/kg/day respectively for 6 weeks) normalized serum concentrations of 25(OH)D3 and 1,25(OH)2D3 in CKD mice. Vitamin D repletion stimulated appetite, normalized weight gain, and improved fat and lean mass content in CKD mice. Vitamin D supplementation attenuated expression of key molecules involved in adipose tissue browning and ameliorated expression of thermogenic genes in adipose tissue and skeletal muscle in CKD mice. Furthermore, repletion of vitamin D improved skeletal muscle fiber size and in vivo muscle function, normalized muscle collagen content and attenuated muscle fat infiltration as well as pathogenetic molecular pathways related to muscle mass regulation in CKD mice. RNAseq analysis was performed on the gastrocnemius muscle. Ingenuity Pathway Analysis revealed that the top 12 differentially expressed genes in CKD were correlated with impaired muscle and neuron regeneration, enhanced muscle thermogenesis and fibrosis. Importantly, vitamin D repletion normalized the expression of those 12 genes in CKD mice. Vitamin D repletion may be an effective therapeutic strategy for adipose tissue browning and muscle wasting in CKD patients.

Osteomalacia in subtropical Auckland.

A 56-year-old man was referred with left-sided hip pain. MRI scans demonstrated an undisplaced stress fracture in the femoral neck and subchondral oedema within the femoral head. Bone densitometry showed T-scores of -2.0 at the spine, -3.5 at the femoral neck and -2.4 for the total hip. Laboratory tests revealed 25-hydroxyvitamin D <10 nmol/L. He was prescribed a 10-day course of calciferol 1.25 mg (50 000 IU)/day and started on calcium carbonate 1.25 g twice daily. Following the correction of vitamin D deficiency, his symptoms resolved. A striking feature of this patient was the complete reversal of 'osteoporosis' within 14 months with vitamin D and calcium supplementation. Bone mineral densities (BMDs) increased by 19.5% and 33.4% at the spine and hip, respectively. Such changes are never seen with conventional pharmacological management of osteoporosis. Vitamin D deficiency should be considered as a cause for reduced BMD in people with risk factors.

Vitamin D C3-epimer levels are proportionally higher with oral vitamin D supplementation compared to ultraviolet irradiation of skin in mice but not humans.

A proportion of circulating 25-hydroxy vitamin D3 (25(OH)D3)) undergoes epimerization to form C3-epi 25(OH)D3 and C3-epi 1,25(OH)2D3. These epimers have less calcaemic activity than non-epimerized metabolites and are not differentiated by many immunoassays when reporting total 25(OH)D3 levels. This study aimed to compare the effect of exposure to ultraviolet radiation (UVR) and oral vitamin D3 supplementation on vitamin D C3-epimer levels. C57Bl/6 female mice were fed either vitamin D-sufficient (vitamin D3 2000 IU/kg) or -deficient diets (no vitamin D3) for 4 weeks. Among the vitamin D-deficient group, the shaved backs of half were irradiated daily for 4 days with 1 kJ/m2 UVR, followed by twice weekly irradiation for 4 weeks. Despite similar 25(OH)D3 levels, the UV-irradiated group had a lower proportion of C3-epi 25(OH)D3 at week 7 (p < 0.05) and week 9 (p < 0.01). C3-epimer concentrations and %C3-epi 25(OH)D3 were also analysed in serum samples from two human clinical trials. These trials investigated the effect of high dose oral vitamin D3 supplementation and narrowband UVB phototherapy, respectively. Serum 25(OH)D3 and the %C3-epi 25(OH)D3 levels measured at 12 months after oral vitamin D3 supplementation were not significantly different to those measured at the time of maximal effect of phototherapy (2 months). Thus, the proportion of 25(OH)D3 that undergoes epimerization is greater with oral vitamin D3 supplementation than exposure to UVR in mice, but not in humans. This important difference between human and murine vitamin D metabolism warrants consideration when interpreting animal studies.

Correction of vitamin D status by calcidiol: pharmacokinetic profile, safety, and biochemical effects on bone and mineral metabolism of daily and weekly dosage regimens.

RATIONALE: Calcidiol can be employed to correct vitamin D deficiency. MAIN RESULTS: Calcidiol administered at daily and weekly regimens over a period of 3 months was able to successfully raise 25-hydroxyvitamin D levels without altering other markers related to bone and mineral metabolism. SIGNIFICANCE: Calcidiol supplementation is effective and safe. INTRODUCTION: The correction of vitamin D status is necessary to maintain an optimal mineral and skeletal homeostasis. Despite cholecalciferol (vitamin D3) is the most commonly used drug for vitamin D supplementation, the more hydrophilic compound calcidiol (25-hydroxyvitamin D3) can be employed at daily, weekly, and monthly regimens to reach in the short term the target levels of serum 25-hydroxyvitamin D [25(OH)D]. In the administration of different doses of calcidiol pharmacokinetic study (ADDI-D study), the efficacy and safety of daily and weekly dosages of calcidiol were tested. METHODS: A total of 87 Caucasian, community-dwelling, postmenopausal women, aged 55 years or older, with vitamin D inadequacy (serum 25(OH)D levels <30 ng/ml, with mean 25(OH)D below 20 ng/ml, namely 16.5 ± 7.5 ng/ml) were randomized to receive three different dosages of calcidiol: 20 µg/day, 40 µg/day, and 125 µg/week for 3 months. The attained level of serum 25(OH)D was selected as primary endpoint to assess efficacy, while other parameters of mineral metabolism, (serum calcium, parathyroid hormone, phosphate, FGF23, urinary calcium, and markers of bone turnover) were assessed as secondary endpoints to establish safety. RESULTS: In all the three groups, serum 25(OH)D values significantly and promptly rose and plateaued above the 30 ng/ml threshold remaining within safety interval after 14 days of treatment, with similar efficacy for the similar daily and weekly dose regimens. The different dosages were also equally effective in controlling secondary hyperparathyroidism. No significant changes in calcium and phosphate metabolism and in bone turnover markers were observed for any of the treatments, confirming the safety of this compound. CONCLUSIONS: The results of this study demonstrate the short- and mid-term efficacy and safety on core parameters of mineral metabolism of different daily or weekly dosages of calcidiol when used to treat vitamin D inadequacy or deficiency in postmenopausal women. Further studies are needed to assess falls as primary outcome of calcidiol supplementation.

Dysfunctional immunometabolic effects of vitamin D deficiency, increased cardiometabolic risk. Potential epidemiological alert in America? / Efectos inmunometabólicos disfuncionales de la deficiencia de vitamina D y aumento de riesgo cardiometabólico. ¿Potencial alerta epidemiológica en América?

Vitamin D deficiency is a serious public health problem worldwide that affects not only skeletal health, but also a wide range of acute and chronic diseases. However, there is still skepticism because of the lack of randomized, controlled trials to support association studies on the benefits of vitamin D for non-skeletal health. This review was based on articles published during the 1980-2015 obtained from the Cochrane Central Register of controlled trials, MEDLINE and PubMed, and focuses on recent challenges with regard to the definition of vitamin D deficiency and how to achieve optimal serum 25-hydroxyvitamin D levels from dietary sources, supplements, and sun exposure. The effect of vitamin D on epigenetic fetal programming and regulation of genes that may potentially explain why vitamin D could have such lifelong comprehensive health benefits is reviewed. Optimization of vitamin D levels in children and adults around the world has potential benefits to improve skeletal health and to reduce the risk of chronic diseases, including some types of cancer, autoimmune diseases, infectious diseases, type 2 diabetes mellitus, and severe cardiovascular disorders such as atherothrombosis, neurocognitive disorders, and mortality.

Impact of 3-Monthly Vitamin D Supplementation Plus Exercise on Survival after Surgery for Osteoporotic Hip Fracture in Adult Patients over 50 Years: A Pragmatic Randomized, Partially Blinded, Controlled Trial.

OBJECTIVE: To determine whether 3-monthly supplementation of an oral vitamin D widely used in Spain (calcifediol) plus daily exercise could influence survival at one and four years after surgery for osteoporotic hip fracture. DESIGN: A pragmatic, randomized, partially single-blind placebo-controlled study. SETTING: Patients admitted to a tertiary university hospital for acute hip fracture. PARTICIPANTS: 675 healthy adult patients undergoing surgery for osteoporotic hip fracture were recruited from January 2004 to December 2007. INTERVENTION: Patients were randomized to receive either 3-monthly oral doses of 3 mg calcifediol (Hidroferol Choque®) or placebo in the 12 months postsurgery. Patients who received calcifediol were also given an exercise programme. The placebo group received standard health recommendations only. MEASUREMENTS: The primary endpoint was survival at 1 year and at 4 year follow-up. We also recorded new fractures, medical complications and anti-osteoporotic treatment compliance. RESULTS: We included a total of 88 patients, aged 62 to 99 years. Mean age was 82 years and 88.6% were women. At 12 months, 10 (11.3%) patients had died, 9 of them, from the non-intervention group. At 4 years after surgery, 20 (22.7%) had died, 3 (3.4%) from the intervention group and 17 (19.3%) from the non-intervention group. At this time, survival curve analysis showed 93% survival in the intervention group and 62% in the non-intervention group (p=0.001). At 12-month follow up, there were 18 new fractures, 9 in each group. The non-intervention group had more medical complications, with significant differences at visit 2 (p = 0.04) and 3 (p = 0.02) but not at visit 4 (p = 0.18). No significant differences between groups were found regarding treatment compliance. CONCLUSION: 3-monthly, oral supplements of 3 mg calcifediol plus daily exercise improved survival at one-year and four-year follow up after surgery for an osteoporotic hip fracture.

[Impact of Vitamin D in Sports: Does Vitamin D Insufficiency Compromise Athletic Performance?] / Bedeutung von Vitamin D im Sport: Reduziert ein Mangel die Leistungsfähigkeit?

Introduction Vitamin D is essential for calcium homeostasis and regulates the expression of over 900 genes. It thereby influences musculoskeletal health and function. Additionally, multiple other effects were observed through the detection of vitamin D receptors (VDR) in numerous tissues of the human body. Material and Methods We reviewed the literature regarding evidence of the impact of vitamin D on musculoskeletal health and peak athletic performance. Results and Discussion It is well known that there is a high prevalence of vitamin D deficiency in the average European population. This article confirmed the same for athletes in different disciplines. Therefore, vitamin D deficiency and its effects are relevant for competitive sports. The surprisingly high prevalence of inadequate vitamin D levels depends on the geographic location, the time of day and year, local climate conditions, and sports disciplines (indoor vs. outdoor). Based on the analysed literature, we found several correlations between 25-OH-D3 serum levels and different aspects of competitive sports. A serum level ≥ 30 ng/ml provides sufficient mineralisation of non-mineralised bone matrix and is therefore crucial for skeletal health. Furthermore, this concentration was positively correlated with an accelerated regeneration of muscular force. Levels above 40 ng/ml provided a protective effect on the development of stress fractures. Researchers suspect that levels above 50 ng/ml are required for athletes to achieve maximal physical performance. While there is an ongoing discussion amongst researchers regarding beneficial effects of such high levels, it is well known that blood levels lower than 30 ng/ml lead to mineralisation defects in bone (rickets, osteomalacia) and muscular function (reversible myopathy). Conclusion This review suggests that athletes should have an evaluation of vitamin D-dependent calcium homeostasis based on laboratory tests of 25-OH-D3, calcium, creatinine, and parathyroid hormone. In case of vitamin D insufficiency, normal blood levels of ≥ 30 ng/ml may be restored by optimising the athlete's lifestyle and, if appropriate, oral substitution of cholecalciferol. This concentration is associated with a protective effect and enhancement of physical performance. Consequently, it is a requirement for restoring and maintaining musculoskeletal health and athletic performance.

Calcifediol-loaded liposomes for local treatment of pulmonary bacterial infections.

The influence of vitamin D3 and its metabolites calcifediol (25(OH)D) and calcitriol on immune regulation and inflammation is well described, and raises the question of potential benefit against bacterial infections. In the current study, 25(OH)D was encapsulated in liposomes to enable aerosolisation, and tested for the ability to prevent pulmonary infection by Pseudomonas aeruginosa. Prepared 25(OH)D-loaded liposomes were nanosized and monodisperse, with a negative surface charge and a 25(OH)D entrapment efficiency of approximately 23%. Jet nebulisation of liposomes was seen to yield an aerosol suitable for tracheo-bronchial deposition. Interestingly, 25(OH)D in either liposomes or ethanolic solution had no effect on the release of the proinflammatory cytokine KC from Pseudomonas-infected murine epithelial cells (LA-4); treatment of infected, human bronchial 16-HBE cells with 25(OH)D liposomes however resulted in a significant reduction in bacterial survival. Together with the importance of selecting an application-appropriate in vitro model, the current study illustrates the feasibility and practicality of employing liposomes as a means to achieve 25(OH)D lung deposition. 25(OH)D-loaded liposomes further demonstrated promising effects regarding prevention of Pseudomonas infection in human bronchial epithelial cells.

Early indicators of survival following exposure to mustard gas: Protective role of 25(OH)D.

The use of sulfur mustard (SM) as a chemical weapon for warfare has once again assumed center stage, endangering civilian and the military safety. SM causes rapid local skin vesication and late-onset systemic toxicity. Most studies on SM rely on obtaining tissue and blood for characterizing burn pathogenesis and assessment of systemic pathology, respectively. However the present study focuses on developing a non-invasive method to predict mortality from high dose skin SM exposure. We demonstrate that exposure to SM leads to a dose dependent increase in wound area size on the dorsal surface of mice that is accompanied by a progressive loss in body weight loss, blood cytopenia, bone marrow destruction, and death. Thus our model utilizes local skin destruction and systemic outcome measures as variables to predict mortality in a novel skin-based model of tissue injury. Based on our recent work using vitamin D (25(OH)D) as an intervention to treat toxicity from SM-related compounds, we explored the use of 25(OH)D in mitigating the toxic effects of SM. Here we show that 25(OH)D offers protection against SM and is the first known demonstration of an intervention that prevents SM-induced mortality. Furthermore, 25(OH)D represents a safe, novel, and readily translatable potential countermeasure following mass toxic exposure.

Attenuation of inflammatory response by 25- hydroxyvitamin D3-loaded polylactic acid microspheres in treatment of periodontitis in diabetic rats.

OBJECTIVE: To investigate the inhibitory effects of 25-hydroxyvitamin D3 (25(OH)D3)-loaded polylactic acid (PLA) microspheres on inflammatory response in diabetic periodontitis. METHODS: 25(OH)D3-loaded PLA microspheres were produced using emulsion-solvent evaporation method. Rat bone marrow stromal cells (BMSCs) cultured with Aggregatibacter actinomycetemcomitans in high glucose medium were chosen to mimic diabetic periodontitis. After cultivation with 25(OH)D3-loaded PLA microspheres, inflammation-related proteins in BMSCs were detected using Western blot analysis. Periodontitis was induced using silk ligatures in diabetic rats, and 25(OH)D3-loaded PLA microspheres were placed into the periodontal pockets. Periodontal tissues were examined using hematoxylin and eosin staining and western blot analysis. RESULTS: Drug release from the 25(OH)D3-loaded microspheres was relatively steady during 70 days. In a diabetic periodontitis-like environment, 25(OH)D3-loaded microspheres upregulated vitamin D receptor expression, and downregulated nuclear factor-κB expression and signal transducer and activator of transcription 3 phosphorylation in the BMSCs. These 25(OH)D3 microspheres also attenuated periodontal inflammatory infiltrate and bone loss in diabetic rats with periodontitis. CONCLUSION: 25(OH)D3-loaded microspheres could ameliorate diabetic periodontitis by inhibiting inflammatory response, and may provide a potential therapy for patients with this disease.

Higher vitamin D serum concentration increases health related quality of life in patients with inflammatory bowel diseases.

AIM: To investigate the effect of vitamin D (VD) concentrations and VD supplementation on health related quality of life in inflammatory bowel disease (IBD) patients. METHODS: A cohort of 220 IBD patients including 141 Crohn's disease (CD) and 79 ulcerative colitis (UC) patients was followed-up at a tertiary IBD center. A subgroup of the cohort (n = 26) took VD supplements for > 3 mo. Health related quality of life was assessed using the short IBD questionnaire (sIBDQ). VD serum concentration and sIBDQ score were assessed between August and October 2012 (summer/autumn period) and between February and April 2013 (winter/spring period). The mean VD serum concentration and its correlation with disease activity of CD were determined for each season separately. In a subgroup of patients, the effects of VD supplementation on winter VD serum concentration, change in VD serum concentration from summer to winter, and winter sIBDQ score were analyzed. RESULTS: During the summer/autumn and the winter/spring period, 28% and 42% of IBD patients were VD-deficient (< 20 ng/mL), respectively. In the winter/spring period, there was a significant correlation between sIBDQ score and VD serum concentration in UC patients (r = 0.35, P = 0.02), with a trend towards significance in CD patients (r = 0.17, P = 0.06). In the winter/spring period, VD-insufficient patients (< 30 ng/mL) had a significantly lower mean sIBDQ score than VD-sufficient patients; this was true of both UC (48.3 ± 2.3 vs 56.7 ± 3.4, P = 0.04) and CD (55.7 ± 1.25 vs 60.8 ± 2.14, P = 0.04) patients. In all analyzed scenarios (UC/CD, the summer/autumn period and the winter/spring period), health related quality of life was the highest in patients with VD serum concentrations of 50-59 ng/mL. Supplementation with a median of 800 IU/d VD day did not influence VD serum concentration or the sIBDQ score. CONCLUSION: VD serum concentration correlated with health related quality of life in UC and CD patients during the winter/spring period.

Vitamin D metabolites and/or analogs: which D for which patient?

Numerous drugs with vitamin D activity are available for clinical use and it may not be easy for the nonspecialist to select the most suitable for the individual patient. In this paper we review the main characteristics of the available drugs and provide evidence about any potential specific clinical indications, with special emphasis on renal patients, in order to facilitate the optimal choice. Natural vitamin D products (i.e. those identical to natural metabolites) are first examined, followed by the most frequently used synthetic molecules (i.e. bioengineered molecules not-existing in nature), which are generally indicated as " analogs". Either cholecalciferol, ergocalciferol or calcifediol can be employed in subjects with normal renal function and in CKD stage 3-5 patients to correct vitamin D deficiency and improve, respectively, age- or growth-related bone disease and secondary hyperparathyroidism. Calcifediol can be considered more rapid and effective. In all cases, especially with increasing doses, the risk of hypercalcemia must be taken into account. Calcitriol, which can be regarded as the active hormonal form of vitamin D, has the most potent hypercalcemic effect in both normal and renal failure patients. In renal patients calcitriol is a potent inhibitor of parathyroid activity, but the risk of hypercalcemia, now regarded as harmful, is evident whenever pharmacologic doses are used. Alfacalcidol, requiring 25-hydroxylation to become the active hormonal form of vitamin D3, is prescribed in normal subjects to treat osteoporosis and in renal patients to cure hyperparathyroidism and renal bone disease. Doxercalciferol, transformed into the active hormonal form of vitamin D2 following 25-hydroxylation, is mostly studied in renal patients in whom it cures secondary hyperparathyroidism, possibly with a lower calcemic effect than calcitriol. Paricalcitol, a vitamin D2 analog not requiring activation, has been specifically developed to suppress PTH in renal patients with a limited calcemic effect. As such it is now regarded as a powerful drug useful to treat even severe cases of secondary hyperparathyroidism. Importantly, reno-protective and cardio-protective effects of this analog have been recently evaluated by means of randomized clinical trials in renal patients with partially positive renal effects and negative cardiac results, thus additional studies are needed for confirmation. 22-oxacalcitriol, a vitamin D3 analog with a limited calcemic effect available in Japan, is mostly used in renal patients affected by secondary hyperparathyroidism. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. In summary, available drugs with vitamin D like activity are not all the same either in terms of pharmacological actions, and side-effects. They have specific characteristics that may be useful to know in order to operate the best choice in the individual patient.

Clinical outcomes of vitamin D deficiency and supplementation in cancer patients.

Results of recent studies suggest that circulating levels of vitamin D may play an important role in cancer-specific outcomes. The present systematic review was undertaken to determine the prevalence of vitamin D deficiency (<25 nmol/L) and insufficiency (25-50 nmol/L) in cancer patients and to evaluate the association between circulating calcidiol (the indicator of vitamin D status) and clinical outcomes. A systematic search of original, peer-reviewed studies on calcidiol at cancer diagnosis, and throughout treatment and survival, was conducted yielding 4,706 studies. A total of 37 studies met the inclusion criteria for this review. Reported mean blood calcidiol levels ranged from 24.7 to 87.4 nmol/L, with up to 31% of patients identified as deficient and 67% as insufficient. The efficacy of cholecalciferol supplementation for raising the concentration of circulating calcidiol is unclear; standard supplement regimens of <1,000 IU D3 /day may not be sufficient to maintain adequate concentrations or prevent decreasing calcidiol. Dose-response studies linking vitamin D status to musculoskeletal and survival outcomes in cancer patients are lacking.

Calcidiol [25(OH)D3]: from diagnostic marker to therapeutical agent.

OBJECTIVE: Osteoporosis is a skeletal disorder characterized by diminished bone strength, which results in an increased risk of fracture. Currently, osteoporosis is a public health priority due to the large number of individuals affected and the detrimental effect on quality of life. Primary osteoporosis, the most common form, usually results from age-related reduction in bone mineral strength. Over time, the individual's capacity to build bone is impaired, as the synthesis of vitamin D, the hormone responsible for calcium absorption, tends to decline. As serum calcium levels decrease, metabolic control serves to increase the removal of calcium from the skeleton to make up for the deficit. The synthesis of the 'hormone' vitamin D and its control therefore become central to intervention in involutional osteoporosis syndromes. In humans, plain vitamin D (cholecalciferol), also called parental or native vitamin D, is photosynthesized in the skin and then hydroxylated in the liver into the vitamin D analog calcidiol [25(OH)D3], which is hydroxylated again in the kidney into the vitamin D analog calcitriol [1,25(OH)2D3]. The advantage of administering vitamin D analogs is that the pro-drug calcidiol avoids the effect of declines in hepatic function, while calcitriol avoids the effect of declines in hepatic and kidney function. A strategy to enhance [25(OH)D3] levels to the optimal threshold of vitamin D is supplementation with the calcidiol metabolite itself. The goal of this paper is to review published studies on the efficacy of the calcidiol metabolite in increasing 25(OH)D3 serum levels and improving skeletal health parameters in humans. METHODS: A library search of published papers in the area of use of calcidiol in humans from 1967 to 2013 was performed (key words: calcidiol, 25-hydroxy-vitamin D3, vitamin D supplementation, vitamin D metabolism, osteomalacia). RESULTS AND CONCLUSION: The results of the survey made it possible to conclude that calcidiol is characterized by a number of features that make the compound ideal in conditions that require supplementation with a 25-hydroxylated metabolite.