The important reactions that occur to the vitamin D molecule and the important reactions involved in the expression of the final active form of vitamin D are reviewed in a critical manner. After an overview of the metabolism of vitamin D to its active form and to its metabolic degradation products, the molecular understanding of the 1alpha-hydroxylation reaction and the 24-hydroxylation reaction of the vitamin D hormone is presented. Furthermore, the role of vitamin D in maintenance of serum calcium is reviewed at the physiological level and at the molecular level whenever possible. Of particular importance is the regulation of the parathyroid gland by the vitamin D hormone. A third section describes the known molecular events involved in the action of 1alpha,25-dihydroxyvitamin D3 on its target cells. This includes reviewing what is now known concerning the overall mechanism of transcriptional regulation by vitamin D. It describes the vitamin D receptors that have been cloned and identified and describes the coactivators and retinoid X receptors required for the function of vitamin D in its genomic actions. The presence of receptor in previously uncharted target organs of vitamin D action has led to a study of the possible function of vitamin D in these organs. A good example of a new function described for 1alpha,25-dihydroxyvitamin D3 is that found in the parathyroid gland. This is also true for the role of vitamin D hormone in skin, the immune system, a possible role in the pancreas, i.e., in the islet cells, and a possible role in female reproduction. This review also raises the intriguing question of whether vitamin D plays an important role in embryonic development, since vitamin D deficiency does not prohibit development, nor does vitamin D receptor knockout. The final section reviews some interesting analogs of the vitamin D hormone and their possible uses. The review ends with possible ideas with regard to future directions of vitamin D drug design.

Current Understanding of the Molecular Actions of Vitamin D

Bone metabolism and disease in chronic kidney disease

Background Elevated calcium and phosphorus levels after therapy with injectable vitamin D for secondary hyperparathyroidism may accelerate vascular disease and hasten death in patients undergoing long-term hemodialysis. Paricalcitol, a new vitamin D analogue, appears to lessen the elevations in serum calcium and phosphorus levels, as compared with calcitriol, the standard form of injectable vitamin D. Methods We conducted a historical cohort study to compare the 36-month survival rate among patients undergoing long-term hemodialysis who started to receive treatment with paricalcitol (29,021 patients) or calcitriol (38,378 patients) between 1999 and 2001. Crude and adjusted survival rates were calculated and stratified analyses were performed. A subgroup of 16,483 patients who switched regimens was also evaluated. Results The mortality rate among patients receiving paricalcitol was 3417 per 19,031 person-years (0.180 per person-year), as compared with 6805 per 30,471 person-years (0.223 per person-year) am...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa022536

Survival of Patients Undergoing Hemodialysis with Paricalcitol or Calcitriol Therapy

Vitamin D insufficiency affects almost 50% of the population worldwide An estimated 1 billion people worldwide, across all ethnicities and age groups, have a vitamin D deficiency (VDD) This pandemic of hypovitaminosis D can mainly be attributed to lifestyle (for example, reduced outdoor activities) and environmental (for example, air pollution) factors that reduce exposure to sunlight, which is required for ultraviolet-B (UVB)-induced vitamin D production in the skin High prevalence of vitamin D insufficiency is a particularly important public health issue because hypovitaminosis D is an independent risk factor for total mortality in the general population Current studies suggest that we may need more vitamin D than presently recommended to prevent chronic disease As the number of people with VDD continues to increase, the importance of this hormone in overall health and the prevention of chronic diseases are at the forefront of research VDD is very common in all age groups As few foods contain vitamin D, guidelines recommended supplementation at suggested daily intake and tolerable upper limit levels It is also suggested to measure the serum 25-hydroxyvitamin D level as the initial diagnostic test in patients at risk for deficiency Treatment with either vitamin D2 or vitamin D3 is recommended for deficient patients A meta-analysis published in 2007 showed that vitamin D supplementation was associated with significantly reduced mortality In this review, we will summarize the mechanisms that are presumed to underlie the relationship between vitamin D and understand its biology and clinical implications

Vitamin D: The "sunshine" vitamin

Renal osteodystrophy

Fractures of the proximal humerus can be described using the Neer and AO fracture classifications. To assess the reproducibility and reliability of these classifications, we investigated 26 proximal humeral fractures with both plain radiographs and CT. 5 specialists in orthopedic surgery and 5 specialists in radiology independently classified all radiographs on 2 occasions. There was a moderate agreement between the observers when using the Neer classification, but only a fair agreement with the AO classification. The Neer system had a kappa value of 0.42 and the AO had a value of 0.31 in the first assessment. In the second assessment the kappa values were 0.45 and 0.30, respectively. Intraobserver reproducibility was slight to almost perfect agreement with Neer (kappa range 0.20-0.85) and slight to moderate agreement with AO (kappa range 0.16-0.60). The observers most familiar with shoulder fracture radiographs and shoulder fracture treatment were more consistent in their classifications. We conclude that even with CT, the fracture classifications of Neer and AO have a low consistency. Neither classification system is reproducible enough to allow comparisons of different studies.

https://www.tandfonline.com/doi/pdf/10.3109/17453679708996692

Poor reproducibility of classification of proximal humeral fractures : Additional CT of minor value

An LD50 of 0.2 mg/kg body wt has been determined for 1 alpha-hydroxyvitamin D3 in the rat. In comparison, the LD50 for 1 alpha-hydroxyvitamin D2 is between 3.5 and 6.5 mg/kg. In terms of chronic toxicity, 1 alpha-hydroxyvitamin D3 at a dose of 5 micrograms/kg/day causes death of one-half the animals in a 4-week period. On the other hand, 20 micrograms/kg/day of 1 alpha-hydroxyvitamin D2 is required to induce similar toxicity. The body weight record and renal calcium accumulation during chronic treatment support the above conclusion. It therefore appears that 1 alpha-hydroxyvitamin D2 is between 5 and 15 times less toxic than 1 alpha-hydroxyvitamin D3. This surprising result prompted a reexamination of the relative biological activity of 1 alpha-hydroxyvitamin D2 and 1 alpha-hydroxyvitamin D3. Both compounds are equally potent in the stimulation of intestinal calcium transport, bone calcium mobilization, in the elevation of serum phosphorus, and in the healing of rickets in the rat. The reason for lower toxicity of 1 alpha-hydroxyvitamin D2 is unknown. The results suggest that 1 alpha-hydroxyvitamin D2 might represent a therapeutically superior compound.

1α-Hydroxyvitamin D2 is Less Toxic than 1α-Hydroxyvitamin D3 in the Rat

https://www.tandfonline.com/doi/pdf/10.3109/17453678509154160

Effects of vitamin D

The Neer and AO fracture classifications for fractures of the proximal humerus have shown poor reproducibility based on plain radiography. We wanted to investigate whether the addition of 3-dimensional (3D) reconstructions would increase the reproducibility of classification. 7 observers independently classified 24 fractures of the proximal humerus using both plain radiographs, CT and 3D and the classification was repeated 2 months later. There was a moderate interobserver agreement when using the Neer classification, but only a fair agreement with the AO classification. The Neer system had a mean kappa value of 0.44 and the AO had a value of 0.32 for the first assessment. In the second assessment, the mean kappa values were 0.49 and 0.34, respectively. Intraobserver reproducibility was fair to substantial agreement for Neer (kappa range 0.27-0.73) and for AO (kappa range 0.29-0.74). In conclusion, the addition of CT and 3D to plain radiographs did not improve the reproducibility of the classifications of Neer and AO of the proximal humerus.

https://www.tandfonline.com/doi/pdf/10.3109/17453679908997818

3D-radiographic analysis does not improve the Neer and AO classifications of proximal humeral fractures

We evaluated the functional outcome 3 (2-12) years after arthroplasty in 29 proximal humerus fractures. The patients' average age at the time of surgery was 71 (47-87) years. The follow-up included a full clinical examination by an independent observer, a questionnaire concerning activities of daily living and pain, and radiographs. The shoulders had a marked reduction of performance, with a Constant score mean of 38 (16-69). All patients were able to eat with utensils, 10 could comb their hair, 19 managed to wash the contralateral armpit, 3 could reach the back pocket and 12 were able to take care of the perineal area. On the VAS-scale (0-100 mm), pain at rest was mean 21 (0-53) mm and on motion 47 (0-91) mm. The patients were stratified regarding surgical treatment within 3 weeks (18 acute vs. 11 late) and prosthetic design (14 Neer II vs. 14 Global modular) without significant differences, as assessed by the Constant scores. We conclude that the treatment of severe proximal humerus fractures with a prosthesis does not give complete pain relief and results in impaired shoulder function.

https://www.tandfonline.com/doi/pdf/10.3109/17453679808999053

Göran O J Sjödén

Papers

Poor reproducibility of classification of proximal humeral fractures : Additional CT of minor value

1α-Hydroxyvitamin D2 is Less Toxic than 1α-Hydroxyvitamin D3 in the Rat

Effects of vitamin D

3D-radiographic analysis does not improve the Neer and AO classifications of proximal humeral fractures

Poor function after shoulder replacement in fracture patients. A retrospective evaluation of 29 patients followed for 2-12 years.