Calcitriol dosage in osteomalacia,hypoparathyroidism and attempted treatment of myositis ossificans progressiva

Summary

Mineral retention was measured during 39 metabolic balance studies in 34 patients with nutritional osteomalacia or late rickets; they were divided into 5 treatment groups consisting of oral vitamin D, artificial ultra-violet irradiation, 25-hydroxychole-calciferol {calcifediol), 1 α-hydroxycholecalciferol (alfacalcidol) and 1α,25-dihydroxy-cholecalciferol (calcitriol). With the 1 α-hydroxylated derivatives, initial dosage of 2 to 6 μg daily was required to achieve optimal healing rates by comparison with other responses. Mineral retention was markedly enhanced by supplementation with micro-crystalline hydroxyapatite compound (MCHC); untreated X-linked hypophosphataemic rickets healed in 7 weeks on 10 μg alfacalcidol daily and 6?g MCHC daily without developing hypercalcaemia. By contrast, adult-presenting hypophosphataemic osteomalacia developed early hypercalcaemia on the same treatment; additional phosphate supplementation, without changing other treatment, abolished hypercalcaemia and improved calcium retention. A long-term crossover trial of the vitamins D in 6 patients with hypoparathyroidism suggested that relative potencies were as follows {assigning to vitamin D an arbitrary potency of 1): vitamin D₂ (or D₃) 1: dihydrotachysterol (DHT) 3: calcifediol 10: alfacalcidol 750: calcitriol 1500. The two-fold superiority of calcitriol over alfacalcidol was evident. Calcifediol and vitamin D controlled plasma calcium at comparable levels of circulating 25-hydroxyvitamin D (25-OH-D), elevated 25-OH-D persisting at least 1 to 2 years after discontinuing long-term (>4 years) vitamin D. In 2 patients with myositis ossificans progessiva treated with 10 to 20 μg calcitriol daily, hypercalcaemia was minimized by a low-calcium diet supplemented with cellulose phosphate, suggesting that bone resorption did not play a major role in vitamin D intoxication. Net mineral loss was documented in a young male patient but not in a menopausal female, suggesting that calcitriol treatment was not likely to produce post-menopausal osteoporosis.     

Vitamin D supplements: The pharmacists’ perspective

ObjectiveThe purpose of this narrative review was to provide guidance for pharmacists concerning vitamin D supplementation.MethodsRelevant studies were identified in a search of MEDLINE/PubMed, EBSCOhost, and Google Scholar from January 1966 to September 2020 using the search terms vitamin D, vitamin D₂, vitamin D₃, calcitriol, and vitamin D deficiency. Abstracts were reviewed for relevance and, if relevant, full-text articles were retrieved and reviewed. References were checked, and citation searches using identified studies were conducted. The literature search included English-language studies involving administration of vitamin D monotherapy compared with placebo.ResultsSerum 25–hydroxyvitamin D levels of less than 12 ng/mL indicate a vitamin D deficiency. The Institute of Medicine recommends a daily intake of 600 IU of vitamin D in individuals aged up to 70 years and 800 IU in those aged above 70 years. Vitamin D is labeled for rickets, osetomalacia, hypophosphatemia (familial or secondary), renal osteodystrophy, and corticosteroid-induced osteoporosis. When used for these indications, vitamin D should be prescribed with appropriate monitoring by a qualified health care practitioner. There is evidence for vitamin D supplementation in individuals aged 75 years or older and in those with problems associated with mobility, gait, or balance. There is insufficient evidence to support vitamin D supplementation in the prevention of cardiovascular disease, cancer, asthma, chronic obstructive pulmonary disease exacerbations, new-onset type 2 diabetes, infectious lung diseases, cognitive dysfunction, Alzheimer disease, and depression, or in prenatal use.ConclusionPharmacists can provide evidence-based recommendations concerning the indications, dosing, monitoring, and adverse effects of vitamin D supplements.     

Effects of calcitriol on the immune system: new possibilities in the treatment of glomerulonephritis

1. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the hormonal form of vitamin D, is widely appreciated to play a central role in calcium and phosphate homeostasis. However, it is becoming increasingly clear that the sterol also play an important role in the regulation of cellular growth, haematopoietic tissues and the immune system, as well as in the modulation of hormone secretion by several endocrine glands. 2. In the present review, some of the mechanisms by which 1,25(OH)2D3 regulates immune function are highlighted. Moreover, a number of studies on the effects of calcitriol in several experimental animal models of renal disease are reported, suggesting new possibilities in the therapy of glomerulonephritis.     

Vitamin D analogs: novel therapeutic agents for cardiovascular disease?

Vitamin D3 plays a key role in regulating calcium and mineral homeostasis in support of normal development and maintenance of bone. The classic effects of vitamin D3 include promoting absorption of dietary calcium in the gut and, through its actions as a steroid endocrine hormone, regulating the synthesis and secretion of parathyroid hormone. The effects of the vitamin D3 system are mediated through the highly regulated generation of the potent, active metabolite 1,25-dihydroxyvitamin D3 (calcitriol). Vitamin D3 exerts its effects through the vitamin D3 receptor (VDR), a ligand-activated nuclear receptor expressed in a wide array of tissue and cell types. Studies performed in mice rendered deficient for VDR suggest that calcitriol and VDR may inhibit the renin-angiotensin system and reduce blood pressure in the long-term. Clinical studies suggest that administration of vitamin D3 analogs produces differential benefit with regards to mortality in dialysis patients; other studies suggest that vitamin D3 analogs may provide cardiovascular benefit in both dialysis and nondialysis patients. This paper reviews clinical and preclinical studies, which suggest that vitamin D3 analogs may provide therapeutic utility in the treatment of cardiovascular disease independent of those mechanisms typically associated with the vitamin D3 endocrine system.     

New insights into the role of vitamin D and calcium in osteoporosis management: an expert roundtable discussion

ABSTRACT

Background: Adequate vitamin D and calcium nutrition play a critical role in the maintenance of musculoskeletal health and are considered the first step in osteoporosis treatment.

Roundtable discussion: In February 2008 Merck Sharp & Dohme sponsored a 2-day, evidence-based expert panel on the benefits of vitamin D for the patient with osteoporosis and the role of vitamin D in combination with antiresorptive therapy for the management of osteo­porosis. One of the primary objectives of the meeting was to review new data on the optimal serum 25-hydroxy­vitamin D [25(OH)D]levels. The symposium was attended by 29 researchers and clinicians from Europe and the Middle East. The discussion focused on optimizing vitamin D and calcium nutrition and reducing falls and fractures in osteoporotic patients.

Conclusions: Current evidence and expert opinion suggests that optimal serum 25(OH)Dconcentrations should be at least 50?nmol/L (20?ng/mL) in all individuals. This implies a population mean close to 75?nmol/L (30?ng/mL). In order to achieve this level, vitamin D intake of at least 20?µg daily is required. There is a wider thera­peutic window for vitamin D than previously believed, and doses of 800?IU per day, regardless of sun exposure, season or additional multivitamin use, appear to present little risk of toxicity. Apart from fracture and fall preven­tion, optimization of vitamin D status may also have additional general health benefits. Based on newly emerging data regarding calcium supplementation, and recommendations for increased vitamin D intake, the current recommendations for calcium intake in postmenopausal women may be unnecessarily high. In addition to vitamin D and calcium, treatment of patients with osteo­porosis at high risk of fractures should also include pharmacologic agents with proven vertebral and non-vertebral fracture efficacy.     

Hepatic drug metabolism after phenobarbital and diphenylhydantoin administration in the rat--influence of vitamin D3 status.

Measurements of aniline hydroxylation, aminopyrine N-demethylation and cytochrome P-450 content after a 3-week treatment with phenobarbital (PB), diphenylhydantoin (DPH) or a combination of the two drugs were undertaken during normal vitamin D status (D +) and vitamin D deficiency (D ?) with or without vitamin D₃(D₃) supplementation. Serum calcium concentrations were reduced after D deprivation but responded by a significant increase toward normal values to a single pharmacological dose of D₃. Serum phosphorus concentrations were also slightly raised by the supplementation. Even in the presence of higher cytochrome P-450 content in D ? rats, aniline hydroxylase and aminopyrine N-demethylase activities were lower in D ? than in D + animals. These two enzymatic parameters, as well as cytochrome P-450 content, were increased by anticonvulsant (ACV) drug treatment regardless of the D nutritional status. The in vivo hexobarbital sleeping time was shortened by ACV drugs but the sleeping time tended to be longer in D ? than in D + rats. Supplementation with 1000 I.U. of D₃, lowered aniline hydroxylase activity both in D + and D? animals; the supplementation had no effect on aminopyrine N-demethylase activity in D + animals but had an inhibitory effect after PB and a stimulatory effect after DPH treatment in D? animals. Cholecalciferol supplementation lowered cytochrome P-450 content toward normal values in D? rats while it had no effect in D + animals. These observations suggest that (1) PB and DPH pretreatment do not alter the normal response of serum calcium and phosphorus to a single pharmacological dose of D₃; (2) in a state of vitamin D deficiency accompanied by hypocalcemia, the inducing capacity of PB and DPH on the liver mixed function oxidase system is not lost; (3) under certain circumstances, vitamin D₃, can influence the catalytic activity of the mono-oxygenase complex; (4) cytochrome P-450 is influenced by vitamin D deficiency and/or changes in extracellular calcium but the forms induced by PB and DPH may not necessarily be the ones specifically involved in vitamin D metabolism.     

The vitamin D metabolites in the pathogenesis and management of osteoporosis

Summary

Studies on post-menopausal osteoporotic patients indicate that 1,25-(OH)₂D₃ concentrations are no different from those in age-matched normal subjects and the data suggest that the malabsorption of calcium found in many osteoporotic patients cannot generally be attributed to low plasma 1,25-(OH)₂D₃ levels. The effects are discussed of three different therapies - sex hormones alone, vitamin D metabolites alone and a combination of both - on calcium balance and peripheral bone loss in treated compared with untreated osteoporotic patients. The results indicate that combined therapy with a vitamin D metabolite and an oestrogen is more effective in inhibiting the rate of bone resorption in post-menopausal osteoporosis than treatment with either agent used alone, and should be regarded as the treatment of choice at the present time. It is suggested that, using this regimen which is suitable for patients up to about 65 years of age, calcium supplementation is not required, provided daily calcium intake is reasonably adequate, and may even be undesirable by increasing the risk of hypercalcaemia.     

Vitamin D and the central nervous system

Vitamin D is formed in human epithelial cells via photochemical synthesis and is also acquired from dietary sources. The so-called classical effect of this vitamin involves the regulation of calcium homeostasis and bone metabolism. Apart from this, non-classical effects of vitamin D have recently gained renewed attention. One important yet little known of the numerous functions of vitamin D is the regulation of nervous system development and function. The neuroprotective effect of vitamin D is associated with its influence on neurotrophin production and release, neuromediator synthesis, intracellular calcium homeostasis, and prevention of oxidative damage to nervous tissue. Clinical studies suggest that vitamin D deficiency may lead to an increased risk of disease of the central nervous system (CNS), particularly schizophrenia and multiple sclerosis. Adequate intake of vitamin D during pregnancy and the neonatal period seems to be crucial in terms of prevention of these diseases.     

1,25-Dihydroxyvitamin D3 regulates genes responsible for detoxification in intestine

1α,25-Dihydroxyvitamin D₃ (1,25-(OH)₂D₃), the biologically active form of vitamin D₃, not only plays a major role in mammalian calcium and phosphorous homeostasis but also exerts pleiotropic effects on cell proliferation, differentiation and the immune system. Further, vitamin D is believed to play a significant role in the prevention of colon, prostate, and breast cancer and in reducing the risk of autoimmune diseases. To gain insight into the mechanism whereby vitamin D can have such diverse actions, we have employed microarray technology. We studied the effect of a single dose of 1,25-(OH)₂D₃ on gene expression in the intestine of vitamin D-deficient rats. Within 6 h, 1,25-(OH)₂D₃ stimulates the expression of several phase I and phase II biotransformation genes. There is also an increased expression of antioxidant genes. These results support the idea that vitamin D is a significant factor in detoxification and protection against environmental toxins.     

超重或肥胖儿童维生素D水平与静息代谢率的相关性分析

目的 探讨超重或肥胖儿童维生素D水平与静息代谢率的相关性。方法 选取2017年6月至2018年8月安徽医科大学第一附属医院儿科门诊或病房7～14岁超重或肥胖儿童67例为研究对象（超重或肥胖组）,并选取83例同期体质量正常的健康体检儿童为对照组,检测两组研究对象血清维生素D水平及静息代谢率,并比较两组维生素D水平、静息代谢率及单位体质量静息代谢率的差异,分析维生素D水平与静息代谢率、单位体质量静息代谢率之间的相关性。结果 超重或肥胖组儿童维生素D水平低于对照组,单位体质量静息代谢率较对照组低,差异均有统计学意义（P<0.05）。对照组儿童单位体质量静息代谢率与维生素D水平正相关（r=0.290,P<0.05）;超重或肥胖组儿童单位体质量静息代谢率与维生素D水平无相关性。结论 血清维生素D缺乏可能在超重或肥胖儿童单位体质量静息代谢率下降中不发挥主要作用。     

Vitamin D levels in children affected by vernal keratoconjunctivitis

Background: Vernal keratoconjunctivitis (VKC) is a chronic and often severe bilateral conjunctivitis. VKC etiology still remains unclear although endocrine, genetic, neurogenic and environmental factors have been implicated. Vitamin D is a fat-soluble prohormone whose main function is the regulation of calcium and phosphate metabolism. The aim of this study was to evaluate serum vitamin D in children affected by VKC compared to the healthy children and investigate the relationship between its levels and disease severity.

Methods: A total of 110 children, 47 affected by VKC, aged between 5 and 12 years were enrolled at the Department of Pediatrics, Division of Allergy and Immunology, “Sapienza” University of Rome. Used as controls were 63 healthy children with negative skin prick test (SPT), without allergic, ocular and systemic disease. Serum samples were obtained in April from all the children included in the study. Vitamin D dosage was repeated in October in 20 patients after therapy and in 20 controls. A conjunctival scraping was performed in all children affected by VKC.

Results: Children affected by VKC had lower vitamin D levels compared to healthy controls and we found an increase in vitamin D levels after therapy with cyclosporine eye drops 1% although this increase was lower than that of healthy controls. Moreover we found significant correlations between vitamin D level and the severity of the disease.

Conclusions: The study shows that children affected by VKC have lower vitamin D levels when compared to healthy controls and highlights a significant correlation between its levels and disease severity.     

Paricalcitol capsules for the control of secondary hyperparathyroidism in chronic kidney disease

Secondary hyperparathyroidism is a common complication of patients with chronic kidney disease. Treatment with calcitriol, the active form of vitamin D, reduces parathyroid hormone levels, but may result in elevations in serum calcium and phosphorus. New vitamin D analogues have been developed to reduce parathyroid hormone secretion without concomitant hypercalcaemia and hyperphosphataemia. Recent data from studies with paricalcitol capsules, the oral formulation of 19-nor-1,25(OH)₂D₂, show a significant reduction in parathyroid hormone levels with no change in calcium and phosphorus levels when compared with placebo. Paricalcitol also compares favourably to other oral vitamin D analogues, effectively decreasing parathyroid secretion with less hypercalcaemia and hypercalciuria than other agents.     

Retiferols – synthesis and biological activity of a conceptually novel class of vitamin D analogs

Introduction: The hypothesis that retiferols are a novel class of vitamin D analogs with therapeutic potential has been recently proved. The CD-ring of vitamin D, originated from a steroid precursor, is not necessary for biological activity. The retiferol, disubstituted at C-13, was bound to the ligand-binding domain (LBD) of vitamin D receptor (VDR) just like the vitamin D hormone [1,25-(OH)₂D₃]. This finding opens the way for retiferols as a novel class of vitamin D therapeutics.

Areas covered: This review presents the concept of retiferols and their structure evolution. Medicinal chemistry and therapeutic perspective of retiferols are reviewed showing how these vitamin D analogs became a source of potential therapeutics.

Expert opinion: Docking experiments and molecular modeling have shown that positioning of vitamin D analog at the LBD of VDR is not disturbed by deletion of a large portion of the vitamin D, exactly as hypothesized. Twenty years of structural modifications have shown that removal of the CD-ring fragment and regioselective methylation results in an almost complete loss of the undesired calcemic activity of retiferol while gaining the agonistic activity comparable to that of 1,25-(OH)₂D₃.     

Inhibition and/or Inactivation of Nitric Oxide Synthase Isoforms

Background: Vitamin D is a steroid hormone known for its role in regulating levels of calcium and phosphorus. Vitamin D has important autocrine/paracrine roles and it is involved in vascular biology. Clinical studies have shown a relationship between vitamin D levels and cardiovascular health, and low levels of vitamin D metabolites have been associated with higher incidence of congestive heart failure and increases in mortality. Objective: To summarise the effect of vitamin D on cardiovascular pathology, the leading cause of death in chronic kidney disease patients. Conclusions: All results indicate a potential effect of vitamin D on cardiovascular health. Therefore, maintaining optimum levels of circulating vitamin D is critical for a healthy cardiovascular system. In patients with low vitamin D status, like renal patients, supplementation with vitamin D metabolites has shown beneficial cardiovascular effects.     

Targeting the vitamin D receptor: advances in drug discovery

The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, mediates the biological action of 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], the active form of vitamin D. VDR regulates bone and calcium homeostasis, immunity, cellular differentiation and other physiological processes. Mutations in the VDR gene were identified in hereditary vitamin D-resistant rickets (HVDRR), and VDR-null mice exhibit the HVDRR phenotype, characterised by rickets and hypocalcaemia. In addition to the treatment of rickets, vitamin D analogues are important therapeutics in osteoporosis and psoriasis. Vitamin D analogues are effective drugs in experimental models of immune disorders and malignancies, such as breast cancer, prostate cancer and leukaemia. The development of functionally selective VDR-targeted drugs is leading to an enhanced understanding and novel therapies for these VDR-related diseases.     

Intraplatelet Free Calcium and Calcium-Regulating Hormones in Plasma are Not Related to the Antihypertensive Effect of Nifedipine in Hypertensive Pregnancy

Abstract: Intracellular free calcium regulates contraction-relaxation processes in vascular smooth muscle. We compared intraplatelet free calcium ([Ca²⁺]_i) and pH ([pH]_i) in hypertensive pregnant women to those in normotensive pregnant and non-pregnant women. Plasma parathormone and vitamin D metabolite were simultaneously assessed. In hypertensive pregnancy, [Ca²⁺]_i tended to be lower than in normotensive pregnant (P=0.08) and non-pregnant subjects (P=0.06). In hypertensive pregnancy, 1,25 (OH)₂ vitamin D in plasma was in the same range as in non-pregnant women and significantly lower than in normotensive pregnancy (p<0.01). The other two vitamin D metabolites, parathormone and [pH]_i were equal in the three groups. A five-day nifedipine treatment (10 mg t.i.d.) increased [Ca²⁺]_i in hypertensive pregnant (P<0.05) and normotensive non-pregnant subjects (P=0.06), whereas [pH]_i (P<0.05) and 25 (OH) vitamin D (P<0.05) decreased in the former and 24,25 (OH)₂ vitamin D increased in the latter group (P<0.05). Initial [Ca²⁺]_i did not correlate with blood pressure in any group. The antihypertensive effect of nifedipine did not correlate with any variable measured. In conclusion, [Ca²⁺]_i and calcium-regulating hormones seem not to be related to the antihypertensive effect of nifedipine in hypertensive pregnancy. In this type of hypertension, intraplatelet calcium may not reflect calcium balance in smooth muscle cells regulating vascular tone and blood pressure.     

Alterations in gene expression in vitamin D‐deficiency: Down‐regulation of liver Cyp7a1 and renal Oat3 in mice

The vitamin D‐deficient model, established in the C57BL/6 mouse after 8 weeks of feeding vitamin D‐deficient diets in the absence or presence of added calcium, was found associated with elevated levels of plasma parathyroid hormone (PTH) and plasma and liver cholesterol, and a reduction in cholesterol 7α‐hydroxylase (Cyp7a1, rate‐limiting enzyme for cholesterol metabolism) and renal Oat3 mRNA/protein expression levels. However, there was no change in plasma calcium and phosphate levels. Appraisal of the liver revealed an up‐regulation of mRNA expressions of the small heterodimer partner (Shp) and attenuation of Cyp7a1, which contributed to hypercholesterolemia in vitamin D‐deficiency. When vitamin D‐sufficient or D‐deficient mice were further rendered hypercholesterolemic with 3 weeks of feeding the respective, high fat/high cholesterol (HF/HC) diets, treatment with 1α,25‐dihydroxyvitamin D₃ [1,25(OH)₂D₃], active vitamin D receptor (VDR) ligand, or vitamin D (cholecalciferol) to HF/HC vitamin D‐deficient mice lowered the cholesterol back to baseline levels. Cholecalciferol treatment partially restored renal Oat3 mRNA/protein expression back to that of vitamin D‐sufficient mice. When the protein expression of protein kinase C (PKC), a known, negative regulator of Oat3, was examined in murine kidney, no difference in PKC expression was observed for any of the diets with/without 1,25(OH)₂D₃/cholecalciferol treatment, inferring that VDR regulation of renal Oat3 did not involve PKC in mice. As expected, plasma calcium levels were not elevated by cholecalciferol treatment of vitamin D‐deficient mice, while 1,25(OH)₂D₃ treatment led to hypercalcemia. In conclusion, vitamin D‐deficiency resulted in down‐regulation of liver Cyp7a1 and renal Oat3, conditions that are alleviated upon replenishment of cholecalciferol.