Parenteral 1,25-dihydroxycholecalciferol in hepatic osteomalacia

Despite regular long-term parenteral vitamin D2 treatment, four patients with biliary cirrhosis had multiple symptoms of bone disease and bone biopsy specimens showed osteomalacia without osteoporosis. Three patients also had a proximal myopathy. Plasma calcium values (after correction for albumin), phosphorus, magnesium, and serum 25-hydroxy-vitamin D were within normal limits. Treatment with 1,25-dihydroxy-cholecalciferol (1,25-(OH)2D3) relieved symptoms in three of the four patients and improved those in the fourth. Histological examination of bone showed improvement in all four patients, but serum and urinary biochemical changes were not pronounced. We conclude that 1,25-(0H)2D3 treatment has a beneficial effect on bone and muscle in hepatic osteomalacia, either because vitamin D 1-hydroxylation fails in biliary cirrhosis or because hepatic osteomalacia is resistant to vitamin D2 metabolites.     

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

Abstract

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.     

Vitamin D inadequacy in postmenopausal women in Eastern Asia

ABSTRACT

Objective: To review data on the prevalence of vitamin D inadequacy and its causes in postmenopausal women in Eastern Asia.

Research design and method: Data were obtained from the published biomedical literature as well as abstracts and posters presented at scientific meetings. Using MEDLINE, EMBASE and BIOSIS databases (to July 2007), epidemiological studies were identified using the search terms: ‘human’, ‘vitamin D’, ‘vitamin D deficiency’, ‘vitamin D inadequacy’, ‘vitamin D insufficiency’ and ‘hypovitaminosis D’, ‘osteomalacia’ and ‘osteoporosis’. Additional references were also identified from the bibliographies of published articles.

Results: The prevalence of vitamin D inadequacy in studies of postmenopausal women (ambulatory or with osteoporosis or related musculoskeletal disorders) in Eastern Asia ranged from 0 to 92%, depending on the cut-off level of serum 25-hydroxycholecalciferol [25(OH)D] that was applied (range ≤6–35?ng/mL [≤15–87?nmol/L]). One large international study found that 71% of postmenopausal women with osteoporosis in Eastern Asia had vitamin D inadequacy, defined as serum levels of 25(OH)D <30?ng/mL (75 nmol/L). Prevalence rates using this cut-off level were 47% in Thailand, 49% in Malaysia, 90% in Japan and 92% in South Korea. High prevalences of vitamin D inadequacy were evident in two studies using a lower 25(OH)D level cut-off value of <12?ng/mL(30?nmol/L) – 21% in China and 57% in South Korea. Dietary deficiency and inadequate exposure or reactivity to sunlight (due to lifestyle choices, cultural customs and/or aging) were identified as important risk factors for vitamin D inadequacy.

Conclusions: Non-uniform, epidemiological studies indicate a high prevalence of vitamin D inadequacy in postmenopausal women in Eastern Asia. Recommended remedial approaches are education campaigns and broad-based provision of vitamin D supplementation.     

An inducible cytochrome P450 3A4-dependent vitamin D catabolic pathway

Vitamin D(3) is critical for the regulation of calcium and phosphate homeostasis. In some individuals, mineral homeostasis can be disrupted by long-term therapy with certain antiepileptic drugs and the antimicrobial agent rifampin, resulting in drug-induced osteomalacia, which is attributed to vitamin D deficiency. We now report a novel CYP3A4-dependent pathway, the 4-hydroxylation of 25-hydroxyvitamin D(3) (25OHD(3)), the induction of which may contribute to drug-induced vitamin D deficiency. The metabolism of 25OHD(3) was fully characterized in vitro. CYP3A4 was the predominant source of 25OHD(3) hydroxylation by human liver microsomes, with the formation of 4β,25-dihydroxyvitamin D(3) [4β,25(OH)(2)D(3)] dominating (V(max)/K(m) = 0.85 ml · min(-1) · nmol enzyme(-1)). 4β,25(OH)(2)D(3) was found in human plasma at concentrations comparable to that of 1α,25-dihydroxyvitamin D(3), and its formation rate in a panel of human liver microsomes was strongly correlated with CYP3A4 content and midazolam hydroxylation activity. Formation of 4β,25(OH)(2)D(3) in primary human hepatocytes was induced by rifampin and inhibited by CYP3A4-specific inhibitors. Short-term treatment of healthy volunteers (n = 6) with rifampin selectively induced CYP3A4-dependent 4β,25(OH)(2)D(3), but not CYP24A1-dependent 24R,25-dihydroxyvitamin D(3) formation, and altered systemic mineral homeostasis. Our results suggest that CYP3A4-dependent 25OHD(3) metabolism may play an important role in the regulation of vitamin D(3) in vivo and in the etiology of drug-induced osteomalacia.     

Decreased serum 24,25-dihydroxy vitamin D concentrations in children receiving chronic anticonvulsant therapy.

Serum 24,25-dihydroxy vitamin D (24,25(OH)2D) and 25-hydroxy vitamin D (25-OHD) concentrations and the ratio between the two were measured in 31 Israeli children and adolescents receiving long-term treatment with phenobarbitone or phenytoin and in controls. 24,25 (OH)2D concentrations were significantly depressed in the patients, although the 25-OHD concentrations were similar to those in the healthy controls. In four patients with radiological evidence of osteopenia very low serum 24,25(OH)2D concentrations and serum 24,25(OH)2D: 25-OHD ratios were recorded. The findings suggest that 24,25(OH)2D deficiency may play an important part in the pathogenesis of osteomalacia in patients treated with anticonvulsant drugs and provide further indirect evidence that 24,25(OH)2D is important for normal bone structure.     

药物联合行为干预治疗维生素D缺乏患儿对骨代谢相关指标的影响

目的：探讨药物联合行为干预治疗维生素D缺乏的疗效,为临床治疗维生素D缺乏提供参考。方法：选取2017-2018年在我院接受健康体检的610例儿童（3个月~3岁）,检测外周血中25-羟维生素D［25（OH）D］水平,并根据25（OH）D水平将所有研究对象分为维生素D缺乏组（n=60）和正常组（n=550）。分析维生素D缺乏的影响因素,制定行为干预手段。将维生素D缺乏组按随机数字表法分为行为干预组（采用行为干预+维生素D滴剂和葡萄糖酸钙锌口服溶液治疗）和常规治疗组（采用维生素D滴剂和葡萄糖酸钙锌口服溶液治疗）各30例,比较行为干预组和常规治疗组临床疗效及治疗前后骨代谢相关指标水平变化情况。结果：喂养方式、户外活动时间、厌食、腹泻与维生素D缺乏具有相关性（P<0.05）。Logistic回归分析结果显示,喂养方式、户外活动时间、腹泻是维生素D缺乏的独立影响因素（P<0.05）,普通奶粉或其他喂养方式、户外活动时间<2 h/d、经常腹泻患儿更易发生维生素D缺乏。治疗前,行为干预组与常规治疗组25（OH）D水平及骨代谢相关指标差异无统计学意义（P>0.05）,治疗2个月后,行为干预组25（OH）D、血钙、血鳞、骨钙素水平高于常规治疗组,骨碱性磷酸酶（BALP）低于常规治疗组,差异有统计学意义（P<0.05）。结论：在药物治疗的基础上,联合针对喂养方式、消化道功能及户外活动时间等制定的行为干预,可提高治疗维生素D缺乏患儿的临床疗效,改善骨代谢指标。     

Vitamin D status in relation to age,bone mineral density of the spine and femur in obese Saudi females – A hospital-based study

The aim of the present study was to evaluate the association between Bone mineral density in lumber spine and femoral neck with serum total levels of vitamin D, sun exposure and Consumption of vitamin D Supplement in obese Saudi females aged between 30 and 54?years old. Recent attention to the high prevalence of osteoporosis and its association with low vitamin D levels in adults has raised the importance of vitamin D evaluation. A low level of vitamin D is considered to be one of the most important risk factors for osteoporosis. In this study; 120 obese Saudi females with no diagnosed chronic diseases attending the Outpatient clinic at king Khalid University hospital in Riyadh. Saudi Arabia, recruited randomly in period of 12?months. In this study, Serum levels of total Vitamin D were considered to be severe deficient if it was lower than 25?ng/mL, mild to moderate deficient if it was between 25 and 60?ng/mL and optimum level if it was 61–200?ng/mL. The results showed that; sun exposure was significantly affect and Correlate with serum level of Vitamin D in the subjects. In addition, daily consumption of Vitamin D supplement was significantly affect and Correlate with serum level of Vitamin D in the subjects of this study. Moreover, the results showed that; 50% of the age group (40–49?years old) having severe deficiency of Vitamin D. While, 50% of the age group (50–59?years old) having optimal level of Vitamin D. And these results mean that age is not Correlated with vitamin D deficiency in subjects of this study.     

Impairment of calcium homeostasis by hexachlorobenzene (HCB) exposure in Fischer 344 rats

Human exposure to hexachlorobenzene (HCB) has resulted in demineralization of bone and development of osteoporosis. Experiments were undertaken to investigate the effects of HCB on the homeostatic mechanism of calcium metabolism. Fischer 344 rats were dosed with 0, 0.1, 1.0, 10.0, or 25.0 mg HCB/kg body weight 5 d/wk for 5 wk while being fed normal rat diet or vitamin D3-deficient diet. Rats receiving the normal diet had a dose-related decrease in body weight gain and increased liver weight when compared to their controls. Serum cholesterol, alanine aminotransferase (ALT), 1, 25-dihydroxy-vitamin D3 [1,25-(OH)2D3], and parathyroid hormone (PTH) were significantly elevated when compared to control values. In the vitamin D3-deficient diet group, there was a dose related increase in liver weight, liver-to-body weight ratio and kidney-to-body weight ratio. Serum cholesterol and 1,25-(OH)2D3 were significantly elevated. Urinary calcium decreased significantly with increasing HCB dosage, indicating conservation of calcium. The data from this study indicate that HCB does affect calcium metabolism by altering the concentrations of two primary controlling factors in calcium homeostasis.     

Graves病患者骨代谢指标的变化

【摘要】目的 观察Graves病患者血中钙、磷、碱性磷酸酶（ALP）、甲状旁腺素（PTH）和25羟维生素D[25（OH） D]水平变化及在骨代谢中的作用。方法 收集62例初发或复发的Graves病患者及91例正常对照人群资料。电化学发光法测定血浆PTH和25（OH）D;生化法测定血钙、磷、ALP。结果 Graves病组血钙、磷、ALP、25（OH）D水平升高, PTH降低（均P＜0.01）。亚组分析显示,女性患者血钙、磷、ALP、25（OH）D水平高于对照组,PTH水平低于对照组;男性患者ALP、25（OH）D水平高于对照组,PTH水平低于对照组（均P＜0.01）。Graves病组维生素D缺乏17例（27.4%）,不足20例（32.3%）,充足25例（40.3%）;对照组维生素D缺乏54例（59.3%）,不足31例（34.1%）,充足6例（6.6%）。Graves病组血PTH、血25（OH）D、血钙及血磷无相关性。结论 Graves病骨转换加速,患者血25（OH）D水平升高,可能与高血钙、血PTH降低、高血磷导致1-α-羟化酶活性降低有关。维生素D缺乏在Graves病骨代谢中的作用不大。     

不同维生素D注射剂对健康女性血25羟维生素D水平的影响

目的比较维生素D2注射液与维生素D3注射液在治疗健康女性维生素D缺乏或不足时对血25羟维生素D水平的影响。方法选择常住成都市且年龄在40-55岁的健康女性94名,随机将其分为D2组和D3组各47例。D2组给予维生素D2注射液,每次7.5mg（30万U）,每2周注射1次,共注射4次;D3组给予维生素D3注射液,每次7.5mg（30万U）,每2周注射1次,共注射4次。分别于治疗前、最后1次注射后2周采静脉血测定血清25羟维生素D,血清钙、磷、镁,血清甲状旁腺素（PTH）及血清骨源性碱性磷酸酶（BAP）。结果治疗后,D2组和D3组血清25羟D水平明显升高,差异有统计学意义（P〈0.01）;且治疗后D3组25羟D水平高于D2组,差异有统计学意义（P〈0.01）。治疗前后,2组血清磷、血清PTH均降低,差异有统计学意义（P〈0.01）,血清钙、血清镁、血清BAP无明显变化,差异无统计学意义（P〉0.05）。未出现维生素D中毒或药物相关不良反应表现。结论维生素D针剂无论是D2还是D3治疗维生素D缺乏或不足都是有效的,但在相同用法条件下D3比D2升高血清25羟D水平的幅度更大。维生素D注射剂30万U每2周1次共4次治疗维生素D不足或缺乏是安全的。     

Using gas chromatography and mass spectrometry to determine 25-hydroxyvitamin D levels for clinical assessment of vitamin D deficiency

Vitamin D is responsible for multiple metabolic functions in humans. Rickets are the most common disease caused by vitamin D deficiency. It is caused by poor calcium intake resulting in poor serum-ionized calcium. The purpose of this study is to develop a rapid, sensitive, and feasible method to determine the 25-hydroxy-vitamin D3 (25(OH)D3) levels in blood samples for clinical assessment. In this study, gas chromatography coupled mass spectrometry with trimethylsilyl derivatization (TMS-GC-MS) is the most suitable protocol for quantitative analyses of 25(OH)D3. Performance of method was evaluated and compared with liquid chromatography and immunoassay. Method validation has been carried out with plasma specimens. The limit of quantitation of TMS-GC-MS method is 1.5 ppb with good linear correlation. Furthermore, the dietary intake and nutritional status of vegetarian and non-vegetarians in Taiwan were assessed by our validated method. As a result, this vitamin D nutrition survey demonstrates that most Taiwanese people have insufficient vitamin D. Due to dietary habits; the male vegans may have the highest risk of vitamin D deficiency.     

Prevalence of Vitamin D deficiency in Pakistan and implications for the future

Background and aims: vitamin D deficiency (25-hydroxyvitamin D) affects over one billion people worldwide. Vitamin D deficiency results in progression of osteoporosis as well as other conditions. Previous studies have shown high rates of vitamin D deficiency in Pakistan despite appreciable levels of sunshine. However, none have assessed vitamin D deficiency across all age groups, genders, incomes, and locations to guide future strategies. Methods: Questionnaire and blood sampling among 4830 randomly selected citizens. Results: High levels of deficiency among all age groups, genders, income levels, and locations. Amongst the selected citizens, 53.5% had vitamin D deficiency, 31.2% had insufficient vitamin D, and only 15.3% normal vitamin D. Conclusion: High rates of vitamin D deficiency in Pakistan despite high levels of sunshine and previous Food Acts asking for food fortification with vitamin D. Public health strategies are needed to address high deficiency rates, including food fortification, i.e. nurture, alongside increasing exposure to sunlight, i.e. nature. This will involve all key stakeholder groups.     

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

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-hydroxy vitamin 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)D concentrations 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 microg 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.     

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.     

Actions of vitamins D2 and D3 and 25-OHD3 in anticonvulsant osteomalacia.

In 54 epileptic outpatients treated for at least one year with anticonvulsants the bone mineral content (B.M.C.), an estimate of total body calcium, and serum calcium were measured before and during treatment with three doses of cholecalciferol (vitamin D3; 200, 100, and 50 mu-g daily) and 25-hydroxycholecalciferol (25-OHD3; 40, 20, and 10 mu-g daily) for 12 weeks. The results, when compared with the effects of calciferol (vitamin D2; 200, 100, and 50 mu-g daily) in 40 epileptic outpatients, showed different actions in anticonvulsant osteomalacia of vitamin D2 on the one hand and vitamin D3 and 25-OHD3 on the other. In the patients who received vitamin D2 an increase in B.M.C. was found whereas serum calcium was unchanged. The patients who received vitamin D3 or 25-OHD3 showed an increase in serum calcium but unchanged values of B.M.C. The results suggest that liver enzyme induction cannot alone explain anticonvulsant osteomalacia.     

The interaction between burn injury and vitamin D metabolism and consequences for the patient

The stress and inflammatory responses to burn injury are associated with bone loss. The stress response entails production of large amounts of endogenous glucocorticoids that decrease osteoblasts on the mineralization surface of bone and decreases differentiation of marrow stromal cells into osteoblasts, thereby decreasing the amount of bone formation. Deficiency of osteoblasts also blocks osteoclastogenesis thus leading to low bone turnover and bone loss. The inflammatory response generates cytokines such as interleukin 1-beta and interleukin-6, which normally increase osteoclastogenic bone resorption via stimulation of osteoblast production of RANK ligand. However, in the absence of osteoblasts as a target we postulate that they attack the parathyroid gland chief cells and up-regulate the calcium-sensing receptor. The consequence of this upregulation is the lowering of the circulating calcium necessary to suppress parathyroid hormone production and the development of hypocalcemia and urinary calcium wasting. It is the parathyroid hormone suppression that causes us to postulate acute deficiency of 1,25-dihydroxyvitamin D and the consequence of this for post-burn metabolism could include derepression of the gene that controls renin production, leading to elevated levels of angiotensin II, which can contribute to insulin resistance, as can vitamin D deficiency itself. Moreover, the skin from burned patients cannot synthesize vitamin D normally. Thus vitamin D supplementation is the only means by which to ensure vitamin D sufficiency for burn victims. The proper requirement for vitamin D in acutely burned patients remains unknown.     

Critical thinking about three meta-analyses: can vitamin D alone or with calcium prevent fractures?

Abstract

Critical thinking is crucially important in both research and practice. This article demonstrates that a lack of critical thinking in two meta-analyses resulted in a conclusion that contradicts another meta-analysis and popular opinions. Kahwati et al. and Zhao et al. drew a conclusion that “Vitamin D supplementation alone or with calcium was not associated with reduced fracture incidence among community-dwelling adults without known vitamin D deficiency, osteoporosis, or prior fracture”, which apparently contradicted that of Tang et al. Kahwati et al. and Zhao et al. meta-analyzed vitamin D and/or calcium supplementation, which can decrease fracture risk factors, in a population with no known disorders of bone metabolism or vitamin D deficiency. They concluded that supplementation did not reduce fracture incidence. It is important to note that osteoporosis, which supplementation can prevent, and fractures are two distinct concepts. Zhao et al. presented their conclusion without including the conditions under which their conclusion was true. Subsequently, their conclusion was misleadingly interpreted by the public media as “Vitamin D and Calcium Don’t Prevent Bone Fractures” and “Vitamin D Does Not Prevent Falls, Calcium Does Not Prevent Fractures—A $2 Billion Waste of Money”. If study conclusions do not specify the applicable conditions, guidelines on medications, including supplements, are clinically unacceptable. Researchers must critically think about every step of their studies, including the way their conclusions are presented.