The role of vitamin D metabolites in bone resorption

Two metabolites of vitamin D₃, 25-hydroxycholecalciferol (25-OHD₃) and 1,25-dihydroxy-cholecalciferol (1,25-(OH)₂D₃) are potent stimulators of bone resorption in two test systems whereas vitamin D₃ itself is inactive. These substances were tested (a) by directly comparing their action on bone explants of mouse half-calvariain vitro, and (b) by injecting them into young mice and measuring the degree of resorptionin vitro when explants were made 18 hours atter the injection. In both tests the 1,25-metabolite was about 100 times more potent than 25-OHD₃. The dose-response curve for 1,25-(OH)₂D₃ indicates that doses above about 0.2 ng/g body weight are capable of inducing an increase in bone resorption in normal young mice. These data show that 1,25-(OH)₂D₃ is one of the most potent substances known that affects bone metabolism. The results are discussed in relation to the possible role of 1,25-(OH)₂D₃ in the normal mobilization of calcium from bone.

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Zusammenfassung Bei Anwendung zweier verschiedener Versuchsanordnungen konnte gezeigt werden, daß die beiden Vitamin D₃-Metaboliten 25-Hydroxycholecalciferol (25-OHD₃) und 1,25-Dihydroxycholecalciferol (1,25-(OH)₂D₃) als starke Stimulatoren der Knochenresorption wirken, während sich Vitamin D₃ selbst inaktiv verhält. Diese Substanzen wurden folgendermaßen geprüft: a) durch direkten Vergleich ihrer Wirkung auf Knochenexplantate (Hälften von Mäusecalvarien)in vitro und b) indem die Metaboliten jungen Mäusen injiziert wurden und der Resorptionsgrad an Explantaten 18 Std nach Injektionin vitro gemessen wurde. Bei beiden Versuchsanordnungen war der 1,25-Metabolit etwa 100mal wirksamer als der 25-OHD₃-Metabolit. Aus der Dosiswirkungskurve für 1,25-(OH)₂D₃ geht hervor, daß es möglich ist, mit Dosen über ca. 0,2 ng/g Körpergewicht bei normalen jungen Mäusen bereits eine erhöhte Knochenresorption auszulösen. Diese Resultate zeigen, daß 1,25-(OH)₂D₃ eine der wirksamsten bisher bekannten Substanzen ist, die auf den Knochenmetabolismus einwirken können. Die Ergebnisse werden im Zusammenhang mit der Rolle, die das 1,25-(OH)₂D₃ bei der normalen Freisetzung von Calcium aus dem Knochen spielt, besprochen.

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Résumé Deux métabolites de la vitamine D₃, le 25-hydroxycholecalciferol (25-OHD₃) et 1,25-dihydroxycholecalciferol (1,25-(OH)₂D₃), stimulent la résorption osseuse dans deux systèmestests alors que la vitamine D₃ est inactive. Ces substances sont testées a) en comparant directement leur action dans les explants osseux de calottes craniennes de sourisin vitro et b) en les injectant dans de jeunes souris et en mesurant le degré de résorptionin vitro, lorsque les explants sont réalisés 18 heures après l'injection. Dans les deux tests, le métabolite 1,25 est environ 100 fois plus puissant que 25-OHD₃. La courbe dose-résponse de 1,25-(OH)₂D₃ indique que des doses au-dessus d'environ 0.2 ng/g de poids corporel sont capables d'induire une augmentation de la résorption osseuse chez de jeunes souris normales. Ces résultats montrent que 1,25-(OH)₂D₃ est une des substances connues les plus actives qui agit sur le métabolisme osseux. Le rôle possible de 1,25-(OH)₂D₃ sur la mobilisation normale du calcium osseux est envisagé.

     

维生素D对预防跌倒和降低骨质疏松骨折的作用

老年人由于下肢神经肌肉功能下降,反应性和平衡能力减退,易发生跌倒,导致骨折。本文重点分析了维生素D与骨质疏松性骨折风险、骨密度、肌力、跌倒风险及认知能力的关系。补充维生素D能有效减少跌倒的发生,从而预防老年人骨质疏松性骨折的发生。     

Longitudinal study of vitamin D metabolites after long bone fracture

Animal models suggest a key role for dihydroxylated vitamin D metabolites in fracture healing, as evidenced by increases in serum concentration of 24R,25‐dihydroxyvitamin D (24R,25[OH]₂D) after long bone fracture. Human studies investigating the kinetics of serum concentrations of 24R,25[OH]₂D, 1,25‐dihydroxyvitamin D (1,25[OH]₂D) and their parent metabolite 25‐hydroxyvitamin D (25[OH]D) are lacking. We, therefore, conducted a longitudinal study to determine whether total, free, or bioavailable concentrations of these vitamin D metabolites fluctuate in humans after long bone fracture. Twenty‐eight patients with cross‐shaft (diaphyseal) long bone fracture presenting to an emergency department in London, UK, were studied. Serum concentrations of 25(OH)D, 24R,25(OH)₂D, 1,25(OH)₂D, vitamin D binding protein, albumin, and calcium were determined within 48 hours of fracture and again at 1 and 6 weeks postfracture. Concentrations of free and bioavailable vitamin D metabolites were calculated using standard equations. No changes in mean serum concentrations of 25(OH)D or 24R,25(OH)₂D were seen at either follow‐up time point versus baseline. In contrast, mean serum 1,25(OH)₂D concentration declined by 21% over the course of the study, from 68.5 pmol/L at baseline to 54.1 pmol/L at 6 weeks (p < 0.05). This decline was associated with an increase in mean serum corrected calcium concentration, from 2.32 mmol/L at baseline to 2.40 mmol/L at 1 week (p < 0.001) that was maintained at 6 weeks. No changes in free or bioavailable concentrations of any vitamin D metabolite investigated were seen over the course of the study. We conclude that serum 1,25(OH)₂D concentration declines after long bone fracture in humans but that the serum 24R,25(OH)₂D concentration does not fluctuate. The latter finding contrasts with those of animal models reporting increases in serum 24R,25(OH)₂D concentration after long bone fracture.     

Serum and bone vitamin D metabolites in elective patients and patients after fracture

Vitamin D metabolite levels were measured in serum and bone samples obtained from 27 patients undergoing elective bony procedures and from 28 patients operated on after a fracture. Serum 25 hydroxyvitamin D3 (25-OH-D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) did not differ significantly between the elective and fracture patients, but serum 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) was significantly reduced in the fracture patients. Very little 25-OH-D3 was found in bone, although it was the major vitamin D metabolite in serum (90%). In elective patients bone levels of 24,25(OH)2D3 and 1,25(OH)2D3 were similar to those in serum; however, in bone from around pertrochanteric fractures, but not from subcapital or patellar fractures, the concentrations of these compounds were considerably increased. These findings may shed light on the mechanism of callus formation and on the role of vitamin D metabolites in bone healing.     

A role for vitamin D and the vitamin D receptor in keloid disorder

Keloids are disfiguring fibroproliferative lesions that can occur in susceptible individuals following any skin injury. They are extremely challenging to treat, with relatively low response rates to current therapies and high rates of recurrence after treatment. Although several distinct genetic loci have been associated with keloid formation in different populations, there has been no single causative gene yet identified and the molecular mechanisms guiding keloid development are incompletely understood. Further, although it is well known that keloids are more commonly observed in populations with dark skin pigmentation, the basis for increased keloid risk in skin of colour is not yet known. Because individuals with dark skin pigmentation are at higher risk for vitamin D deficiency, the role of vitamin D in keloid pathology has gained interest in the keloid research community. A limited number of studies have found lower serum vitamin D levels in patients with keloids, and reduced expression of the vitamin D receptor (VDR) in keloid lesions compared with uninjured skin. Vitamin D has documented anti-inflammatory, anti-proliferative and pro-differentiation activities, suggesting it may have a therapeutic role in suppression of keloid fibrosis. Here we review the evidence supporting a role for vitamin D and VDR in keloid pathology.     

Role of calcium and vitamin D in the prevention (and treatment) of osteoporotic fracture

The skeleton requires optimum development and maintenance of its integrity to prevent fracture throughout the life cycle. It is now generally accepted that bones break because the loads placed on them exceed their ability to absorb the energy involved. Current figures for the UK suggest that 1 in 3 women and 1 in 12 men over the age of 55 years will suffer from osteoporosis in their lifetime, at a cost of £1.7 billion per annum to the NHS. The pathogenesis of osteoporosis is multifactorial. Both the development of peak bone mass and the rate of bone loss are determined by key endogenous and exogenous factors. Re-defining vitamin D requirements in the UK is urgently needed because there is evidence of extensive hypovitaminosis D in men and women, which is especially prevalent in Asian population groups. Low vitamin D status is associated with an increased risk of falling and a variety of other health outcomes, and is an area that requires urgent attention. Calcium supplementation seems to have little effect on bone mineral density in younger post-menopausal women (< 5 years past the menopause) who are not vitamin D deficient, but calcium supplements may be effective in reducing bone loss in late menopausal women (> 5 years post-menopause), particularly in those with low habitual calcium intake (< 400 mg/day). Vitamin D and calcium supplementation have been shown to reduce fracture rates in the institutionalized elderly, but controversy remains about whether supplementation is effective in reducing fracture in free-living populations.     

维生素D与成年人骨骼健康应用指南 (2014年 简化版)

维生素D对人体健康产生广泛作用,维生素D缺乏症(Vitamin D deficiency)可能会导致骨质疏松症进展、跌倒和骨折;同时,在西方国家出现了不一致的维生素D标准和实践方案。鉴于此,中国老年学会骨质疏松委员会相关专业人员,制定了《维生素D与成年人骨骼健康应用指南》。该《指南》分为《简化版》和《标准版》,主要证据来源于2013年英国骨质疏松学会指南、2011年美国健康研究院报告,以及国内文献。该指南适用于成年人骨骼疾病,或有骨病风险患者的维生素D缺乏症管理。需说明,该指南不针对儿童期、妊娠期、以及患有严重或终末期慢性肾脏病(4~5期)的人群。指南内容包括中国成年人群维生素D阈值设定、维生素D状况评价、25OHD测量值解释、维生素D缺乏症的详细治疗计划和预防战略等。     

The effects of vitamin D analogues on bone resorption

A series of analogues of vitamin D have been tested for their ability to stimulate bone resorption in two test systems used previously to investigate the metabolites of vitamine D. These analogues were tested (a) by directly comparing their action on bone explants of mouse half-calvariain vitro, and (b) by injecting them into young mice and measuring the degree of resorptionin vitro when explants were prepared 18 hours after the injection. It is concluded that the key functional groups concerned with enhancing the activity of vitamin D₃ are the 1- and the 25-hydroxyl,both together; the cis ring structure for ring A appears necessary. 1-Hydroxycholecalciferol (1-OHD₃) is about as active as 25-OHD₃ in the direct test, but its potency is much nearer to that of 1,25-(OH)₂D₃ when tested by the second (indirect) method; it seems likely that 1-OHD₃ is converted into 1,25-(OH)₂D₃ in vivo. The results are discussed in relation to the designing of analogues for clinical and experimental use.     

Adequate vitamin D status and adiposity contribute to bone health in peripubertal nonobese children

The dietary reference intake (DRI) of vitamin D for Korean children was reduced from 400 IU/day in 2005 to 200 IU/day in 2010. We evaluated the risk factors for low 25-hydroxyvitamin D [25(OH)D] status and its relationships with bone health in peripubertal nonobese children living in Seoul or Gyeonggi-do. One hundred children (9.3 ± 1.9 years, 71 prepubertal, 45 boys) participated in the winter (n = 38, December through March) and summer (June through September). Bone mineral content (Z_BMC), fat mass (Z_FM), lean mass (Z_LM), and bone mineral density for the total body (Z_TB) and lumbar spine (Z_L1–4) were measured using dual-energy X-ray absorptiometry. Twenty-nine percent of children (47.4 % in winter, 17.7 % in summer) were vitamin D deficient (25(OH)D level of <20 ng/mL). The winter season (P = 0.008) and low vitamin D intake (P = 0.044) were associated with low 25(OH)D level. The 25(OH)D level correlated positively with Z_BMC (P = 0.040), Z_TB (P = 0.027), and Z_L1–4 (P = 0.045) independently of sex, puberty, Z_FM, Z_LM, physical activity level, and calcium intake. Z_FM correlated independently with Z_BMC (P < 0.001), Z_TB (P = 0.037), and Z_L1–4 (P < 0.001). In conclusion, almost half of peripubertal nonobese children were vitamin D deficient in winter. Adequate vitamin D status and adiposity contributed to good bone health in nonobese children. Considering the beneficial effects of adequate vitamin D status on bone health, the current DRI may be insufficient for preventing vitamin D deficiency in winter among Korean children.     

The dualistic role of vitamin D in vascular calcifications

Vitamin D is a multifunctional hormone that can affect many essential biological functions, ranging from the immune regulation to mineral ion metabolism. A close association between altered activity of vitamin D and vascular calcification has been reported in various human diseases, including in patients with atherosclerosis, osteoporosis, and chronic kidney disease (CKD). Vascular calcification is a progressive disorder and is a major determinant of morbidity and mortality of the affected patients. Experimental studies have shown that excessive vitamin D activities can induce vascular calcification, and such vascular pathology can be reversed by reducing vitamin D activities. The human relevance of these experimental studies is not clear, as vitamin D toxicity is relatively rare in the general population. Contrary to the relationship between vitamin D and vascular calcification, in experimental uremic models, low levels of vitamin D were shown to be associated with extensive vascular calcification, a phenomenon that is very similar to the vascular pathology seen in patients with CKD. The current treatment approach of providing vitamin D analogs to patients with CKD often poses a dilemma, as studies linked vitamin D treatment to subsequent vascular calcification. Recent genetic studies, however, have shown that vascular calcification can be prevented by reducing serum phosphate levels, even in the presence of extremely high serum 1,25-dihydroxyvitamin D and calcium levels. This article will briefly summarize the dual effects of vitamin D in vascular calcification and will provide evidence of vitamin D-dependent and -independent vascular calcification.     

Carboxylation of osteocalcin may be related to bone quality: a possible mechanism of bone fracture prevention by vitamin K

Vitamin K is essential for the carboxylation of glutamic acid residues, such as osteocalcin. Recent studies have reported that vitamin K reduces vertebral and hip fractures without increasing bone mass in patients with osteoporosis, suggesting that vitamin K could affect bone quality. However, the mechanism is unknown. To investigate the involvement of the carboxylation of osteocalcin in bone quality, the present preliminary study examined serum bone markers and ultrasound velocity, a possible indicator of bone quality, in 14 healthy prepubertal children (eight boys and six girls) aged between 7 and 12 years. Venous blood was collected between 0800 and 0900 h after an overnight fast, and serum levels of intact, carboxylated and undercarboxylated osteocalcin, bone-specific alkaline phosphatase and type I procollagen carboxyl extension peptide were measured. Speed of sound in the right tibia was measured using a SoundScan 2000 Compact (Myriad Ultrasound System, Rehovot, Israel). As a result, there was no significant correlation between the serum bone markers and the Z score for the speed of sound. In contrast, the ratio of serum carboxylated osteocalcin to serum intact osteocalcin was positively correlated with the Z score for the speed of sound (r = 0.621, P = 0.016). These findings suggest, for the first time, that carboxylation of osteocalcin is related to bone quality. Further studies are needed to clarify the role of carboxylation of osteocalcin in bone, and this will provide a new insight into the mechanism of vitamin K treatment in osteoporosis. Received: September 9, 2000 / Accepted: November 30, 2000     

Associations of vitamin D status with bone mineral density, bone turnover, bone loss and fracture risk in healthy postmenopausal women. The OFELY study

INTRODUCTION: Vitamin D status is considered as an important determinant of bone health but supplementation trials with vitamin D(3) have yielded conflicting results. The aim of this study was to investigate the associations between serum 25-hydroxyvitamin D (25-OH D), bone turnover markers, bone mineral density (BMD), radius bone loss and incidence of fracture in postmenopausal women. METHODS: 669 postmenopausal women (mean age: 62.2 years) belonging to a population-based cohort were followed prospectively for a median of 11.2 years. At baseline, 25-OH D levels, BMD, bone turnover markers and clinical risk factors of osteoporosis were assessed. BMD loss at the radius was estimated by annual measurements of BMD and all incident fractures which occurred in 134 women were confirmed by radiographs. RESULTS: 73% and 35% of women had serum 25-OH D levels below 75 and 50 nmol/l which correspond respectively to the median and lowest optimal values recently proposed for fracture prevention. 11% of women had levels below 30 nmol/l. Serum 25-OH D correlated modestly with intact PTH (r(2)=0.023, p<0.0001), but not with bone turnover markers or BMD at the hip and radius after adjustment for age. When levels of 25-OH D were considered as a continuous variable, there was no significant association between 25-OH D levels and radius BMD loss or fracture risk. After adjustment for age, there was no significant difference in incidence of fracture, BMD, radius BMD loss, bone turnover markers, grip strength and the percentage of fallers in the previous year between women with 25-OH D levels below or above 75, 50 or 30 nmol/l. CONCLUSIONS: In a population of home-dwelling healthy postmenopausal women with few of them with severe vitamin D deficiency, vitamin D status may not be an important determinant of bone health.