The effect of a new vitamin D analog, 22-oxa-1α,25(OH)2D3, on bone mineral metabolism in normal male rats

Summary Thein vivo effects of 22-oxa-1, 25 dihydroxyvitamin D₃ (OCT), on bone mineral metabolism were investigated in normal male Sprague-Dawley rats. The rats were administered either vehicle (control), low-dose OCT (25 ng/100 g body weight), or high-dose OCT (250 ng/100 g body wt). High-dose OCT increased serum ionized calcium (P<0.05) and decreased serum parathyroid hormone (PTH) (P<0.05) at all time points and increased serum bone Gla protein on days 7 and 28 (P<0.05) compared with controls. Lowdose OCT decreased serum PTH at all the time points (P<0.05) compared with controls. Tibial bone histomorphometry showed no significant differences between the two doses of OCT and controls. We found that OCT has minimal direct effects on bone metabolism in normal male rats in contrast to 1,25 dihydroxyvitamin D₃. This property may be advantageous in the treatment with OCT of cell-proliferative diseases.Michael Fallon is deceased     

The Vitamin D Analog 1��,25-Dihydroxy-2��-(3-Hydroxypropyloxy) Vitamin D3 (Eldecalcitol) is a Potent Regulator of Calcium and Phosphate Metabolism

The vitamin D analog 1α,25-dihydroxy-2β-(3-hydroxypropyloxy)vitamin D(3) (ED-71 or eldecalcitol) has been developed for treatment of osteoporosis, but its effects on mineral metabolism have not been investigated in detail. In the present study, we compared the effects of eldecalcitol and calcitriol on calcium (Ca) and phosphate (Pi) handling in rats. Oral administration of eldecalcitol (0, 7.5, 20, or 50?pmol) q.o.d. for 2?weeks dose-dependently increased ionized Ca, intestinal Ca absorption, and urinary Ca excretion, while these doses of calcitriol had no significant effects. The highest dose of eldecalcitol did not alter serum Pi but stimulated both intestinal Pi absorption and urinary Pi excretion; the latter was attributable, in part, to increased serum FGF-23. The effects of high-dose eldecalcitol on Ca and Pi absorption and urinary excretion and FGF-23 persisted for several days following cessation of treatment. The higher potency of eldecalcitol on Ca and Pi handling was also observed in parathyroidectomized rats infused with PTH, excluding a role for differential regulation of PTH. Direct measurement of duodenal Ca absorption by the in situ loop method confirmed the higher potency of eldecalcitol in this segment via induction of TRPV6. These studies indicated that with chronic administration eldecalcitol is more potent than calcitriol at stimulating intestinal absorption of Ca and Pi, as well as FGF-23. The mechanisms responsible for the higher potency of eldecalcitol are speculated to be its higher vitamin D-binding protein (DBP) affinity and resistance to metabolism.     

A novel synthetic vitamin D analogue, 2β-(3-hydroxypropoxy)1α, 25-dihydroxyvitamin D3 (ED-71), increases bone mass by stimulating the bone formation in normal and ovariectomized rats

We performed dosing experiments to evaluate the bone mass increasing action of a novel, synthetic vitamin D derivative, 2-(3-hydroxypropoxy)-1, 25(OH)₂D₃ (ED-71), in normal and estrogen-deficient rats. The first experiment consisted of 31 Sprague-Dawley rats, 28 weeks of age. The second experiment consisted of 44 animals who were ovariectomized (OVX) or sham operated at the age of 12 weeks. ED-71 was given twice a week for the duration of 12 weeks. At the end of the experiments, serum chemistries were examined and lumbar vertebrae were assessed histomorphometrically. Serum alkaline-phosphatase levels tended to decrease by ED-71 administration in the first experiment and their elevated values after ovariectomy were also depressed by ED-71 in the second experiment. Serum osteocalcin levels, however, increased by the agent. In the first experiment, cancellous bone volume (BV/TV) increased dose dependently. Bone formation rates (BFR/BS) also increased. In the second experiment, BV/TV significantly decreased by ovariectomy and it increased in ED-71-treated groups, but not in 1-(OH)D₃-treated group. BFR/BS increased by ED-71. Activation frequency did not decreased by ED-71 in either experiment. These data clearly demonstrated that ED-71 administration was capable of increasing the bone mass by stimulating bone formation in normal and estrogen-deficient rats.     

1，25（OH）2D3与糖尿病肾病

我国2003年有2380万的糖尿病患者,2010年已超过了9200万,给国计民生带来沉重的负担.糖尿病肾病(DN)是糖尿病最常见的慢性并发症之一,也是导致终末期肾病(ESRD)的主要原因.目前,肾素血管紧张素系统(RAS)抑制剂、血管紧张素转换酶抑制剂(ACEI)和(或)血管紧张素受体阻滞剂(ARB)是治疗DN的一线药物,临床已证实这些药物能延缓肾小球硬化、小管问质纤维化和蛋白尿进展[1-2],然而,RAS抑制剂的1个主要问题是肾素逃逸,导致肾素代偿性增加[3-4].     

1，25(OH)2D3对模拟失重大鼠股骨远端松质骨的扫描电镜观察

目的 观察1,25-二羟维生素D3对模拟失重状态下大鼠股骨远端松质骨超微结构的影响.方法 SPF级雄性SD大鼠66只,随机分为自由活动组、悬吊对照组和悬吊实验组,同时悬吊实验组给予1,25-二羟维生素D3皮下注射（0.05 μg/kg·d）,实验期为14 d、28 d.取股骨远端沿冠状面切开,蒸馏水冲洗净骨髓腔,乙醇梯度脱水,表面喷金后利用扫描电镜对大鼠股骨远端松质骨的形态结构进行观察.结果 悬吊对照组与自由活动组比较大鼠骨小梁变细,断裂,数目减少,胶原纤维排列杂乱,微损伤增多;悬吊实验组较悬吊对照组大鼠骨小梁数目增多,胶原纤维排列规整,未见明显微骨折发生,且悬吊14 d实验组较悬吊28 d实验组保持了更好的微结构.结论 1,25-二羟维生素D3能够对模拟失重状态下大鼠股骨远端松质骨的超微结构产生有利影响.     

老年骨质疏松症患者监测25(OH) D3 水平的临床意义

从老年骨质疏松症发病情况入手,探讨维生素D治疗骨质疏松的作用机制、活性代谢产物种类以及活性维生素D监测的临床意义,有利于指导临床用药,使老年骨质疏松症患者做到个体化治疗。     

Bone-resorbing activities of 24-epi-1α-hydroxyvitamin D2 and 24-epi-1α,25-dihydroxyvitamin D2

Bone-resorbing activities of 24-epi-1-hydroxyvitamin D₂ [24-epi-1(OH)D₂], 24-epi-1,25-dihydroxyvitamin D₂ [24-epi-1,25(OH)₂D₂], and 1,24S,25-trihydroxyvitamin D₂ [1,24S,25(OH)₃D₂], which might be a metabolite of 24-epi-1,25(OH)₂D₂, were investigated. In an in vitro bone resorption test, the activity of 24-epi-1(OH)D₂ was similar to that of 1-hydroxyvitamin D₃ [1(OH)D₃] at 10^-9 M-10^-6 M. The activity of 24-epi-1,25(OH)₂D₂ was weaker than that of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] at 10^-11 M-10^-8 M. On the other hand, the activity of 1,24S,25(OH)₃D₂ was similar to that of 24-epi-1,25(OH)₂D₂ at 10^-11 M-10^-9 M. In the formation assay of osteoclast-like cells, the activity of 24-epi-1(OH)D₂ was weaker than that of 1(OH)D₃ at 10^-7 M. The activity of 24-epi-1,25(OH)₂D₂ was almost similar to that of 1,25(OH)₂D₃ at 10^-11 M-10^-7 M. The activity of 1,24S,25(OH)₃D₂ was significantly weaker than that of 24-epi-1,25(OH)₂D₂ at 10^-11 M-10^-9 M. In the two experiments, the potencies of 24-epi-1,25(OH)₂D₂ were about 100 times higher than those of 24-epi-1(OH)D₂. In an in vivo/in vitro bone resorption test, the activity of 24-epi-1(OH)D₂ was almost similar to those of 1(OH)D₃ and 1,25(OH)₂D₃ and higher than those of 24-epi-1,25(OH)₂D₂ and 1,24S,25(OH)₃D₂. 24-epi-1-(OH)D₂ and 1(OH)D₃ were longer lasting than 24-epi-1,25(OH)₂D₂ and 1,25(OH)₂D₃ in this experiment. These results suggested that 24-epi-1(OH)D₂ as well as 1(OH)D₃ was converted into dihydroxy form in vivo.     

Calcium regulating activity of 24a-homo-24,24-difluoro-1α,25-dihydroxyvitamin D3 and 26,27-dimethyl-24,24-difluoro-1α,25-dihydroxyvitamin D3

Summary Two fluoro analogs of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], 24a-homo-24,24-difluoro-1,25-dihydroxyvitamin D₃ [24aF₂-homo-1,25(OH)₂D₃], and 26,27-dimethyl-24,24-difluoro-1,25-dihydroxyvitamin D₃ [24F₂-1,25(OH)₂(Me)₂D₃] were examined for calcium (Ca)-regulating activity. The objective of the present study was to determine whether or not fluoro substitution at 24-position would alter activities of the original compounds, that is, 26,27-dimethyl 1, 25-dihydroxyvitamin. D₃[1,25(OH)₂ (Me)₂D₃] and 24-homo-1,25-dihydroxyvitaminD₃[24homo-1,25(OH)₂D₃], respectively. The relative activities of 24aF₂-homo-1,25(OH)₂D₃, 24F₂-1,25(OH)₂(Me)₂D₃, and 1,25(OH)₂D₃ in competing with 1,25(OH)₂D₃ for binding to chick intestinal cytosol receptor were 0.28:0.5:1.0. The relative potencies of the same series of compounds in competition for the vitamin D-deficient rat serum binding sites were 0.04:0.15:1. Bone-resorbing activities of two fluoro analogs in cultures of neonatal mouse parietal bones were more potent than that of 1,25(OH)₂D₃. Similar results were recognized in stimulating activities of osteoclast-like cell formation. Responses of two fluoro analogs to intestinal Ca absorption were similar to that of 1,25(OH)₂D₃. The potencies of 1,25(OH)₂D₃. and its fluoro analogs in bone Ca mobilization were the highest with 1,25(OH)₂D₃. followed by 24F₂ 1,25(OH)₂(Me)₂D₃ and 24aF₂-homo-1,25(OH)₂D₃, in that order. From these results and the data of Paulson et al. [24], fluoro substitution in 24-position of 1,25(OH)₂D₃. apparently does not alter their activities, hence, the fluoro substitution at 24-position of 1,25(OH)₂D₃. and the elongation of side chain of 1,25(OH)₂D₃. may not intensify Ca-regulating activity.     

26,27-F6-1,25(OH)2D3, 1,25(OH)2D3和17-βEstradiol对培养胎鼠头盖骨的影响

26，26．26，27，27，27-Hexafuoro-la，25-dihydroxy vitamin D3[26，27-F8-1,25(()H)2D2]是一种新合成的具有刺激骨代谢和细胞分裂生物活性的药物。实验研究了26，27-F6-1，1，25(()H)2D2、1a，25-dihvdroxvvitamin D3[1,25(()H)2D4和17β-Estradio! Estradiol]在骨形成和骨吸收等方面的作用，以探讨其对治疗骨质疏松症的基本作用。实验使用妊娠20日龄大鼠胎鼠的成对头盖骨，于强化BGJb培养基中培养7天，测定骨干重、Ca含量及羟脯氨酸含量。26，27-Fa-25(OH)2DD3对胎鼠头盖骨干重、Ca含量和羟晡氨酸含量都有较明显的增加作用。其作用优于Estradiol单纯提高胎鼠头盖骨中Ca的古量．而对骨的干重和羟脯氨酸含量无显著影响；也强于1，25(OH)2D3仅增加胎鼠头盖骨干重和羟脯氨酸含量，却不能提高骨Ca古量的作用，由于26．27-F3-1，25(OH)2D2在骨形成中对胎鼠头盖骨包括骨盐和骨基质中的重要物质Ca和羟晡氨酸都有促进作用。目此它很可能成为一种有潜力的冶疔骨质疏松症的新型药物。     

25( OH) D3、维生素D受体与糖皮质激素性骨质疏松关系的研究

目的 观察地塞米松(Dex)不同作用时间对大鼠骨量、骨组织维生素D受体（VDR)和血清25羟维生素D3(25( OH) D3)的影响。方法 40只3.5月龄的sprague-dawley( SD)雌性大鼠,随机分为Dex组和对照组,每组20只,分别干预4周和9 周。Dex组肌肉注射Dex 2.5 mg/kg,每周2次,对照组注射等量生理盐水。干预4周和9周分别用双能X线骨密度仪测骨密度,逆转录聚合酶链反应和免疫组化法检测骨组织VDR mRNA和蛋白的表达水平,用ELISA法检测血清25( OH) D3的含量。 结果干预4周,Dex组大鼠体重下降(56. 67 ±24. 43) g,9周下降(85. 83 ±26. 35) g( P < 0. 05); Dex组体重低于对照组（P < 0.01)。干预9周,Dex组骨密度低于对照组(P < 0. 05)。干预4周,Dex组大鼠骨组织VDR mRNA表达高于对照组（1. 48 士 0. 32 vs 1. 15 ±0. 19)( P <0.05);9 周,Dex 组大鼠骨组织 VDR mRNA 表达低于对照组（1. 07 ± 0. 35 vs 1.38 ±0. 29) (P <0.05.。Dex组大鼠骨组织VDR蛋白表达在4周和9周与对照组均无差异(P >0.05)。干预4周,Dex组血清25( OH) D3含 量与对照组无差异（P >0.05);9周,Dex组血清25( OH) D3含量低于对照组（P <0.05)。结论 SD大鼠肌肉注射Dex 2.5mg/kg,每周2次,9周能成功建立糖皮质激素性骨质疏松模型。Dex可能通过减少VDR的转录和25( OH) D3的含量来引起骨密度下降,导致骨质疏松的发生。     

T2DM伴骨质疏松Cys-C、25(OH)D3、BGP变化及临床意义

目的 探究老年2型糖尿病（T2DM）伴骨质疏松患者血清胱抑素C（Cys-C）、25羟维生素D3[25(OH)D3]、骨钙素（BGP）水平变化,并分析其对骨质疏松性骨折的预测价值。方法 选取2020年2月至2022年5月本院88例老年T2DM伴骨质疏松患者作为研究组,另选同期88例老年T2DM骨量减少患者作为对照A组,88例老年T2DM骨量正常患者作为对照B组。比较各组血清Cys-C、25(OH)D3、BGP水平、血糖指标、血脂指标、骨矿物质密度（BMD）,分析研究组血清各指标水平与血糖指标、血脂指标、BMD的相关性。研究组均行常规对症治疗6个月,依据是否发生骨质疏松性骨折分为发生者、未发生者,比较治疗前后血清各指标水平及变化值,分析其对骨折的预测价值。结果 研究组血清Cys-C水平高于对照A组、对照B组,25(OH)D3、BGP水平低于对照A组、对照B组（P＜0.05）;Cys-C水平与BMD呈负相关,25(OH)D3、BGP水平与BMD呈正相关（P＜0.05）;发生者治疗前后血清Cys-C水平高于未发生者,25(OH)D3、BGP水平低于未发生者,各指标变化值低于未发生者（P＜0.05）;血清各指标变化值降低可增加骨质疏松性骨折发生风险（P＜0.05）;治疗3个月后血清各指标变化值联合预测骨质疏松性骨折的AUC大于治疗1个月后（P＜0.05）。结论 老年T2DM伴骨质疏松患者血清Cys-C水平升高,25(OH)D3、BGP水平降低,联合检测其水平变化对骨质疏松性骨折具有一定预测价值。