CURRICULUM VITAE
作者：ANTHONY W.NORMAN
单位：
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中国骨质疏松杂志000102CURRICULUM VITAE
ANTHONY W.NORMAN
Introduction to Vitamin D:The molecular structure of vitamin D(see Figure 1)is closely allied to that of classical steroid hormones (e.g.progesterone ,estradiol , testosterone,glucocorticoids and aldosterone).All of these steroid hormones and also vitamin D are metabolically produced from the same common precursor,namely the sterol cholesterol(1).Technically,vitamin D is a secosteroid.Secosteroids are those in which one of the four ring structures of cholesterol(the cyclopentanoperhydrophenanthrene rings)have undergone breakage of one carbon-carbon bond;in the instance of vitamin D this is the 9,10-carbon bond of rign B.
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There is a family of vitamin D-related steroids with variations in the precise structure of the side chain attached to carbon-17.The naturally occurring form of vitamin D is that which has the side chain structure identical to that of cholesterol and 7-dehydrocholesterol;this is known as vitamin D3 or cholecalciferol.Vitamin D2,or ergocalciferol,has the side chain of ergosterol and is not a naturally occurring form of the vitamin.Collectively vitamin D3 plus vitamin D2 can be termed as the calciferols or simply vitamin D(see Figure 1).
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The substance vitamin D3 is officially classified as being a vitamin,which implies that the body does not have the capability to metabolically produce this substance.The fact that vitamin D3 is classified as a vitamin is an experimental accident which occurred at the time of its discovery in 1921.By 1925 it was clearly established that vitamin D3 had a precursor in skin,namely 7-dehydrocholesterol,which when exposed to ultraviolet light or sunlight could be efficiently converted into the molecule vitamin D3.Thus while it is scientifically correct that vitamin D3 is not a vitamin,it has proven beneficial to public health to have this molecule made nutritionally available either by food supplementation or incorporation into vitamin capsules.The Recommended Dietary Allowance (RDA) of vitamin D3 for an adult is 200 IU(5μg)per day or 400 IU for pregnant women and children less than 4 years [Tony,what about elderly?].However if an individual does not have access to vitamin D supplemented foods, he/she can still meet their nutritional RDA requirement for vitamin D3 by exposure of their face and hands to sunlight three times per week for approximately 20 minutes[1].
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Vitamin D Endocrine System:A totally new era in the field of vitamin D has opened since 1964 with the discovery of the metabolism of vitamin D.Altogether,some 37 metabolites of vitamin D3 have been isolated and chemically characterized.It is now recognized that there is an endocrine system for processing the prohormone,vitamin D,into its hormonally active daughter metabolite(s)via a two step process involving first the liver which introduces a hydroxyl group on carbon-25 and then the kidney which introduces a second hydroxyl on carbon-1.The molecule vitamin D itself has no intrinsic biological activity.All biological responses attributed to vitamin D are now known to arise only as a consequence of the metabolism of this seco-steroid into its biologically active daughter metabolites,namely,1α,25(OH)2D3 and 24R,25(OH)2D3[2].
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Figure 1:Structural relationship of vitamin D3 (cholecalciferol)and vitamin D2(ergocalciferol)with their respective provitamins,7-dehydrocholesterol and ergosterol.The two structural representations presented at the bottom for both vitamin D3 and vitamin D2 are equialent;thse are simply different ways of drawing the same molecule.
Figure 2 presents a summary of the vitamin D endocrine system.A detailed discussion of the vitamin D endocrine system is presented in reference[2].There are four key components of the vitamin D endocrine system:(a)the parent vitamin D3(upper left corner)which is the precursor of the hormone form of vitamin D;(b)the kidney which is the endocrine gland which produce the two steroid hormones 1α,25(OH)2D3 and 24R,25(OH)2D3;(c)the vitamin D binding protein (DBP)which transports the hormone 1α,25(OH)2D3,vitamin D3 and other vitamin D metabolites [because of their poor water solubility] through the blood compartment;and (d)the target organs which produces the biological responses that we attribute to vitamin D3.Thus the DBP delivers the hormone 1α,25(OH)2D3 to its various target tissues.Target tissues,by definition,possess the nuclear receptor for 1α,25(OH)2D3[known as the vitamin D receptor or VDR].As a consequence 1α,25(OH)2D3 enters the cell and binds to the VDR in the nucleus of the cell.The VDR+ligand(occupied receptor)then interacts with specific nucleotide sequences on the promoters of genes(vitamin D response elements;VDRE)so that either stimulation or repression of gene transcription occures.This results in the production of more or less messenger RNAs for selective proteins; only those genes which have a VDRE of the are subject to regulation.
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The VDR for the hormone 1α，25(OH)2D3 is found not only in the classic target organs(intestine,bone and kidney)but also in at least 32 additional target tissues.Only through the use of modern biochemical and molecular biological techniques,which allowed detection of the VDR in these new locations,was it discovered that the hormone form of vitamin D had far reaching effects in many other tissues(e.g.pancreas,skin,B and T lymphocytes,cancer cells,etc).Also recent results from a number of laboratories indicate that some 1α，25(OH)2D3-mediated biological responses occur too quickly to be explained via the VDR regulation of gene transcription.Thus these rapid responses have been shown to occur within seconds to minutes and have been demonstrated in the intestine,bone osteoblasts,parathyroid cells as well as the pancreas β-cell.The current thinking is that these rapid responses occur as a consequence of 1α，25(OH)2D3 interacting with a different membrane receptor which initiates a different signal transduction system,possibly involving activtion of protein kinase C(PKC) and opening of voltage gated Ca2+ channels.
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Figure 2 Summary of the vitamin D endocrine system.The key components are the prohormone,vitamin D3;the kidney functioning as an endocrine gland to produce the two steroid hormones,namely 1α,25(OH)2D3 and 24R,25(OH)2D3;and the target organs,both classical (intestine,bone and kidney and the approximately 32 other tissues which possess the nuclear receptor for 1α,25(OH)2D3
While interaction of 1α，25(OH)2D3 with its VDR is believed to be responsible for most of the important biological responses attributable to the parent vitamin D,there is also evidence that some parent vitamin D responses involve the second renal hormone 24R，25(OH)2O3.Receptors for 24R,25(OH)2D3 have been demonstrated in cartilage cells and in bone fracture-healing callus(2).These new developments are currently under intensive investigation
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The steroid hormone 1α，25(OH)2D3 is produced only in accord with strict physiological signals dictated by the calcium“demand”of the organism;a bimodal mode of regulation has been suggested.Thus,under normal physiological circumstances,both renal dihydroxylated metabolites [1α,25(OH)2D3 ad 24R,25(OH)2D3]are secreted and are circulating in the plasma.Parathyroid hormone(PTH) is the major stimulator of the 25(OH)D3-l-hydroxylase,[the kidney enzyme that produces 1α,25(OH)2D3].In instances of hypocalcemia PTH will become elevated and stimulate the production of more 1α，25(OH)2D3.Conversely,when serum Ca2+ is normal,PTH secretions is diminished,and there is a reduction in the production of 1α,25(OH)2D3 and an increase in the production of 24R,25(OH)2D3.There is evidence for a“short feedback loop”for both of these metabolites to modulate and/or reduce the secretion of PTH.There is also some evidence that other endocrine modulators such as estrogens,androgens,growth hormone,prolactin,and insulin may affect the renal production of 1α,25(OH)2D3.Thus,the kidney is clearly an endocrine gland,in the classic sense,which is capable of producing in a physiologically regulated manner appropriate amounts of 1α,25(OH)2D3.
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Clinical disorders:Human clinical disorders related to vitamin D can be considered to arise because of one of the following:(a)altered availability of the parent vitamin D;(b)altered conversion of vitamin D to its two principal daugter metabolites,1α,25(OH)2D3 and 24R,25(OH)2D3;(c)conditions that may be due to variations in organ responsiveness to these dihydroxylated metabolites;and (d) perturbations in the integrated interactions of these metabolites with PTH and calcitonin.A wide variety of organs have diseases related to vitamin D:the intestine(malabsorption),the parathyroid gland (hyper-and hypoparathyroidism),the kidney(chronic renal failure),the skin(psoriasis),and the bone(osteomalacia,rickets,and osteoporosis).All of these,in their own way,reflect a disturbance in or a malfunction of the body's normal endocrine processing of vitamin D and its interaction with the other calcemic hormones.
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Osteoporosis:Osteoporosis is most simply characterized as a state of insufficiently calcified bone;the poor bone mineralization can frequently result in fractures of the vertebra,hip or arm.Osteoporosis is the most common generalized disorder of bone and affects hundreds of millions of women and men worldwide.Osteoporosis normally begins in middle life and becomes progressively more frequent with advancing age,when it manifests itself with a bone fracture.
As summarized in Table 1,osteoporosis can be classified from a pathophysiological perspective as resulting from:(a)insufficient dietary vitamin D intake or sunlight exposure (designated as vitamin D insufficiency),(b)estrogen deficiency in females which is associated with the menopause [designated as type I];or(c)the aging process in both women and men which occurs because of changes in calcium homeostasis [designated as type II][3，4]
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Table 1 Osteoporosis Classification Category of Osteoporosis
Description
Site of major fracture(s)
Vitamin D insufficiency
Inappropriately low dietary intake of
vitamin D3 or sun light exposure
Hip and vertebra
Type I
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Estrogen deficiency in females(after the
menopause
Vertebra and forearm
Type II
Aging process in both males and females
(60-90 years of age)
Vertebra and proximal femur
As discussed by Meunier there are clinical differences between being vitamin D deficient versus vitamin D insufficient[4].The term “deficient” is defined as empty;clinically a person who is vitamin D deplete,will develop rickets(child)or osteomalacia (adult),not osteoporosis.In contrast,the term “insufficient”is defined as lacking in something necessary for completeness;clinically an elderly person who has suboptimal vitamin D nutrition may develop osteoporosis.Practically speaking,vitamin D deficiency versus vitamin D insufficiency is defined according to the blood concentrations of 25(OH)D3.Vitamin D deficiency occurs with serum 25(OH)D3 levels from 0-10nmol/liter,whereas in vitamin D insufficiency,the plasma 25(OH)D3 levels range form 10-50 nmol/liter.In contrast,in the healthy vitamin D replete state,the serum 25(OH)D3 levels fall in the range of 50-200 nmol/liter.
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Vitamin D Endocrine System and Osteoporosis:Evaluation of the vitamin D endocrine system as presented in Figure 2 and the pathogenesis of osteoporosis as classified in Table 1,and with consideration to the information and concepts presented in references(3-7),it is possible to identify six significant linkages between these two entities(see Table 2).Each of these topics will be briefly discussed.Table 2 Linkages between osteoporosis and the vitamin D endocrine system Vitamin D availability
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1α，25(OH)2D3 availability
Receptor for 1α,25(OH2)D3
Parathyroid hormon
Intestinal calcium absorption
Bone remodeling:osteoclasts vs.osteoblasts
It is obvious that the concentration of plasma vitamin D and 25(OH)D3 will determine the ability to produce the hormone 1α,25(OH)2D3.When the plasma 25(OH)D3 level falls below 30nmol/liter,there is a documentable impairment in bone mineral formation[4].Importantly,several studies have shown that plasma levels of 25(OH)D3 decrease with age.Thus by age 70 there is frequently a 50% reduction of the age 30 level of 25(OH)D3 in both men and women[3,4].In fact 25-50% of the elderly in Europe were found to be vitamin D insufficient and for those elderly persons who do not leave their homes (no sunlight)75% were vitamin D insufficient.
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There are four possible mechanisms to describe the age-related decrease in plasma 25(OH)D3 levels:(a)many elderly subjects may not consume the recommended dietary allowances(RDA)for vitamin D3;(b)elderly individuals may have an impaired intestinal absorption of vitamin D;(c)exposure to sunlight is often reduced in the elderly population than in the young and also the aging process may adversely affect the irradiation process that converts skin 7-dehydrocholesterol into vitamin D3;and (d) there may be an effect of age so as to increase the metabolic clearance rate of 25(OH)D3 which would then impair the ability to produce adequate quantities of 1α,25(OH)2D3 from a lowered serum 25(OH)D3 level.
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A second linkage between the vitamin D endocrine system and osteoporosis occurs because of the well documented reduction in plasma levels of 1α,25(OH)2D3 which occurs particularly after age 65[3].There are five possible mechanisms to describe the age-related reduction in plasma 1α,25(OH)2D3 levels.(a) A reduction in the plasma transport protein,DBP,with aging would lower the “free”concentration of 1α,25(OH)2D3.However there is no evidence that this occurs in the elderly population.(b) A marked reduction in the serum 25(OH)D3 levels,as in vitamin D deficiency,would significantly impair the production of 1α,25(OH)2D3.However as discussed above,the elderly population is more likely to be vitamin D insufficient than deficient.(c)The onset of the menopause which creates an estrogen deficiency might contribute to the age-related reduction in 1α,25(OH)2D3 levels,however there is no clear data to support this possibility.(d)The aging process may decrease the levels of the 25(OH)D3-1-hydroxylase enzyme present in the kidney.Thus this key enzyme could become less responsive to the stimulatory effects of parathyroid hormone(PTH)or growth hormone which would result in a reduction in the amount of 1α,25(OH)2D3 produced;there is evidence to support this possibility[3].(e)There may be an effect of aging to increase the metabolic clearance rate of 1α,25(OH)2D3.This would have the consequence of decreasing the plasma levels of 1α,25(OH)2D3.While there is evidence of this effect in rats,there is no convincing data in man.
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A third connection between the vitamin D endocrine system and osteoporosis relates to the possibility of an age related reduction in the levels of the nuclear receptor for 1α,25(OH)2D3(VDR)in key target organs such as the intestine or bone.Clear evidence has been published that the intestinal levels of VDR decrease with age[6].Thus in an elderly person there could be a reduction in the fractional absorption of dietary calcium due to the fall in intestinal levels of the VDR.
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Several studies have documented that in the aging process there is a modest increase in the plasma levels of immunoreactive PTH[3].The consequences of the increased levels of PTH could be either to increase the kidney production of 1α,25(OH)2D3(through elvent of the 25(OH)D3-l-hydroxylase enzyme activity)or to stimulate bone calcium resorption directly at the osteoblast-osteoclast level.It is not clear what is the stimulatory signal for the increased PTH levels,but a small reduction in serum calcium with aging is the most likely.Alternatively there could be a change in the setpoint for suppression of PTH secretion by serum calcium,which would imply that there would be a higher PTH secretion at any given ionized calcium concentration.
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There is clear evidence that the efficiency of intestinal calcium absorption decreases with age[3,4,6].Also it is known that the primary form of vitamin D which stimulates intestinal calcium absorption is 1α,25(OH)2D3.There are four possible mechanisms which can explain a decreased calcium absorption with aging.(a) A reduction in serum levels of 1α,25(OH)2D3 will result in an obligatory reduction in intestinal calcium absorption.(b)There can be an age-related decrease in intestinal responsiveness to 1α,25(OH)2D3.This could be due to an age-related decrease in the VDR levels.(c)In the female after the menopause,the absence of estrogen can result in a reduction in the efficiency ICA.Estrogen therapy is known to increase ICA.(d)Reductions in the kidney output of 1α,25(OH)2D3 will reduce intestinal Ca2+ absorption.
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The final linkage between the vitamin D endocrine system and osteoporosis is changes in the process of bone remodeling.The steady state amount of bone calcium is determined by the balance between osteoclast mediated resorption and the osteoblast mediated bone formation process.In osteoporosis there is evidence that there is a decreased rate of bone formation.Thus over time the amount of calcium in the skeleton will decrease.The rate of bone formation,of course,is linked to the availability of calcium(intestinal absorption)and to the circulating levels of 1α,25(OH)2D3.Because of the presence of the VDR in the osteoblast,it is a target organ for 1α,25(OH)2D3.
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Summary:In type I osteoporosis after the menopause the primary stimulus of the vitamin D endocrine system that occurs is the absence of estrogen.Estrogen deficiency is believed to cause a fundamental change in bone metabolism.The resulting loss of bone mineral leads to an increased urinary calcium excretion and mild hypocalcemia.This will lead to a decreased PTH section and results in a lowered serum level of 1α,25(OH)2D3 which has the ultimate consequence of decreasing intestinal calcium absorption.Thus over time,there is an inevitable continued loss of bone mineral that is characteristic of osteoporosis.
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In type II osteoporosis,the process of aging results in a decrease in plasma levels of 25(OH)D3 as a consequence of reduced sunlight exposure and reduction in skin levels of 7-dehydrocholesterol,and a decrease in the activity of the 1α-hydroxylase activity.Collectively this will result in a decreased production of 1α,25(OH)2D3,a decreased intestinal calcium absorption.and secondary hyperparathyroidism which stimulates the bone loss characteristic of osteoporosis.
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Treatment of osteoporosis with vitamin D and/or 1α,25(OH)2D3:The rationale for treatment of osteoporosis in any individual will clearly depend upon the physician's evaluation of the patient to determine what is the nature of the dysfunction,if any,of the vitamin D endocrine system.In the event of nutritional vitamin D deficiency or insufficiency,then use of physiological replacement dosages of vitamin D3 is the therapy of choice.Small daily doses of 1000 International Units(IU) of vitamin D3 will easily provide the appropriate dosage level.Torgerson et al.have evaluated the cost effectiveness of preventing hip fractures in the elderly population using dietary vitamin D and calcium supplementation[7].
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However there is evidence that many patients with type I and type II osteoporosis have an impairment in the metabolism of vitamin D3 to its hormonal form,1α,25(OH)2D3.In this circumstance it is appropriate to consider treatment with replacement doses of 1α,25(OH)2D3.Tilyard et al.have described a comprehensive study of treatment of postmenopausal women who had experienced a vertebral crush fracture with two daily doses of 0.25 micrograms of 1α,25(OH)2D3[Rocaltrol][5].Their conclusion after three years of treatment was that 1α,25(OH)2D3 was effective in preventing the occurrence of additional crush fractures[5].ANTHONY W.NORMAN，Distinguished Professor of Biochemistry and Biomedical Sciences,University of California-Riverside;B.A.1959 Oberlin College;M.S.1961 University of Wisconsin;Ph.D.1963 University of Wisconsin.
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Service:NIH Urolithiasis SCOR Study Section(1977);NIH General Medicine B Study Section(1980-84)；Riverside Community Hospital Board of Directors(1991-present);many ad hoc Special NIH Study Sections(1975-present);University of California-Riverside Faculty Athletic Representative to the NCAA,(8/96-present).
Research Interests:Mechanism of action of steroid hormones and in particular,1,25(OH)2-vitamin D3;Vitamin D structure-function relationships.
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Biomedical Sciences,University of California-Riverside
Reference
1 Norman AW,Vitamin D.chap.12.In:Ziegler EE,Filer LJ,eds.Present knowledge in nutrution (PKN7),7th edn.International Life Sciences Institute,1996;120-129.
2 Bouillon R,Okamura WH,Norman,AW.Structure-function relationships in the vitamin D endocrine system.Endocr Rev,1995,16:200-257.
3 Eastell R,Riggs BL.Vitamin D and osteoporosis.,chap.44.In:Feldman D,Glorieux FH,Pike JW,eds.Vitamin D.Academic Press,1997;695-711.
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4 Meunier P.Prevention of hip fractures by correcting calcium and vitamin D insufficiencies in elderly people.Scand J.Rheumatol.1996,25:75-278.
5 Tilyard MW,Spears GFS,Thomson J,et al.Treatment of postmenopausal osteoporosis with calcitriol or calcium.New Engl J Med,1992,326:357-362.
6 Åkesson K,Lau KHW,Baylink DJ.Rationale for active vitamin D analog therapy in senile osteoporosis.Calcif.Tissue Int.1997,60:100-105.
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7 Torgerson DJ,Kanis JA.Cost-effectiveness of preventing hip fractures in the elderly population using vitamin D and calcium.Quarterly J.Med.1995;88:135-139.维生素D与骨质疏松概述
王淑萍 宋新德译
摘要 作为营养成分的维生素D在维持正常骨钙化，钙平衡及肠道钙吸收等方面起着十分重要的作用。然而维生素D本身并不是生物活性物质。维生素D经过肝脏及肾脏转化，形成其生物代谢活性产物——1，25(OH)2D3。1，25(OH)2D3为甾体激素，其生物学效应由细胞核受体(VDR)介导，在人体许多脏器包括肠道及骨组织发挥其生物学作用。在上述维生素D代谢系统中，任何环节发生异常均可导致人体疾病，包括骨质疏松(OP)。OP为最常见的骨代谢异常疾病。简言概括，OP为钙化骨不足，结果导致脊柱骨、髋骨及前臂骨骨折。OP病因大致为①维生素D摄入或阳光照射不足。②雌激素不足(I)型。③老年性(包括男性或女性)(Ⅱ型)。本文的目的是概述维生素D，从而加深对OP形成的理解。
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维生素D简述
图1(见英文稿)为维生素D分子结构式。其结构与其他甾体激素如孕酮，雌二醇，睾丸酮，糖皮质激素及醛固酮相似。所有甾体激素的前体均为胆固醇[1]。从结构上讲，维生素D为开环甾体物质(secosteroid)。由胆固醇A，B，C，D，4环结构上的B环9，10碳链断裂而形成。由于17位碳上的侧链结构变化，使维生素D成为具有许多成员的大家族。天然形成的维生素D侧链与胆固醇或7-脱氢胆固醇侧链相同，可称为维生素D3或胆钙化醇(cholecalciferol)简称VD3。维生素D2(ergocalciferol)的侧链与麦角固醇相同，故不属于自然形成的维生素形式。然而D3或D2均可以称为钙化醇(calciferol)或简称维生素D(图1)。
1921年VD3首次发现并命名，归属于维生素类。实际上这种分类是错误的。维生素物质是人体不能自身合成的，而VD3在人体内有前体。人体皮肤中存在的维生素前体在1925年被证实，命名为7-脱氢胆固醇。在阳光或紫外线的照射下，即可转化为VD3。因而从科学角度上讲，VD3不是维生素。但从公共健康卫生的角度上讲，人工合成的维生素D可掺于食品中或制成供口服的胶囊而有利于健康。VD3建议每日口服量(RDA)为200IU(成人)400IU(怀孕妇女或4岁以下儿童)。对于那些没有能力从食品添加剂或口服胶囊中获得VD3者，阳光照射每周三次，每次20分钟仍可以获得足够的VD3需要量[1]。
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维生素D的内分泌系统
1964年维生素D代谢产物的发现，在维生素D研究领域中又开创了一个新的篇章。现已有37种分离命名及确定化学结构式的代谢产物。现已共认，人体具有一个维生素D代谢的内分泌系统。有两个步骤才使VD3成为有活性的激素形式—1，25(OH)2D3。首先在肝脏，由肝脏产生的25羟化酶将VD3转化为25(OH)D3。然后在肾脏，由肾脏产生的1d羟化酶，将25(OH)D3转化为真正的甾体激素1α，25(OH)2D3。现已证实，VD3本身不具生物活性，所有VD3介导的生化学反应均由VD3代谢产物，1α,25(OH)2D3及24R，25(OH)2D3引起[2]。
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图2(见英文稿)为维生素D的内分泌系统总结。索引文章[2]中有对这一系统更为详细的描述。概括讲，维生素D内分泌系统包括四个主要部分。①维生素D前体(图2的左上角)。②肾脏(右上角)为内分泌腺体产生1α,25(OH)2D3及24R，25(OH)2D3。③维生素D结合蛋白(DBP)，运转血液中所有的VD3代谢产物(VD3代谢产物均为脂溶性)。④靶器官，为活性激素1α,25(OH)2D3及24R，25(OH)2D3作用部位。DBP将1α,25(OH)2D3运转到各靶器官组织，靶器官及组织有1α,25(OH)2D3的核受体(VDR)。1α,25(OH)2D3与VDR结合并形成复合物。复合物可识别并特异结合到VDRE启动子(promoter)，调节VDRE启动子的功能可刺激或抑制该基因的翻译或复制，从而产生生物学效应。1α,25(OH)2D3只调节含有VDRE的基因。
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应用现代生化分子学技术，现已发现VDR不仅存在于传统的靶器官(肠、骨、肾脏)，人体共有32个组织或器官含有VDR。而维生素D在胰腺，皮肤，B及T淋巴细胞；肿瘤细胞等的生物效应远比我们想像的要多。值得提出的是，在近年的研究中，许多实验表明1α,25(OH)2D3介导的快速反应。多种细胞种系均有这种快速反应。如肠细胞，破骨细胞2，甲旁腺组织及胰岛β细胞。其反应时间仅为几秒钟。现有假说认为1α,25(OH)2D3介导的快速反应由细胞膜受体，并通过一系列蛋白激酶反应，而引起基因效应。报道最多的是信使传导系统中蛋白激酶C，细胞膜上的钙通道开放等。
1α,25(OH)2D3与VDR之间的相互反应在维生素D产生的生物学反应中起主要作用。另一由肾脏产生的维生素D代谢产物24R，25(OH)2D3亦不可忽视。现在在软骨细胞及骨折愈合骨痂中已发现24R，25(OH)2D3受体[2]，对该受体的深入研究正在进行之中。
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组织器官对钙的需求(demand)决定1α,25(OH)2D3的产生量。在正常生理情况下，肾脏产生定量的1α,25(OH)2D3及24R，25(OH)2D3并分泌入血。甲状旁腺素(PTH)对肾脏1α-羟化酶活性起主要调节作用。(1α-羟化酶在肾脏使25(OH)D3转化为1α,25(OH)2D3)当血钙降低时，PTH升高，促进产生更多的1α,25(OH)2D3。当血钙水平恢复正常后，PTH水平下降，1α,25(OH)2D3的产生也随之减少，但在同时增加24R，25(OH)2D3产生。现已有证据表明VD3代谢产物1α,25(OH)2D3及24R，25(OH)2D3可通过短程负反馈来调节PTH的产生及分泌。除PTH外，其它内分泌激素，如雌激素，雄激素，生长激素，泌乳素及胰岛素亦可影响1α,25(OH)2D3分泌。
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维生素D代谢紊乱
维生素D代谢紊乱可由多种原因引起：①VD3前体来源不足。②VD3转化为两个主要代谢活性产物1α,25(OH)2D3及24R，25(OH)2D2减少。③机体对这些代谢活性产物的反应改变。④某些因素导致代谢活性产物与PTH及降钙素之间的相互反应发生变化。维生素D与多种脏器病变有关。小肠(钙吸收障碍)，甲旁腺(甲旁亢成甲旁低)，肾脏(慢性肾衰)，皮肤(牛皮癣)，骨组织(骨软化，佝偻病，骨质疏松)。所有这些疾病均与维生素D代谢紊乱成VD3与其它钙调节激素之间的相互反应发生改变有关。
骨质疏松(OP)
OP特征性改变是钙化骨不足，因而导致脊柱骨，髋骨及上臂骨骨折。OP为最常见骨代谢疾病。世界上有成百万的女性或男性患病。常见发病年龄在中年之后。进行性病变导致骨折在老年人更常见。
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从表1概况可见，OP可按照病因分为：①服VD3或日光照射不足。②女性绝经后雌激素水平不足(I型)。③老年性OP，男性或女性钙平衡改变(Ⅱ型)[3，4]。
表1 骨质疏松分类 分类
描述
骨折部位
维生素D不足
维生素D3摄入不足或阳光照射不足
髋骨及脊柱骨
Ⅰ型
女性绝经后雌激素缺乏
脊柱骨及前臂骨
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Ⅱ型
男性及女性随年龄而发生的OP(60～90岁)
脊柱骨及股骨近端
Meunier曾经讨论过维生素D不足(insufficcenct)与缺乏(deficient)之间的关系[4]。缺乏的定义为“empty”。临床上患者体内的VD3耗尽，故发生儿童佝楼病或成人骨软化。但不是OP。相比较，不足的定为“Lacking”。是完善的必需部分。临床上可见到老年人因VD3不足而患OP。临床上可用血浓度将不足与缺乏加以区分。VD3不足时，血浓度为10～50 nmol/L，缺乏时为0～10 nmol/L。相比较，健康人的VD3水平为50～200μmol/L。
维生素D内分泌系统与OP
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从图2的VD3内分泌系统及表1的OP分类，我们可以推断6种与VD3缺乏或不足有关的因素(表2)。
表2 维生素D内分泌系统及骨质疏松的关系 维生素D利用率(availability)
1α,25(OH)2D3利用率
1α,25(OH)2D3受体(VDR)
甲状旁腺素(PTH)
肠道钙吸收
骨重塑，成骨及破骨细胞
(一)25(OH)D3：
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显而易见，1α,25(OH)2D3血浓度与VD3及25(OH)D3水平有关。文献记载显示，当血浆25(OH)D3水平低于30 nmol/L时，即可见到骨钙化不足[4]。尤为重要的是，多个研究已证实随年龄增加，血浆25(OH)D3水平下降。不论男女，超过70岁的老人血浆25(OH)2D3已降为30岁年青人的一半(50%)。在欧洲，25%～50%居住在家中及75%居住在老年护理中心(nuring home)老人均有VD3不足(多由于阳光照射不足)。
有四种机制可以用来描述与年龄有关的血浆25(OH)2D3水平降低。①进食含VD3食物量不足(没有按照RDA推荐水平添加VD3)。②小肠VD3吸收障碍。③接受日光照射较年青人少。同时年龄老化会影响7-脱氢胆固醇转化为VD3的光化作用。④25(OH)D3代谢清除率增加。
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(二)1α,25(OH)2D3：
许多文献对1,25(OH)2D3水平降低(尤其是年龄超过65岁)均有报道。推断与年龄有关的1α,25(OH)2D3水平变化有五个方面。①DBP水平随年龄降低，导致游离1α,25(OH)2D3水平减低。尚无直接证据或文献报道证实老年人血浆游离1α,25(OH)2D3水平降低。②VD3缺乏时，低水平的25(OH)2D3导致低水平的1,25(OH)2D3。然而不支持这一假说，为老年人大多为VD3不足，而不是VD3缺乏。③绝经后雌激素水平降低也可能与1α,25(OH)2D3水平降低有关。目前尚无证据对此加以证实。④年龄老化导致肾脏25(OH)2D3—1α羟化酶活性降低；机体对PTH及生长激素的反应性降低，进一步导致1α,25(OH)2D3生成减少。已有文献证实这一推论[3]。⑤老年人1,25(OH)2D3代谢分解增加导致血浆水平降低。已有大鼠动物实验结果，但尚无人类实验结果证实。
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(三)VDR
造成老年人OP的第三个原因可能与VDR水平降低有关。VDR主要靶器官为小肠及骨组织。已有证据表明小肠VDR水平随年龄降低[6]。因此可以推论老年人小肠DVR水平降低导致小肠钙吸收不足，从而减少钙化骨，造成OP。
(四)PTH
多个研究结果证实在年龄老化过程中，PTH水平明显上升[3]。PTH水平上升的结果不仅是增加肾脏25羟化酶水平造成1,25(OH)2D3增加，同时也直接刺激破骨细胞功能，使骨吸收增加，造成OP。目前尚不清楚哪些刺激因素引起PTH水平增加。其最大可能性是年龄老化导致血钙水平降低而刺激PTH水平上升。另一可能性为PTH调节且钙的调节点(set-point)发生改变，使微量的血钙变化导致大量PTH分泌。
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大量充足的证据表明小肠钙吸收能力随年龄降低[3，4，6]。刺激小肠钙吸收的主要调节因素为1α,25(OH)2D3。有四种机制可用来解释随年龄而发生的钙吸收减少。①血浆1α,25(OH)2D3水平下降造成相应的小肠钙吸收减少。②随年龄而减少的VDR水平，造成小肠组织对1α,25(OH)2D3反应迟钝。③老年女性由于绝经造成雌激素消失，可能会影响小肠钙吸收。已有雌激素替代疗法增加小肠钙吸收的报道。④肾脏产生1,25(OH)2D3减少，而1,25(OH)2D3减少导致小肠钙吸收减少。
(六)维生素D内分泌系统改变与骨再塑
骨钙储存量取决于成骨细胞与破骨细胞之间的平衡。OP时，成骨不足，骨钙量减少。成骨的速度与小肠吸收的钙量及血循环中的1α,25(OH)2D3水平直接相关。成骨细胞表面有VDR，因此成骨细胞也为1α,25(OH)2D3的靶细胞。
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小结
I型OP：绝经后对维生素D内分泌系统的主要刺激因素是雌激素缺乏。雌激素缺乏被认为是造成骨代谢改变的最主要因素。丧失骨矿化的结果是增加尿钙以及轻度的低血钙。尿钙增加的结果使PTH分泌相对减少及血浆1,25(OH)2D3水平相对下降。进一步导致小肠钙吸收减少。久而久之，形成不可逆的骨矿丢失。而骨矿丢失是OP的显著特征。
Ⅱ型OP：在年龄老化过程中由于阳光照射不足使血浆25(OH)D3水平降低。而皮肤7-脱氢胆固醇的减少及其1α羟化酶活性下降导致1,25(OH)2D3生成减少。从而影响小肠钙吸收。钙缺乏又引起继发性甲旁亢。最终导致破骨细胞活性增加，骨吸收，发生OP。
VD3及其1,25(OH)2D3治疗OP
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在治疗OP时，医师应全面估价患者的维生素D内分泌系统。如发现有维生素D缺乏或不足，维生素D或1,25(OH)2D3替代疗法则成治疗的选择。每日1000国际单位的维生素D即可达到治疗药物剂量。Torgerson等人曾评价过给老年人服用维生素D及其钙剂有效预防髋骨骨折。[7]
然而许多Ⅰ型或Ⅱ型的患者有1,25(OH)2D3代谢障碍。在这种情况下，给予1,25(OH)2D3是适宜的。Tilqard等人报导了用Rocaltrol0、25μg，每日两次的剂量治疗绝经后妇女的脊柱压缩性骨折[5]。在三年的治疗之后，他们的结论是：用1,25(OH)2D3可以予防再发脊柱骨骨折。, 百拇医药
单位：
关键词：
中国骨质疏松杂志000102CURRICULUM VITAE
ANTHONY W.NORMAN
Introduction to Vitamin D:The molecular structure of vitamin D(see Figure 1)is closely allied to that of classical steroid hormones (e.g.progesterone ,estradiol , testosterone,glucocorticoids and aldosterone).All of these steroid hormones and also vitamin D are metabolically produced from the same common precursor,namely the sterol cholesterol(1).Technically,vitamin D is a secosteroid.Secosteroids are those in which one of the four ring structures of cholesterol(the cyclopentanoperhydrophenanthrene rings)have undergone breakage of one carbon-carbon bond;in the instance of vitamin D this is the 9,10-carbon bond of rign B.
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There is a family of vitamin D-related steroids with variations in the precise structure of the side chain attached to carbon-17.The naturally occurring form of vitamin D is that which has the side chain structure identical to that of cholesterol and 7-dehydrocholesterol;this is known as vitamin D3 or cholecalciferol.Vitamin D2,or ergocalciferol,has the side chain of ergosterol and is not a naturally occurring form of the vitamin.Collectively vitamin D3 plus vitamin D2 can be termed as the calciferols or simply vitamin D(see Figure 1).
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The substance vitamin D3 is officially classified as being a vitamin,which implies that the body does not have the capability to metabolically produce this substance.The fact that vitamin D3 is classified as a vitamin is an experimental accident which occurred at the time of its discovery in 1921.By 1925 it was clearly established that vitamin D3 had a precursor in skin,namely 7-dehydrocholesterol,which when exposed to ultraviolet light or sunlight could be efficiently converted into the molecule vitamin D3.Thus while it is scientifically correct that vitamin D3 is not a vitamin,it has proven beneficial to public health to have this molecule made nutritionally available either by food supplementation or incorporation into vitamin capsules.The Recommended Dietary Allowance (RDA) of vitamin D3 for an adult is 200 IU(5μg)per day or 400 IU for pregnant women and children less than 4 years [Tony,what about elderly?].However if an individual does not have access to vitamin D supplemented foods, he/she can still meet their nutritional RDA requirement for vitamin D3 by exposure of their face and hands to sunlight three times per week for approximately 20 minutes[1].
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Vitamin D Endocrine System:A totally new era in the field of vitamin D has opened since 1964 with the discovery of the metabolism of vitamin D.Altogether,some 37 metabolites of vitamin D3 have been isolated and chemically characterized.It is now recognized that there is an endocrine system for processing the prohormone,vitamin D,into its hormonally active daughter metabolite(s)via a two step process involving first the liver which introduces a hydroxyl group on carbon-25 and then the kidney which introduces a second hydroxyl on carbon-1.The molecule vitamin D itself has no intrinsic biological activity.All biological responses attributed to vitamin D are now known to arise only as a consequence of the metabolism of this seco-steroid into its biologically active daughter metabolites,namely,1α,25(OH)2D3 and 24R,25(OH)2D3[2].
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Figure 1:Structural relationship of vitamin D3 (cholecalciferol)and vitamin D2(ergocalciferol)with their respective provitamins,7-dehydrocholesterol and ergosterol.The two structural representations presented at the bottom for both vitamin D3 and vitamin D2 are equialent;thse are simply different ways of drawing the same molecule.
Figure 2 presents a summary of the vitamin D endocrine system.A detailed discussion of the vitamin D endocrine system is presented in reference[2].There are four key components of the vitamin D endocrine system:(a)the parent vitamin D3(upper left corner)which is the precursor of the hormone form of vitamin D;(b)the kidney which is the endocrine gland which produce the two steroid hormones 1α,25(OH)2D3 and 24R,25(OH)2D3;(c)the vitamin D binding protein (DBP)which transports the hormone 1α,25(OH)2D3,vitamin D3 and other vitamin D metabolites [because of their poor water solubility] through the blood compartment;and (d)the target organs which produces the biological responses that we attribute to vitamin D3.Thus the DBP delivers the hormone 1α,25(OH)2D3 to its various target tissues.Target tissues,by definition,possess the nuclear receptor for 1α,25(OH)2D3[known as the vitamin D receptor or VDR].As a consequence 1α,25(OH)2D3 enters the cell and binds to the VDR in the nucleus of the cell.The VDR+ligand(occupied receptor)then interacts with specific nucleotide sequences on the promoters of genes(vitamin D response elements;VDRE)so that either stimulation or repression of gene transcription occures.This results in the production of more or less messenger RNAs for selective proteins; only those genes which have a VDRE of the are subject to regulation.
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The VDR for the hormone 1α，25(OH)2D3 is found not only in the classic target organs(intestine,bone and kidney)but also in at least 32 additional target tissues.Only through the use of modern biochemical and molecular biological techniques,which allowed detection of the VDR in these new locations,was it discovered that the hormone form of vitamin D had far reaching effects in many other tissues(e.g.pancreas,skin,B and T lymphocytes,cancer cells,etc).Also recent results from a number of laboratories indicate that some 1α，25(OH)2D3-mediated biological responses occur too quickly to be explained via the VDR regulation of gene transcription.Thus these rapid responses have been shown to occur within seconds to minutes and have been demonstrated in the intestine,bone osteoblasts,parathyroid cells as well as the pancreas β-cell.The current thinking is that these rapid responses occur as a consequence of 1α，25(OH)2D3 interacting with a different membrane receptor which initiates a different signal transduction system,possibly involving activtion of protein kinase C(PKC) and opening of voltage gated Ca2+ channels.
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Figure 2 Summary of the vitamin D endocrine system.The key components are the prohormone,vitamin D3;the kidney functioning as an endocrine gland to produce the two steroid hormones,namely 1α,25(OH)2D3 and 24R,25(OH)2D3;and the target organs,both classical (intestine,bone and kidney and the approximately 32 other tissues which possess the nuclear receptor for 1α,25(OH)2D3
While interaction of 1α，25(OH)2D3 with its VDR is believed to be responsible for most of the important biological responses attributable to the parent vitamin D,there is also evidence that some parent vitamin D responses involve the second renal hormone 24R，25(OH)2O3.Receptors for 24R,25(OH)2D3 have been demonstrated in cartilage cells and in bone fracture-healing callus(2).These new developments are currently under intensive investigation
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The steroid hormone 1α，25(OH)2D3 is produced only in accord with strict physiological signals dictated by the calcium“demand”of the organism;a bimodal mode of regulation has been suggested.Thus,under normal physiological circumstances,both renal dihydroxylated metabolites [1α,25(OH)2D3 ad 24R,25(OH)2D3]are secreted and are circulating in the plasma.Parathyroid hormone(PTH) is the major stimulator of the 25(OH)D3-l-hydroxylase,[the kidney enzyme that produces 1α,25(OH)2D3].In instances of hypocalcemia PTH will become elevated and stimulate the production of more 1α，25(OH)2D3.Conversely,when serum Ca2+ is normal,PTH secretions is diminished,and there is a reduction in the production of 1α,25(OH)2D3 and an increase in the production of 24R,25(OH)2D3.There is evidence for a“short feedback loop”for both of these metabolites to modulate and/or reduce the secretion of PTH.There is also some evidence that other endocrine modulators such as estrogens,androgens,growth hormone,prolactin,and insulin may affect the renal production of 1α,25(OH)2D3.Thus,the kidney is clearly an endocrine gland,in the classic sense,which is capable of producing in a physiologically regulated manner appropriate amounts of 1α,25(OH)2D3.
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Clinical disorders:Human clinical disorders related to vitamin D can be considered to arise because of one of the following:(a)altered availability of the parent vitamin D;(b)altered conversion of vitamin D to its two principal daugter metabolites,1α,25(OH)2D3 and 24R,25(OH)2D3;(c)conditions that may be due to variations in organ responsiveness to these dihydroxylated metabolites;and (d) perturbations in the integrated interactions of these metabolites with PTH and calcitonin.A wide variety of organs have diseases related to vitamin D:the intestine(malabsorption),the parathyroid gland (hyper-and hypoparathyroidism),the kidney(chronic renal failure),the skin(psoriasis),and the bone(osteomalacia,rickets,and osteoporosis).All of these,in their own way,reflect a disturbance in or a malfunction of the body's normal endocrine processing of vitamin D and its interaction with the other calcemic hormones.
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Osteoporosis:Osteoporosis is most simply characterized as a state of insufficiently calcified bone;the poor bone mineralization can frequently result in fractures of the vertebra,hip or arm.Osteoporosis is the most common generalized disorder of bone and affects hundreds of millions of women and men worldwide.Osteoporosis normally begins in middle life and becomes progressively more frequent with advancing age,when it manifests itself with a bone fracture.
As summarized in Table 1,osteoporosis can be classified from a pathophysiological perspective as resulting from:(a)insufficient dietary vitamin D intake or sunlight exposure (designated as vitamin D insufficiency),(b)estrogen deficiency in females which is associated with the menopause [designated as type I];or(c)the aging process in both women and men which occurs because of changes in calcium homeostasis [designated as type II][3，4]
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Table 1 Osteoporosis Classification Category of Osteoporosis
Description
Site of major fracture(s)
Vitamin D insufficiency
Inappropriately low dietary intake of
vitamin D3 or sun light exposure
Hip and vertebra
Type I
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Estrogen deficiency in females(after the
menopause
Vertebra and forearm
Type II
Aging process in both males and females
(60-90 years of age)
Vertebra and proximal femur
As discussed by Meunier there are clinical differences between being vitamin D deficient versus vitamin D insufficient[4].The term “deficient” is defined as empty;clinically a person who is vitamin D deplete,will develop rickets(child)or osteomalacia (adult),not osteoporosis.In contrast,the term “insufficient”is defined as lacking in something necessary for completeness;clinically an elderly person who has suboptimal vitamin D nutrition may develop osteoporosis.Practically speaking,vitamin D deficiency versus vitamin D insufficiency is defined according to the blood concentrations of 25(OH)D3.Vitamin D deficiency occurs with serum 25(OH)D3 levels from 0-10nmol/liter,whereas in vitamin D insufficiency,the plasma 25(OH)D3 levels range form 10-50 nmol/liter.In contrast,in the healthy vitamin D replete state,the serum 25(OH)D3 levels fall in the range of 50-200 nmol/liter.
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Vitamin D Endocrine System and Osteoporosis:Evaluation of the vitamin D endocrine system as presented in Figure 2 and the pathogenesis of osteoporosis as classified in Table 1,and with consideration to the information and concepts presented in references(3-7),it is possible to identify six significant linkages between these two entities(see Table 2).Each of these topics will be briefly discussed.Table 2 Linkages between osteoporosis and the vitamin D endocrine system Vitamin D availability
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1α，25(OH)2D3 availability
Receptor for 1α,25(OH2)D3
Parathyroid hormon
Intestinal calcium absorption
Bone remodeling:osteoclasts vs.osteoblasts
It is obvious that the concentration of plasma vitamin D and 25(OH)D3 will determine the ability to produce the hormone 1α,25(OH)2D3.When the plasma 25(OH)D3 level falls below 30nmol/liter,there is a documentable impairment in bone mineral formation[4].Importantly,several studies have shown that plasma levels of 25(OH)D3 decrease with age.Thus by age 70 there is frequently a 50% reduction of the age 30 level of 25(OH)D3 in both men and women[3,4].In fact 25-50% of the elderly in Europe were found to be vitamin D insufficient and for those elderly persons who do not leave their homes (no sunlight)75% were vitamin D insufficient.
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There are four possible mechanisms to describe the age-related decrease in plasma 25(OH)D3 levels:(a)many elderly subjects may not consume the recommended dietary allowances(RDA)for vitamin D3;(b)elderly individuals may have an impaired intestinal absorption of vitamin D;(c)exposure to sunlight is often reduced in the elderly population than in the young and also the aging process may adversely affect the irradiation process that converts skin 7-dehydrocholesterol into vitamin D3;and (d) there may be an effect of age so as to increase the metabolic clearance rate of 25(OH)D3 which would then impair the ability to produce adequate quantities of 1α,25(OH)2D3 from a lowered serum 25(OH)D3 level.
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A second linkage between the vitamin D endocrine system and osteoporosis occurs because of the well documented reduction in plasma levels of 1α,25(OH)2D3 which occurs particularly after age 65[3].There are five possible mechanisms to describe the age-related reduction in plasma 1α,25(OH)2D3 levels.(a) A reduction in the plasma transport protein,DBP,with aging would lower the “free”concentration of 1α,25(OH)2D3.However there is no evidence that this occurs in the elderly population.(b) A marked reduction in the serum 25(OH)D3 levels,as in vitamin D deficiency,would significantly impair the production of 1α,25(OH)2D3.However as discussed above,the elderly population is more likely to be vitamin D insufficient than deficient.(c)The onset of the menopause which creates an estrogen deficiency might contribute to the age-related reduction in 1α,25(OH)2D3 levels,however there is no clear data to support this possibility.(d)The aging process may decrease the levels of the 25(OH)D3-1-hydroxylase enzyme present in the kidney.Thus this key enzyme could become less responsive to the stimulatory effects of parathyroid hormone(PTH)or growth hormone which would result in a reduction in the amount of 1α,25(OH)2D3 produced;there is evidence to support this possibility[3].(e)There may be an effect of aging to increase the metabolic clearance rate of 1α,25(OH)2D3.This would have the consequence of decreasing the plasma levels of 1α,25(OH)2D3.While there is evidence of this effect in rats,there is no convincing data in man.
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A third connection between the vitamin D endocrine system and osteoporosis relates to the possibility of an age related reduction in the levels of the nuclear receptor for 1α,25(OH)2D3(VDR)in key target organs such as the intestine or bone.Clear evidence has been published that the intestinal levels of VDR decrease with age[6].Thus in an elderly person there could be a reduction in the fractional absorption of dietary calcium due to the fall in intestinal levels of the VDR.
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Several studies have documented that in the aging process there is a modest increase in the plasma levels of immunoreactive PTH[3].The consequences of the increased levels of PTH could be either to increase the kidney production of 1α,25(OH)2D3(through elvent of the 25(OH)D3-l-hydroxylase enzyme activity)or to stimulate bone calcium resorption directly at the osteoblast-osteoclast level.It is not clear what is the stimulatory signal for the increased PTH levels,but a small reduction in serum calcium with aging is the most likely.Alternatively there could be a change in the setpoint for suppression of PTH secretion by serum calcium,which would imply that there would be a higher PTH secretion at any given ionized calcium concentration.
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There is clear evidence that the efficiency of intestinal calcium absorption decreases with age[3,4,6].Also it is known that the primary form of vitamin D which stimulates intestinal calcium absorption is 1α,25(OH)2D3.There are four possible mechanisms which can explain a decreased calcium absorption with aging.(a) A reduction in serum levels of 1α,25(OH)2D3 will result in an obligatory reduction in intestinal calcium absorption.(b)There can be an age-related decrease in intestinal responsiveness to 1α,25(OH)2D3.This could be due to an age-related decrease in the VDR levels.(c)In the female after the menopause,the absence of estrogen can result in a reduction in the efficiency ICA.Estrogen therapy is known to increase ICA.(d)Reductions in the kidney output of 1α,25(OH)2D3 will reduce intestinal Ca2+ absorption.
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The final linkage between the vitamin D endocrine system and osteoporosis is changes in the process of bone remodeling.The steady state amount of bone calcium is determined by the balance between osteoclast mediated resorption and the osteoblast mediated bone formation process.In osteoporosis there is evidence that there is a decreased rate of bone formation.Thus over time the amount of calcium in the skeleton will decrease.The rate of bone formation,of course,is linked to the availability of calcium(intestinal absorption)and to the circulating levels of 1α,25(OH)2D3.Because of the presence of the VDR in the osteoblast,it is a target organ for 1α,25(OH)2D3.
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Summary:In type I osteoporosis after the menopause the primary stimulus of the vitamin D endocrine system that occurs is the absence of estrogen.Estrogen deficiency is believed to cause a fundamental change in bone metabolism.The resulting loss of bone mineral leads to an increased urinary calcium excretion and mild hypocalcemia.This will lead to a decreased PTH section and results in a lowered serum level of 1α,25(OH)2D3 which has the ultimate consequence of decreasing intestinal calcium absorption.Thus over time,there is an inevitable continued loss of bone mineral that is characteristic of osteoporosis.
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In type II osteoporosis,the process of aging results in a decrease in plasma levels of 25(OH)D3 as a consequence of reduced sunlight exposure and reduction in skin levels of 7-dehydrocholesterol,and a decrease in the activity of the 1α-hydroxylase activity.Collectively this will result in a decreased production of 1α,25(OH)2D3,a decreased intestinal calcium absorption.and secondary hyperparathyroidism which stimulates the bone loss characteristic of osteoporosis.
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Treatment of osteoporosis with vitamin D and/or 1α,25(OH)2D3:The rationale for treatment of osteoporosis in any individual will clearly depend upon the physician's evaluation of the patient to determine what is the nature of the dysfunction,if any,of the vitamin D endocrine system.In the event of nutritional vitamin D deficiency or insufficiency,then use of physiological replacement dosages of vitamin D3 is the therapy of choice.Small daily doses of 1000 International Units(IU) of vitamin D3 will easily provide the appropriate dosage level.Torgerson et al.have evaluated the cost effectiveness of preventing hip fractures in the elderly population using dietary vitamin D and calcium supplementation[7].
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However there is evidence that many patients with type I and type II osteoporosis have an impairment in the metabolism of vitamin D3 to its hormonal form,1α,25(OH)2D3.In this circumstance it is appropriate to consider treatment with replacement doses of 1α,25(OH)2D3.Tilyard et al.have described a comprehensive study of treatment of postmenopausal women who had experienced a vertebral crush fracture with two daily doses of 0.25 micrograms of 1α,25(OH)2D3[Rocaltrol][5].Their conclusion after three years of treatment was that 1α,25(OH)2D3 was effective in preventing the occurrence of additional crush fractures[5].ANTHONY W.NORMAN，Distinguished Professor of Biochemistry and Biomedical Sciences,University of California-Riverside;B.A.1959 Oberlin College;M.S.1961 University of Wisconsin;Ph.D.1963 University of Wisconsin.
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Service:NIH Urolithiasis SCOR Study Section(1977);NIH General Medicine B Study Section(1980-84)；Riverside Community Hospital Board of Directors(1991-present);many ad hoc Special NIH Study Sections(1975-present);University of California-Riverside Faculty Athletic Representative to the NCAA,(8/96-present).
Research Interests:Mechanism of action of steroid hormones and in particular,1,25(OH)2-vitamin D3;Vitamin D structure-function relationships.
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Biomedical Sciences,University of California-Riverside
Reference
1 Norman AW,Vitamin D.chap.12.In:Ziegler EE,Filer LJ,eds.Present knowledge in nutrution (PKN7),7th edn.International Life Sciences Institute,1996;120-129.
2 Bouillon R,Okamura WH,Norman,AW.Structure-function relationships in the vitamin D endocrine system.Endocr Rev,1995,16:200-257.
3 Eastell R,Riggs BL.Vitamin D and osteoporosis.,chap.44.In:Feldman D,Glorieux FH,Pike JW,eds.Vitamin D.Academic Press,1997;695-711.
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4 Meunier P.Prevention of hip fractures by correcting calcium and vitamin D insufficiencies in elderly people.Scand J.Rheumatol.1996,25:75-278.
5 Tilyard MW,Spears GFS,Thomson J,et al.Treatment of postmenopausal osteoporosis with calcitriol or calcium.New Engl J Med,1992,326:357-362.
6 Åkesson K,Lau KHW,Baylink DJ.Rationale for active vitamin D analog therapy in senile osteoporosis.Calcif.Tissue Int.1997,60:100-105.
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7 Torgerson DJ,Kanis JA.Cost-effectiveness of preventing hip fractures in the elderly population using vitamin D and calcium.Quarterly J.Med.1995;88:135-139.维生素D与骨质疏松概述
王淑萍 宋新德译
摘要 作为营养成分的维生素D在维持正常骨钙化，钙平衡及肠道钙吸收等方面起着十分重要的作用。然而维生素D本身并不是生物活性物质。维生素D经过肝脏及肾脏转化，形成其生物代谢活性产物——1，25(OH)2D3。1，25(OH)2D3为甾体激素，其生物学效应由细胞核受体(VDR)介导，在人体许多脏器包括肠道及骨组织发挥其生物学作用。在上述维生素D代谢系统中，任何环节发生异常均可导致人体疾病，包括骨质疏松(OP)。OP为最常见的骨代谢异常疾病。简言概括，OP为钙化骨不足，结果导致脊柱骨、髋骨及前臂骨骨折。OP病因大致为①维生素D摄入或阳光照射不足。②雌激素不足(I)型。③老年性(包括男性或女性)(Ⅱ型)。本文的目的是概述维生素D，从而加深对OP形成的理解。
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维生素D简述
图1(见英文稿)为维生素D分子结构式。其结构与其他甾体激素如孕酮，雌二醇，睾丸酮，糖皮质激素及醛固酮相似。所有甾体激素的前体均为胆固醇[1]。从结构上讲，维生素D为开环甾体物质(secosteroid)。由胆固醇A，B，C，D，4环结构上的B环9，10碳链断裂而形成。由于17位碳上的侧链结构变化，使维生素D成为具有许多成员的大家族。天然形成的维生素D侧链与胆固醇或7-脱氢胆固醇侧链相同，可称为维生素D3或胆钙化醇(cholecalciferol)简称VD3。维生素D2(ergocalciferol)的侧链与麦角固醇相同，故不属于自然形成的维生素形式。然而D3或D2均可以称为钙化醇(calciferol)或简称维生素D(图1)。
1921年VD3首次发现并命名，归属于维生素类。实际上这种分类是错误的。维生素物质是人体不能自身合成的，而VD3在人体内有前体。人体皮肤中存在的维生素前体在1925年被证实，命名为7-脱氢胆固醇。在阳光或紫外线的照射下，即可转化为VD3。因而从科学角度上讲，VD3不是维生素。但从公共健康卫生的角度上讲，人工合成的维生素D可掺于食品中或制成供口服的胶囊而有利于健康。VD3建议每日口服量(RDA)为200IU(成人)400IU(怀孕妇女或4岁以下儿童)。对于那些没有能力从食品添加剂或口服胶囊中获得VD3者，阳光照射每周三次，每次20分钟仍可以获得足够的VD3需要量[1]。
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维生素D的内分泌系统
1964年维生素D代谢产物的发现，在维生素D研究领域中又开创了一个新的篇章。现已有37种分离命名及确定化学结构式的代谢产物。现已共认，人体具有一个维生素D代谢的内分泌系统。有两个步骤才使VD3成为有活性的激素形式—1，25(OH)2D3。首先在肝脏，由肝脏产生的25羟化酶将VD3转化为25(OH)D3。然后在肾脏，由肾脏产生的1d羟化酶，将25(OH)D3转化为真正的甾体激素1α，25(OH)2D3。现已证实，VD3本身不具生物活性，所有VD3介导的生化学反应均由VD3代谢产物，1α,25(OH)2D3及24R，25(OH)2D3引起[2]。
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图2(见英文稿)为维生素D的内分泌系统总结。索引文章[2]中有对这一系统更为详细的描述。概括讲，维生素D内分泌系统包括四个主要部分。①维生素D前体(图2的左上角)。②肾脏(右上角)为内分泌腺体产生1α,25(OH)2D3及24R，25(OH)2D3。③维生素D结合蛋白(DBP)，运转血液中所有的VD3代谢产物(VD3代谢产物均为脂溶性)。④靶器官，为活性激素1α,25(OH)2D3及24R，25(OH)2D3作用部位。DBP将1α,25(OH)2D3运转到各靶器官组织，靶器官及组织有1α,25(OH)2D3的核受体(VDR)。1α,25(OH)2D3与VDR结合并形成复合物。复合物可识别并特异结合到VDRE启动子(promoter)，调节VDRE启动子的功能可刺激或抑制该基因的翻译或复制，从而产生生物学效应。1α,25(OH)2D3只调节含有VDRE的基因。
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应用现代生化分子学技术，现已发现VDR不仅存在于传统的靶器官(肠、骨、肾脏)，人体共有32个组织或器官含有VDR。而维生素D在胰腺，皮肤，B及T淋巴细胞；肿瘤细胞等的生物效应远比我们想像的要多。值得提出的是，在近年的研究中，许多实验表明1α,25(OH)2D3介导的快速反应。多种细胞种系均有这种快速反应。如肠细胞，破骨细胞2，甲旁腺组织及胰岛β细胞。其反应时间仅为几秒钟。现有假说认为1α,25(OH)2D3介导的快速反应由细胞膜受体，并通过一系列蛋白激酶反应，而引起基因效应。报道最多的是信使传导系统中蛋白激酶C，细胞膜上的钙通道开放等。
1α,25(OH)2D3与VDR之间的相互反应在维生素D产生的生物学反应中起主要作用。另一由肾脏产生的维生素D代谢产物24R，25(OH)2D3亦不可忽视。现在在软骨细胞及骨折愈合骨痂中已发现24R，25(OH)2D3受体[2]，对该受体的深入研究正在进行之中。
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组织器官对钙的需求(demand)决定1α,25(OH)2D3的产生量。在正常生理情况下，肾脏产生定量的1α,25(OH)2D3及24R，25(OH)2D3并分泌入血。甲状旁腺素(PTH)对肾脏1α-羟化酶活性起主要调节作用。(1α-羟化酶在肾脏使25(OH)D3转化为1α,25(OH)2D3)当血钙降低时，PTH升高，促进产生更多的1α,25(OH)2D3。当血钙水平恢复正常后，PTH水平下降，1α,25(OH)2D3的产生也随之减少，但在同时增加24R，25(OH)2D3产生。现已有证据表明VD3代谢产物1α,25(OH)2D3及24R，25(OH)2D3可通过短程负反馈来调节PTH的产生及分泌。除PTH外，其它内分泌激素，如雌激素，雄激素，生长激素，泌乳素及胰岛素亦可影响1α,25(OH)2D3分泌。
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维生素D代谢紊乱
维生素D代谢紊乱可由多种原因引起：①VD3前体来源不足。②VD3转化为两个主要代谢活性产物1α,25(OH)2D3及24R，25(OH)2D2减少。③机体对这些代谢活性产物的反应改变。④某些因素导致代谢活性产物与PTH及降钙素之间的相互反应发生变化。维生素D与多种脏器病变有关。小肠(钙吸收障碍)，甲旁腺(甲旁亢成甲旁低)，肾脏(慢性肾衰)，皮肤(牛皮癣)，骨组织(骨软化，佝偻病，骨质疏松)。所有这些疾病均与维生素D代谢紊乱成VD3与其它钙调节激素之间的相互反应发生改变有关。
骨质疏松(OP)
OP特征性改变是钙化骨不足，因而导致脊柱骨，髋骨及上臂骨骨折。OP为最常见骨代谢疾病。世界上有成百万的女性或男性患病。常见发病年龄在中年之后。进行性病变导致骨折在老年人更常见。
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从表1概况可见，OP可按照病因分为：①服VD3或日光照射不足。②女性绝经后雌激素水平不足(I型)。③老年性OP，男性或女性钙平衡改变(Ⅱ型)[3，4]。
表1 骨质疏松分类 分类
描述
骨折部位
维生素D不足
维生素D3摄入不足或阳光照射不足
髋骨及脊柱骨
Ⅰ型
女性绝经后雌激素缺乏
脊柱骨及前臂骨
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Ⅱ型
男性及女性随年龄而发生的OP(60～90岁)
脊柱骨及股骨近端
Meunier曾经讨论过维生素D不足(insufficcenct)与缺乏(deficient)之间的关系[4]。缺乏的定义为“empty”。临床上患者体内的VD3耗尽，故发生儿童佝楼病或成人骨软化。但不是OP。相比较，不足的定为“Lacking”。是完善的必需部分。临床上可见到老年人因VD3不足而患OP。临床上可用血浓度将不足与缺乏加以区分。VD3不足时，血浓度为10～50 nmol/L，缺乏时为0～10 nmol/L。相比较，健康人的VD3水平为50～200μmol/L。
维生素D内分泌系统与OP
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从图2的VD3内分泌系统及表1的OP分类，我们可以推断6种与VD3缺乏或不足有关的因素(表2)。
表2 维生素D内分泌系统及骨质疏松的关系 维生素D利用率(availability)
1α,25(OH)2D3利用率
1α,25(OH)2D3受体(VDR)
甲状旁腺素(PTH)
肠道钙吸收
骨重塑，成骨及破骨细胞
(一)25(OH)D3：
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显而易见，1α,25(OH)2D3血浓度与VD3及25(OH)D3水平有关。文献记载显示，当血浆25(OH)D3水平低于30 nmol/L时，即可见到骨钙化不足[4]。尤为重要的是，多个研究已证实随年龄增加，血浆25(OH)D3水平下降。不论男女，超过70岁的老人血浆25(OH)2D3已降为30岁年青人的一半(50%)。在欧洲，25%～50%居住在家中及75%居住在老年护理中心(nuring home)老人均有VD3不足(多由于阳光照射不足)。
有四种机制可以用来描述与年龄有关的血浆25(OH)2D3水平降低。①进食含VD3食物量不足(没有按照RDA推荐水平添加VD3)。②小肠VD3吸收障碍。③接受日光照射较年青人少。同时年龄老化会影响7-脱氢胆固醇转化为VD3的光化作用。④25(OH)D3代谢清除率增加。
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(二)1α,25(OH)2D3：
许多文献对1,25(OH)2D3水平降低(尤其是年龄超过65岁)均有报道。推断与年龄有关的1α,25(OH)2D3水平变化有五个方面。①DBP水平随年龄降低，导致游离1α,25(OH)2D3水平减低。尚无直接证据或文献报道证实老年人血浆游离1α,25(OH)2D3水平降低。②VD3缺乏时，低水平的25(OH)2D3导致低水平的1,25(OH)2D3。然而不支持这一假说，为老年人大多为VD3不足，而不是VD3缺乏。③绝经后雌激素水平降低也可能与1α,25(OH)2D3水平降低有关。目前尚无证据对此加以证实。④年龄老化导致肾脏25(OH)2D3—1α羟化酶活性降低；机体对PTH及生长激素的反应性降低，进一步导致1α,25(OH)2D3生成减少。已有文献证实这一推论[3]。⑤老年人1,25(OH)2D3代谢分解增加导致血浆水平降低。已有大鼠动物实验结果，但尚无人类实验结果证实。
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(三)VDR
造成老年人OP的第三个原因可能与VDR水平降低有关。VDR主要靶器官为小肠及骨组织。已有证据表明小肠VDR水平随年龄降低[6]。因此可以推论老年人小肠DVR水平降低导致小肠钙吸收不足，从而减少钙化骨，造成OP。
(四)PTH
多个研究结果证实在年龄老化过程中，PTH水平明显上升[3]。PTH水平上升的结果不仅是增加肾脏25羟化酶水平造成1,25(OH)2D3增加，同时也直接刺激破骨细胞功能，使骨吸收增加，造成OP。目前尚不清楚哪些刺激因素引起PTH水平增加。其最大可能性是年龄老化导致血钙水平降低而刺激PTH水平上升。另一可能性为PTH调节且钙的调节点(set-point)发生改变，使微量的血钙变化导致大量PTH分泌。
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大量充足的证据表明小肠钙吸收能力随年龄降低[3，4，6]。刺激小肠钙吸收的主要调节因素为1α,25(OH)2D3。有四种机制可用来解释随年龄而发生的钙吸收减少。①血浆1α,25(OH)2D3水平下降造成相应的小肠钙吸收减少。②随年龄而减少的VDR水平，造成小肠组织对1α,25(OH)2D3反应迟钝。③老年女性由于绝经造成雌激素消失，可能会影响小肠钙吸收。已有雌激素替代疗法增加小肠钙吸收的报道。④肾脏产生1,25(OH)2D3减少，而1,25(OH)2D3减少导致小肠钙吸收减少。
(六)维生素D内分泌系统改变与骨再塑
骨钙储存量取决于成骨细胞与破骨细胞之间的平衡。OP时，成骨不足，骨钙量减少。成骨的速度与小肠吸收的钙量及血循环中的1α,25(OH)2D3水平直接相关。成骨细胞表面有VDR，因此成骨细胞也为1α,25(OH)2D3的靶细胞。
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小结
I型OP：绝经后对维生素D内分泌系统的主要刺激因素是雌激素缺乏。雌激素缺乏被认为是造成骨代谢改变的最主要因素。丧失骨矿化的结果是增加尿钙以及轻度的低血钙。尿钙增加的结果使PTH分泌相对减少及血浆1,25(OH)2D3水平相对下降。进一步导致小肠钙吸收减少。久而久之，形成不可逆的骨矿丢失。而骨矿丢失是OP的显著特征。
Ⅱ型OP：在年龄老化过程中由于阳光照射不足使血浆25(OH)D3水平降低。而皮肤7-脱氢胆固醇的减少及其1α羟化酶活性下降导致1,25(OH)2D3生成减少。从而影响小肠钙吸收。钙缺乏又引起继发性甲旁亢。最终导致破骨细胞活性增加，骨吸收，发生OP。
VD3及其1,25(OH)2D3治疗OP
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在治疗OP时，医师应全面估价患者的维生素D内分泌系统。如发现有维生素D缺乏或不足，维生素D或1,25(OH)2D3替代疗法则成治疗的选择。每日1000国际单位的维生素D即可达到治疗药物剂量。Torgerson等人曾评价过给老年人服用维生素D及其钙剂有效预防髋骨骨折。[7]
然而许多Ⅰ型或Ⅱ型的患者有1,25(OH)2D3代谢障碍。在这种情况下，给予1,25(OH)2D3是适宜的。Tilqard等人报导了用Rocaltrol0、25μg，每日两次的剂量治疗绝经后妇女的脊柱压缩性骨折[5]。在三年的治疗之后，他们的结论是：用1,25(OH)2D3可以予防再发脊柱骨骨折。, 百拇医药