第五屆“維生素D爭(zhēng)議”國(guó)際會(huì)議

——老年人群中的維生素D：共識(shí)聲明

Vitamin D in the older population: a consensus statement

Giustina A, Bouillon R, Dawson-Hughes B, etal.
Endocrine. 2023 Jan;79(1):31-44.

介紹

第五屆“維生素D爭(zhēng)議”國(guó)際會(huì)議于2021年9月15日至18日在意大利Stresa舉行，這是2017年開始的系列會(huì)議之一。國(guó)際專家和領(lǐng)導(dǎo)人參加了本次會(huì)議，旨在回顧和討論有關(guān)維生素D的爭(zhēng)議性話題。四場(chǎng)會(huì)議討論了維生素D的不同主要方面：衰老、胃腸道系統(tǒng)、指南和COVID-19。會(huì)前參與者回顧了他們指定主題的現(xiàn)有文獻(xiàn)，并在會(huì)議期間進(jìn)行了充分的討論以達(dá)成共識(shí)。本文總結(jié)了專家們對(duì)衰老與維生素D的討論。這部分回顧的文章類型沒(méi)有限制，優(yōu)先考慮隨機(jī)臨床試驗(yàn)；沒(méi)有這些資料時(shí)，會(huì)考慮觀察、實(shí)驗(yàn)或意見(jiàn)研究。此外，研究中“老年人口”的年齡界限從>65歲到>75歲各不相同，其中以>65歲為界限的居多。

年齡對(duì)維生素D的影響

維生素D的產(chǎn)生和代謝都會(huì)隨著衰老而變化，原因包括：皮膚產(chǎn)生維生素D的能力降低和陽(yáng)光照射減少、刺激胃腸道鈣吸收的維生素D相對(duì)抵抗以及腎功能下降（衰老的腎臟通過(guò)25-羥基維生素D(25[OH]D)產(chǎn)生1,25-二羥基維生素D的能力也較差）。此外，吸煙、較高的身體脂肪百分比也可能會(huì)導(dǎo)致血清25(OH)D濃度降低。

1）皮膚產(chǎn)生維生素D的能力降低

皮膚樣本顯示，從20歲到80歲，7-脫氫膽固醇的濃度下降了50%以上，老化皮膚產(chǎn)生的維生素D大約比年輕皮膚少40%。Chalcraft及其同事通過(guò)十年為自變量和對(duì)數(shù)D₃產(chǎn)量的簡(jiǎn)單線性回歸模型算出：與年齡相關(guān)的維生素D₃產(chǎn)量每十年減少13%，表明70歲時(shí)的維生素D₃產(chǎn)量?jī)H為20歲時(shí)的一半（圖1）。當(dāng)然，皮膚中維生素D生成的潛力取決于一系列因素，季節(jié)、一天中的時(shí)間、緯度、海拔、云量、空氣污染、皮膚類型、衣服、防曬霜和生活方式等都會(huì)影響太陽(yáng)UV-B能量刺激皮膚合成維生素D的能力。

圖1. 維生素D₃生產(chǎn)年齡連續(xù)模型

2）陽(yáng)光照射減少

在皮膚中，波長(zhǎng)為290-315nm的太陽(yáng)紫外線（UV-B）會(huì)將7-脫氫膽固醇轉(zhuǎn)化為前維生素D₃。單次15分鐘的陽(yáng)光照射（>40%身體面積）會(huì)導(dǎo)致皮膚產(chǎn)生大量維生素D。雖然衰老可能會(huì)減少皮膚合成，陽(yáng)光照射仍然是維生素D₃的重要來(lái)源。隨著年齡的增長(zhǎng)，維生素D的產(chǎn)生量會(huì)減少，但皮膚的生產(chǎn)儲(chǔ)備能力是充足的。因此，大多數(shù)老年人可能可以從陽(yáng)光中產(chǎn)生足夠的維生素D，但居家人士仍然需要補(bǔ)充維生素D才能滿足維生素D需求。

經(jīng)證實(shí)，每周三次，在背部1000cm²的表面上以最小紅斑劑量的一半進(jìn)行人工紫外線照射，可在3個(gè)月內(nèi)使平均血清25(OH)D從25nmol/L增加到60nmol/L，與每日口服維生素D₃ 400IU的效果相似。這一觀察結(jié)果表明，在這些條件下，每天1000cm²的皮膚暴露可能導(dǎo)致血清25(OH)D的增加，相當(dāng)于每天補(bǔ)充約800IU的維生素D(>70歲人群的每日推薦量)。在另一項(xiàng)研究中，8名缺乏維生素D的老年精神科患者每周接受一次半身紫外線照射，照射劑量為最小紅斑劑量的一半（2分鐘），持續(xù)8周。中位血清25(OH)D從基線時(shí)的26.5nmol/L（范圍12-58）增加至43.5nmol/L（范圍36-71）。皮膚表面積超過(guò)15000cm²，理論上皮膚中可能產(chǎn)生的維生素D量可能很高，即使是老年患者，紫外線照射也能有效觸發(fā)皮膚維生素D的合成。

維生素D缺乏對(duì)老年人的影響

1.骨骼

嚴(yán)重的維生素D缺乏會(huì)對(duì)骨骼產(chǎn)生不利影響，包括骨軟化、高骨轉(zhuǎn)換和骨質(zhì)流失，以及老年人髖部骨折的風(fēng)險(xiǎn)增加（圖2）。維生素D是一種閾值營(yíng)養(yǎng)素，在嚴(yán)重缺乏維生素D的個(gè)體中，維生素D可以降低老年人骨折風(fēng)險(xiǎn)；輕度維生素D缺乏會(huì)導(dǎo)致骨質(zhì)疏松癥的發(fā)生，但單獨(dú)補(bǔ)充維生素D似乎并不能減少骨折。Chapuy等人研究發(fā)現(xiàn)，法國(guó)老年非臥床療養(yǎng)院和公寓婦女在18個(gè)月內(nèi)，每日補(bǔ)充維生素D（800IU）和鈣（1200mg），髖部和其他非椎骨骨折分別減少43%和32%。在該人群中，平均基線血清25(OH)D濃度僅為36nmol/L。然而，測(cè)試采用的是老式競(jìng)爭(zhēng)性蛋白質(zhì)結(jié)合法，測(cè)值比高效液相色譜法高80%。高效液相色譜交叉校準(zhǔn)濃度平均值約為20nmol/L，表明大多數(shù)參與者患有中度或重度維生素D缺乏癥。

嚴(yán)重缺乏維生素D的個(gè)體甲狀旁腺激素（PTH）水平會(huì)升高，這種繼發(fā)性甲狀旁腺功能亢進(jìn)癥可能導(dǎo)致骨質(zhì)流失和骨折風(fēng)險(xiǎn)的病理生理學(xué)變化。兩項(xiàng)較早的研究提供了可參考的25(OH)D閾值，低于該閾值PTH水平可能會(huì)上升。在MORE試驗(yàn)中，與血清25(OH)D>50nmol/L（3.5±1.5pmol/L）的女性相比，兩組不同程度維生素D缺乏的女性血清PTH較高（血清25(OH)D<25nmol/L和25(OH)D 25-50nmol/L；PTH分別為4.8±2.2和4.1±1.8pmol/L）。血清25(OH)D>50nmol/L組血清PTH無(wú)明顯下降，維生素D處理后兩組血清PTH均顯著降低。一項(xiàng)基于LASA內(nèi)收集數(shù)據(jù)的研究發(fā)現(xiàn)25(OH)D的閾值范圍為40-60nmol/L。在另一項(xiàng)針對(duì)絕經(jīng)后骨質(zhì)疏松婦女的研究中，PTH繼發(fā)性升高的閾值也出現(xiàn)在血清25(OH)D 50nmol/L濃度時(shí)。關(guān)于25(OH)D的精確水平仍然存在一些爭(zhēng)議，如果能夠清楚地確定這樣一個(gè)閾值，人們就可以通過(guò)維生素D缺乏引起的繼發(fā)性甲狀旁腺功能亢進(jìn)的程度來(lái)定義維生素D缺乏的程度。然而，這個(gè)閾值也可能取決于其他因素，如鈣攝入量和體力活動(dòng)。

圖2. 老年人維生素D缺乏對(duì)骨骼的影響以及維生素D在預(yù)防中的作用

2.骨密度

新西蘭維生素D評(píng)估(ViDA)研究的一項(xiàng)針對(duì)老年社區(qū)居住男性和女性的研究表明，連續(xù)2年每月服用100000IU維生素D，平均基線血清25(OH)D水平為55nmol/L的人群股骨頸和髖部骨質(zhì)流失無(wú)改善?；€血清25(OH)D<30nmol/L的人群，脊柱、股骨頸和全髖骨丟失有所改善，并且在脊柱和股骨頸處具有統(tǒng)計(jì)學(xué)顯著性。相比之下，基線血清25(OH)D>30nmol/L的患者僅全髖部骨質(zhì)流失，減少幅度較小。在ViDA研究的整個(gè)隊(duì)列中，平均基線血清25(OH)D濃度為66nmol/L且鈣攝入量充足，補(bǔ)充維生素D₃超過(guò)3.3年并沒(méi)有降低骨折的發(fā)生率。

在第二項(xiàng)研究，即Aberdeen研究中，在冬末招募了305名絕經(jīng)后婦女，并隨機(jī)讓她們接受維生素D 400IU/天、1000IU/天或安慰劑，為期一年。事后分析顯示，維生素D 1000IU/天對(duì)基線25(OH)D≤30nmol/L的患者的脊柱和髖部BMD具有顯著改善作用，但對(duì)基線25(OH)D高于這一水平的患者沒(méi)有顯著影響。血清25(OH)D水平<30nmol/L的老年人最有可能出現(xiàn)骨骼負(fù)面影響，而補(bǔ)充維生素D有明顯的改善作用。

3.跌倒

Meta分析的結(jié)果相互矛盾，但適度劑量的維生素D（每天700-1000IU）似乎可以降低缺乏維生素D的老年人跌倒的風(fēng)險(xiǎn)。相反，不頻繁的較大劑量補(bǔ)充可能會(huì)增加跌倒風(fēng)險(xiǎn)。在基線25(OH)D水平<50nmol/L的絕經(jīng)后婦女中進(jìn)行的一項(xiàng)隨機(jī)前瞻性、安慰劑對(duì)照的多劑量維生素D試驗(yàn)發(fā)現(xiàn)，低劑量維生素D治療可降低跌倒的風(fēng)險(xiǎn)，而每天4000和4800IU的劑量可增加跌倒的風(fēng)險(xiǎn)。因此，每日應(yīng)低至中劑量的維生素D補(bǔ)充，避免每日或間歇性高劑量補(bǔ)充。

4.骨骼外效應(yīng)

維生素D被代謝成大約50種代謝物，它的活性形式1,25(OH)²D為維生素D受體（VDR）的配體。VDR在大多數(shù)組織中表達(dá)，它的普遍存在是維生素D具有許多骨骼外作用這一假設(shè)的基礎(chǔ)，這一主題在小組之前會(huì)議上最近發(fā)表的幾篇文章中進(jìn)行了回顧（圖3）。

圖3. 老年人缺乏維生素D對(duì)骨骼的額外影響以及維生素D的預(yù)防作用

注：實(shí)線表示已知的效果，虛線表示可能的影響。

5.骨骼肌

一般認(rèn)為維生素D缺乏影響兩種不同的肌肉骨骼途徑，一種涉及神經(jīng)肌肉組織的影響，導(dǎo)致跌倒和骨折；另一種通過(guò)鈣吸收減少，導(dǎo)致甲狀旁腺激素（PTH）水平升高，骨吸收增加，骨質(zhì)流失導(dǎo)致骨折風(fēng)險(xiǎn)增加。維生素D和鈣缺乏時(shí)，可能導(dǎo)致循環(huán)甲狀旁腺激素水平的增加，對(duì)肌肉造成直接的不良影響。臨床前和臨床證據(jù)表明甲狀旁腺激素對(duì)肌肉有直接影響，完整的牛PTH和合成的PTH1-34片段增加了大鼠骨骼肌的肌肉降解和新合成的丙氨酸和谷氨酰胺的釋放。

臨床上，晚期原發(fā)性甲狀旁腺功能亢進(jìn)患者有神經(jīng)肌肉體征和癥狀以及肌肉無(wú)力，甲狀旁腺手術(shù)成功后肌肉無(wú)力很快逆轉(zhuǎn)。兩組老年婦女具有相似的臨床特征，25(OH)D水平低，但PTH水平不同（高于或在范圍內(nèi)），在幾項(xiàng)肌肉力量和功能測(cè)試中表現(xiàn)不同。PTH水平較高的組膝關(guān)節(jié)屈曲強(qiáng)度較低，最大肌力產(chǎn)生較低，姿勢(shì)穩(wěn)定性降低。一項(xiàng)小型觀察性研究，調(diào)查了83名平均年齡為84歲的養(yǎng)老院居民{25(OH)D平均水平為27nmol/L、PTH中位水平為5.2pmol/L(參考范圍1-6.5pmol/L)}，評(píng)估了甲狀旁腺激素在跌倒中的作用。在此期間，33名參與者至少跌倒一次。那些跌倒的人有較低的25(OH)D水平和較高的甲狀旁腺激素水平，而兩組的1,25(OH)₂D水平?jīng)]有顯著差異。Logistic回歸分析表明甲狀旁腺激素水平是跌倒的獨(dú)立決定因素。Sambrook等人對(duì)637名普遍缺乏維生素D的老年人進(jìn)行了一項(xiàng)大型觀察性研究，這些老年人平均年齡為86歲，居住在澳大利亞的中等全面護(hù)理機(jī)構(gòu)。跌倒者和非跌倒者血清25(OH)D水平分別為28.8和33.2nmol/L，PTH水平分別為64.8和57.0pg/ml。邏輯回歸顯示甲狀旁腺激素是跌倒的獨(dú)立預(yù)測(cè)因子。每天低劑量的維生素D可能會(huì)降低缺乏維生素D的老年人跌倒的風(fēng)險(xiǎn)，進(jìn)一步檢查跌倒的獨(dú)立預(yù)測(cè)因子——甲狀旁腺激素也是必要的。

6.心血管疾病

臨床前數(shù)據(jù)表明缺乏維生素D與心血管風(fēng)險(xiǎn)有關(guān)。實(shí)驗(yàn)表明，缺乏VDR可引起高腎素高血壓、心肌肥大和纖維化、血栓形成增強(qiáng)。兩項(xiàng)大型隨機(jī)對(duì)照試驗(yàn)（VIDA和VITAL）清楚地表明，補(bǔ)充維生素D不會(huì)減少心血管疾病，VIDA試驗(yàn)顯示補(bǔ)充維生素D對(duì)中心血壓有輕微的改善作用。

孟德?tīng)栯S機(jī)化（MR）研究沒(méi)有發(fā)現(xiàn)遺傳性低血清25(OH)D濃度與CV疾病之間的聯(lián)系，但這些研究中的綜合多態(tài)性不允許任何大于5%的血清25(OH)D變異的預(yù)測(cè)值。最近一項(xiàng)大型磁共振研究的總體結(jié)果證實(shí)了這一結(jié)論，但通過(guò)結(jié)合磁共振和血清25(OH)D水平來(lái)看，嚴(yán)重缺乏維生素D組血清25(OH)D的遺傳水平較低（<10 ng/mL）會(huì)增加CV疾病和死亡率。維生素D狀態(tài)不是心血管疾病負(fù)擔(dān)的主要因素，但終身嚴(yán)重缺乏維生素D可能起心血管疾病。

7.癌癥

許多受維生素D內(nèi)分泌系統(tǒng)調(diào)控的基因參與調(diào)控細(xì)胞周期和細(xì)胞分化。動(dòng)物和臨床前數(shù)據(jù)表明，維生素D作用的完全缺乏易導(dǎo)致癌癥，且在早期補(bǔ)充維生素D可預(yù)防癌變。維生素D缺乏與許多癌癥有關(guān)，尤其是結(jié)腸癌、乳腺癌和前列腺癌。兩個(gè)主要的大型隨機(jī)對(duì)照試驗(yàn)（VITAL和VIDA）沒(méi)有發(fā)現(xiàn)長(zhǎng)期補(bǔ)充維生素D對(duì)癌癥發(fā)病率的影響。然而，根據(jù)VITAL、四項(xiàng)類似的Meta分析研究及D-health研究，發(fā)現(xiàn)每天補(bǔ)充2000IU維生素D的患者，癌癥死亡率顯著降低；每月高劑量（60000IU）維生素D補(bǔ)充的患者癌癥的死亡風(fēng)險(xiǎn)增加。

8.糖尿病

許多臨床前和觀察性研究表明，維生素D水平低與2型糖尿病（T2D）之間存在聯(lián)系。兩項(xiàng)專門用于預(yù)防糖尿病的試驗(yàn)表明，與安慰劑相比，補(bǔ)充維生素D可使未選擇維生素D缺乏癥的糖尿病前期患者患糖尿病的風(fēng)險(xiǎn)降低10-13%。這與最近的兩項(xiàng)Meta分析結(jié)論一致，即補(bǔ)充維生素D可使T2D進(jìn)展的風(fēng)險(xiǎn)降低約10%，特別是在使用劑量超過(guò)1000IU/天且非肥胖受試者中。然而，在維生素D與2型糖尿病研究（D2d）的大型隨機(jī)對(duì)照試驗(yàn)中，補(bǔ)充維生素D僅顯示出減緩糖尿病前期向T2D進(jìn)展的非顯著趨勢(shì)（0.88CI為0.75-1.04；P=0.12）。

維生素D和鈣

維生素D的膳食來(lái)源很少。大多數(shù)采用西方飲食的體弱老年人每天的維生素D攝入量較低（即約150IU），他們的陽(yáng)光照射和皮膚維生素D合成能力受到限制，含鈣食物也可能攝入不足。隨機(jī)對(duì)照試驗(yàn)（RCT）的Meta分析表明，維生素D與鈣結(jié)合使用且依從率>80%時(shí)，可使髖部骨折和其他非椎骨骨折的發(fā)生率分別降低16%和14%。與60-70歲的人相比，70-80歲以上的人對(duì)骨折的影響更大。Yao及其同事最近進(jìn)行的一項(xiàng)Meta分析得出了類似的結(jié)論，維生素D可使任何骨折的風(fēng)險(xiǎn)降低6%，髖部骨折的風(fēng)險(xiǎn)降低16%，但前提是同時(shí)服用鈣補(bǔ)充劑。因此，大多數(shù)老年人應(yīng)該補(bǔ)充維生素D和鈣。

預(yù)防維生素D缺乏的策略

當(dāng)前各國(guó)面臨的一個(gè)共問(wèn)題是如何實(shí)施公共衛(wèi)生政策來(lái)預(yù)防老年人維生素D缺乏。除了充足的飲食之外，關(guān)鍵是陽(yáng)光照射、食物強(qiáng)化及補(bǔ)充劑（圖4）。

圖4. 老年人避免維生素D缺乏的策略及相關(guān)限制

1.陽(yáng)光照射

增加紫外線照射來(lái)提高維生素D水平是有爭(zhēng)議的。世界衛(wèi)生組織認(rèn)為，紫外線照射造成的健康威脅可能超過(guò)維生素D缺乏造成的健康風(fēng)險(xiǎn)。非黑色素瘤皮膚癌占全球所有癌癥的三分之一，主要存在于老年人群中，紫外線照射是其主要原因。盡管這一策略存在爭(zhēng)議，但應(yīng)該清楚地認(rèn)識(shí)到，血清25(OH)D水平在世界范圍內(nèi)存在季節(jié)性變化，夏季后增加。陽(yáng)光充足的國(guó)家維生素D含量較高，佝僂病和骨軟化癥的患病率較低。年齡和陽(yáng)光照射是影響血清25(OH)D水平的重要因素。戶外活動(dòng)被視為預(yù)防嚴(yán)重維生素D缺乏、改善健康的合理措施，但人們必須了解過(guò)度日曬的風(fēng)險(xiǎn)，以避免曬傷、防曬霜的使用以及如何及早識(shí)別癌性皮膚病變。

2.食品和食品強(qiáng)化

在過(guò)去3年中，發(fā)表了兩項(xiàng)重要聲明，一項(xiàng)來(lái)自關(guān)于維生素D的二等獎(jiǎng)基金論壇，一項(xiàng)來(lái)自歐洲鈣化組織協(xié)會(huì)。這些強(qiáng)調(diào)了公共衛(wèi)生目標(biāo)是降低佝僂病和骨軟化癥的風(fēng)險(xiǎn)，并避免血清25(OH)D水平低于25nmol/L。食物中維生素D的天然來(lái)源很少（西方飲食中每天約為150IU）。因此，在食品中添加維生素D是一種有效的策略，適用于大量人群以避免嚴(yán)重缺乏，特別是對(duì)于陽(yáng)光照射有限的國(guó)家。加拿大，牛奶中維生素D強(qiáng)化是強(qiáng)制性的，與英國(guó)、美國(guó)和德國(guó)相比，血清水平低于25nmol/l的發(fā)生率較低。

3.補(bǔ)充維生素D

補(bǔ)充維生素D似乎是有效實(shí)現(xiàn)維生素D充足的最簡(jiǎn)單方法。大多數(shù)已測(cè)試的方案均顯示血清25(OH)D水平呈劑量依賴性增加，但存在顯著個(gè)體差異。結(jié)合強(qiáng)化和補(bǔ)充來(lái)解決維生素D缺乏問(wèn)題，理想情況下可將整個(gè)人群的血清25(OH)D水平提高至50nmol/L。一些使用間歇性高劑量維生素D補(bǔ)充劑的研究表明，跌倒和骨折的風(fēng)險(xiǎn)會(huì)增加，因此優(yōu)選每日或每周補(bǔ)充劑量。

Cashman及其同事根據(jù)7項(xiàng)基于冬季的隨機(jī)對(duì)照試驗(yàn)（包括882項(xiàng)）的Meta回歸分析，計(jì)算了達(dá)到血液中目標(biāo)血清25(OH)D水平的每日劑量，參與者年齡從4歲到90歲。結(jié)論是避免嚴(yán)重缺乏（即97.5%的個(gè)體達(dá)到25nmol/L）的每日劑量是400IU。每天則需要1000IU才能達(dá)到50nmol/L的安全水平；然而，每天1000IU的劑量比醫(yī)學(xué)研究所(IOM)和其他監(jiān)管機(jī)構(gòu)先前推薦的劑量要高。

總結(jié)

老年人群中應(yīng)避免血清25(OH)D<30nmol/L，以防維生素D缺乏會(huì)對(duì)骨骼產(chǎn)生影響，如BMD下降、繼發(fā)性甲狀旁腺功能亢進(jìn)和骨軟化癥。治療目標(biāo)應(yīng)側(cè)重于避免25(OH)D血清水平<30nmol/L，目標(biāo)是達(dá)到>50nmol/L水平，以避免維生素D缺乏帶來(lái)的不利影響。為了減少老年人骨折，充足的維生素D和鈣是必要的。

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