第五屆“維生素D爭議”國際會議

——老年人群中的維生素D：共識聲明

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爭議”國際會議于2021年9月15日至18日在意大利Stresa舉行，這是2017年開始的系列會議之一。國際專家和領(lǐng)導人參加了本次會議，旨在回顧和討論有關(guān)維生素D的爭議性話題。四場會議討論了維生素D的不同主要方面：衰老、胃腸道系統(tǒng)、指南和COVID-19。會前參與者回顧了他們指定主題的現(xiàn)有文獻，并在會議期間進行了充分的討論以達成共識。本文總結(jié)了專家們對衰老與維生素D的討論。這部分回顧的文章類型沒有限制，優(yōu)先考慮隨機臨床試驗；沒有這些資料時，會考慮觀察、實驗或意見研究。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。

年齡對維生素D的影響

維生素D的產(chǎn)生和代謝都會隨著衰老而變化，原因包括：皮膚產(chǎn)生維生素D的能力降低和陽光照射減少、刺激胃腸道鈣吸收的維生素D相對抵抗以及腎功能下降（衰老的腎臟通過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導致血清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及其同事通過十年為自變量和對數(shù)D₃產(chǎn)量的簡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歲時的維生素D₃產(chǎn)量僅為20歲時的一半（圖1）。當然，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影響太陽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）陽光照射減少

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

經(jīng)證實，每周三次，在背部1000cm²的表面上以最小紅斑劑量的一半進行人工紫外線照射，可在3個月內(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的皮膚暴露可能導致血清25(OH)D的增加，相當于每天補充約800IU的維生素D(>70歲人群的每日推薦量)。在另一項研究中，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缺乏對老年人的影響

1.骨骼

嚴重的維生素D缺乏會對骨骼產(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險增加（圖2）。維生素D是一種閾值營養(yǎng)素，在嚴重缺乏維生素D的個體中，維生素D可以降低老年人骨折風險；輕度維生素D缺乏會導致骨質(zhì)疏松癥的發(fā)生，但單獨補充維生素D似乎并不能減少骨折。Chapuy等人研究發(fā)現(xiàn)，法國老年非臥床療養(yǎng)院和公寓婦女在18個月內(nèi)，每日補充維生素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，測試采用的是老式競爭性蛋白質(zhì)結(jié)合法，測值比高效液相色譜法高80%。高效液相色譜交叉校準濃度平均值約為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。

嚴重缺乏維生素D的個體甲狀旁腺激素（PTH）水平會升高，這種繼發(fā)性甲狀旁腺功能亢進癥可能導致骨質(zhì)流失和骨折風險的病理生理學變化。兩項較早的研究提供了可參考的25(OH)D閾值，低于該閾值PTH水平可能會上升。在MORE試驗中，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無明顯下降，維生素D處理后兩組血清PTH均顯著降低。一項基于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。在另一項針對絕經(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。關(guān)于25(OH)D的精確水平仍然存在一些爭議，如果能夠清楚地確定這樣一個閾值，人們就可以通過維生素D缺乏引起的繼發(fā)性甲狀旁腺功能亢進的程度來定義維生素D缺乏的程度。然而，這個閾值也可能取決于其他因素，如鈣攝入量和體力活動。

圖2. 老年人維生素D缺乏對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評估(ViDA)研究的一項針對老年社區(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)計學顯著性。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研究的整個隊列中，平均基線血清25(OH)D濃度為66nmol/L且鈣攝入量充足，補充維生素D₃超過3.3年并沒有降低骨折的發(fā)生率。

在第二項研究，即Aberdeen研究中，在冬末招募了305名絕經(jīng)后婦女，并隨機讓她們接受維生素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，但對基線25(OH)D高于這一水平的患者沒有顯著影響。血清25(OH)D水平<30nmol/L的老年人最有可能出現(xiàn)骨骼負面影響，而補充維生素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的老年人跌倒的風險。相反，不頻繁的較大劑量補充可能會增加跌倒風險。在基線25(OH)D水平<50nmol/L的絕經(jīng)后婦女中進行的一項隨機前瞻性、安慰劑對照的多劑量維生素D試驗發(fā)現(xiàn)，低劑量維生素D治療可降低跌倒的風險，而每天4000和4800IU的劑量可增加跌倒的風險。因此，每日應(yīng)低至中劑量的維生素D補充，避免每日或間歇性高劑量補充。

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，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議上最近發(fā)表的幾篇文章中進行了回顧（圖3）。

圖3. 老年人缺乏維生素D對骨骼的額外影響以及維生素D的預(yù)防作用

注：實線表示已知的效果，虛線表示可能的影響。

5.骨骼肌

一般認為維生素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，導致跌倒和骨折；另一種通過鈣吸收減少，導致甲狀旁腺激素（PTH）水平升高，骨吸收增加，骨質(zhì)流失導致骨折風險增加。維生素D和鈣缺乏時，可能導致循環(huán)甲狀旁腺激素水平的增加，對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患者有神經(jīng)肌肉體征和癥狀以及肌肉無力，甲狀旁腺手術(shù)成功后肌肉無力很快逆轉(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)），在幾項肌肉力量和功能測試中表現(xiàn)不同。PTH水平較高的組膝關(guān)節(jié)屈曲強度較低，最大肌力產(chǎn)生較低，姿勢穩(wěn)定性降低。一項小型觀察性研究，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立決定因素。Sambrook等人對637名普遍缺乏維生素D的老年人進行了一項大型觀察性研究，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理機構(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立預(yù)測因子。每天低劑量的維生素D可能會降低缺乏維生素D的老年人跌倒的風險，進一步檢查跌倒的獨立預(yù)測因子——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與心血管風險有關(guān)。實驗表明，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。兩項大型隨機對照試驗（VIDA和VITAL）清楚地表明，補充維生素D不會減少心血管疾病，VIDA試驗顯示補充維生素D對中心血壓有輕微的改善作用。

孟德爾隨機化（MR）研究沒有發(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)測值。最近一項大型磁共振研究的總體結(jié)果證實了這一結(jié)論，但通過結(jié)合磁共振和血清25(OH)D水平來看，嚴重缺乏維生素D組血清25(OH)D的遺傳水平較低（<10 ng/mL）會增加CV疾病和死亡率。維生素D狀態(tài)不是心血管疾病負擔的主要因素，但終身嚴重缺乏維生素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)控細胞周期和細胞分化。動物和臨床前數(shù)據(jù)表明，維生素D作用的完全缺乏易導致癌癥，且在早期補充維生素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。兩個主要的大型隨機對照試驗（VITAL和VIDA）沒有發(fā)現(xiàn)長期補充維生素D對癌癥發(fā)病率的影響。然而，根據(jù)VITAL、四項類似的Meta分析研究及D-health研究，發(fā)現(xiàn)每天補充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補充的患者癌癥的死亡風險增加。

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?。═2D）之間存在聯(lián)系。兩項專門用于預(yù)防糖尿病的試驗表明，與安慰劑相比，補充維生素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險降低10-13%。這與最近的兩項Meta分析結(jié)論一致，即補充維生素D可使T2D進展的風險降低約10%，特別是在使用劑量超過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）的大型隨機對照試驗中，補充維生素D僅顯示出減緩糖尿病前期向T2D進展的非顯著趨勢（0.88CI為0.75-1.04；P=0.12）。

維生素D和鈣

維生素D的膳食來源很少。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。隨機對照試驗（RCT）的Meta分析表明，維生素D與鈣結(jié)合使用且依從率>80%時，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歲以上的人對骨折的影響更大。Yao及其同事最近進行的一項Meta分析得出了類似的結(jié)論，維生素D可使任何骨折的風險降低6%，髖部骨折的風險降低16%，但前提是同時服用鈣補充劑。因此，大多數(shù)老年人應(yīng)該補充維生素D和鈣。

預(yù)防維生素D缺乏的策略

當前各國面臨的一個共問題是如何實施公共衛(wèi)生政策來預(yù)防老年人維生素D缺乏。除了充足的飲食之外，關(guān)鍵是陽光照射、食物強化及補充劑（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.陽光照射

增加紫外線照射來提高維生素D水平是有爭議的。世界衛(wèi)生組織認為，紫外線照射造成的健康威脅可能超過維生素D缺乏造成的健康風險。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議，但應(yīng)該清楚地認識到，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。陽光充足的國家維生素D含量較高，佝僂病和骨軟化癥的患病率較低。年齡和陽光照射是影響血清25(OH)D水平的重要因素。戶外活動被視為預(yù)防嚴重維生素D缺乏、改善健康的合理措施，但人們必須了解過度日曬的風險，以避免曬傷、防曬霜的使用以及如何及早識別癌性皮膚病變。

2.食品和食品強化

在過去3年中，發(fā)表了兩項重要聲明，一項來自關(guān)于維生素D的二等獎基金論壇，一項來自歐洲鈣化組織協(xié)會。這些強調(diào)了公共衛(wèi)生目標是降低佝僂病和骨軟化癥的風險，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重缺乏，特別是對于陽光照射有限的國家。加拿大，牛奶中維生素D強化是強制性的，與英國、美國和德國相比，血清水平低于25nmol/l的發(fā)生率較低。

3.補充維生素D

補充維生素D似乎是有效實現(xiàn)維生素D充足的最簡單方法。大多數(shù)已測試的方案均顯示血清25(OH)D水平呈劑量依賴性增加，但存在顯著個體差異。結(jié)合強化和補充來解決維生素D缺乏問題，理想情況下可將整個人群的血清25(OH)D水平提高至50nmol/L。一些使用間歇性高劑量維生素D補充劑的研究表明，跌倒和骨折的風險會增加，因此優(yōu)選每日或每周補充劑量。

Cashman及其同事根據(jù)7項基于冬季的隨機對照試驗（包括882項）的Meta回歸分析，計算了達到血液中目標血清25(OH)D水平的每日劑量，參與者年齡從4歲到90歲。結(jié)論是避免嚴重缺乏（即97.5%的個體達到25nmol/L）的每日劑量是400IU。每天則需要1000IU才能達到50nmol/L的安全水平；然而，每天1000IU的劑量比醫(yī)學研究所(IOM)和其他監(jiān)管機構(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缺乏會對骨骼產(chǎn)生影響，如BMD下降、繼發(fā)性甲狀旁腺功能亢進和骨軟化癥。治療目標應(yīng)側(cè)重于避免25(OH)D血清水平<30nmol/L，目標是達到>50nmol/L水平，以避免維生素D缺乏帶來的不利影響。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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