繼發(fā)性骨質(zhì)疏松癥的治療方案：藥物性、糖尿病性、腎病性、白血病相關、感染相關、風濕病相關骨質(zhì)疏松癥、與妊娠相關的短暫性髖關節(jié)骨質(zhì)疏松癥：2010年

作者：Lorenz C Hofbauer, Christine Hamann, Peter R Ebeling.

作者單位: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III and Center of Regenerative Therapies Dresden (CRTD), Technical University Medical Center, Fetscherstrasse 74, Dresden, Germany. [email protected]

譯者：陶可（北京大學人民醫(yī)院骨關節(jié)科）

摘要

繼發(fā)性骨質(zhì)疏松癥的特征是骨量低，骨微結(jié)構(gòu)改變導致在存在潛在疾病或藥物治療的情況下發(fā)生脆性骨折。高度懷疑繼發(fā)性骨質(zhì)疏松癥的情況，包括年輕男性或絕經(jīng)前女性的脆性骨折、極低的骨礦物質(zhì)密度(BMD)值以及抗骨質(zhì)疏松癥治療后的骨折。一種開放的方法，詳細的病史和體格檢查，結(jié)合一線實驗室檢查，旨在確定骨折、骨質(zhì)疏松癥誘導藥物，以及潛在的內(nèi)分泌、胃腸道、血液學或風濕病的臨床危險因素，然后需要通過特定的和/或更具有創(chuàng)性的檢測來確認（繼發(fā)性骨質(zhì)疏松癥）。礦物質(zhì)密度BMD應通過髖部和脊柱的骨密度測定法進行評估。同時，應進行胸椎和腰椎側(cè)位X線檢查，以識別或排除臨床上可能無癥狀的常見椎體骨折。繼發(fā)性骨質(zhì)疏松癥的治療包括基礎疾病的治療、已知會影響骨骼的藥物的改良以及特定的抗骨質(zhì)疏松癥治療。鈣和維生素D的補充應以導致正常血鈣和血清25-羥基維生素D濃度至少為30 ng/ml的劑量開始。口服和靜脈注射雙膦酸鹽是治療大多數(shù)繼發(fā)性骨質(zhì)疏松癥的有效且安全的藥物。嚴重的骨質(zhì)疏松癥可能需要使用特立帕肽（特立帕肽注射液(Teriparatide Injection)是禮來公司的原研產(chǎn)品，系采用大腸桿菌表達制備的重組人甲狀旁腺素(1-34)注射液。是國內(nèi)唯一批準上市的促骨形成類抗骨松藥物，能夠有效改善骨微結(jié)構(gòu)、增加骨強度，同時能促進骨愈合，降低椎體和非椎體骨折風險，是治療骨質(zhì)疏松癥的理想藥物之一。在過去的二十年中，在絕經(jīng)后和糖皮質(zhì)激素引起的骨質(zhì)疏松癥的臨床試驗中，特立帕肽已被證明可有效減少椎骨和非椎骨骨折）。

冬日多曬太陽，以增加維生素D的皮膚合成。

正常人每天在三餐基礎上，保證1杯牛奶（300ml）或1片鈣片攝入；日曬不足時，可每日增加1粒骨化三醇膠囊（可定期檢測血鈣和25-羥維生素D水平，調(diào)整用藥）。

保持良好心態(tài)，保證良好睡眠，堅持每周適當戶外有氧體育鍛煉。

表1 繼發(fā)性骨質(zhì)疏松癥的常見原因

內(nèi)分泌疾病

糖尿病

生長激素GH缺乏（罕見）

肢端肥大癥（罕見）

皮質(zhì)醇增多癥

甲狀旁腺功能亢進

甲亢

過早絕經(jīng)

男性性腺機能減退

胃腸道疾病

胃切除術

乳糜瀉（習慣性腹瀉）

炎癥性腸病

肝硬化

慢性膽道梗阻

質(zhì)子泵抑制劑的慢性治療（即長時間使用抑制胃酸藥，如奧美拉唑腸溶片、潘多拉唑腸溶膠囊等）

血液系統(tǒng)疾病

骨髓瘤

意義不明的單克隆丙種球蛋白病

淋巴瘤/白血病

系統(tǒng)性肥大細胞增多癥（罕見）

播散性癌

化療

風濕病

類風濕關節(jié)炎

強直性脊柱炎

系統(tǒng)性紅斑狼瘡

結(jié)締組織疾病

成骨不全癥

馬凡氏綜合癥（罕見）

Ehlers-Danlos綜合征（罕見）

彈性假黃瘤（罕見）

其他

神經(jīng)性厭食癥

背景

繼發(fā)性骨質(zhì)疏松癥被定義為由于潛在疾病或同時使用藥物所導致的骨質(zhì)流失、骨微結(jié)構(gòu)改變和脆性骨折(1)。繼發(fā)性骨質(zhì)疏松癥仍然是一個診斷和治療挑戰(zhàn)，因為它經(jīng)常影響患者群體，例如絕經(jīng)前女性或年輕男性通常不是骨質(zhì)疏松癥常規(guī)篩查的目標人群。此外，潛在的條件多種多樣且罕見，需要特定的診斷測試(1)。此外，如果潛在疾病未被識別并且存在其他危險因素，則對骨質(zhì)疏松癥治療的反應可能會受到限制。例如，在分化型甲狀腺癌治療后，阿侖膦酸鹽對絕經(jīng)后骨質(zhì)疏松癥和TSH抑制性L-甲狀腺素(L-T4)治療的女性療效降低(2)。需要注意的是，許多藥物的抗骨折功效尚未得到明確證明，除了糖皮質(zhì)激素誘導的骨質(zhì)疏松癥（GIO）和繼發(fā)性骨質(zhì)疏松癥中的男性性腺功能減退癥外，特定抗骨質(zhì)疏松癥藥物的使用基于骨礦物質(zhì)密度（BMD）作為臨床療效的觀察指標。

除了眾所周知的內(nèi)分泌疾病，包括庫欣綜合征、性腺機能減退、甲狀腺機能亢進和甲狀旁腺功能亢進癥，糖尿病的副作用最近才得到承認（與繼發(fā)性骨質(zhì)疏松癥有關）(3)。事實上，與非糖尿病患者相比，1型糖尿病患者發(fā)生骨質(zhì)疏松性骨折的風險高出12倍(4)。此外，炎癥性腸病和類風濕性關節(jié)炎中存在的慢性炎癥會導致骨質(zhì)疏松癥，部分原因是促炎細胞因子環(huán)境和免疫抑制方案(5)。噻唑烷二酮類(TZD) (6)、芳香化酶抑制劑(AI) (7)、男性前列腺癌患者的雄激素剝奪療法(8)以及不斷增長的減肥手術領域(9)的新興應用，已成為新的且重要的繼發(fā)性骨質(zhì)疏松癥的病因領域。

在這里，我們總結(jié)了關于繼發(fā)性骨質(zhì)疏松癥機制的知識現(xiàn)狀，概述了實用的診斷策略，并提供了臨床治療建議。

機制

內(nèi)分泌疾病

糖皮質(zhì)激素過量

糖皮質(zhì)激素的內(nèi)源性過度表達或全身給藥通過各種細胞效應損害骨骼健康，其中由于誘導成骨細胞和骨細胞凋亡而抑制骨形成是最關鍵的(10)。主要的脊柱骨丟失和椎骨骨折是特征性變化，由于肌肉萎縮和神經(jīng)肌肉功能改變導致跌倒的風險增加（11）。即使是低劑量的糖皮質(zhì)激素（每天2.5-7.5 mg潑尼松龍），椎體骨折的風險也會增加2.6倍，而每天超過7.5 mg潑尼松龍的風險會增加5倍（12）。

在大多數(shù)患有表1中列出的風濕性疾病，特別是類風濕性關節(jié)炎、強直性脊柱炎和系統(tǒng)性紅斑狼瘡的患者中，快速骨質(zhì)流失和骨折風險增加是由促炎細胞因子環(huán)境或免疫抑制方案引起的，最初包括糖皮質(zhì)激素，或兩者之間的平衡。

甲狀腺功能亢進

明顯的甲狀腺功能亢進病史是骨質(zhì)疏松性骨折的既定危險因素(13)。一項針對686名絕經(jīng)后婦女的大型研究表明，血清甲狀腺刺激激素TSH水平≥0.1 mU/l與髖部和椎骨骨折的風險分別為4倍和5倍（14）。對21項研究的薈萃分析表明，在導致亞臨床甲狀腺功能亢進的分化型甲狀腺癌中抑制甲狀腺刺激激素TSH的甲狀腺激素治療與絕經(jīng)后婦女的骨質(zhì)疏松癥有關(15)。根據(jù)動物模型，甲狀腺激素過量(16)以及促甲狀腺激素水平(17)受到抑制。成骨細胞和破骨細胞上甲狀腺激素受體a的激活導致骨吸收和骨丟失增強(16)。

原發(fā)性甲狀旁腺功能亢進癥

女性患原發(fā)性甲狀旁腺功能亢進癥的幾率是男性的三倍，在老年女性（骨質(zhì)疏松癥的高危人群）中其發(fā)病率高達1:500 (18)。慢性甲狀旁腺激素(PTH)過量對骨骼具有分解*謝作用，并且優(yōu)先影響皮質(zhì)而不是松質(zhì)骨。因此，骨丟失在由皮質(zhì)骨組成的骨骼部位（前臂和股骨頸的中間三分之一）最為突出，而主要由松質(zhì)骨組成的脊柱受影響較?。?8）。骨質(zhì)疏松性骨折或T評分＜2.5是其他無癥狀患者進行甲狀旁腺手術的指征(18)。最近一項為期15年的觀察性研究表明，甲狀旁腺切除術使骨轉(zhuǎn)換的生化指標正?；⒈Ａ袅斯敲芏菳MD，而在長期隨訪期間，大多數(shù)未經(jīng)手術的受試者的皮質(zhì)骨密度下降(19)。

男性性腺機能減退

雄激素對于男性骨量峰值的增加和此后骨強度的維持至關重要(8, 20, 21)。雄激素對骨骼的影響可能是由雌激素介導的(22)。

男性性腺機能減退是男性低骨密度BMD和骨質(zhì)疏松性骨折的主要危險因素，并導致骨重塑增加和快速骨丟失(21)。由于使用促性腺激素釋放激素（Gonadotropin-Releasing Hormone, GnRH）激動劑的雄激素剝奪療法，已成為前列腺癌多模式管理的主要方案，因此與治療相關的性腺機能減退，已成為這些男性骨質(zhì)疏松性骨折的重要危險因素(8, 23)。

妊娠相關骨質(zhì)疏松癥

該實體的機制知之甚少。相關因素包括先前存在的維生素D缺乏、鈣和蛋白質(zhì)攝入量低、骨量低、甲狀旁腺激素PTH相關蛋白增加和骨轉(zhuǎn)換率高(24, 25)。多胎妊娠或長時間哺乳本身與骨質(zhì)疏松癥無關。然而，如果女性使用普通肝素治療血栓栓塞性疾病，她們就有患妊娠相關骨質(zhì)疏松癥的風險(26, 27)。低分子量肝素的骨骼副作用目前尚不清楚(28)。

1型糖尿病

1型糖尿病患者發(fā)生骨質(zhì)疏松性骨折的風險增加了12倍(4)。據(jù)推測，缺乏胰島素和其他b細胞衍生蛋白（如胰淀素）的骨合成*謝作用會導致低骨密度BMD和骨折風險受損(3)。在長期存在的疾病中，糖尿病并發(fā)癥，如視網(wǎng)膜病變、多發(fā)性神經(jīng)病變和腎病，是骨量減少和骨折風險增加的主要決定因素，部分原因是跌倒傾向增加(3)。來自女性健康倡議觀察研究的數(shù)據(jù)還表明，在2型糖尿病女性中，在調(diào)整頻繁跌倒和骨密度BMD增加后，骨折風險增加20%（29）。患有2型糖尿病的絕經(jīng)后婦女骨折的另一個重要風險因素是使用TZD型胰島素增敏劑，這與髖部、肱骨和手足小骨的骨折有關(30)。

生長激素GH缺乏

胰島素樣生長因子1 (IGF1)和IGF結(jié)合蛋白在人生長激素GH刺激其肝臟受體時產(chǎn)生，是成骨細胞功能和骨形成的有效刺激物(31, 32)。未經(jīng)治療的成年發(fā)病生長激素GH缺乏癥患者發(fā)生骨質(zhì)疏松性骨折的風險高出2至3倍(32)，并且骨質(zhì)減少的程度與生長激素GH缺乏癥的程度有關(33)。由于身材矮小和骨骼尺寸小，兒童發(fā)病生長激素GH缺乏癥患者骨密度BMD的準確測量很復雜。

胃腸道疾病

乳糜瀉

由胃腸道上皮絨毛萎縮引起的慢性腹瀉和吸收不良是乳糜瀉的標志。鈣的腸道吸收受損，維生素D缺乏很常見（表1），導致骨軟化和繼發(fā)性甲狀旁腺功能亢進（34）。相關的自身免疫性疾病，如伴有胃酸缺乏的A型胃炎、伴有甲狀腺功能亢進的Graves病或1型糖尿病可能會進一步損害骨骼健康。最近的一項研究表明，與非骨質(zhì)疏松癥個體相比，骨質(zhì)疏松癥個體的乳糜瀉患病率高出17倍，支持對所有骨質(zhì)疏松癥患者進行乳糜瀉血清學篩查(35)。

炎癥性腸病

炎癥性腸病中骨質(zhì)疏松癥的發(fā)病機制復雜，與潰瘍性結(jié)腸炎患者相比，克羅恩病患者的影響更為嚴重（36）。慢性炎癥、腹瀉和/或吸收不良、低體重指數(shù)(BMI)以及針對發(fā)作的間歇性或慢性全身性糖皮質(zhì)激素治療是骨質(zhì)疏松癥的主要原因。此外，短腸綜合征或回腸末端完整性功能喪失、反復住院和長期不動的患者缺乏維生素D可能導致骨量低。短腸綜合征是骨質(zhì)流失的一個特殊危險因素(36)。

胃切除術和慢性質(zhì)子泵抑制劑治療

胃切除術后，多達三分之一的患者在術后出現(xiàn)骨質(zhì)疏松癥，這可能與由于胃腸道pH值較高導致鈣吸收減少有關(37)。同樣，長期大劑量使用質(zhì)子泵抑制劑會使絕經(jīng)后婦女發(fā)生脊椎骨折的風險增加3.5倍(38)。與葡萄糖酸鈣或檸檬酸鈣相比，胃酸化的喪失可能會損害碳酸鈣的吸收，葡萄糖酸鈣或檸檬酸鈣的吸收與pH值無關，但使用較少。

減肥手術

減肥手術后的骨質(zhì)流失已成為臨床挑戰(zhàn)(39)。各種術式，包括使用十二指腸開關的膽胰分流術、胃束帶術和Roux-en-Y胃旁路術是美國首選的最后一種方法，它與不同程度的鈣吸收分數(shù)降低和維生素D吸收不良有關(9, 39)。骨質(zhì)流失可能是中度嚴重的，并且似乎與體重減輕的程度密切相關(9)。一項初步研究表明，減肥手術后骨折風險增加了一倍。

骨髓瘤骨病和全身性肥大細胞增多癥

骨髓瘤骨病和意義不明的單克隆丙種球蛋白病

骨髓瘤細胞和骨細胞之間的各種細胞和體液通訊導致骨質(zhì)疏松癥，主要影響中軸骨骼。骨髓瘤細胞表達NF-kB配體(RANKL)和其他促破骨細胞因子的受體激活因子導致破骨細胞生成增強和骨吸收增加(40)。此外，骨髓瘤細胞分泌dickkopf-1，一種可溶性Wnt信號抑制劑，可顯著抑制成骨細胞分化(41)。一項針對165名骨髓瘤患者537人年的基于人群的回顧性隊列研究報告稱，在骨髓瘤確診前一年，觀察到的骨折比預期多16倍，其中三分之二是病理性脊柱或肋骨骨折(42)。

隨后發(fā)生骨質(zhì)疏松性骨折的風險增加了兩到三倍。每20名新診斷的骨質(zhì)疏松癥患者中，多達1名患有多發(fā)性骨髓瘤或意義不明的單克隆丙種球蛋白病(MGUS)(43)。值得注意的是，單克隆丙種球蛋白病MGUS患者（一種可發(fā)展為多發(fā)性骨髓瘤的疾?。┮苍黾恿斯琴|(zhì)疏松性骨折的風險(44)。一項對488名MGUS患者的回顧性隊列研究發(fā)現(xiàn)，軸向骨折的風險增加了2.7倍，但肢體骨折的風險沒有增加(44)。

全身性肥大細胞增多癥

由肥大細胞增多癥引起的骨丟失可能是快速而嚴重的，并且會影響長骨和脊柱。骨質(zhì)疏松癥是由肥大細胞產(chǎn)物過度脫粒引起的，包括白介素(IL)-1、IL-3、IL-6和組胺，它們促進破骨細胞從前體細胞分化(45)。超過90%的肥大細胞增多癥成年患者存在酪氨酸激酶c-kit的激活突變（D816V突變），導致骨吸收增加。

艾滋病毒疾病

患有HIV疾病的女性和男性因骨質(zhì)疏松癥而發(fā)生脊柱、髖關節(jié)、橈骨遠端和其他骨折的風險增加。在患有HIV疾病的老年人中，與未感染HIV的對照組相比，骨折風險增加了三到四倍(46)。與對照組相比，HIV感染者患骨質(zhì)疏松性骨密度的風險也增加了3.7倍 (47)。

除了使用抗逆轉(zhuǎn)錄病毒藥物外，骨質(zhì)疏松癥風險的增加還與低體重指數(shù)BMI、性腺機能減退、感染和炎癥、維生素D缺乏、生長激素缺乏、吸煙和酗酒有關。因此，對HIV患者的骨骼健康和維生素D狀態(tài)進行評估非常重要。

藥物性骨質(zhì)疏松癥

許多藥物通過與維生素D、鈣和磷酸鹽的吸收或維生素D*謝和作用的相互作用、對成骨細胞、破骨細胞和骨細胞的直接細胞作用或干擾骨的數(shù)量或質(zhì)量，來影響骨*謝（表2）基質(zhì)蛋白。糖皮質(zhì)激素(11)和鈣調(diào)神經(jīng)磷酸酶抑制劑型免疫抑制劑如環(huán)孢素A(48)的不良骨骼效應，在炎癥性疾病的管理和移植醫(yī)學中得到了充分的證實。為了最大限度地減少骨骼副作用，越來越多地采用非鈣調(diào)神經(jīng)磷酸酶抑制劑、疫抑制劑和糖皮質(zhì)激素節(jié)約方案。

使用作為過氧化物酶體增殖物激活受體-γ激動劑的胰島素增敏劑TZD（羅格列酮和吡格列酮），與絕經(jīng)后婦女肱骨、股骨和髖部骨折的風險高出三到五倍是相關的（49）。這些改變可能是由于以成骨細胞譜系為*價，將多能間充質(zhì)干細胞分流到脂肪細胞表型，這類似于隨著年齡增長而發(fā)生的骨骼變化（50）。特別是，羅格列酮會在持續(xù)的骨吸收過程中減少骨形成，導致骨丟失(51)。

雄激素或雌激素產(chǎn)生或作用的剝奪，已分別成為現(xiàn)*前列腺癌和乳腺癌治療的支柱。雄激素剝奪療法包括GnRH激動劑（戈舍瑞林、布舍瑞林、亮丙瑞林和曲普瑞林），它們會導致低促性腺激素性腺功能減退癥，或抗雄激素（比卡魯胺和醋酸環(huán)丙孕酮），它們會阻斷雄激素的外周作用。同樣，使用阿那曲唑、來曲唑和依西美坦可減少腎上腺雄激素向雌激素的轉(zhuǎn)化。因此，這兩種策略都旨在減少作為促腫瘤激素的生物可利用雄激素和雌激素的量；然而，它們會導致嚴重且快速的高周轉(zhuǎn)骨質(zhì)流失和骨折(7, 52)。其他已知影響骨*謝的藥物包括注射避孕藥長效醋酸甲羥孕酮(53)、質(zhì)子泵抑制劑(54)、肝素(26)、誘導肝酶的抗癲癇藥物（苯妥英、苯巴比妥、撲米酮和卡馬西平）(55, 56)、選擇性血清素再攝取抑制劑類抗抑郁藥(57-59)和用于治療HIV的抗逆轉(zhuǎn)錄病毒藥物(47)。

表2 已知會導致骨質(zhì)疏松癥和/或脆性骨折的藥物

藥物類別：例子：適應癥

糖皮質(zhì)激素a,b：潑尼松龍：自身免疫性疾病

鈣調(diào)神經(jīng)磷酸酶抑制劑a,b ：環(huán)孢素A：同種異體器官移植

化療藥物：甲氨蝶呤、異環(huán)磷酰胺：其他

酪氨酸激酶抑制劑：伊馬替尼：慢性粒細胞白血病

噻唑烷二酮a,b：羅格列酮, 吡格列酮：2型糖尿病

GnRH 激動劑ab：戈舍瑞林、布舍瑞林、氟他胺：前列腺癌、子宮內(nèi)膜異位癥

芳香酶抑制劑a,b：阿那曲唑、來曲唑、依西美坦：ER陽性乳腺癌

黃體酮Progesterone：Depot-醋酸甲羥孕酮：避孕藥

質(zhì)子泵抑制劑a,b：奧美拉唑和泮托拉唑：消化性潰瘍和反流病

普通肝素a,b：血栓栓塞性疾病

脂肪酶抑制劑：奧利司他：病態(tài)肥胖

甲狀腺激素b：甲狀腺功能減退癥、甲狀腺癌的L-甲狀腺素替*療法

抗驚厥藥：丙戊酸：慢性癲癇癥

抗抑郁藥a,b：選擇性5-羥色胺再攝取抑制劑：慢性抑郁癥

抗逆轉(zhuǎn)錄病毒藥物：替諾福韋：HIV疾病

a 有力的證據(jù)。

b 藥物與骨折增加有關。

繼發(fā)性骨質(zhì)疏松癥的診斷

繼發(fā)性骨質(zhì)疏松癥的初步評估應包括骨折臨床危險因素的詳細病史，以及導致骨質(zhì)流失的潛在疾病和使用的藥物、徹底的體格檢查和實驗室檢查（表3）。

對所有使用過的藥物進行全面審查是必不可少的，對吸煙和飲酒習慣以及骨質(zhì)疏松癥或骨折的遺傳傾向進行評估也是如此。應特別注意1型糖尿病、神經(jīng)性厭食癥和長期性激素缺乏癥以及原則上可以治愈的內(nèi)分泌疾病（表1）。對于報告反復跌倒的骨質(zhì)疏松性骨折患者，應評估跌倒的風險（60）。推薦的臨床方法包括評估高風險藥物（安眠藥、抗抑郁藥和抗驚厥藥）、視力、平衡和步態(tài)以及肌肉力量。一個合理的篩選測試是“限時站立和行走Timed Up and Go”測試，它集成了許多這些功能。

基于這些初步發(fā)現(xiàn)和懷疑的臨床指標，需要進一步的實驗室和影像學研究以及有創(chuàng)檢查。

使用雙光能X線骨密度儀進行的骨密度BMD測試是診斷繼發(fā)性骨質(zhì)疏松癥的首選方法，應在腰椎和髖部進行檢查(61)。在男性中特別常見的主動脈鈣化和骨贅可能會干擾脊柱骨密度BMD測量，因此只能使用髖關節(jié)測量。在存在潛在原因的情況下，骨折風險可能會獨立于 骨密度BMD增加(57)。例如，盡管骨密度BMD值正常，慢性腎功能衰竭患者的骨骼脆弱性可能增加。此外，全身性糖皮質(zhì)激素患者的骨密度BMD骨折閾值較高，因此大多數(shù)人會支持對骨質(zhì)減少患者進行干預。對于有局部背痛、近期脊柱畸形或身高縮減超過3 cm的患者，應進行脊柱X線片檢查，以發(fā)現(xiàn)常見的椎體骨折、溶骨性病變或腫瘤（表3）。由于敏感性低，不應使用脊柱X線來篩查骨質(zhì)疏松癥。最近的一種替*方法是雙光能X射線吸收測定法的椎體骨折評估工具，它提供橫向椎體形態(tài)測量，并且與較少的輻射相關，并且在可用時是一種有用的椎體骨折篩查測試。使用FRAX工具(http://www.shef.ac.uk/FRAX/)可以輕松評估骨折風險，這是一種基于計算機的計算器，除了性別、年齡、骨密度BMD和體重指數(shù)BMI之外，還包括風險吸煙、酗酒、使用糖皮質(zhì)激素以及存在類風濕性關節(jié)炎和繼發(fā)性骨質(zhì)疏松癥等因素。

我們建議進行初步實驗室評估，包括標準腎功能和肝功能檢查、全血細胞計數(shù)、血清鈣和磷酸鹽水平、C反應蛋白、骨特異性（或總）堿性磷酸酶、血清25-羥基維生素D、血清基礎水平促甲狀腺激素和男性血清睪酮水平（表3）。我們還建議測量血清甲狀腺激素PTH水平、血清蛋白電泳和24小時尿鈣排泄量。后者應包括測量肌酐作為內(nèi)部質(zhì)量控制和鈉排泄以排除鹽限制和隨后的假低鈣排泄。

為了篩查乳糜瀉，應檢測抗組織轉(zhuǎn)谷氨酰胺酶抗體，尤其是在缺鐵性貧血和25-羥基維生素D水平低的情況下，如果陽性，應進行十二指腸活檢以明確診斷。為了排除庫欣綜合征，我們在前一天午夜服用1 mg地塞米松后測量了早晨空腹血清皮質(zhì)醇水平。如果懷疑全身性肥大細胞增多癥，我們建議測量肥大細胞衍生產(chǎn)物、血清類胰蛋白酶水平或24小時尿組胺排泄量，盡管這些可能是正常的，部分原因是組胺不耐熱。因此，如果可能的話，N-甲基組胺或11-b前列腺素F2a的尿排泄可能比組胺的尿排泄更穩(wěn)健和可靠。需要COL1A基因檢測來確認成骨不全癥的診斷。這通常根據(jù)陽性家族史、復發(fā)性脆性骨折、藍色鞏膜和聽力損失進行診斷，并且很少需要通過COL1A1基因分型進行基因確認。

我們建議上述評估產(chǎn)生無法解釋的實驗室檢查結(jié)果，或仍不確定的個體進行髂嵴骨活檢（病理檢查），這些個體在抗骨吸收治療期間發(fā)生多處骨折或骨折的年輕成人。骨活檢具有明確作用的典型情況是區(qū)分骨軟化癥和骨質(zhì)疏松癥，建立系統(tǒng)性肥大細胞增多癥的診斷，并協(xié)助診斷浸潤性惡性疾病，包括多發(fā)性骨髓瘤、淋巴瘤、白血病或播散性癌。

骨轉(zhuǎn)換的生化標志物在確定骨質(zhì)疏松癥的次要原因方面的用途有限；但是，它們可用于監(jiān)測治療效果或患者對治療的依從性/依從性。

繼發(fā)性骨質(zhì)疏松癥的治療

繼發(fā)性骨質(zhì)疏松癥的治療旨在：①治療潛在疾?。ㄈ绻阎约阿谥委煿琴|(zhì)疏松癥并防止進一步骨折。需要一種以患者為中心的個體化治療的實用方法。由于繼發(fā)性骨質(zhì)疏松癥的各種病因，和該領域有限的隨機安慰劑對照試驗，治療指南主要基于專業(yè)意見，而不是最高水平的臨床證據(jù)。

基礎疾病的治療

內(nèi)分泌疾病

基礎內(nèi)分泌疾病的完整和持續(xù)治療可能具有挑戰(zhàn)性。如果存在骨質(zhì)疏松癥，應手術治療庫欣綜合征和原發(fā)性甲狀旁腺功能亢進癥。內(nèi)源性甲亢應采用抗甲狀腺藥物、放射性碘治療或手術治療，而外源性甲亢則需要調(diào)整L-T4劑量，使血清促甲狀腺激素水平在正常范圍內(nèi)。如果需要對分化型甲狀腺癌進行TSH抑制治療，應給予將TSH抑制到檢測限以下的最低L-T4劑量。

如果存在激素缺乏的體征和癥狀，如性欲下降、肌肉減少和內(nèi)臟性肥胖，則應更換患有骨質(zhì)疏松癥的絕經(jīng)前女性和男性的性激素缺乏癥。睪酮替*療法未顯示骨折風險降低，但在接受睪酮治療的性腺功能減退男性中發(fā)現(xiàn)骨密度BMD增加(8)。特定的禁忌癥，如女性的乳腺癌和血栓栓塞性疾病，以及男性的良性前列腺肥大和前列腺癌，需要仔細考慮。

雖然成人生長激素GH缺乏癥的生長激素GH替*療法會增加男性的骨密度BMD(62, 63)，但沒有關于骨折減少的數(shù)據(jù)，而且這種療法的成本效益仍不清楚?；加?型糖尿病和低骨量的患者受益于強化胰島素治療(64)和積極預防糖尿病血管并發(fā)癥，包括視網(wǎng)膜病、腎病和多發(fā)性神經(jīng)病(3)。此外，同時患有1型和2型糖尿病的患者需要評估跌倒風險。

一項關于神經(jīng)性厭食癥骨骼健康的系統(tǒng)評價(65)表明，雌激素替*療法導致BMD的不同增加，這沒有達到年齡匹配的對照組，而雙膦酸鹽在很大程度上是無效的。正如預期的那樣，最一致的發(fā)現(xiàn)是增加熱量攝入，導致體重增加和排*導致骨密度顯著增加。

胃腸道疾病

恢復或維持正常體重和胃腸道吸收對于因胃腸道疾病導致的骨質(zhì)疏松癥患者至關重要（表1）。乳糜瀉患者需要營養(yǎng)咨詢，強調(diào)堅持無麩質(zhì)飲食，這可能需要密切監(jiān)測。在由于胰腺功能不全導致吸收不良的狀態(tài)下，應更換外分泌胰酶。對于炎癥性腸病患者，尤其是克羅恩病患者，應嘗試調(diào)整免疫抑制方案以控制炎癥活動并減少糖皮質(zhì)激素劑量。后一種策略也可以應用于其他并發(fā)骨質(zhì)疏松癥的炎癥性疾病。兩項小型研究表明，通過英夫利昔單抗阻斷腫瘤壞死因子抑制炎癥可增加克羅恩病(66)和類風濕性關節(jié)炎(67)患者的骨密度BMD。使用生物制品也可能有助于減少糖皮質(zhì)激素的劑量?？肆_恩病的小腸手術應謹慎使用，以避免短腸綜合征，從而保護回腸末端。

接受胃腸道手術的患者，特別是減肥手術后的患者的內(nèi)分泌和骨骼狀況，應進行終生監(jiān)測，因為沒有長期的安全性數(shù)據(jù)。

表3 繼發(fā)性骨質(zhì)疏松癥診斷方法和目的、意義（解釋）

診斷測試：目的

病史和體格檢查：為了確定骨折的危險因素，潛在的疾病和潛在藥物

雙光能X線骨密度儀（腰椎和臀部）：量化骨礦物質(zhì)密度BMD

脊椎X線檢測：常見的椎體骨折，排除溶骨性病變或腫瘤

診斷測試：檢測或排除

全血細胞計數(shù)：貧血，如骨髓瘤/乳糜瀉

白血病中的白細胞增多

腎和肝功能檢查：腎或肝功能衰竭、酗酒

血清鈣和磷酸鹽水平：原發(fā)性甲狀旁腺功能亢進癥、骨髓瘤

血清C反應蛋白：慢性感染/炎癥

血清骨特異性或總AP活性：佩吉特??；骨軟化癥

血清25-羥基維生素D：維生素D 缺乏癥，骨軟化癥

血清基礎TSH水平：甲亢

血清游離睪酮水平（男性）：男性性腺機能減退

空腹血糖水平：糖尿病

完整的甲狀旁腺激素：原發(fā)性甲狀旁腺功能亢進

血清蛋白電泳、免疫固定：MGUS、骨髓瘤

24小時尿鈣排泄（肌酐和鈉控制）：高鈣尿

抗組織轉(zhuǎn)谷氨酰胺酶抗體：乳糜瀉

抗HIV抗體：HIV疾病、艾滋病

地塞米松抑制后晨間空腹血清皮質(zhì)醇：庫欣綜合征

血清類胰蛋白酶水平、尿組胺排泄：全身性肥大細胞增多癥

COL1A基因檢測：成骨不全癥

髂嵴骨活檢：系統(tǒng)性肥大細胞增多癥，MGUS/骨髓瘤，骨軟化癥、淋巴瘤/白血病

AP：堿性磷酸酶。

惡性疾病

患有惡性疾病的骨質(zhì)疏松癥患者應轉(zhuǎn)診至綜合性癌癥中心。下文將討論因激素剝奪治療而患有乳腺癌或前列腺癌且骨密度低的患者。

藥物性骨質(zhì)疏松癥

如果正在服用疑似促進骨質(zhì)疏松癥的藥物（表2），則需要評估其持續(xù)使用情況并尋找替*品。對于替*給藥途徑尤其如此，尤其是使用局部藥物（用于炎癥性氣道疾病的糖皮質(zhì)激素氣霧劑或用于直腸受累的炎癥性腸病的灌腸劑）。在同種異體器官移植和炎癥性疾病中，不含鈣調(diào)神經(jīng)磷酸酶抑制劑和糖皮質(zhì)激素的新方案可能是可行的。

對于需要長期抗驚厥治療的癲癇患者，有多種不干擾維生素D和礦物質(zhì)*謝的新型藥物可供選擇。在糖尿病患者中，如果可能，應停用TZD并用其他胰島素增敏劑*替。需要抗凝的肝素誘導的骨質(zhì)疏松癥患者應改用口服維生素K拮抗劑。注射避孕藥長效醋酸甲羥孕酮對骨密度BMD的不利影響需要與預防意外懷孕的益處相平衡(53)。

應特別注意單獨或聯(lián)合使用抗高血壓、鎮(zhèn)靜、精神和抗抑郁藥物，因為它們可能通過增加跌倒傾向而間接導致骨質(zhì)疏松性骨折。我們建議所有繼發(fā)性骨質(zhì)疏松癥患者將飲酒量限制在每天不超過兩標準杯，并戒煙。高鈣尿癥患者可能會受益于噻嗪類藥物（每天12.5-25 mg氫氯噻嗪）。

特定的骨質(zhì)疏松癥治療

維生素D和鈣劑

建議通過膳食攝入或補充劑攝入足夠的鈣（800-1200毫克/天）。建議補充維生素D（至少800 IU/天），因為維生素D缺乏癥的患病率很高，除了各種不利的骨骼外影響外，還可能導致骨量低并增加跌倒傾向(68)。此外，僅在維生素D和鈣補充劑存在的情況下，才能證明抗骨質(zhì)疏松藥物的功效。治療應使用導致血鈣正常和血清25-羥基維生素D濃度至少為30 ng/ml的劑量。在腎功能正常的患者中，血清PTH水平從升高降至正常水平表明25-羥基維生素D缺乏癥已得到糾正。一些抗癲癇藥物，例如苯妥英、苯巴比妥、撲米酮和卡馬西平會增加維生素D的肝臟*謝，需要更高的維生素D劑量(56)。

在廣泛的克羅恩病、胃切除術后或長期使用質(zhì)子泵抑制劑以及減肥手術后，腸道鈣和維生素D的吸收可能會嚴重受損。在這些情況下，維生素D應通過胃腸外給藥（每3個月100 000-200 000 IU），并通過滴定劑量使血清25-羥基維生素D濃度至少達到30 ng/ml。一種替*方法是口服維生素D制劑，劑量為50 000–100 000 IU，每周一次或兩次，如果需要，可以每天一次。

一項在心臟移植受者中比較α骨化醇和依替膦酸鹽的小型隨機研究表明，α骨化醇在保持骨密度BMD和減少骨折方面具有優(yōu)勢(69)。一項更大規(guī)模的研究在GIO患者中比較了α骨化醇與更有效的氨基二膦酸鹽阿侖膦酸鹽，結(jié)果表明阿侖膦酸鹽，但不是α骨化醇和，能促進骨密度BMD增加和椎體骨折減少(70)。一項薈萃分析表明，α-骨化醇和骨化三醇可增加骨密度BMD并可能減少骨折，尤其是在未服用全身性糖皮質(zhì)激素的患者中(71)?；谶@些研究，如果不能使用雙膦酸鹽，活性維生素D*謝物可能在繼發(fā)性骨質(zhì)疏松癥（糖皮質(zhì)激素誘導性骨質(zhì)疏松癥：glucocorticoid induced osteoporosis, GIO除外）的管理中發(fā)揮作用。

雙膦酸鹽

口服和靜脈注射雙膦酸鹽已用于治療繼發(fā)性骨質(zhì)疏松癥。一般來說，阿侖膦酸鹽（70 mg/周）和利塞膦酸鹽（35 mg/周）是治療繼發(fā)性骨質(zhì)疏松癥的合理抗骨質(zhì)疏松藥物。

然而，許多繼發(fā)于胃腸道疾病的骨質(zhì)疏松癥患者，或不能耐受或堅持口服雙膦酸鹽類藥物的并發(fā)藥物患者，以及禁用口服雙膦酸鹽類藥物的患者，可能會受益于靜脈注射伊班膦酸鹽或唑來膦酸治療。靜脈注射雙膦酸鹽也有利于口服雙膦酸鹽，后者在吸收不良患者中吸收較差。由于它的效力和方便的給藥，唑來膦酸（4或5毫克/年）最近已在各種形式的繼發(fā)性骨質(zhì)疏松癥中進行了評估。需要注意的是，對于大多數(shù)繼發(fā)性骨質(zhì)疏松癥，雙膦酸鹽類藥物的抗骨折作用的證據(jù)是有限的，除了患有糖皮質(zhì)激素誘導性骨質(zhì)疏松癥GIO的女性和男性、男性性腺功能減退癥和心臟移植后的男性。

此外，大多數(shù)研究沒有評估骨折風險降低的功效。在腎功能不全患者中使用雙膦酸鹽一直是一個問題。然而，骨折干預試驗(FIT)的事后分析表明，阿侖膦酸鹽可減少患有骨質(zhì)疏松癥和腎功能受損（腎小球濾過率，GFR ≥45 ml/min）的絕經(jīng)后婦女的骨折（72）。在定期血液透析的骨質(zhì)減少患者中進行的一項小型研究表明，使用伊班膦酸鹽（48周內(nèi)每4周2毫克）可使脊柱骨密度BMD增加5.1%，盡管沒有評估骨折風險降低（73）。

糖皮質(zhì)激素引起的骨質(zhì)疏松癥

口服阿侖膦酸鹽（10毫克/天）和利塞膦酸鹽（5毫克/天）可增加糖皮質(zhì)激素引起的骨質(zhì)疏松癥GIO女性和男性的骨密度BMD并減少椎體骨折(74, 75)。在一項為期12個月的研究中，唑來膦酸在預防糖皮質(zhì)激素引起的骨質(zhì)疏松癥GIO男性和女性骨質(zhì)流失方面，比利塞膦酸鹽更有效(76)。在一項隨機研究中，與利塞膦酸鹽（5mg/天）（2.7%）相比，接受唑來膦酸（5mg/年）治療的糖皮質(zhì)激素引起的骨質(zhì)疏松癥GIO患者12個月后骨密度BMD增加更高（C4.1%）。 76)。然而，該研究不足以評估骨折復位的差異。

在育齡婦女中使用雙膦酸鹽仍然是一個治療困境，需要在有效避孕的情況下根據(jù)個人情況做出使用決定。一項系統(tǒng)評價確定了51例在懷孕前或懷孕期間接觸雙膦酸鹽的病例，但均未發(fā)現(xiàn)后*骨骼異常(77)。

男性骨質(zhì)疏松癥

與女性相比，對男性骨質(zhì)疏松癥治療的研究較少且數(shù)量較少。男性的治療效果主要基于對骨密度BMD和骨轉(zhuǎn)換的積極影響。在性腺功能減退和性腺功能正常的男性中，阿侖膦酸鹽（10毫克/天）在2年內(nèi)增加了脊柱和股骨頸骨密度BMD，并將椎骨骨折的發(fā)生率降低了80% (78)。在一項非對照研究中，利塞膦酸鹽（5毫克/天）在1年內(nèi)增加了脊柱和股骨頸骨密度BMD，并將脊柱骨折減少了60%，盡管它包括患有原發(fā)性和繼發(fā)性骨質(zhì)疏松癥的男性(79)。這兩項研究都沒有足夠的統(tǒng)計能力來衡量非椎體部位骨折率的差異。在髖部骨折后給予老年男性（和女性）唑來膦酸（每年5毫克）可增加股骨頸骨密度BMD，將所有臨床骨折的風險降低35%，并在3年內(nèi)將全因死亡率降低28% (80)。該研究包括原發(fā)性和繼發(fā)性骨質(zhì)疏松癥患者，但沒有分別評估這兩者。

與前列腺癌的雄激素剝奪療法相關的骨質(zhì)流失

雙膦酸鹽已被證明可以預防接受雄激素剝奪治療的非轉(zhuǎn)移性前列腺癌男性的骨質(zhì)流失?？诜鲮⑺猁}（70毫克/周）（81）和 i.v.帕米膦酸鹽（每3個月90毫克）(82)可以防止骨質(zhì)流失，事實上，它可以增加腰椎和髖部的骨密度BMD，并減少骨轉(zhuǎn)換。最近，i.v.唑來膦酸（5毫克/年）被證明可以預防前列腺癌男性，與雄激素剝奪治療相關的骨質(zhì)流失(83)。然而，這些研究都無法證明抗骨折的功效。

與芳香化酶抑制劑AI治療乳腺癌相關的骨質(zhì)流失

兩項針對患有乳腺癌的絕經(jīng)后婦女服用芳香化酶抑制劑AI的小型試驗報告稱，口服利塞膦酸鹽（35毫克/周）（84）和伊班膦酸鹽（150毫克/月）可減少骨質(zhì)流失（85）。與口服雙膦酸鹽相比，接受為期3年的4 mg唑來膦酸半年治療（Z-和ZO-FAST試驗）在更大程度上預防了接受AI治療乳腺癌的女性的骨質(zhì)流失(86, 87)。綜合起來，口服和靜脈注射雙膦酸鹽可減少AI治療期間的骨質(zhì)流失；然而，沒有一項研究有足夠的能力來評估抗骨折的功效。

口服阿侖膦酸鹽（70毫克/周或10毫克/天）已被證明可增加原發(fā)性甲狀旁腺功能亢進癥患者(88, 89)以及患有2型糖尿病(90)以及妊娠和哺乳相關骨質(zhì)疏松癥的女性的骨密度BMD在分娩和哺乳后（91），盡管這些研究都沒有能力評估骨折。使用4 mg唑來膦酸的半年治療可預防MGUS患者的骨質(zhì)流失(92)。唑來膦酸（每年5次給予4 mg）還可以預防肝移植(93)和異基因骨髓移植(94, 95)后的骨質(zhì)流失。同樣，i.v.伊班膦酸鹽（2毫克，每年4次）可預防心臟移植后男性的骨質(zhì)流失和減少骨折(96)。靜脈注射奈立膦酸鹽增加了脊柱和髖部的骨密度BMD，減少了成骨不全兒童的骨折(97)?？诜鲮⑺猁}或靜脈注射如果沒有奈立膦酸鹽，帕米膦酸鹽可能同樣有效(98)。一項包含403名參與者的8項研究的大型薈萃分析表明，口服和靜脈注射雙膦酸鹽也可改善OI成人的骨密度BMD，盡管沒有可用于骨折復位的數(shù)據(jù)(99)。

特立帕肽

骨形成在糖皮質(zhì)激素誘導的骨質(zhì)疏松癥GIO和許多患有骨質(zhì)疏松癥的男性中嚴重受損，因此為使用骨合成*謝特立帕肽提供了依據(jù)。糖皮質(zhì)激素引起的骨質(zhì)疏松癥。在一項為期18個月的對照試驗中，直接比較了特立帕肽（皮下20毫克/天）與阿侖膦酸鹽（口服10毫克/天）在糖皮質(zhì)激素誘導的骨質(zhì)疏松癥GIO患者中的療效，特立帕肽增加了7.2%的脊柱骨密度，而阿侖膦酸鹽組增加了3.4%。

早在研究開始后6個月就觀察到特立帕肽對腰椎骨密度BMD的顯著影響。雖然25-30%的患者有椎體骨折，但新椎體骨折的發(fā)生率在特立帕肽組為0.6%，在阿侖膦酸鹽組為6.1% (100)。

男性骨質(zhì)疏松癥

在患有骨質(zhì)疏松癥的性腺功能減退和性腺功能正常的男性中，特立帕肽（20毫克/天，皮下）增加了脊柱和股骨近端骨密度BMD（101），并且在后續(xù)研究中，它降低了脊柱骨折的風險。

同時使用阿侖膦酸鹽和特立帕肽可減弱男性特立帕肽的骨合成*謝作用(102)。因此，只有在停用特立帕肽后才能使用口服雙膦酸鹽。這種策略可以保持骨密度BMD增益。由于成本高且需要每日注射，特立帕肽通常推薦用于嚴重骨質(zhì)疏松癥或?qū)﹄p膦酸鹽反應不充分的個體。

地舒單抗

地舒單抗是一種針對RANKL的人MAB，RANKL是破骨細胞生成的必需細胞因子(103)。在接受前列腺癌雄激素剝奪治療的男性中，狄諾塞麥（60 mg s.c. 每6個月一次，持續(xù)2年）脊柱骨密度BMD增加7%，椎骨骨折減少62% (104)。同樣，在接受AI治療乳腺癌的女性中，狄諾塞麥增加了脊柱和股骨頸的骨密度BMD (105)，盡管這項研究無法評估骨折。地舒單抗尚未被批準用于原發(fā)性或繼發(fā)性骨質(zhì)疏松癥，但可能會擴大我們的設備以治療骨質(zhì)流失。（2022-11-21譯者注：目前已經(jīng)批準，且臨床較廣泛使用）

結(jié)論

男性或絕經(jīng)前女性的脆性骨折、極低的骨密度BMD值以及在抗骨質(zhì)疏松治療期間發(fā)生的骨折應促使對繼發(fā)性骨質(zhì)疏松癥進行檢查。應通過髖部和脊柱的骨密度測定法評估骨密度BMD，并通過胸椎和腰椎側(cè)位X線檢查是否存在普遍的椎骨骨折。詳細的病史和體格檢查與一線實驗室檢查相結(jié)合，可能會發(fā)現(xiàn)需要通過明確的診斷測試確認的潛在疾病。

如果可能，使用不會進一步傷害骨骼的方案治療潛在疾病是關鍵。所有繼發(fā)性骨質(zhì)疏松癥患者均應補充足夠的鈣和維生素D，確保血清鈣和PTH水平正常，血清25-羥基維生素D3濃度至少為30 ng/ml。每周一次口服雙膦酸鹽（阿侖膦酸鹽和利塞膦酸鹽）具有抗吸收作用并防止骨質(zhì)流失?？诜p膦酸鹽的依從性差、吸收不良或胃腸道耐受性受損，可以考慮使用非腸道雙膦酸鹽（靜脈滴注伊班膦酸鹽和唑來膦酸）。在這方面，根據(jù)治療適應癥，每年一次或兩次靜脈內(nèi)輸注唑來膦酸可有效預防骨質(zhì)流失。然而，急性期反應是一種常見的副作用，尤其是在第一次輸注后。當需要合成*謝治療時，特立帕肽可用于嚴重糖皮質(zhì)激素誘導的骨質(zhì)疏松癥GIO患者或具有極低骨密度BMD的椎骨骨折的男性。目前正在研究新療法，包括地舒單單抗（一種針對RANKL的人類抗體）、odanacatib（一種特定的組織蛋白酶K抑制劑）和第三*選擇性雌激素受體調(diào)節(jié)劑。

Abstract

Secondary osteoporosis is characterized by low bone mass with microarchitectural alterations in bone leading to fragility fractures in the presence of an underlying disease or medication. Scenarios that are highly suspicious for secondary osteoporosis include fragility fractures in younger men or premenopausal women, very low bone mineral density (BMD) values, and fractures despite anti-osteoporotic therapy. An open-minded approach with a detailed history and physical examination combined with first-line laboratory tests are aimed at identifying clinical risk factors for fractures, osteoporosis-inducing drugs, and underlying endocrine, gastrointestinal, hematologic, or rheumatic diseases, which then need to be confirmed by specific and/or more invasive tests. BMD should be assessed with bone densitometry at the hip and spine. Lateral X-rays of the thoracic and lumbar spine should be performed to identify or exclude prevalent vertebral fractures which may be clinically silent. Management of secondary osteoporosis includes treatment of the underlying disease, modification of medications known to affect the skeleton, and specific anti-osteoporotic therapy. Calcium and vitamin D supplementation should be initiated with doses that result in normocalcemia and serum 25-hydroxyvitamin D concentrations of at least 30 ng/ml. Oral and i.v. bisphosphonates are effective and safe drugs for most forms of secondary osteoporosis. Severe osteoporosis may require the use of teriparatide.

Background

Secondary osteoporosis is defined as bone loss, microarchitecural alterations, and fragility fractures due to an underlying disease or concurrent medication (1). Secondary osteoporosis remains a diagnostic and therapeutic challenge as it frequently affects patient populations, e.g. premenopausal women or younger men who are usually not target populations for routine screening for osteoporosis. In addition, the underlying conditions are diverse and rare, and require specific diagnostic tests (1). Moreover, response to osteoporosis therapy may be limited if the underlying disorder goes unrecognized and if other risk factors are present. For example, alendronate displayed a reduced efficacy in women with postmenopausal osteoporosis and TSH-suppressive L-thyroxine (L-T4) therapy after treatment for differentiated thyroid cancer (2). As a caveat, the anti-fracture efficacy of many drugs has not been clearly demonstrated, except for glucocorticoid induced osteoporosis (GIO) and male hypogonadism in secondary osteoporosis, and the use of specific anti-osteoporosis drugs is based on bone mineral density (BMD) as a surrogate.

Apart from the more well-known endocrine disorders, including Cushing’s syndrome, hypogonadism, hyperthyroidism, and hyperparathyroidism, the adverse effects of diabetes mellitus have just recently been acknowledged (3). In fact, patients with type 1 diabetes mellitus have a 12-fold higher risk of sustaining osteoporotic fractures, compared with non-diabetic controls (4). In addition, chronic inflammation present in inflammatory bowel disease and rheumatoid arthritis cause osteoporosis, in part because of the pro-inflammatory cytokine milieu and immunosuppressive regimens (5). The emerging use of thiazolidinediones (TZDs) (6), aromatase inhibitors (AIs) (7), androgen-deprivation therapy in men with prostate cancer (8), and the growing field of bariatric surgery (9) have emerged as novel and important etiologies of secondary osteoporosis.

Here, we summarize the current state of knowledge on the mechanisms of secondary osteoporosis, outline a practical diagnostic strategy, and provide management recommendations.

Mechanisms

Endocrine diseases

Glucocorticoid

excess Endogenous overexpression or systemic administration of glucocorticoids impairs skeletal health through various cellular effects, of which inhibition of bone formation due to induction of osteoblast and osteocyte apoptosis is the most critical (10). Predominant spinal bone loss and vertebral fractures are characteristic features, as is an increased risk of falls due to muscular atrophy and altered neuromuscular function (11). Even low doses of glucocorticoids (2.5–7.5 mg of prednisolone per day) are associated with a 2.6-fold higher risk of vertebral fractures, whereas doses higher than 7.5 mg of prednisolone per day carry a fivefold higher risk (12).

In most patients suffering from rheumatological diseases as listed in Table 1, in particular rheumatoid arthritis, ankylosing spondylitis, and systemic lupus erythematosus, rapid bone loss and increased fracture risk are caused by the pro-inflammatory cytokine milieu or the immunosuppressive regimen, which initially includes glucocorticoids, or a balance between both.

Hyperthyroidism

A history of overt hyperthyroidism is an established risk factor for osteoporotic fractures (13). A large study of 686 postmenopausal women demonstrated that a serum TSH level !0.1 mU/l was associated with a four- and fivefold risk of hip and vertebral fractures respectively (14). A meta-analysis of 21 studies indicated that thyroid hormone therapy for TSH suppression in differentiated thyroid cancer which results in subclinical hyperthyroidism is associated with osteoporosis in postmenopausal women (15). Based on animal models, thyroid hormone excess (16) as well as suppressed thyrotropin levels (17) has been implicated.

Activation of thyroid hormone receptor a on osteoblasts and osteoclasts results in enhanced bone resorption and bone loss (16).

Primary hyperparathyroidism Women are three times more often affected by primary hyperparathyroidism than men, and its incidence is as high as 1:500 in elderly women, a high-risk population for osteoporosis (18). Chronic parathyroid hormone (PTH) excess is catabolic to the skeleton, and preferentially affects cortical rather than cancellous bone. Thus, bone loss is most prominent at skeletal sites that consist of cortical bone (middle third of the forearm and femoral neck), while the spine, mainly composed of cancellous bone, is less severely affected (18). Either osteoporotic fractures or a T score of ＜2.5 is an indication for parathyroid surgery in otherwise asymptomatic patients (18). A recent observational study over the course of 15 years showed that parathyroidectomy normalized biochemical indices of bone turnover and preserved BMD, whereas cortical bone density decreased in the majority of subjects without surgery during long-term follow-up (19).

Androgens are crucial for the accrual of peak bone mass in men and the maintenance of bone strength thereafter (8, 20, 21). The effects of androgens on bone may be mediated by estrogens (22).

Hypogonadism is a major risk factor for low BMD and osteoporotic fractures in men, and results in increased bone remodeling with rapid bone loss (21). As androgen-deprivation therapy using GnRH agonists has become a mainstay in the multimodal management of prostate cancer, treatment-related hypogonadism has emerged as an important risk factor for osteoporotic fractures in these men (8, 23).

Pregnancy-associated osteoporosis The mechanisms of this entity are poorly understood. Factors that have been implicated include preexisting vitamin D deficiency, low intake of calcium and protein, low bone mass, increased PTH-related protein, and high bone turnover (24, 25). Multiple pregnancies or prolonged periods of lactation per se are not associated with osteoporosis.

However, women are at risk of pregnancy-associated osteoporosis, if they use unfractionated heparins for thromboembolic disorders (26, 27). The skeletal side effects of low-molecular weight heparin are currently unknown (28).

Diabetes mellitus type 1 The risk of osteoporotic fractures is increased by 12-fold in patients with type 1 diabetes (4). Lack of the bone anabolic actions of insulin and other b-cell-derived proteins such as amylin have been postulated to contribute to low BMD and impaired fracture risk (3). In long-standing disease, diabetic complications, such as retinopathy, polyneuropathy, and nephropathy, are the major determinants of lowbone mass and increased fracture risk, in part due to the enhanced propensity of falls (3). Data from theWomen’s Health Initiative Observational Study also indicate a 20% higher risk for fractures after adjustment for frequent falls and increased BMD (4–5% higher at the hip) in women with type 2 diabetes mellitus (29). An important additional risk factor for fractures in postmenopausal women with type 2 diabetes mellitus is the use of a TZD type insulin sensitizer, associated with fractures of the hip, humerus, and small bones of the hands and feet (30).

GH deficiency Insulin-like growth factor 1 (IGF1) and IGF-binding proteins, which are produced upon stimulation of its hepatic receptor by human GH, represent a potent stimulator of osteoblastic functions and bone formation (31, 32). Patients with untreated adult-onset GH deficiency have a two- to threefold higher risk of osteoporotic fractures (32), and the degree of osteopenia is related to the extent of GH deficiency (33). Accurate measurement of BMD in patients with pediatric-onset GH deficiency is complicated because of short stature and small bone size.

Gastrointestinal diseases Celiac disease Chronic diarrhea and malabsorption due to villous atrophy are the hallmarks of celiac disease. Intestinal absorption of calcium is impaired, and vitamin D deficiency is common (Table 1), resulting in osteomalacia and secondary hyperparathyroidism (34). Associated autoimmune disorders such as type A gastritis with achlorhydria, Graves’ disease with hyperthyroidism, or type 1 diabetes mellitus may further impair skeletal health. A recent study demonstrated a 17-fold higher prevalence of celiac disease among osteoporotic individuals compared with nonosteoporotic individuals, supporting serologic screening of all patients with osteoporosis for celiac disease (35).

Inflammatory bowel disease The pathogenesis of osteoporosis in inflammatory bowel disease is complex, and patients with Crohn’s disease are more severely affected compared with those with ulcerative colitis (36). Chronic inflammation, diarrhea and/or malabsorption, low body mass index (BMI), and intermittent or chronic systemic glucocorticoid therapy for flares are major causes of osteoporosis. In addition, vitamin D deficiency in those with short bowel syndrome or functional loss of terminal ileum integrity, repeated hospitalizations, and prolonged immobility may contribute to low bone mass. Short bowel syndrome is a particular risk factor for bone loss (36).

Gastrectomy and chronic proton pump inhibitor therapy After gastrectomy, osteoporosis develops in up to one-third of patients postoperatively, and may be related to decreased calcium absorption due to the higher gastrointestinal pH value (37). Similarly, a prolonged high-dose use of proton pump inhibitors carries a 3.5-fold increased risk of vertebral fractures in postmenopausal women (38). Loss of gastric acidification may impair the absorption of calcium carbonate compared with calcium gluconate or calcium citrate, which are absorbed in a pH-independent manner, but are used less commonly.

Bariatric surgery Bone loss after bariatric surgery has become a clinical challenge (39). The various procedures, including biliopancreatic diversion with duodenal switch, gastric banding, and Roux-en-Y

gastric bypass, the last of which is the preferred method in the US, are associated with variable degrees of reduced fractional calcium absorption and vitamin D malabsorption (9, 39). Bone loss may be moderately severe, and appears to be closely related to the degree of weight loss (9). A preliminary study indicated a doubling of fracture risk after bariatric surgery.

Myeloma bone disease and systemic mastocytosis Myeloma bone disease and monoclonal gammopathy of undetermined significance Various cellular and humoral communications between myeloma cells and bone cells contribute to osteoporosis, and mainly affect the axial skeleton. Expression of receptor activator of NF-kB ligand (RANKL) and other pro-osteoclastogenic factors by myeloma cells results in enhanced osteoclastogenesis and increased bone resorption (40). In addition, myeloma cells secrete dickkopf-1, a soluble Wnt signaling inhibitor, which markedly suppresses osteoblastic differentiation (41). A populationbased retrospective cohort study that followed 165 patients with myeloma for 537 person-years reported that in the year beforemyelomawas diagnosed, 16 times more fractures were observed than expected, of which two-thirds were pathologic spinal or rib fractures (42).

The risk of subsequent osteoporotic fractures was elevated two- to threefold. Up to 1 in 20 patients with newly diagnosed osteoporosis have multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS) (43). Of note, patients with MGUS, a disease that can progress to multiple myeloma, also carry an increased risk for osteoporotic fractures (44). A retrospective cohort study of 488 patients with MGUS found a 2.7-fold increased risk of axial fractures, but no increase in limb fractures (44).

Systemic mastocytosis Bone loss due to mastocytosis may be rapid and severe, and affects both the long bones and the spine. Osteoporosis results from excessive degranulation of mast cell products, including interleukin (IL)-1, IL-3, IL-6, and histamine, which promote osteoclast differentiation from precursor cells (45). An activating mutation of the tyrosine kinase c-kit (D816V mutation), present in over 90% of adult patients with mastocytosis, contributes to elevated bone resorption.

HIV disease

Women and men with HIV disease are at increased risk of spinal, hip, distal radius, and other fractures due to osteoporosis. In older individuals with HIV disease, fracture risk is increased three- to fourfold compared with non-HIV-infected controls (46). The risk of having osteoporotic bone density is also increased 3.7-fold for HIV-infected individuals compared with controls (47).

In addition to anti-retroviral drug use, the increase in osteoporosis risk is related to low BMI, hypogonadism, infection and inflammation, vitamin D deficiency, GH deficiency, smoking, and alcohol abuse. An assessment of bone health and vitamin D status is therefore important in individuals with HIV disease.

Drug-induced osteoporosis

Numerous drugs affect bone metabolism (Table 2) through interaction with the absorption of vitamin D, calcium, and phosphate or vitamin D metabolism and action, direct cellular effects on osteoblasts, osteoclasts, and osteocytes, or interference with either the amount or quality of bone matrix proteins. The adverse skeletal effects of glucocorticoids (11) and calcineurin inhibitortype immunosuppressants such as cyclosporine A (48) are well established in the management of inflammatory diseases and in transplantation medicine.

To minimize skeletal side effects, non-calcineurin inhibitor immunosuppressants and glucocorticoidsparing regimens are increasingly employed.

The use of the insulin sensitizers TZDs (rosiglitazone and pioglitazone) which act as agonists of the peroxisome proliferator-activated receptor-g is associated

with a three- to five-fold higher risk of fractures of the humerus, femur, and hip in postmenopausal women (49). These alterations may result from shunting pluripotent mesenchymal stem cells toward the adipocyte phenotype at the cost of the osteoblastic lineage, which resembles the bone changes that occur with aging (50). In particular, rosiglitazone decreases bone formation in the face of on-going bone resorption, leading to bone loss (51).

Ablation of androgen or estrogen production or action has become a mainstay in modern therapy of prostate and breast cancer respectively. Androgen-deprivation therapy includes GnRH agonists (goserelin, buserelin, leuprolide, and triptorelin), which cause hypogonadotropic hypogonadism, or anti-androgens (bicalutamide and cyproterone acetate) that block the peripheral action of androgens. Similarly, the use of the Ais anastrozole, letrozole, and exemestane reduces the conversion from adrenal androgens into estrogens.

Thus, both strategies are aimed at reducing the amount of bioavailable androgens and estrogens, which act as tumor-promoting hormones; however, they cause severe and rapid high turnover bone loss and fractures (7, 52). Other drugs known to affect bone metabolism include the injectable contraceptive depot-medroxyprogesterone acetate (53), proton pump inhibitors (54), heparins (26), antiepileptic drugs that induce hepatic enzymes (phenytoin, phenobarbitone, primidone, and carbamazepine) (55, 56), antidepressants of the selective serotonin re-uptake inhibitor class (57–59), and anti-retroviral drugs used to treat HIV (47).

Diagnosis

The initial evaluation of secondary osteoporosis should include a detailed history of clinical risk factors for fractures and the underlying medical conditions and medications that cause bone loss, a thorough physical examination and laboratory tests (Table 3).

A comprehensive review of all used medications is essential, as is an evaluation of the smoking and alcohol habits, and the hereditary disposition of osteoporosis or fractures. Particular attention should be given to type 1 diabetes mellitus, anorexia nervosa, and prolonged sex hormone deficiency as well as those endocrine disorders that can in principle be cured (Table 1). The risk for falling should be assessed in patients with osteoporotic fractures who reported repeated falls (60).

A recommended clinical approach includes evaluation of high-risk medications (sleeping medications, antidepressants, and anticonvulsants), vision, balance and gait, and muscle strength. A reasonable screening test is the ‘Timed Up and Go’ tests which integrates many of these functions.

Based on these initial findings and the clinical index of suspicion, further laboratory and imaging studies as well as invasive tests are required.

BMD testing using dual-energy X-ray absorptiometry is the method of choice for the diagnosis of secondary osteoporosis and should be conducted at the lumbar spine and hip (61). Aortic calcification and osteophytes, which are particularly common in men, may interfere with spinal BMD measurement, allowing only hip measurement to be used. In the presence of an underlying cause, fracture risk may be increased independently of BMD (57). For example, patients with chronic renal failure may have increased skeletal fragility despite normal BMD values. In addition, there is a higher BMD fracture threshold in patients on systemic glucocorticoids, so that most would support intervention for patients with osteopenia. Spinal X-rays should be performed in those with localized back pain, recent spinal deformities, or a loss of more than 3 cm in height in order to detect prevalent vertebral fractures, osteolytic lesions, or tumors (Table 3). Owing to their low sensitivity, spinal X-rays should not be used to screen for osteoporosis. A recent alternative has been the vertebral fracture assessment tool of the dualenergy X-ray absorptiometry which provides a lateral vertebral morphometry and is associated with less radiation and, when available, is a useful screening test for vertebral fractures. The fracture risk can be easily assessed with the FRAX tool (http://www.shef.ac. uk/FRAX/), a computer-based calculator that, in addition to gender, age, BMD, and BMI, also includes risk factors such as smoking, alcohol abuse, glucocorticoid use, and the presence of rheumatoid arthritis and secondary osteoporosis.

We recommend an initial laboratory evaluation with standard renal and liver function tests, a complete blood count, serum calcium and phosphate levels, C-reactive protein, bone-specific (or total) alkaline phosphatase, serum 25-hydroxyvitamin D, serum levels of basal thyrotropin, and serum testosterone levels in men (Table 3). We also recommend free measurements of serum levels of PTH, serum protein electrophoresis, and 24-h urinary calcium excretion. The latter should be performed including measurement of creatinine as internal quality control and sodium excretion to exclude salt restriction with subsequent false-low calcium excretion.

To screen for celiac disease, anti-tissue transglutaminase antibodies should be measured, especially if irondeficiency anemia and low 25-hydroxyvitamin D levels are present, and if positive, a duodenal biopsy should be performed to confirm the diagnosis. To rule out Cushing’s syndrome, we measured morning fasting serum cortisol levels after administration of 1 mg dexamethasone at midnight the previous day. If systemic mastocytosis is suspected, we recommend the measurement of mast cell-derived products, serum tryptase levels, or 24-h urinary excretion of histamine, although these may be normal, in part because histamine is thermolabile. Thus, if available, urinary excretion of N-methylhistamine or 11-b prostaglandin F2a may be more robust and reliable than urinary excretion of histamine. COL1A genetic testing is required to confirm the diagnosis of osteogenesis imperfecta. This is most commonly diagnosed based on a positive family history, recurrent fragility fractures, blue sclerae, and hearing loss, and only rarely requires genetic confirmation by COL1A1 genotyping.

We advocate iliac crest bone biopsy for those individuals where the evaluation described above yields unexplained laboratory findings or remains inconclusive, in young adults with multiple fractures or fractures that occur during antiresorptive treatment. Typical scenarios for a definitive role of bone biopsy are to distinguish osteomalacia from osteoporosis, to establish a diagnosis of systemic mastocytosis, and to assist in diagnosing infiltrating malignant diseases, including multiple myeloma, lymphoma, leukemia, or disseminated carcinoma.

Biochemical markers of bone turnover are of limited use in establishing a secondary cause of osteoporosis; however, they may be used to monitor therapeutic efficacy or the patient’s adherence/compliance with treatment.

Treatment

The management of secondary osteoporosis is aimed at i) treating the underlying disease, if known, and ii) treating osteoporosis and preventing further fractures.

A practical approach with patient-centered, individualized therapy is warranted. Because of the various etiologies of secondary osteoporosis and limited randomized placebo-controlled trials in this area, treatment guidelines are largely based on professional opinion rather than the highest level clinical evidence.

Treatment of the underlying disease Endocrine diseases Complete and sustained therapy of the underlying endocrine disorder can be challenging.

Cushing’s syndrome and primary hyperparathyroidism should be surgically treated if osteoporosis is present.

Endogenous hyperthyroidism should be treated with anti-thyroid drugs, radioiodine therapy, or surgery, while exogenous hyperthyroidism requires adjustment of the L-T4 dosage with a target serum thyrotropin level within the normal range. If TSH-suppressive therapy for differentiated thyroid carcinoma is required, the lowest L-T4 dose that suppresses TSH below the limit of detection should be administered.

Sex hormone deficiency in premenopausal women and men with osteoporosis should be replaced, if signs and symptoms of hormone deficiency, such as decreased libido, sarcopenia, and visceral obesity, are present.

Fracture risk reduction has not been shown for testosterone replacement therapy, but increases in BMD are seen in hypogonadal men treated with testosterone (8). Specific contraindications, such as breast cancer and thromboembolic diseases in women, and benign prostatic hypertrophy and prostate cancer in men, need to be carefully considered.

While GH replacement therapy in adult GH deficiency increases BMD in men (62, 63), no data on fracture reduction are available, and the cost–effectiveness of this therapy remains unclear. Patients with type 1 diabetes mellitus and low bone mass benefit from intensive insulin therapy (64) and aggressive prevention of diabetic vascular complications, including retinopathy, nephropathy, and polyneuropathy (3). In addition, patients with both type 1 and type 2 diabetes mellitus require assessment of falls risk.

A systematic review on bone health in anorexia nervosa (65) suggests that estrogen replacement therapy resulted in variable increase in BMD, which did not reach that of age-matched controls, whereas bisphosphonates were largely ineffective. As expected, the most consistent finding was that enhanced caloric intake that led to weight gain and ovulations resulted in a substantial gain of BMD.

Gastrointestinal diseases Restoration or maintenance of normal body weight and gastrointestinal absorption are pivotal for patients with osteoporosis due to gastrointestinal diseases (Table 1). Patients with celiac disease require nutritional counseling emphasizing adherence to a gluten-free diet, which may require close monitoring. Exocrine pancreatic enzymes should be replaced in states of malabsorption due to pancreatic insufficiency. For patients with inflammatory bowel disease, in particular those with Crohn’s disease, an attempt should be made to modify the immunosuppressive regimen to control inflammatory activity and to reduce the glucocorticoid dose. The latter strategy should also be applied in other inflammatory disorders complicated by osteoporosis. Two small studies indicate that suppression of the inflammation by tumour necrosis factor-a blockade with infliximab increases BMD in patients with Crohn’s disease (66) and rheumatoid arthritis (67). The use of biologicals may also help to reduce the glucocorticoid dose. Small bowel surgery in Crohn’s disease should be used sparingly to avoid short bowel syndrome and to thus preserve the terminal ileum.

The endocrine and skeletal status of patients who underwent gastrointestinal surgery, particularly those after bariatric surgery, should be monitored for life, as no long-term safety data are available.

Malignant diseases Patients with osteoporosis in the setting of a malignant disease should be referred to a comprehensive cancer center. Patients with breast or prostate cancer and low bone density due to hormoneablative therapy will be discussed below.

Drug-induced osteoporosis If drugs suspected to promote osteoporosis are being taken (Table 2), their continued use needs to be evaluated and alternatives should be sought. This holds particularly true for alternative routes of administration, especially the use of topical drugs (glucocorticoid aerosol for inflammatory airway disease or enema for inflammatory bowel diseases with rectal involvement). In allogeneic organ transplantation and inflammatory disorders, novel regimens without calcineurin inhibitors and glucocorticoids may be feasible.

For patients with seizure disorders requiring prolonged anticonvulsive therapy, a variety of novel drugs are available that do not interfere with vitamin D and mineral metabolism. In patients with diabetes, TZDs should be discontinued and replaced by other insulin sensitizers, if possible. Patients with heparin-induced osteoporosis who require anticoagulation should be switched to oral vitamin K antagonists. The adverse effects of the injectable contraceptive depot-medroxyprogesterone acetate on BMD need to be balanced against the benefits of preventing unintended pregnancy (53).

Particular attention should be paid to anti-hypertensive, sedative, psychotropic, and antidepressant drugs alone or in combination, as they may indirectly cause osteoporotic fractures by enhancing the propensity of falls. We recommend all patients with secondary osteoporosis to limit alcohol consumption to no more than two standard drinks per day and to stop smoking.

Patients with hypercalciuria may benefit from a thiazide (12.5–25 mg hydrochlorothiazide per day). Specific osteoporosis treatment Vitamin D and calcium An adequate intake of calcium (800–1200 mg/day) via dietary intake or supplements is recommended. Vitamin D supplementation (at least 800 IU/day) is recommended as vitamin D deficiency has a high prevalence and, in addition to various adverse extraskeletal effects, may contribute to low bone mass and increase the propensity to falls (68). In addition, the efficacy of anti-osteoporotic drugs has only been demonstrated in the presence of vitamin D and calcium supplementation. Therapy should be titrated with doses that result in normocalcemia and serum 25-hydroxyvitamin D concentrations of at least 30 ng/ml. In patients with normal renal function, a decrease in serum PTH levels from elevated to normal levels indicates that 25-hydroxyvitamin D deficiency has been corrected. Some anti-epileptic drugs, e.g. phenytoin, phenobarbitone, primidone, and carbamazepine, increase hepatic metabolism of vitamin D, requiring higher vitamin D doses (56).

Intestinal calcium and vitamin D absorption may be severely impaired in widespread Crohn’s disease, after gastrectomy or with chronic use of proton pump inhibitors, and after bariatric surgery. In these circumstances, vitamin D should be administered parenterally (100 000–200 000 IU every 3 months) with titration of doses to achieve serum 25-hydroxyvitamin D concentrations of at least 30 ng/ml. An alternative is oral vitamin D preparations administered at 50 000–100 000 IU once or twice a week, or daily, if needed.

A small randomized study comparing alphacalcidol and etidronate in cardiac transplant recipients indicated that alphacalcidol was superior with respect to the preservation of BMD and fracture reduction (69).

A larger study that compared alphacalcidol with the more potent aminobisphosphonate alendronate in patients with GIO indicated that alendronate, but not alphacalcidiol, resulted in an increase in BMD and reduced vertebral fractures (70). A meta-analysis suggests that alphacalcidol as well as calcitriol increases BMD and may reduce fractures, in particular in patients not taking systemic glucocorticoids (71). Based on these studies, active vitamin D metabolites may play a role in the management of secondary osteoporosis (other than GIO), if bisphosphonates cannot be used.

Bisphosphonates Both oral and i.v. bisphosphonates have been used in the treatment of secondary osteoporosis. In general, alendronate (70 mg/week) and risedronate (35 mg/week) are reasonable antiosteoporotic drugs for secondary osteoporosis.

However, many patients with osteoporosis secondary to gastrointestinal diseases or concurrent medications not tolerating, or adhering to, oral bisphosphonates and those in whom oral bisphosphonates are contraindicated may benefit from treatment with i.v. ibandronate or zoledronic acid. I.v. bisphosphonates are also favorable to oral bisphosphonates which are poorly absorbed in malabsorption. Because of its potency and convenient administration, zoledronic acid (4 or 5 mg/year) has recently been evaluated in various forms of secondary osteoporosis. It is important to note that the evidence for an anti-fracture effect of bisphosphonates is limited for most forms of secondary osteoporosis, except for women and men with GIO, men with hypogonadism, and men after cardiac transplantation.

In addition, most studies were not powered to assess fracture risk reduction. The use of bisphosphonates in patients with renal insufficiency has been a concern. However, a post-hoc analysis of the fracture intervention trial (FIT) demonstrated that alendronate reduced fractures in postmenopausal women with osteoporosis and impaired renal function (glomerular filtration rate, GFR !45 ml/min) (72). A small study conducted in patients with osteopenia on regular hemodialysis demonstrated an increase in the spinal BMD with ibandronate (2 mg every 4 weeks over 48 weeks) by 5.1%, although no fracture risk reduction was assessed (73).

Glucocorticoid-induced osteoporosis. Oral alendronate (10 mg/day) and risedronate (5 mg/day) increased BMD and reduced vertebral fractures in women and men with GIO (74, 75). In a 12-month study, zoledronic acid was more effective than risedronate in preventing bone loss in men and women with GIO (76). In a randomized headto-head study, the BMD increase after 12 months was higher in patients with GIO treated with zoledronic acid (5 mg/year) (C4.1%) compared to risedronate (5 mg/day) (2.7%) (76). However, the study had insufficient power to assess differences in fracture reduction.

The use of bisphosphonates in women of childbearing age still represents a therapeutic dilemma, and the decision on its use needs to be made on an individual basis under effective contraception. A systematic review identified 51 cases of bisphosphonate exposure before or during pregnancy, none of which revealed skeletal abnormalities in the offspring (77).

Osteoporosis in men. Studies of treatment in men with osteoporosis have been smaller and fewer in number than those in women. Treatment efficacy in men is mostly based on positive effects on BMD and bone turnover. In hypogonadal and eugonadal men, alendronate (10 mg/day) increased spinal and femoral neck BMD and reduced the incidence of vertebral fractures by 80% over 2 years (78). Risedronate (5 mg/day) increased spinal and femoral neck BMD, and reduced spinal fractures by 60% over 1 year in an uncontrolled study, although it included men with primary and secondary osteoporosis (79). Both studies had insufficient statistical power to measure differences in fracture rates at non-vertebral sites. Zoledronic acid (5 mg annually) given to elderly men (and women) after hip fractures increased femoral neck BMD, reduced risk of all clinical fractures by 35%, and lowered all-cause mortality by 28% over 3 years (80). This study included patients with primary and secondary osteoporosis, but did not assess those both separately.

Bone loss associated with androgen-deprivation therapy for prostate cancer. Bisphosphonates have been shown to prevent bone loss in men with non-metastatic prostate cancer receiving androgen-deprivation therapy. Oral alendronate (70 mg/week) (81) and i.v. pamidronate (90 mg every 3 months) (82) have prevented bone loss and, in fact, increased BMD at the lumbar spine and the hip, and decreased bone turnover. More recently, i.v. zoledronic acid (5 mg/year) was shown to prevent bone loss associated with androgen-deprivation therapy in men with prostate cancer (83). However, none of these studies were powered to demonstrate anti-fracture efficacy.

Bone loss associated with AI therapy for breast cancer. Two small trials of postmenopausal women with breast cancer taking AI reported that oral risedronate (35 mg/week) (84) and ibandronate (150 mg/month) (85) reduced bone loss. Semi-annual therapy with 4 mg of zoledronic acid for 3 years (Z- and ZO-FAST trials) prevented bone loss in women receiving AI therapy for breast cancer to a greater extent compared with oral bisphosphonates (86, 87). Taken together, both oral and i.v. bisphosphonates reduce bone loss during AI therapy; however, none of the studies had sufficient power to assess anti-fracture efficacy.

Miscellaneous. Oral alendronate (70 mg/week or 10 mg/day) has been shown to increase BMD in patients with primary hyperparathyroidism (88, 89) as well as women with type 2 diabetes mellitus (90) and with pregnancy- and lactation-associated osteoporosis after delivery and lactation (91), although none of these studies were powered to assess fractures. Semi-annual therapy with 4 mg of zoledronic acid prevented bone loss in patients with MGUS (92). Zoledronic acid (4 mg given five times per year) also prevented bone loss after liver transplantation (93) and after allogeneic bone marrow transplantation (94, 95). Similarly, i.v. ibandronate (2 mg given four times per year) prevented bone loss and reduced fractures in men after cardiac transplantation (96). I.v. neridronate increased BMD at the spine and hip and reduced fractures in children with osteogenesis imperfecta (97). Oral alendronate or i.v. pamidronate may work equally well if neridronate is not available (98). A large meta-analysis that included eight studies with 403 participants indicated that oral and i.v. bisphosphonates improved BMD also in adults with OI, although no data were available for fracture reduction (99).

Teriparatide Bone formation is severely impaired in GIO and in many men with osteoporosis, thus providing a rationale to use the bone anabolic teriparatide. Glucocorticoid-induced osteoporosis. In an 18-month controlled trial that directly compared teriparatide (20 mg/day s.c.) with alendronate (10 mg/day orally) in patients with GIO, teriparatide increased spinal BMD by 7.2% compared with 3.4% in the alendronate group.

A superior effect of teriparatide on BMD at the lumbar spine was observed as early as 6 months after the start of the study. While 25–30% of the patients had established vertebral fractures, the incidence of new vertebral fractures was 0.6% in the teriparatide and 6.1% in the alendronate group (100).

Osteoporosis in men. In hypogonadal and eugonadal men with osteoporosis, teriparatide (20 mg/day s.c.) increased spinal and proximal femur BMD (101), and in follow-up studies, it reduced the risk of spinal fractures.

The concurrent use of alendronate and teriparatide blunted the bone anabolic effect of teriparatide in men (102). Thus, oral bisphosphonates should be used only after teriparatide has been discontinued. This strategy may preserve the BMD gain. Owing to the high cost and need for daily injection, teriparatide is generally recommended for severe osteoporosis or individuals who do not respond adequately to bisphosphonates.

Denosumab Denosumab is a human MAB directed against RANKL, an essential cytokine for osteoclastogenesis (103). In men receiving androgen-deprivation therapy for prostate cancer, denosumab (60 mg s.c. every 6 months for 2 years) increased spinal BMD by 7% and reduced vertebral fractures by 62% (104). Similarly, in women on AI therapy for breast cancer, denosumab increased BMD at the spine and the femoral neck (105), although this study was not powered to assess fractures. Denosumab has not been approved for primary or secondary osteoporosis, but may expand our armamentarium to treat bone loss conditions.

Conclusion

Fragility fractures in men or premenopausal women, very low values of BMD, and fractures that occur while on anti-osteoporotic therapy should prompt a work-up for secondary osteoporosis. BMD should be assessed with bone densitometry at the hip and spine, and the presence of prevalent vertebral fractures with lateral X-rays of the thoracic and lumbar spine. A detailed history and physical examination combined with firstline laboratory tests may reveal an underlying disease that needs to be confirmed by definitive diagnostic tests.

Treatment of the underlying disease is pivotal, if possible, using a regimen that does not harm the skeleton further. All patients with secondary osteoporosis should receive adequate calcium and vitamin D supplementation, ensuring normal calcium and PTH serum levels and 25-hydroxyvitamin D3 serum concentrations of at least 30 ng/ml. Oral bisphosphonates (alendronate and risedronate) given once per week are antiresorptive and prevent bone loss. Poor compliance, malabsorption, or impaired gastrointestinal tolerance of oral bisphosphonates may favor the use of parenteral bisphosphonates (ibandronate and zoledronic acid). In this regard, zoledronic acid infused intravenously once or twice per year, depending on the indication for treatment, is potent in preventing bone loss. However, an acute phase reaction is a frequent side effect, particularly after the first infusion. Teriparatide may be used in patients with severe GIO or men with vertebral fractures of very low BMD when anabolic therapy is warranted. New therapies are currently under investigation, including denosumab, a human antibody against RANKL, odanacatib, a specific cathepsin K inhibitor, and third-generation selective estrogen receptor modulators.

文獻出處：Lorenz C Hofbauer, Christine Hamann, Peter R Ebeling. Approach to the patient with secondary osteoporosis. Eur J Endocrinol. 2010 Jun;162(6):1009-20.doi: 10.1530/EJE-10-0015.