繼發(fā)性骨質(zhì)疏松癥的病因深度分析：藥物性、糖尿病性、腎病性、白血病相關(guān)、肝炎、各類(lèi)感染、風(fēng)濕病、甲亢、新冠病毒感染COVID-19感染相關(guān)骨質(zhì)疏松癥等

繼發(fā)性骨質(zhì)疏松癥與*謝性骨病的治療方案：2020年

作者：Mahmoud M Sobh, Mohamed Abdalbary, Sherouk Elnagar, Eman Nagy, Nehal Elshabrawy, Mostafa Abdelsalam, Kamyar Asadipooya, Amr El-Husseini

作者單位: Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura 35516, Egypt.

譯者：陶可（北京大學(xué)人民醫(yī)院骨關(guān)節(jié)科）

摘要

脆性骨折是一個(gè)世界性的難題，也是導(dǎo)致殘疾和生活質(zhì)量受損的主要原因。它主要由骨質(zhì)疏松癥引起，其特征是骨骼數(shù)量和/或質(zhì)量受損。正確診斷骨質(zhì)疏松癥對(duì)于預(yù)防脆性骨折至關(guān)重要。由于雌激素缺乏，骨質(zhì)疏松癥可能是絕經(jīng)后婦女的原發(fā)性骨質(zhì)疏松癥。繼發(fā)性骨質(zhì)疏松癥在男性和女性中并不少見(jiàn)。大多數(shù)全身性疾病和器官功能障礙可導(dǎo)致骨質(zhì)疏松癥。腎臟通過(guò)控制礦物質(zhì)、電解質(zhì)、酸堿、維生素D和甲狀旁腺功能，在維持生理性骨穩(wěn)態(tài)方面發(fā)揮著至關(guān)重要的作用。慢性腎病及其尿毒癥環(huán)境擾亂了這種平衡，導(dǎo)致腎性骨營(yíng)養(yǎng)不良。糖尿病是骨質(zhì)疏松癥最常見(jiàn)的繼發(fā)性原因。甲狀腺和甲狀旁腺疾病可以使成骨細(xì)胞/破骨細(xì)胞功能失調(diào)。胃腸道疾病、營(yíng)養(yǎng)不良和吸收不良可導(dǎo)致礦物質(zhì)和維生素D缺乏以及骨質(zhì)流失。慢性肝病患者因肝性骨營(yíng)養(yǎng)不良而骨折的風(fēng)險(xiǎn)更高。感染性、自身免疫性和血液系統(tǒng)疾病中的促炎細(xì)胞因子可刺激破骨細(xì)胞生成，導(dǎo)致骨質(zhì)疏松癥。此外，藥物性骨質(zhì)疏松癥并不少見(jiàn)。在這篇綜述中，我們關(guān)注繼發(fā)性骨質(zhì)疏松癥的病因、發(fā)病機(jī)制和治療。

關(guān)鍵詞：骨質(zhì)流失，骨折，骨礦物質(zhì)密度，原因，治療

在病情允許的條件下，多多參加戶(hù)外活動(dòng)，親近大自然和沐浴陽(yáng)光，讓身心得到充分放松的同時(shí)，皮膚合成更多的維生素D，從而更好地預(yù)防骨質(zhì)疏松癥。

Figure 1. Causes of secondary osteoporosis. Various causes of secondary osteoporosis are illustrated in this figure. They include ROD, DM, thyroid and parathyroid disorders, malabsorption, IBD, IBS, nutritional causes, drug-induced, infections, anemia, malignancies, inflammatory arthritis, SLE, smoking, and genetic causes. PPIs: proton pump inhibitors, ROD: renal osteodystrophy, DM: diabetes mellitus, PTH: parathyroid, IBD: inflammatory bowel disease, IBS: irritable bowel syndrome, SLE: systemic lupus erythematosus. HIV: human immunodeficiency virus, HCV: hepatitis C virus, HBV: hepatitis B virus, HZV: herpes zoster virus, TB: tuberculosis. This Figure was created with BioRender.com (accessed on 1 February 2022).

圖1. 繼發(fā)性骨質(zhì)疏松癥的原因。該圖說(shuō)明了繼發(fā)性骨質(zhì)疏松癥的各種原因。它們包括腎性骨營(yíng)養(yǎng)不良ROD、糖尿病DM、甲狀腺和甲狀旁腺疾病、吸收不良、炎癥性腸病IBD、腸易激綜合征IBS、營(yíng)養(yǎng)原因、藥物引起的、感染、貧血、惡性腫瘤、炎性關(guān)節(jié)炎、系統(tǒng)性紅斑狼瘡S(chǎng)LE、吸煙和遺傳原因。

PPI：質(zhì)子泵抑制劑，ROD：腎性骨營(yíng)養(yǎng)不良，DM：糖尿病，PTH：甲狀旁腺，IBD：炎癥性腸病，IBS：腸易激綜合征，SLE：系統(tǒng)性紅斑狼瘡。HIV：人類(lèi)免疫缺陷病毒，HCV：丙型肝炎病毒，HBV：乙型肝炎病毒，HZV：帶狀皰疹病毒，TB：結(jié)核病。

Figure 2. Pragmatic diagnostic approach for newly diagnosed patients with osteoporosis. A systematic approach for the analysis and detection of a secondary cause of osteoporosis is recommended for all patients with a new diagnosis of osteoporosis. A full history and physical examination followed by a routine laboratory investigation for the most common and simple underlying causes of osteoporosis are required for most cases. Some additional investigation may be considered after routine lab for the suspected cases. CKD, chronic kidney disease, CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; IBD: inflammatory bowel diseases; HCV: hepatitis C virus; HBV: hepatitis B virus; HIV: human immunodeficiency virus; TB: tuberculosis; FSH: follicle stimulating hormone; LH: luteinizing hormone.

圖2. 新診斷的骨質(zhì)疏松癥患者的實(shí)用診斷方法。建議對(duì)所有新診斷為骨質(zhì)疏松癥的患者采用系統(tǒng)的方法來(lái)分析和檢測(cè)骨質(zhì)疏松癥的繼發(fā)性原因。大多數(shù)病例都需要完整的病史和體格檢查，然后進(jìn)行常規(guī)實(shí)驗(yàn)室檢查，以了解最常見(jiàn)和最簡(jiǎn)單的骨質(zhì)疏松癥根本原因。在對(duì)疑似病例進(jìn)行常規(guī)化驗(yàn)后，可能會(huì)考慮進(jìn)行一些額外的調(diào)查。CKD，慢性腎病，CRP：C反應(yīng)蛋白；ESR：紅細(xì)胞沉降率；IBD：炎癥性腸病；HCV：丙型肝炎病毒；HBV：乙型肝炎病毒；HIV：人類(lèi)免疫缺陷病毒；結(jié)核病：肺結(jié)核；FSH：促*泡激素；LH：促黃體激素。

Figure 3. Approach for prevention and management of secondary osteoporosis. Correction of the underlying causes of secondary osteoporosis is the cornerstone of prevention and treatment. All patients can benefit from non-pharmacological intervention, DEXA scan and assessment of fracture risk. Anti-osteoporotic medications (antiresorptives and osteoanabolics) can be used in selected cases with high fracture risk. DEXA: dual-energy X-ray absorptiometry, FRAX: fracture-risk algorithm, SERM: Selective estrogen receptor modulators.

圖3. 繼發(fā)性骨質(zhì)疏松癥的預(yù)防和管理方法。糾正繼發(fā)性骨質(zhì)疏松癥的根本原因是防治的基石。所有患者都可以從非藥物干預(yù)、雙光能X線(xiàn)掃描確定骨密度BMD（DEXA）和骨折風(fēng)險(xiǎn)評(píng)估中受益?？构琴|(zhì)疏松藥物（抗骨吸收藥物和骨合成*謝藥物）可用于骨折風(fēng)險(xiǎn)較高的特定病例。DEXA：雙能X射線(xiàn)吸收測(cè)定法，F(xiàn)RAX：骨折風(fēng)險(xiǎn)算法，SERM：選擇性雌激素受體調(diào)節(jié)劑。

Figure 4. Mechanism of action of common antiosteoporotic medications. Antiosteoporotic medications can be divided into two main categories: 1. Antiresorptives “on the right side” act mainly by inhibiting osteoclasts. Bisphosphonates act by inhibiting osteoclast differentiation from osteoclast precursors. The monoclonal antibody “denausumab” inhibits osteoclast differentiation by binding to RANKL, preventing its interaction with RANK. SERMs increase OPG production, thus inhibiting osteoclastogenesis. 2. Osteoanabolics “on the left side” stimulate bone formation via activation of PTH (teriparatide) or PTH-related peptide (abaloparatide) receptors. Romosuzumab is an anti-sclerostin monoclonal antibody. Thus, it stimulates osteoblast differentiation and function. MSC: mesenchymal stem cells, HSC: hematopoietic stem cells, SERMs: selective estrogen receptor modulators, OPG: osteoprotegerin, RANK: Receptor activator of nuclear factor κ B, RANKL: receptor activator of nuclear factor kappa-Β ligand. this figure was created with BioRender.com (accessed on 1 February 2022).

圖4. 常見(jiàn)抗骨質(zhì)疏松藥物的作用機(jī)制?？构琴|(zhì)疏松藥物可分為兩大類(lèi)：

1. “右側(cè)”抗吸收劑：主要通過(guò)抑制破骨細(xì)胞起作用。雙膦酸鹽通過(guò)抑制破骨細(xì)胞從破骨細(xì)胞前體分化而起作用。單克隆抗體“denausumab”通過(guò)與RANKL 結(jié)合來(lái)抑制破骨細(xì)胞分化，防止其與RANK相互作用。SERM增加OPG的產(chǎn)生，從而抑制破骨細(xì)胞生成。

2. “左側(cè)”的骨合成*謝物：通過(guò)激活PTH（特立帕肽）或PTH相關(guān)肽（abaloparatide）受體來(lái)刺激骨形成。Romosuzumab是一種抗硬化蛋白單克隆抗體。因此，它刺激成骨細(xì)胞分化和功能。MSC：間充質(zhì)干細(xì)胞，HSC：造血干細(xì)胞，SERM：選擇性雌激素受體調(diào)節(jié)劑，OPG：骨保護(hù)素，RANK：核因子κB受體激活劑，RANKL：核因子κ-B配體受體激活劑。

Osteocyte：骨細(xì)胞；Osteoclast：破骨細(xì)胞；Osteoblast：成骨細(xì)胞。

1. 簡(jiǎn)介

骨質(zhì)疏松癥是一種以骨脆性為特征的疾病，繼發(fā)于低骨礦物質(zhì)密度(BMD)和/或增加骨折風(fēng)險(xiǎn)的微結(jié)構(gòu)惡化。絕經(jīng)后雌激素缺乏是骨質(zhì)疏松癥的主要原因。除了患有原發(fā)性骨質(zhì)疏松癥（絕經(jīng)后或與年齡相關(guān)）的絕經(jīng)后婦女外，超過(guò)一半的被轉(zhuǎn)診到骨質(zhì)疏松癥中心的圍絕經(jīng)期和絕經(jīng)后婦女，有一個(gè)或多個(gè)繼發(fā)性骨質(zhì)疏松癥的危險(xiǎn)因素[1]。骨折風(fēng)險(xiǎn)評(píng)估工具(FRAX)通過(guò)使用臨床和放射學(xué)數(shù)據(jù)幫助估計(jì)10年骨折風(fēng)險(xiǎn)。這些臨床數(shù)據(jù)包括一些（但不是全部）骨質(zhì)疏松癥的繼發(fā)原因，例如吸煙、過(guò)量飲酒、I型糖尿病、甲狀腺功能亢進(jìn)、慢性肝病和營(yíng)養(yǎng)不良[2]。圖1中提到了骨質(zhì)疏松癥的各種繼發(fā)性原因。新診斷的骨質(zhì)疏松癥患者應(yīng)進(jìn)行全面評(píng)估，包括他們的病史、體格檢查和用于檢測(cè)繼發(fā)性原因的常規(guī)實(shí)驗(yàn)室檢測(cè)。圖2說(shuō)明了檢測(cè)根本原因的系統(tǒng)方法。圖3總結(jié)了繼發(fā)性骨質(zhì)疏松癥患者的管理方法。正確識(shí)別骨質(zhì)疏松癥的病因是改善骨骼健康、防止進(jìn)一步骨質(zhì)流失的重要步驟。這些患者可以受益于均衡的營(yíng)養(yǎng)、體育鍛煉以及避免長(zhǎng)期使用糖皮質(zhì)激素和其他對(duì)骨骼健康有負(fù)面影響的藥物。推薦對(duì)骨折高風(fēng)險(xiǎn)患者使用抗骨質(zhì)疏松治療；常用抗骨質(zhì)疏松藥物的作用機(jī)制如圖4所示。本文全面討論了繼發(fā)性骨質(zhì)疏松癥的流行病學(xué)、各種原因和發(fā)病機(jī)制。本主題不僅涵蓋骨量問(wèn)題，還關(guān)注質(zhì)量問(wèn)題。此外，還對(duì)繼發(fā)性骨質(zhì)疏松癥的最新治療進(jìn)行了深入討論。

2. 腎臟原因

慢性腎臟疾病(CKD)是公認(rèn)的骨質(zhì)流失危險(xiǎn)因素[3]。骨丟失和骨折風(fēng)險(xiǎn)的發(fā)生率隨著腎功能的下降而增加。據(jù)報(bào)道，高達(dá)32%的慢性腎臟疾病CKD患者出現(xiàn)骨質(zhì)疏松癥，而大約一半的患者發(fā)現(xiàn)骨質(zhì)疏松癥[3,4,5,6]。但是，由于各種原因，問(wèn)題的嚴(yán)重性可能更高。首先，慢性腎臟疾病CKD患者血管鈣化的發(fā)生率很高，這導(dǎo)致雙光能X線(xiàn)骨密度檢測(cè)DXA對(duì)椎骨骨量的估計(jì)更高[7]。其次，慢性腎臟疾病CKD患者不僅有骨量/數(shù)量問(wèn)題，還有骨質(zhì)量問(wèn)題[8]。第三，盡管有KDIGO的建議，慢性腎臟疾病CKD患者的骨質(zhì)疏松癥診斷工具仍未得到充分利用。高達(dá)30-50%的慢性腎臟疾病CKD骨折患者的T評(píng)分高于-2.5 [9,10]。與一般人群相比，晚期慢性腎臟疾病CKD患者的骨折風(fēng)險(xiǎn)高達(dá)8倍[11]。骨質(zhì)疏松性骨折會(huì)對(duì)慢性腎臟疾病CKD患者的生活質(zhì)量產(chǎn)生有害影響。在一般人群中，髖部骨折后的一年死亡率為17-27% [12,13]，而在終末期腎病(ESKD)患者中則高達(dá)64% [14,15]。

腎性骨營(yíng)養(yǎng)不良(ROD)、藥物使用、性腺功能減退、全身炎癥、酸中毒和并發(fā)的全身性疾病會(huì)導(dǎo)致慢性腎臟疾病CKD患者的骨質(zhì)流失。*謝性酸中毒會(huì)刺激破骨細(xì)胞并誘導(dǎo)強(qiáng)烈的骨吸收。腎性骨營(yíng)養(yǎng)不良ROD在慢性腎臟疾病CKD的早期階段發(fā)展，并隨著腎功能的進(jìn)一步喪失而進(jìn)展[16]。腎性骨營(yíng)養(yǎng)不良ROD的發(fā)病機(jī)制中有許多共同參與者。FGF-23是一種骨細(xì)胞分泌的磷酸鹽激素，在慢性腎臟疾病CKD的早期階段升高以預(yù)防高磷血癥[17,18]。盡管由于klotho缺乏/抵抗導(dǎo)致FGF-23水平升高，但高磷血癥發(fā)生在慢性腎臟疾病CKD晚期階段[19]。FGF-23抑制維生素D活化并增加其分解*謝[20,21]。維生素D缺乏/不足和高磷血癥會(huì)導(dǎo)致慢性腎臟疾病CKD患者繼發(fā)性甲狀旁腺功能亢進(jìn)[22,23,24,25]。硬化蛋白、DKK-1和WNT通路抑制劑的水平隨著腎功能的惡化而增加[26]。它們抑制骨形成并促進(jìn)低周轉(zhuǎn)率骨病[27]。另一方面，慢性腎臟疾病CKD患者的骨保護(hù)素(OPG)和核因子kappa B配體(RANKL)受體激活劑水平之間的不平衡會(huì)增加破骨細(xì)胞生成并誘導(dǎo)高周轉(zhuǎn)性骨病[28,29]。此外，性腺激素紊亂可能是骨質(zhì)疏松癥的主要原因。慢性腎臟疾病CKD患者常用的許多藥物，如肝素、華法林、糖皮質(zhì)激素、質(zhì)子泵抑制劑和利尿劑，都會(huì)對(duì)骨骼健康產(chǎn)生負(fù)面影響[30,31]。

許多工具可用于診斷慢性腎臟疾病CKD患者的骨質(zhì)疏松癥，但對(duì)于最佳工具尚無(wú)共識(shí)。雙光能X線(xiàn)骨密度檢測(cè)DXA是使用最廣泛的方法。骨折風(fēng)險(xiǎn)評(píng)估工具(FRAX)有助于估計(jì)10年骨折風(fēng)險(xiǎn)；然而，它不包括慢性腎臟疾病CKD作為骨質(zhì)疏松癥的次要原因[32]。與雙光能X線(xiàn)骨密度檢測(cè)DXA相比，定量計(jì)算機(jī)斷層掃描(QCT)不受血管鈣化的影響，可能是更好的工具，特別是對(duì)于縱向隨訪(fǎng)和肥胖患者[33]。然而，由于較高的成本和輻射暴露，它的使用不太常見(jiàn)。這兩種工具都有助于評(píng)估骨量/骨量。另一方面，TBS、高分辨率成像技術(shù)、有限元分析和傅里葉變換紅外光譜可用于評(píng)估骨質(zhì)量。骨轉(zhuǎn)換標(biāo)志物提供骨形成和骨吸收的動(dòng)態(tài)評(píng)估，并促進(jìn) ROD 管理 [34]。在慢性腎臟疾病CKD患者中，骨特異性堿性磷酸酶(BSAP)和完整的procollagen-1 N末端肽(P1NP)作為骨形成標(biāo)志物，以及抗酒石酸酸性磷酸酶5b (TRAP 5b)作為骨吸收標(biāo)志物在慢性腎臟疾病CKD患者中是可靠的[35]。骨轉(zhuǎn)換標(biāo)志物和甲狀旁腺激素(PTH)不僅有助于了解骨轉(zhuǎn)換狀態(tài)[36]，還有助于預(yù)測(cè)骨折風(fēng)險(xiǎn)[37,38]。骨活檢仍然是確定骨丟失機(jī)制和嚴(yán)重程度的金標(biāo)準(zhǔn)[39]。它也有助于選擇合適的藥物，但受到其侵入性和缺乏專(zhuān)業(yè)知識(shí)的限制。慢性腎臟疾病CKD患者骨組織學(xué)評(píng)估應(yīng)包括三個(gè)要素：更新、礦化和體積[16,40]。目前，慢性腎臟疾病CKD患者最常見(jiàn)的病理表現(xiàn)是低周轉(zhuǎn)骨?。↙TBD）、高周轉(zhuǎn)骨?。℉TBD）、混合性腎性骨營(yíng)養(yǎng)不良ROD，而骨軟化癥在成人中較少見(jiàn)[41]。最近發(fā)表的評(píng)論描述了慢性腎臟疾病CKD患者的骨質(zhì)量評(píng)估和管理[7,42]。

骨質(zhì)疏松癥管理的首要步驟是控制慢性腎臟疾病CKD*謝紊亂。維生素D缺乏、高磷血癥和甲狀旁腺功能亢進(jìn)是這些患者的常見(jiàn)表現(xiàn)，對(duì)骨骼有不利影響。應(yīng)指導(dǎo)患者預(yù)防跌倒風(fēng)險(xiǎn)和非藥物干預(yù)以改善骨骼健康。戒煙、限制酒精、個(gè)性化運(yùn)動(dòng)方案和均衡營(yíng)養(yǎng)對(duì)骨骼有積極影響，但在慢性腎臟疾病CKD患者中未得到充分利用[42]。優(yōu)化鈣攝入量和正確使用降磷酸鹽療法、維生素D和擬鈣劑可通過(guò)改善腎性骨營(yíng)養(yǎng)不良ROD來(lái)降低骨折風(fēng)險(xiǎn)[43]。

確定腎性骨營(yíng)養(yǎng)不良ROD的類(lèi)型并包括高周轉(zhuǎn)率和低周轉(zhuǎn)率有助于選擇具有更高療效和更低不良事件的適當(dāng)治療方法。預(yù)計(jì)高周轉(zhuǎn)骨?。℉TBD）患者將從抗骨吸收藥物中獲益更多，例如雙膦酸鹽和地諾塞麥，而低周轉(zhuǎn)骨?。↙TBD）患者可能從骨合成*謝藥物中獲益，以改善骨形成。

盡管由腎臟排泄，但雙膦酸鹽可用于輕度至中度慢性腎臟疾病CKD患者，而沒(méi)有重大安全問(wèn)題 [44]。它們?cè)谕砥诼阅I臟疾病CKD患者中的使用應(yīng)謹(jǐn)慎對(duì)待慢性腎臟疾病CKD進(jìn)展[45]。此外，在晚期慢性腎臟疾病CKD患者中長(zhǎng)期使用雙膦酸鹽可能會(huì)誘發(fā)低周轉(zhuǎn)骨?。↙TBD）并增加非典型股骨骨折的風(fēng)險(xiǎn)[46]。在觀(guān)察性研究和小型隨機(jī)對(duì)照試驗(yàn)(RCT)中，地舒單抗已被證明可以改善慢性腎臟疾病CKD患者的骨密度BMD并減少骨轉(zhuǎn)換[47,48]。與雙膦酸鹽相反，它不通過(guò)腎臟排泄，但應(yīng)密切監(jiān)測(cè)血清鈣和維生素D的低鈣血癥風(fēng)險(xiǎn)。

另一方面，骨合成*謝藥物（特立帕肽、abaloparatide和romosozumab）在減輕低周轉(zhuǎn)骨病（LTBD）患者的骨質(zhì)流失方面具有良好的作用。特立帕肽已在多項(xiàng)研究中用于晚期慢性腎臟疾病CKD患者[49,50,51,52]。Abaloparatide在慢性腎臟疾病CKD的早期階段是安全有效的[53]。Romosozumab增加了輕至中度慢性腎臟疾病CKD[54]和透析患者[55]的骨密度BMD。

3. 內(nèi)分泌原因

3.1 糖尿病

糖尿病是一種與脆性骨折風(fēng)險(xiǎn)增加相關(guān)的慢性*謝疾病。與2型糖尿病(T2DM)患者相比，患有1型糖尿病(T1DM)的成年人發(fā)生骨折的風(fēng)險(xiǎn)更高，尤其是非椎體骨折[56,57]。盡管如此，椎骨骨折并不少見(jiàn)，并且與死亡率增加有關(guān)，但由于它們可能無(wú)癥狀，因此經(jīng)常被漏診[58]。糖尿病會(huì)損害骨*謝、損害細(xì)胞功能或破壞細(xì)胞外基質(zhì)。這會(huì)導(dǎo)致骨質(zhì)流失、骨微結(jié)構(gòu)改變、骨轉(zhuǎn)換減少和易患低創(chuàng)傷性骨折。糖尿病中脆性骨的發(fā)病機(jī)制和危險(xiǎn)因素包括肥胖、胰島素抵抗增加、血糖紊亂、晚期糖基化終產(chǎn)物的產(chǎn)生、肌肉功能障礙、大血管和微血管并發(fā)癥以及藥物治療。此外，相關(guān)的合并癥，如甲狀腺疾病、性腺功能障礙和吸收不良可能會(huì)導(dǎo)致骨質(zhì)流失[59,60]。值得注意的是，1型糖尿病T1DM與成骨細(xì)胞活性降低、骨密度BMD降低或相似以及骨折風(fēng)險(xiǎn)升高有關(guān)[56,61,62,63]。而2型糖尿病T2DM與骨丟失和骨折率增加有關(guān)，即使骨密度BMD正?；蜉^高[56,64]。建議將-2.0的T評(píng)分閾值作為2型糖尿病T2DM治療干預(yù)的觸發(fā)因素[65]。然而，與骨密度BMD相比，全髖骨區(qū)域是老年2型糖尿病T2DM患者脆性骨折的更好替*指標(biāo)[66]。

糖尿病主要影響骨質(zhì)量，包括破壞骨材料特性和增加皮質(zhì)孔隙率，這些是骨密度BMD-DXA無(wú)法測(cè)量的[59,67]。這強(qiáng)調(diào)了雙光能X線(xiàn)片檢測(cè)骨密度DXA的骨密度測(cè)量低估了糖尿病患者的骨折風(fēng)險(xiǎn)[68]。骨小梁評(píng)分[69]、外周定量計(jì)算機(jī)斷層掃描(pQCT)、基于pQCT的有限元分析(pQCT-FEA) [70]和高分辨率外周定量計(jì)算機(jī)斷層掃描(HR-pQCT) [71]是更好的估計(jì)工具糖尿病患者的骨折風(fēng)險(xiǎn)。有創(chuàng)性檢查方法，例如顯微壓痕和骨組織形態(tài)測(cè)量法，價(jià)格昂貴且無(wú)法廣泛使用[68,72]。

糖尿病導(dǎo)致骨骼脆弱，應(yīng)用減少骨折的策略至關(guān)重要。此外，似乎血糖控制程度與骨折風(fēng)險(xiǎn)之間存在相關(guān)性[73,74]。在一項(xiàng)大型隊(duì)列研究中，糖化血紅蛋白HbA1c與骨折風(fēng)險(xiǎn)之間存在三次關(guān)系[75]。對(duì)于骨脆性增加的糖尿病患者，應(yīng)避免使用噻唑烷二酮類(lèi)藥物[76]。此外，越來(lái)越多的證據(jù)表明鈉葡萄糖協(xié)同轉(zhuǎn)運(yùn)蛋白2 (SGLT2)抑制劑對(duì)骨骼健康有負(fù)面影響。使用阿侖膦酸鹽3年導(dǎo)致糖尿病合并骨質(zhì)疏松癥患者的骨密度BMD增加[77]。在最近的一項(xiàng)系統(tǒng)評(píng)價(jià)中，抗骨質(zhì)疏松藥物（主要是雙膦酸鹽）似乎可以防止糖尿病和非糖尿病個(gè)體脊柱的骨質(zhì)流失[78]。每天皮下注射特立帕肽abaloparatide (80 mcg)與糖尿病患者骨密度BMD的改善有關(guān)[79]。

3.2.性腺疾病

性腺機(jī)能減退是骨質(zhì)疏松癥的危險(xiǎn)因素。男性的峰值骨量和骨密度BMD較高；但是，如果男性和女性的骨密度BMD相似，則男性骨折的風(fēng)險(xiǎn)更高。與女性相比，70歲以下男性的骨質(zhì)疏松癥發(fā)病率顯著降低，因?yàn)榕怨琴|(zhì)流失發(fā)生得更早且發(fā)生率更高[80,81]。睪酮替*療法可以改善骨密度BMD，但對(duì)性腺功能減退的老年男性的結(jié)果尚無(wú)定論。然而，接受睪酮治療一年的性腺功能減退老年男性的體積骨密度BMD和骨強(qiáng)度顯著改善[82,83]。

3.3.甲狀旁腺疾?。谞钆韵俟δ艿拖潞驮l(fā)性甲狀旁腺功能亢進(jìn)）

甲狀旁腺功能減退癥是一種骨轉(zhuǎn)換率低的疾病。關(guān)于骨折風(fēng)險(xiǎn)的信息不一致[84,85,86]，但非手術(shù)性甲狀旁腺功能減退癥患者的椎體骨折風(fēng)險(xiǎn)似乎更高[86,87,88]。這可能是由于與手術(shù)性甲狀旁腺功能減退癥相比，非手術(shù)性甲狀旁腺功能減退癥的骨骼變化時(shí)間更長(zhǎng)[86]。因此，我們推測(cè)較高的骨折風(fēng)險(xiǎn)是由于骨骼過(guò)度成熟和質(zhì)量受損。通過(guò)雙光能X線(xiàn)片檢測(cè)骨密度DXA，他們?cè)谒泄趋啦课欢加休^高的骨密度BMD，尤其是在腰椎[89]。此外，它們通常具有正常[89,90,91]或低[92]小梁骨評(píng)分，并被歸類(lèi)為退化的微架構(gòu)。與年齡和性別匹配的對(duì)照組相比，他們通常具有更高的體積骨密度BMD（小梁和皮質(zhì)），并且pQCT的皮質(zhì)面積和厚度更高[89,93]。盡管如此，HR-pQCT顯示皮質(zhì)體積骨密度BMD增加，但皮質(zhì)厚度和皮質(zhì)孔隙率降低[89,94]。它們似乎也具有由有限元建模確定的正常生物力學(xué)強(qiáng)度[94,95]，但通過(guò)沖擊顯微壓痕測(cè)量的骨材料強(qiáng)度指數(shù)低于對(duì)照組[86,96]。鈣和維生素D補(bǔ)充劑被廣泛使用。然而，這種做法的長(zhǎng)期安全性和有效性并未得到很好的研究。Donovan Tay等據(jù)報(bào)道，長(zhǎng)期使用PTH (1-84)治療可減少補(bǔ)充鈣和維生素D的需求，并增加腰椎和全髖骨密度BMD [97]。與傳統(tǒng)管理相比，PTH (1-84)可降低尿鈣和血清磷水平并改善生活質(zhì)量，而不會(huì)增加嚴(yán)重不良事件[98,99,100]。在最近的一項(xiàng)薈萃分析中，與PTH相比，活性維生素D的使用與相似的血清鈣水平相關(guān)，但有降低尿鈣水平的趨勢(shì)[101]。此外，長(zhǎng)期安全性尚未完全認(rèn)識(shí)到，大鼠研究報(bào)告了劑量依賴(lài)性增加的骨肉瘤風(fēng)險(xiǎn)[102,103]。這種擔(dān)憂(yōu)限制了PTH (1-84)作為甲狀旁腺功能減退癥的替*療法的長(zhǎng)期使用。小型研究報(bào)告了甲狀旁腺組織同種異體移植治療甲狀旁腺功能減退癥的療效存在異質(zhì)性[104]。

原發(fā)性甲狀旁腺功能亢進(jìn)癥(PHPT)與不同骨骼部位的骨密度BMD降低和骨折風(fēng)險(xiǎn)增加有關(guān)，尤其是在腰椎處[105,106]。雙光能X線(xiàn)片檢測(cè)骨密度DXA測(cè)量的骨密度BMD是髖部和前臂骨折可接受的預(yù)測(cè)指標(biāo)，但無(wú)法診斷椎體脆性[107]。有一些有價(jià)值的工具，例如骨小梁評(píng)分、3D-DXA [108]、通過(guò)雙光能X線(xiàn)片檢測(cè)骨密度DXA [109]和HR-pQCT [110]的有限元分析得出的骨應(yīng)變指數(shù)(BSI)來(lái)評(píng)估骨骼健康和預(yù)測(cè)骨骼脆性[105]。HR-pQCT揭示了皮質(zhì)和骨小梁微結(jié)構(gòu)的改變，包括皮質(zhì)和骨小梁體積密度降低、皮質(zhì)孔隙率增加以及骨小梁分布的異質(zhì)性[110,111]。這幾乎與組織形態(tài)學(xué)研究一致，除了保留甚至改善骨小梁結(jié)構(gòu)[112]。使用沖擊顯微壓痕技術(shù)評(píng)估脛骨骨材料強(qiáng)度指數(shù)顯示PHPT受試者的骨材料特性受損，尤其是脆性骨折患者 [113]。甲狀旁腺切除術(shù)可降低不同骨骼部位的鈣濃度并增加骨密度BMD。它可能比主動(dòng)監(jiān)測(cè)更好地降低骨折風(fēng)險(xiǎn)[114]，但它在骨折風(fēng)險(xiǎn)、腎結(jié)石和生活質(zhì)量方面優(yōu)于藥物治療的優(yōu)勢(shì)缺乏足夠的證據(jù)[114,115]。盡管如此，甲狀旁腺切除術(shù)可以改善通過(guò)HR-pQCT和有限元分析評(píng)估的骨強(qiáng)度[116]。在藥物治療方面，建議優(yōu)化鈣和維生素D的攝入量[117]。鈣補(bǔ)充劑可降低無(wú)癥狀原發(fā)性甲狀旁腺功能亢進(jìn)癥PHPT患者的甲狀旁腺激素PTH并增加股骨頸骨密度BMD [118]。沒(méi)有理由限制輕度原發(fā)性甲狀旁腺功能亢進(jìn)癥PHPT患者的膳食鈣攝入量，但需要密切監(jiān)測(cè)鈣，在1,25(OH)2D升高和血清甲狀旁腺激素PTH水平較高的重度原發(fā)性甲狀旁腺功能亢進(jìn)癥PHPT中應(yīng)避免補(bǔ)鈣。其他藥物療法包括雙膦酸鹽、西那卡塞、地諾塞麥和雌激素，它們適用于降低鈣、增加骨密度BMD或兩者兼而有之[117]。

3.4.甲狀腺疾病

甲狀腺激素在骨*謝中起關(guān)鍵作用。甲狀腺功能亢進(jìn)，即使是亞臨床的，也是骨質(zhì)疏松癥的已知危險(xiǎn)因素。它與骨轉(zhuǎn)換增加、骨量減少和骨折風(fēng)險(xiǎn)增加有關(guān)[119,120]。此外，分化型甲狀腺癌患者的長(zhǎng)期促甲狀腺激素TSH抑制與絕經(jīng)后婦女的骨密度BMD降低有關(guān)[121]。HR-pQCT報(bào)告的甲狀腺功能亢進(jìn)女性骨質(zhì)量和數(shù)量受損。甲狀腺功能正?？梢愿纳企w積骨密度BMD和皮質(zhì)微結(jié)構(gòu)[119]。明顯的甲狀腺功能減退會(huì)減少骨形成。然而，關(guān)于骨密度BMD和骨折風(fēng)險(xiǎn)的數(shù)據(jù)尚無(wú)定論[122]。

3.5.腎上腺疾病

庫(kù)欣綜合征患者中30-50% [123,124,125]發(fā)生骨質(zhì)疏松癥，30-70%發(fā)生脊椎骨折[126,127]。庫(kù)欣綜合征會(huì)導(dǎo)致過(guò)量的糖皮質(zhì)激素產(chǎn)生，除了改變甲狀旁腺激素的節(jié)律性產(chǎn)生外，還會(huì)通過(guò)抑制生長(zhǎng)激素和性腺軸對(duì)骨*謝產(chǎn)生負(fù)面影響[126]。庫(kù)欣綜合征患者的骨小梁丟失更為明顯。具有自主皮質(zhì)醇分泌的腎上腺結(jié)節(jié)[128]、原發(fā)性醛固酮增多癥[129]、嗜鉻細(xì)胞瘤[130,131]和先天性腎上腺增生[132]與骨質(zhì)量和數(shù)量的惡化有關(guān)。

3.6.生長(zhǎng)激素

盡管肢端肥大癥患者的骨形成率較高，但由于骨轉(zhuǎn)換增加和骨質(zhì)量差，他們椎體骨折的風(fēng)險(xiǎn)增加。然而，與一般人群相比，他們的骨密度BMD可能增加、減少或相似[133,134]。它們具有更高的皮質(zhì)孔隙率和改變的骨微結(jié)構(gòu)，這歸因于改變的骨重塑和Wnt信號(hào)傳導(dǎo)。

生長(zhǎng)激素缺乏與低骨轉(zhuǎn)換骨質(zhì)疏松癥和皮質(zhì)損失大于骨小梁有關(guān)，這導(dǎo)致骨折風(fēng)險(xiǎn)增加[135]。生長(zhǎng)激素替*物最初會(huì)增加骨轉(zhuǎn)換并降低骨密度。維持治療有助于改善骨量，但其對(duì)骨折風(fēng)險(xiǎn)的影響尚不明確[136]。這可能是由于DKK-1（一種Wnt抑制劑）增加，因此增加了皮質(zhì)孔隙率[137]。

4. 胃腸道原因

吸收不良和慢性肝病是眾所周知的骨質(zhì)疏松癥原因，它們被包括在FRAX中。生理性骨*謝需要最佳量的營(yíng)養(yǎng)物質(zhì)，尤其是礦物質(zhì)和維生素。維生素D是一種脂溶性維生素，因此在與脂肪吸收不良相關(guān)的疾病中骨質(zhì)流失很明顯[138,139,140,141,142,143]。此外，在脂肪瀉的情況下，鈣的吸收可能會(huì)因與胃腸道(GI)腔中過(guò)量的脂肪酸結(jié)合而受到阻礙[144]。在本節(jié)中，我們將討論胃腸道相關(guān)骨質(zhì)疏松癥的最常見(jiàn)原因。

4.1。乳糜瀉

即使在排除絕經(jīng)后婦女后，乳糜瀉患者的骨質(zhì)減少和骨質(zhì)疏松癥的患病率也很高，分別為40%和15% [145]。據(jù)報(bào)道，8%的特發(fā)性低骨密度BMD患者的IgA抗肌內(nèi)膜抗體陽(yáng)性，即使他們沒(méi)有癥狀。在特發(fā)性骨質(zhì)疏松癥病例中，可以考慮對(duì)乳糜瀉進(jìn)行常規(guī)篩查[146,147]。無(wú)麩質(zhì)飲食可以顯著改善骨密度BMD [148,149]。然而，由于持續(xù)的炎癥過(guò)程導(dǎo)致更高的破骨細(xì)胞活性和更低的生成骨基質(zhì)的能力，骨質(zhì)流失可能會(huì)持續(xù)存在[150]。

4.2.慢性胰腺炎

超過(guò)50%的慢性胰腺炎患者，尤其是吸煙者和酗酒者，骨密度BMD較低。胰酶和維生素D替*品顯著降低了骨折的風(fēng)險(xiǎn)[151]。胰腺炎囊性纖維化可通過(guò)吸收不良以外的機(jī)制干擾骨骼健康。胰腺炎囊性纖維化跨膜電導(dǎo)調(diào)節(jié)劑在骨細(xì)胞中表達(dá)，因此可能對(duì)骨*謝產(chǎn)生負(fù)面影響。此外，由于促炎細(xì)胞因子刺激破骨細(xì)胞活性，肺部惡化期間骨吸收增加[152]。

4.3.短腸綜合征

與匹配的對(duì)照組相比，短腸綜合征患者的骨質(zhì)疏松癥患病率高出2倍 [141]。由于微量和大量營(yíng)養(yǎng)素的吸收不良，會(huì)發(fā)生骨質(zhì)流失。由慢性腹瀉或由細(xì)菌過(guò)度生長(zhǎng)引起的D-乳酸酸中毒引起的*謝性酸中毒也會(huì)損害骨骼健康[153]。

4.4.肝性骨營(yíng)養(yǎng)不良

脂溶性維生素的腸肝循環(huán)受到干擾會(huì)損害骨*謝。這是原發(fā)性膽汁性膽管炎(PBC)和硬化性膽管炎等膽道疾病中骨丟失的主要原因之一。原發(fā)性膽汁性膽管炎PBC中骨質(zhì)疏松癥和骨折的患病率分別高達(dá)50%和20% [154,155,156]。慢性肝病、酒精、病毒性肝炎和自身免疫性疾病的病因可能有助于肝性骨營(yíng)養(yǎng)不良的發(fā)病機(jī)制[154,157,158,159,160,161]。肝硬化并發(fā)癥，如營(yíng)養(yǎng)不良、身體活動(dòng)受損和性腺機(jī)能減退，以及維生素D和K*謝紊亂 [162,163]，會(huì)加重骨質(zhì)流失。

4.5.消化性潰瘍病

消化性潰瘍病與骨質(zhì)疏松癥有關(guān)，尤其是在男性中。某些種類(lèi)的幽門(mén)螺桿菌感染可能通過(guò)增強(qiáng)炎癥狀態(tài)、降低循環(huán)生長(zhǎng)素釋放肽和雌激素水平以及增加餐后血清素水平來(lái)影響骨*謝。此外，長(zhǎng)期使用抑制胃酸藥PPI（如洛賽克膠囊）會(huì)損害骨骼健康[164,165]。

4.6.炎癥性腸病(IBD)

炎癥性腸病IBD患者發(fā)生骨丟失[166]、骨質(zhì)量差[167,168]和骨折[169,170,171,172]的風(fēng)險(xiǎn)更高。這可以通過(guò)營(yíng)養(yǎng)不良、慢性炎癥過(guò)程和免疫抑制藥物來(lái)解釋[171,173,174]。低周轉(zhuǎn)骨病是骨質(zhì)疏松癥和炎癥性腸病IBD患者的主要潛在病理[175,176]。美國(guó)胃腸病學(xué)會(huì)建議使用常規(guī)危險(xiǎn)因素作為炎癥性腸病IBD患者使用雙光能X線(xiàn)片骨密度檢測(cè)DXA掃描進(jìn)行骨密度BMD篩查的指征[177]。Cornerstone Health組織擴(kuò)大了骨密度BMD篩查的適應(yīng)癥，包括有骨質(zhì)疏松癥的產(chǎn)婦史、營(yíng)養(yǎng)不良或非常瘦的患者以及絕經(jīng)后婦女的閉經(jīng)[178]。Maldonado及其同事強(qiáng)調(diào)了生物力學(xué)CT在檢測(cè)骨折風(fēng)險(xiǎn)增加患者中的作用。這些患者中有40%未包括在基石檢查表中。因此，接受CT小腸造影的炎癥性腸病IBD患者可能受益于生物力學(xué)CT篩查骨折風(fēng)險(xiǎn) [179]?？筎NF對(duì)炎癥過(guò)程的早期抑制與更好的骨保存有關(guān)[169,180]。除了鈣和維生素D優(yōu)化之外，雙膦酸鹽是相對(duì)安全和有效的治療選擇[181]。在一項(xiàng)動(dòng)物研究中，據(jù)報(bào)道，一種天然化合物（大黃素）可抑制破骨細(xì)胞功能并預(yù)防炎癥性腸病IBD相關(guān)的骨質(zhì)疏松癥[182]。

4.7. 腸易激綜合癥

腸易激綜合征患者骨質(zhì)疏松癥和脆性骨折的發(fā)生率較高[183]。這可能是由慢性炎癥、下丘腦-垂體-腎上腺軸過(guò)度激活、營(yíng)養(yǎng)缺乏和吸煙所致。需要進(jìn)一步研究以確認(rèn)潛在機(jī)制并建立治療方法[184]。

4.8. 微生物群生態(tài)失調(diào)

微生物群被認(rèn)為是與細(xì)胞反應(yīng)具有雙向相互作用的隱藏器官。某些微生物群與骨質(zhì)疏松癥和自身免疫性疾病有關(guān)，例如IBD、PBC和硬化性膽管炎[185,186]。通過(guò)控制OPG/RANKL、Wnt10b和炎性細(xì)胞因子的表達(dá)，實(shí)驗(yàn)性地解釋了益生菌的有益作用[186,187]。

其他增加骨質(zhì)疏松癥風(fēng)險(xiǎn)的胃腸道疾病包括胃切除術(shù)后[188]、萎縮性胃炎[189,190]和減肥手術(shù)[191]。

5. 營(yíng)養(yǎng)原因

營(yíng)養(yǎng)因素可能會(huì)影響骨量、*謝、基質(zhì)和微結(jié)構(gòu)。營(yíng)養(yǎng)不足會(huì)導(dǎo)致蛋白質(zhì)、維生素和礦物質(zhì)缺乏，尤其是鈣、磷和鎂，這些對(duì)骨骼健康至關(guān)重要[192]。成人推薦的每日鈣攝入量為每天800-1200毫克[32,193]，而磷和鎂的攝入量分別為700毫克和320-420毫克[194]。建議成人每日蛋白質(zhì)需求量為0.8 gm/kg，老年人為1-1.2 gm/kg [195,196]。維生素D的每日需求量為800至1000 IU [197]。

營(yíng)養(yǎng)不良的發(fā)生可能是由于營(yíng)養(yǎng)攝入不足、損失增加和/或需求增加[198]。不良的飲食習(xí)慣、神經(jīng)性厭食癥、神經(jīng)性貪食癥、長(zhǎng)期的全胃腸外營(yíng)養(yǎng)(TPN)、減肥干預(yù)和過(guò)量飲酒可導(dǎo)致繼發(fā)性骨質(zhì)疏松癥[199]。由于骨質(zhì)疏松癥和骨折與許多危及生命的事件有關(guān)，因此必須通過(guò)均衡飲食和體育鍛煉來(lái)預(yù)防它們[200]。

饑餓是最嚴(yán)重的營(yíng)養(yǎng)不良形式，可由各種社會(huì)經(jīng)濟(jì)、環(huán)境和醫(yī)學(xué)因素引起[201]。饑餓會(huì)通過(guò)礦物質(zhì)、維生素和I型膠原蛋白缺乏對(duì)骨骼數(shù)量和質(zhì)量產(chǎn)生負(fù)面影響[201,202]。生命早期甚至子宮內(nèi)的營(yíng)養(yǎng)不良與骨質(zhì)疏松癥和骨折的早期發(fā)病率之間存在正相關(guān)關(guān)系[203,204,205,206,207]。

維生素D缺乏會(huì)導(dǎo)致鈣吸收減少和低鈣血癥，從而導(dǎo)致繼發(fā)性甲狀旁腺功能亢進(jìn)，從而刺激骨轉(zhuǎn)換并降低骨密度BMD [208]。維生素D補(bǔ)充劑治療對(duì)25-羥基維生素D水平低于30 nmol/L 患者的骨骼健康有益[209,210]。另一方面，預(yù)防劑量的維生素D在預(yù)防骨質(zhì)疏松癥和骨折方面的作用值得商榷[211,212,213,214,215,216]。

許多觀(guān)察性研究報(bào)告了體重指數(shù)(BMI)和骨密度BMD之間的正相關(guān)關(guān)系[217]。此外，先前的研究表明，肥胖可以預(yù)防骨折[218,219]。然而，最近的研究并未顯示肥胖對(duì)骨骼的積極影響[220]。Look AHEAD試驗(yàn)報(bào)告稱(chēng)，肥胖2型糖尿病患者通過(guò)強(qiáng)化非手術(shù)減重干預(yù)可適度增加髖部骨質(zhì)流失[221,222]。此外，大多數(shù)減肥手術(shù)與骨質(zhì)流失和脆性有關(guān)[191,223]。這可以通過(guò)機(jī)械卸載、鈣和維生素D吸收不良引起的繼發(fā)性甲狀旁腺功能亢進(jìn)、雌激素、瘦素和生長(zhǎng)素釋放肽減少以及脂聯(lián)素水平升高來(lái)解釋[191,224,225]。因此，建議在減肥手術(shù)后接受足夠的鈣和維生素D并監(jiān)測(cè)骨密度BMD [226]。

神經(jīng)性厭食癥患者極度限制他們的食物攝入，因?yàn)樗麄兒ε麦w重增加[227]。這可能導(dǎo)致多種醫(yī)療并發(fā)癥，包括骨質(zhì)流失[228]，骨折風(fēng)險(xiǎn)增加2-7倍[229,230]。這不僅是因?yàn)闋I(yíng)養(yǎng)缺乏，還因?yàn)楹蔂柮墒д{(diào)[231]。另一方面，改善營(yíng)養(yǎng)狀況可以糾正這些患者的內(nèi)分泌疾病和骨密度BMD [232]。抗骨質(zhì)疏松藥物可能有助于改善體重指數(shù)BMI持續(xù)偏低和閉經(jīng)患者的骨質(zhì)流失[233]。單獨(dú)使用或與透皮睪酮聯(lián)合使用Residronate可改善脊柱骨密度BMD [234,235]。此外，生理劑量的透皮雌激素會(huì)導(dǎo)致脊柱和髖部骨密度BMD增加[236]。在最近的一項(xiàng)RCT中，重組人IGF-1和利塞膦酸鹽的序貫治療在改善神經(jīng)性厭食癥女性的腰椎骨密度BMD方面優(yōu)于單獨(dú)使用利塞膦酸鹽 [237]。此外，F(xiàn)azeli等報(bào)道使用特立帕肽6個(gè)月后腰椎骨密度BMD顯著增加[238]。

全胃腸外營(yíng)養(yǎng)TPN延長(zhǎng)的患者骨質(zhì)疏松癥患病率為40%至100% [239,240,241]。盡管全胃腸外營(yíng)養(yǎng)TPN改善了營(yíng)養(yǎng)狀況，但長(zhǎng)期需要全胃腸外營(yíng)養(yǎng)TPN可能會(huì)導(dǎo)致生態(tài)失調(diào)[242]，減少腸道鈣和磷的吸收[239]。此外，由于高氨基酸輸注繼發(fā)的超濾作用，它可以誘導(dǎo)高鈣尿癥[243]。對(duì)于全胃腸外營(yíng)養(yǎng)TPN延長(zhǎng)的患者，常規(guī)維生素D監(jiān)測(cè)和管理是必要的，因?yàn)榫S生素D缺乏癥在這些患者中非常普遍[239]。雙膦酸鹽可改善全胃腸外營(yíng)養(yǎng)TPN相關(guān)骨質(zhì)疏松癥患者的骨密度BMD [244,245]。

據(jù)報(bào)道，不良飲食習(xí)慣與骨質(zhì)疏松癥有關(guān)。高膳食糖可能通過(guò)葡萄糖誘導(dǎo)的高鈣尿癥、高鎂尿癥[247,248]和降低維生素D活化[249]導(dǎo)致骨質(zhì)疏松癥[246]。此外，高血糖可降低成骨細(xì)胞增殖并增加破骨細(xì)胞活化[250,251]。另一方面，膳食鹽對(duì)骨骼健康的影響尚不清楚[252]。

大量飲酒與骨密度BMD降低有關(guān)[253]。從機(jī)制上講，它直接降低成骨細(xì)胞活性并增加破骨細(xì)胞生成[254,255,256]。間接地，它會(huì)導(dǎo)致身體成分的變化[257]和各種激素的改變，包括PTH、維生素D、睪酮和皮質(zhì)醇[258]。戒酒可能會(huì)改善骨*謝并增加骨密度BMD [259,260]。

6. 藥物引起的所致的骨質(zhì)疏松癥

藥物性骨質(zhì)疏松癥是繼發(fā)性骨質(zhì)疏松癥的第二大常見(jiàn)原因。盡管有眾所周知的不良事件，糖皮質(zhì)激素仍然是免疫抑制/調(diào)節(jié)劑和抗炎療法的基石之一。高達(dá)40%的接受長(zhǎng)期糖皮質(zhì)激素治療的患者在其一生中遭受骨折[261,262]。

具有高骨小梁的區(qū)域，例如腰椎和髖部轉(zhuǎn)子，是糖皮質(zhì)激素誘發(fā)骨折的典型部位[263]。在治療的第一年內(nèi)，嚴(yán)重的骨質(zhì)流失可能高達(dá)20%，隨后每年下降至1%至3% [264,265]。糖皮質(zhì)激素治療的骨折風(fēng)險(xiǎn)與劑量和時(shí)間有關(guān)[262]。糖皮質(zhì)激素對(duì)骨骼的影響與其累積效應(yīng)有關(guān)，這會(huì)擾亂骨骼的數(shù)量和質(zhì)量。無(wú)論給藥途徑如何，糖皮質(zhì)激素均可誘導(dǎo)骨丟失。例如，長(zhǎng)期吸入糖皮質(zhì)激素與10%的骨密度BMD損失有關(guān)[266,267]。即使是控釋布地奈德和外用皮質(zhì)類(lèi)固醇也會(huì)對(duì)骨骼健康產(chǎn)生負(fù)面影響[268,269]。

糖皮質(zhì)激素最初會(huì)減少骨形成并增加RANKL/骨保護(hù)素比率，從而誘導(dǎo)高骨吸收[270,271]。長(zhǎng)期使用導(dǎo)致骨丟失的機(jī)制更多地歸因于抑制骨形成而不是增加骨吸收。這可能是由于Wnt信號(hào)通路的下調(diào)削弱了成骨細(xì)胞的活性[272]。此外，糖皮質(zhì)激素通過(guò)影響鈣穩(wěn)態(tài)、甲狀旁腺活動(dòng)和維生素D*謝對(duì)骨骼產(chǎn)生間接影響[273,274]。此外，糖皮質(zhì)激素會(huì)導(dǎo)致肌肉質(zhì)量和力量下降，從而增加跌倒和骨折的風(fēng)險(xiǎn)。它們還可以誘導(dǎo)性腺機(jī)能減退，從而降低睪酮和/或雌激素的抗吸收作用[275]。

對(duì)于有脆性骨折病史的患者、40歲或以上的患者以及有主要骨質(zhì)疏松危險(xiǎn)因素的患者，建議在糖皮質(zhì)激素治療6個(gè)月后使用雙光能X線(xiàn)片骨密度檢測(cè)DXA掃描和脆性骨折評(píng)估FRAX [276]。

為了預(yù)防糖皮質(zhì)激素引起的骨質(zhì)疏松癥，強(qiáng)烈建議每天攝入1000-1200毫克鈣和600-800單位的維生素D，同時(shí)改變生活方式[275]。對(duì)于骨折風(fēng)險(xiǎn)高的成人，口服雙膦酸鹽是首選的治療方案[276]。特立帕肽還可有效預(yù)防和治療糖皮質(zhì)激素引起的骨丟失[277]。

選擇性5-羥色胺再攝取抑制劑和單胺氧化酶抑制劑等抗抑郁藥可導(dǎo)致骨密度降低并增加骨折的發(fā)生率[278,279,280,281]。目前尚不清楚這些藥物如何影響骨骼健康，但可能歸因于通過(guò)5-羥色胺受體和轉(zhuǎn)運(yùn)蛋白減少的成骨細(xì)胞增殖[282]。

許多研究表明，長(zhǎng)期使用抗癲癇藥物會(huì)導(dǎo)致明顯的骨質(zhì)流失[283,284,285]。發(fā)病機(jī)制是多因素的，但加速的維生素D*謝是一個(gè)關(guān)鍵的共同因素[286,287,288,289]。骨丟失是由于骨重塑異常而不是異常礦化造成的[290,291,292]。

芳香酶抑制劑是乳腺癌的長(zhǎng)期輔助療法，會(huì)導(dǎo)致雌激素的突然喪失，從而導(dǎo)致骨質(zhì)流失[293]。此外，同時(shí)使用促性腺激素釋放激素激動(dòng)劑可導(dǎo)致每年高達(dá)7%的骨密度BMD損失[294]。在前列腺癌患者中使用促性腺激素釋放激素激動(dòng)劑與骨折風(fēng)險(xiǎn)增加有關(guān)[295,296,297]。

抗糖尿病藥物可以積極或消極地影響骨骼健康。過(guò)氧化物酶體增殖物激活受體γ (PPARγ)在調(diào)節(jié)骨形成和能量*謝以及胰島素敏感性方面發(fā)揮著重要作用[298,299]。噻唑烷二酮對(duì)它的刺激誘導(dǎo)骨吸收并抑制骨形成[300]。與其他抗糖尿病藥物相比，噻唑烷二酮類(lèi)藥物可降低骨密度BMD并增加骨質(zhì)疏松癥的風(fēng)險(xiǎn)[301]。鈉-葡萄糖協(xié)同轉(zhuǎn)運(yùn)蛋白2 (SGLT2)抑制劑對(duì)骨*謝和骨折風(fēng)險(xiǎn)的影響因其廣泛使用而受到更多關(guān)注。它們可能會(huì)增加骨轉(zhuǎn)換、擾亂骨微結(jié)構(gòu)并降低骨密度BMD [302]。在最近的一項(xiàng)研究中，Koshizaka及其同事報(bào)告了在24周RCT中TRAP 5b增加而骨密度BMD沒(méi)有變化[303]。

2010年，F(xiàn)DA發(fā)布了對(duì)長(zhǎng)期使用質(zhì)子泵抑制劑(PPI)（抑制胃酸藥物，如洛賽克等）的警告，因?yàn)樗赡軙?huì)增加骨質(zhì)疏松癥和骨折風(fēng)險(xiǎn)的發(fā)生率[304]。有限的可用證據(jù)表明，這可能是通過(guò)組胺過(guò)度分泌[305]并影響礦物質(zhì)穩(wěn)態(tài)[306,307]而發(fā)生的。關(guān)于PPI對(duì)骨密度BMD影響的數(shù)據(jù)不一致。

盡管抗凝劑對(duì)骨*謝的負(fù)面影響已經(jīng)研究了很長(zhǎng)時(shí)間，但這種影響仍然存在爭(zhēng)議，其潛在機(jī)制仍然知之甚少[308]。與低分子量肝素相比，普通肝素與顯著的骨質(zhì)流失有關(guān)[309,310,311]。長(zhǎng)期使用華法林與骨密度BMD和TBS降低有關(guān)[312]。在最近的一項(xiàng)研究中，這種對(duì)骨骼的負(fù)面影響在華法林中更為明顯，但在直接口服抗凝劑中也有發(fā)現(xiàn)[313]。

7. 感染所致的骨質(zhì)疏松癥

慢性活動(dòng)性感染并非罕見(jiàn)的骨丟失原因，主要是由于細(xì)胞因子釋放刺激破骨細(xì)胞生成并抑制成骨細(xì)胞功能。與普通人群相比，人類(lèi)免疫缺陷病毒(HIV)艾滋病感染患者的骨質(zhì)疏松癥患病率高出三倍，骨折風(fēng)險(xiǎn)增加四倍[314,315]。這可能直接歸因于HIV感染或繼發(fā)于使用抗逆轉(zhuǎn)錄病毒療法(ART)、同時(shí)使用酒精、吸煙、相關(guān)性腺功能減退、營(yíng)養(yǎng)不良、乙型和/或丙型肝炎合并感染以及維生素D不足[316,317,318,319,320]。HIV感染促進(jìn)成骨細(xì)胞凋亡和破骨細(xì)胞活化[321,322,323,324,325]。此外，除了影響骨骼健康的免疫系統(tǒng)激活之外，HIV感染還會(huì)誘發(fā)慢性炎癥狀態(tài)[326,327,328]。富馬酸替諾福韋二吡呋酯(TDF)與骨質(zhì)疏松癥和骨折的相關(guān)性高于新的ART[329,330,331,332]，因?yàn)樗鼤?huì)導(dǎo)致多發(fā)性腎小管缺陷和礦物質(zhì)丟失[333,334]。歐洲艾滋病臨床協(xié)會(huì)(EACS) [335]指南推薦替諾福韋艾拉酚胺(TAF)作為進(jìn)行性骨質(zhì)減少或骨質(zhì)疏松癥患者的一線(xiàn)治療，而不是富馬酸替諾福韋二吡呋酯TDF，因?yàn)樗鼘?duì)腎小管的毒性較小[336,337]。雙膦酸鹽可有效用于治療HIV相關(guān)的骨病[338]；然而，尚未對(duì)骨合成*謝藥物進(jìn)行充分研究[315]。

即使沒(méi)有隨后的肝硬化，乙型和丙型肝炎病毒(HBV; HCV)感染也會(huì)增加骨質(zhì)減少和骨質(zhì)疏松癥的風(fēng)險(xiǎn)[158,339,340,341]。此外，先前的研究報(bào)告稱(chēng)，即使在調(diào)整了其他骨質(zhì)疏松癥危險(xiǎn)因素后，乙型和丙型肝炎病毒HBV和HCV感染患者的骨質(zhì)疏松癥風(fēng)險(xiǎn)仍然較高[158,342]。值得注意的是，以前的研究報(bào)告說(shuō)，與HIV感染患者相比，HIV和HCV合并感染患者的骨折風(fēng)險(xiǎn)增加[319]。有趣的是，HCV清除使絕經(jīng)后骨質(zhì)疏松癥婦女的骨折風(fēng)險(xiǎn)降低了三分之二[343]。

帶狀皰疹感染與骨質(zhì)疏松癥有關(guān)[344,345]。這種對(duì)骨骼健康的負(fù)面影響可能是由于炎癥細(xì)胞因子的上調(diào)，尤其是在帶狀皰疹后神經(jīng)痛患者中[346,347]。

新冠病毒感染COVID-19可能使患者易患骨質(zhì)疏松癥[348]。這可能是因?yàn)樵趪?yán)重病例中相關(guān)的促炎細(xì)胞因子產(chǎn)生和長(zhǎng)期固定[349]。此外，骨骼感染可能有直接后遺癥[350]。該病毒可以降低成骨細(xì)胞和破骨細(xì)胞中ACE2的表達(dá)[351]，導(dǎo)致骨形成和骨吸收紊亂。此外，用于治療COVID-19的皮質(zhì)類(lèi)固醇對(duì)骨骼有負(fù)面影響。

骨髓炎通常與顯著的骨質(zhì)流失和隨后的脆性骨折有關(guān)[352]。這主要?dú)w因于炎癥細(xì)胞因子如IL-1、IL-6和TNFα的上調(diào)，隨后激活RANKL和抑制骨保護(hù)素[353,354]。

患有活動(dòng)性肺結(jié)核TB的患者和患有肺纖維化的TB幸存者患骨質(zhì)疏松癥的風(fēng)險(xiǎn)增加[342,355]。慢性全身炎癥、伴隨的營(yíng)養(yǎng)不良和維生素D缺乏是骨質(zhì)流失的主要原因[354,356,357,358]。

8. 血液腫瘤學(xué)原因所致的骨質(zhì)疏松癥

血液系統(tǒng)疾病可能通過(guò)直接的細(xì)胞作用或由幾種循環(huán)因子介導(dǎo)的間接損害骨骼[359]。骨丟失的發(fā)生主要是由于RANKL/RANK和WNT信號(hào)通路之間的不平衡，隨后骨吸收增加和骨形成減少[360,361,362,363]。

貧血可導(dǎo)致骨吸收并增加骨脆性[364,365]。缺鐵可能會(huì)對(duì)細(xì)胞色素的P450活性產(chǎn)生負(fù)面影響，這對(duì)維生素D*謝和骨骼健康至關(guān)重要[366]。β地中海貧血會(huì)導(dǎo)致無(wú)效的紅細(xì)胞生成和骨髓擴(kuò)張，導(dǎo)致髓質(zhì)破壞和皮質(zhì)變薄[367]。此外，青春期延遲、細(xì)胞因子紊亂、生長(zhǎng)激素缺乏、鐵骨沉積、去鐵胺誘導(dǎo)的骨發(fā)育不良和維生素D缺乏會(huì)進(jìn)一步導(dǎo)致地中海貧血患者的骨骼健康不足[368,369,370,371,372,373]。雙膦酸鹽可改善骨密度BMD[373,374]，但其對(duì)地中海貧血患者骨折率的影響尚不確定[375]。使用地舒單抗或特立帕肽增加地中海貧血患者的骨密度的信息有限，但觀(guān)察到的結(jié)果令人鼓舞[376,377]。

血友病患者繼發(fā)性骨質(zhì)疏松癥的估計(jì)患病率高達(dá)58.7%[378]。低骨量的潛在機(jī)制包括維生素D缺乏、繼發(fā)于血友病性關(guān)節(jié)病的有限體力活動(dòng)，以及獲得與骨質(zhì)疏松癥相關(guān)的血源性感染，如HIV [379,380,381]。此外，因子VIII缺乏與OPG/RANK/RANKL 統(tǒng)失衡繼發(fā)的骨吸收增加和骨形成減少直接相關(guān)[382,383]。應(yīng)在體重過(guò)輕、患有脆性骨折、HIV和/或晚期血友病性關(guān)節(jié)病的患者中進(jìn)行骨質(zhì)疏松癥篩查[384]。替*缺乏因子可以最大限度地減少關(guān)節(jié)出血和血液關(guān)節(jié)病，從而降低骨質(zhì)疏松癥的風(fēng)險(xiǎn)和進(jìn)展[385]。

意義不明的單克隆丙種球蛋白病和多發(fā)性骨髓瘤患者發(fā)生骨質(zhì)疏松癥和脆性骨折的風(fēng)險(xiǎn)增加[386,387]。骨髓瘤細(xì)胞刺激細(xì)胞因子、IL-6和IL- 的釋放，從而激活RANKL/RANK通路并增強(qiáng)骨吸收[361]。另一方面，WNT抑制劑Dkk-1和分泌的卷曲蛋白2的表達(dá)增強(qiáng)，導(dǎo)致骨形成減少[388,389]。一些指南建議對(duì)患有骨質(zhì)疏松癥和/或脆性骨折的老年患者進(jìn)行骨髓瘤篩查[390,391]。雙膦酸鹽被推薦用于骨髓瘤患者，因?yàn)樗鼈兙哂锌鼓[瘤、免疫調(diào)節(jié)和抗分解*謝作用[392,393]。然而，在這些患者中常見(jiàn)的腎功能損害仍然是一個(gè)重要的障礙[394]，并且可能需要使用其他更安全的藥物，例如地舒單抗[395]。此外，多發(fā)性骨髓瘤的治療，如硼替佐米和靶向DKK1或硬化蛋白的單克隆抗體可以減少骨質(zhì)流失[396,397,398]。

骨質(zhì)疏松癥是最常見(jiàn)的骨骼病理學(xué)，發(fā)生在18%至40%的全身性肥大細(xì)胞增多癥患者中[399,400,401]。除了釋放循環(huán)因子如組胺、前列腺素和白細(xì)胞介素（IL-1、IL-3、IL-6）外，肥大細(xì)胞浸潤(rùn)骨髓會(huì)導(dǎo)致骨受累，這些因子會(huì)增強(qiáng)破骨細(xì)胞的活性[402]。表現(xiàn)包括從無(wú)癥狀狀況到不同程度的骨損傷的廣泛臨床范圍，例如骨質(zhì)減少、骨質(zhì)疏松癥、溶骨性病變和骨硬化[403]。除了雙膦酸鹽和地舒單抗[404,405]等抗骨吸收藥物外，干擾素還可以通過(guò)控制疾病活動(dòng)來(lái)改善骨病理學(xué)[406]。相反，使用特立帕肽存在安全問(wèn)題，因?yàn)樗赡軙?huì)增強(qiáng)惡性細(xì)胞的增殖[407]。

在實(shí)體瘤患者中，骨損傷通常作為抗癌治療的副作用或繼發(fā)于溶骨性轉(zhuǎn)移，最常見(jiàn)于乳腺癌[408]。此外，細(xì)胞毒性化學(xué)療法和激素剝奪療法對(duì)骨骼數(shù)量和質(zhì)量都有不利影響[409,410,411]。接受芳香化酶抑制劑或雄激素剝奪治療的患者的骨丟失量是年齡匹配的健康對(duì)照組的十倍[412,413]。因此，根據(jù)基礎(chǔ)疾病連續(xù)推薦基線(xiàn)和后續(xù)DXA掃描[414,415]。建議在骨折風(fēng)險(xiǎn)較高的芳香化酶抑制劑接受者中使用雙膦酸鹽[416]。

9. 風(fēng)濕免疫原因所致的骨質(zhì)疏松癥

免疫系統(tǒng)在骨穩(wěn)態(tài)中起重要作用?；罨腡細(xì)胞通過(guò)分泌各種細(xì)胞因子影響骨骼健康 [417]。一些實(shí)驗(yàn)研究發(fā)現(xiàn)Th17細(xì)胞負(fù)責(zé)刺激骨吸收，而Treg細(xì)胞與抑制骨吸收特別相關(guān)[418]。此外，CD8+ T細(xì)胞可能通過(guò)分泌多種因子發(fā)揮保護(hù)作用，例如具有抗破骨細(xì)胞生成作用的骨保護(hù)素和干擾素-γ [419]。

9.1 炎癥性關(guān)節(jié)炎

炎癥性關(guān)節(jié)炎，包括類(lèi)風(fēng)濕性關(guān)節(jié)炎(RA)、銀屑病關(guān)節(jié)炎和脊柱關(guān)節(jié)病，通常與全身性骨骼并發(fā)癥有關(guān)，例如骨質(zhì)疏松癥和脆性骨折[420]。

類(lèi)風(fēng)濕性關(guān)節(jié)炎R(shí)A患者的骨質(zhì)疏松癥患病率約為30%，絕經(jīng)后婦女的患病率高達(dá)50% [421,422]。此外，一項(xiàng)大型薈萃分析顯示，RA患者骨折的風(fēng)險(xiǎn)更高[423]。

類(lèi)風(fēng)濕性關(guān)節(jié)炎R(shí)A相關(guān)的骨質(zhì)疏松癥有兩個(gè)主要特征：局部和全身性骨質(zhì)流失[424]。骨丟失的發(fā)病機(jī)制涉及多種機(jī)制，包括持續(xù)炎癥、糖皮質(zhì)激素的使用、體力活動(dòng)減少和促炎細(xì)胞因子（如IL-6、IL-1和TNF-α）分泌增加[422,425]。此外，RANK 的過(guò)表達(dá)促進(jìn)破骨細(xì)胞生成[426]。有足夠的證據(jù)支持自身抗體在通過(guò)破骨細(xì)胞激活引起的局部和全身性骨丟失的發(fā)病機(jī)制中的作用[427,428,429]。

改善疾病的抗風(fēng)濕藥物(DMARD)不僅可以控制炎癥狀態(tài)，還有助于避免皮質(zhì)類(lèi)固醇對(duì)骨骼健康的長(zhǎng)期負(fù)面影響[430]。來(lái)氟米特的使用與腰椎骨密度BMD的顯著增加有關(guān)[431]。此外，TNF抑制劑改善了骨密度BMD并降低了骨折率[432]。其他生物制劑，如托珠單抗、利妥昔單抗和阿巴西普，可顯著降低骨吸收標(biāo)志物和RANKL表達(dá) [433,434]。另一方面，甲氨蝶呤對(duì)骨質(zhì)流失的影響存在爭(zhēng)議[435]。

盡管有幾項(xiàng)研究表明銀屑病關(guān)節(jié)炎與骨質(zhì)流失/脆性骨折之間存在顯著關(guān)聯(lián)[436,437]，但其他研究并未發(fā)現(xiàn)這種關(guān)聯(lián)[438]。促炎細(xì)胞因子參與局部骨丟失的機(jī)制[439]。

另一方面，強(qiáng)直性脊柱炎(AS)患者的骨密度BMD較低，即使在疾病的早期階段也是如此[440]。在疾病發(fā)作的10年內(nèi)，骨質(zhì)減少和骨質(zhì)疏松癥的患病率分別約為54%和16%[440]。一個(gè)大型數(shù)據(jù)庫(kù)顯示AS患者的椎體和非椎體骨折風(fēng)險(xiǎn)較高[441]。使用非甾體類(lèi)抗炎藥與降低骨折風(fēng)險(xiǎn)相關(guān)[441]。TNF抑制劑增加了腰椎和全髖骨密度BMD，但并未降低椎體骨折的發(fā)生率[442]。

9.2. 系統(tǒng)性紅斑狼瘡(SLE)

眾所周知，骨質(zhì)疏松癥和脆性骨折是系統(tǒng)性紅斑狼瘡S(chǎng)LE患者較常見(jiàn)的合并癥[443]。在該患者群體中，骨折的發(fā)生率高達(dá)35% [444]。此外，無(wú)癥狀椎體和非椎體骨折與生活質(zhì)量下降和死亡風(fēng)險(xiǎn)增加有關(guān)[445,446]。促炎細(xì)胞因子直接影響骨量[447]。器官損傷可間接導(dǎo)致骨量減少。除了長(zhǎng)期使用糖皮質(zhì)激素外，疾病持續(xù)時(shí)間和嚴(yán)重程度是骨丟失的主要決定因素[448,449]。較低水平的P1NP可預(yù)測(cè)絕經(jīng)前系統(tǒng)性紅斑狼瘡S(chǎng)LE患者12個(gè)月內(nèi)的骨丟失和骨密度BMD [450]。

9.3. 多發(fā)性硬化癥(MS)

幾項(xiàng)研究表明，與健康對(duì)照組相比，多發(fā)性硬化癥MS患者的骨密度BMD較低、骨質(zhì)疏松癥發(fā)生率較高且骨折風(fēng)險(xiǎn)增加[451,452,453]。各種風(fēng)險(xiǎn)因素會(huì)導(dǎo)致多發(fā)性硬化癥MS患者的骨質(zhì)流失，包括疾病持續(xù)時(shí)間和嚴(yán)重程度、維生素D不足、累積類(lèi)固醇劑量、行走減少和炎癥過(guò)程 [453,454]。多發(fā)性硬化癥MS患者的促炎性骨橋蛋白水平升高，并與股骨頸骨密度BMD相關(guān)[455]。

10. 其他原因所致的骨質(zhì)疏松癥

10.1 抽煙所致的骨質(zhì)疏松癥

吸煙作為骨質(zhì)疏松癥的危險(xiǎn)因素納入FRAX評(píng)分[456]。它對(duì)成骨和骨血流有直接的有害影響[457]。間接地，它會(huì)影響維生素D、PTH [458,459]和性激素的血清水平，尤其是女性[460]。戒煙對(duì)骨密度BMD的影響尚不清楚；然而，已經(jīng)表明它可以增加股骨和全髖的骨密度BMD [461]并減少椎骨骨折[462]。

10.2.廢用性骨質(zhì)疏松癥

骨細(xì)胞具有某些機(jī)械受體，它們使用負(fù)重誘導(dǎo)的信號(hào)來(lái)協(xié)調(diào)骨轉(zhuǎn)換。不活動(dòng)導(dǎo)致骨細(xì)胞功能障礙和隨后通過(guò)下調(diào)Wnt/β-連環(huán)蛋白通路抑制骨形成[463]。這可能是長(zhǎng)期固定的全身性疾病，也可能是偏癱、脊髓損傷或神經(jīng)肌肉疾病患者的局部疾病。體育鍛煉和康復(fù)計(jì)劃對(duì)于預(yù)防和治療這種類(lèi)型的骨質(zhì)流失至關(guān)重要。難治性病例可能需要使用抗骨質(zhì)疏松藥物，例如雙膦酸鹽、地諾單抗、特立帕肽和romosozumab [463,464,465]。

10.3.骨質(zhì)疏松癥的遺傳原因

遺傳學(xué)在骨骼微結(jié)構(gòu)特性、骨骼強(qiáng)度和骨質(zhì)疏松癥風(fēng)險(xiǎn)中起著至關(guān)重要的作用。罕見(jiàn)的單基因形式的骨質(zhì)疏松癥始于兒童期或青年期[466]。最常見(jiàn)的是成骨不全癥(OI)，也稱(chēng)為“脆性骨病”[467]。成骨不全癥是一種由骨形成缺陷引起的遺傳性結(jié)締組織疾病，主要是由于1型膠原蛋白的產(chǎn)生和/或加工受損[468]。它的特點(diǎn)是骨基質(zhì)礦化異常高。這與具有相同體積基質(zhì)的大量晶體有關(guān)[469,470]。皮質(zhì)疏松、小梁細(xì)小、骨質(zhì)量異常和骨密度低與骨折風(fēng)險(xiǎn)增加相關(guān)是成骨不全癥OI的常見(jiàn)發(fā)現(xiàn)[471,472,473]。有限的證據(jù)表明雙膦酸鹽可增加成骨不全癥OI患者的骨密度BMD并降低骨折風(fēng)險(xiǎn)[474]。此外，狄諾塞麥（地舒單抗）的結(jié)果很差且不確定[475]。值得注意的是，romosuzumab增加了這些患者的骨密度BMD并改善了周轉(zhuǎn)生物標(biāo)志物[419]。除了成骨不全癥OI，全基因組測(cè)序研究還能夠揭示與骨質(zhì)疏松癥相關(guān)的新基因變異。這些遺傳變異的表達(dá)涉及不同的骨保護(hù)功能，例如維生素D*謝、間充質(zhì)干細(xì)胞成骨分化和骨形態(tài)發(fā)生蛋白。其中一些變體是人群特異性的，其他變體在來(lái)自不同種族的低骨密度BMD患者之間共享[476,477]。

骨質(zhì)疏松性骨折呈指數(shù)增長(zhǎng)[478]，被認(rèn)為是主要的醫(yī)療保健問(wèn)題之一[479]。骨質(zhì)疏松癥對(duì)骨折愈合有負(fù)面影響，特別是在不穩(wěn)定和粉碎性骨折中，這表明需要內(nèi)固定[480,481]。骨質(zhì)疏松骨中的螺釘固定力降低，進(jìn)而導(dǎo)致植入物松動(dòng)、固定喪失和愈合受損。應(yīng)考慮使用抗骨質(zhì)疏松藥物來(lái)改善骨質(zhì)形成和骨質(zhì)疏松性骨折中骨植入物的成功率[482]。

目前的審查受到該領(lǐng)域臨床研究的數(shù)量和質(zhì)量的限制。很少有隨機(jī)對(duì)照試驗(yàn)證明了不同抗骨質(zhì)疏松藥物對(duì)骨骼的影響。

11. 結(jié)論

繼發(fā)性骨質(zhì)疏松癥是由疾病、藥物或營(yíng)養(yǎng)缺乏引起的骨脆性診斷。這是一個(gè)不斷發(fā)展的、毀滅性的健康問(wèn)題。正確的診斷和預(yù)防是防止進(jìn)一步骨質(zhì)流失和脆性骨折的基石。雖然因果治療是必不可少的，但抗骨質(zhì)疏松藥物可以進(jìn)一步降低骨折的風(fēng)險(xiǎn)，并改善骨折愈合。需要更多的隨機(jī)對(duì)照試驗(yàn)來(lái)探索抗骨質(zhì)疏松藥物在各種臨床環(huán)境中的安全性和有效性。

Secondary Osteoporosis and Metabolic Bone Diseases.

文獻(xiàn)來(lái)源：Mahmoud M. Sobh, Mohamed Abdalbary, Sherouk Elnagar, Eman Nagy, Nehal Elshabrawy, Mostafa Abdelsalam, Kamyar Asadipooya, and Amr El-Husseini. Secondary Osteoporosis and Metabolic Bone Diseases. J Clin Med. 2022 May; 11(9): 2382. doi: 10.3390/jcm11092382.

作者單位：Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura 35516, Egypt.

Abstract

Fragility fracture is a worldwide problem and a main cause of disability and impaired quality of life. It is primarily caused by osteoporosis, characterized by impaired bone quantity and or quality. Proper diagnosis of osteoporosis is essential for prevention of fragility fractures. Osteoporosis can be primary in postmenopausal women because of estrogen deficiency. Secondary forms of osteoporosis are not uncommon in both men and women. Most systemic illnesses and organ dysfunction can lead to osteoporosis. The kidney plays a crucial role in maintaining physiological bone homeostasis by controlling minerals, electrolytes, acid-base, vitamin D and parathyroid function. Chronic kidney disease with its uremic milieu disturbs this balance, leading to renal osteodystrophy. Diabetes mellitus represents the most common secondary cause of osteoporosis. Thyroid and parathyroid disorders can dysregulate the osteoblast/osteoclast functions. Gastrointestinal disorders, malnutrition and malabsorption can result in mineral and vitamin D deficiencies and bone loss. Patients with chronic liver disease have a higher risk of fracture due to hepatic osteodystrophy. Proinflammatory cytokines in infectious, autoimmune, and hematological disorders can stimulate osteoclastogenesis, leading to osteoporosis. Moreover, drug-induced osteoporosis is not uncommon. In this review, we focus on causes, pathogenesis, and management of secondary osteoporosis.

Keywords: bone loss, fracture, bone mineral density, causes, management

1. Introduction

Osteoporosis is a condition characterized by bone fragility, secondary to either low bone mineral density (BMD) and/or microarchitectural deterioration that increases fracture risk. Postmenopausal estrogen deficiency is the primary cause of osteoporosis. In addition to postmenopausal women with primary osteoporosis (postmenopausal or age-related), more than half of perimenopausal and postmenopausal women referred to an osteoporosis center had one or more risk factors of secondary osteoporosis [1]. A fracture risk assessment tool (FRAX) helps to estimate the 10-year fracture risk by using clinical and radiological data. These clinical data include some, but not all, secondary causes of osteoporosis, such as smoking, excessive alcohol intake, type I diabetes mellitus, hyperthyroidism, chronic liver disease, and malnutrition [2]. Various secondary causes of osteoporosis are mentioned in Figure 1. Patients with newly diagnosed osteoporosis should be thoroughly evaluated including their history, a physical examination, and routine laboratory testing for detection of secondary causes. A systematic approach for detection of the underlying causes is illustrated in Figure 2. The management approach of patients with secondary osteoporosis is summarized in Figure 3. Proper recognition of the etiology of osteoporosis is an essential step in improving bone health, preventing further bone loss. Those patients can benefit from balanced nutrition, physical exercise, and avoiding long term glucocorticoid usage and other drugs that have negative impact on bone health. Using antiosteoporotic therapies in patients with high risk of fractures is recommended; the mechanism of action of the commonly used antiosteoporotic medications are illustrated in Figure 4. This article comprehensively discusses epidemiology, the various causes and pathogenesis of secondary osteoporosis. This topic not only covers the bone quantity problem but focuses on quality as well. Furthermore, the up-to-date management of secondary osteoporosis is thoroughly discussed.

2. Renal Causes

Chronic kidney disease (CKD) is a well-established risk factor for bone loss [3]. The incidence of bone loss and fracture risk increases with decline in kidney function. Osteoporosis was reported in up to 32% of CKD patients, while osteopenia was found in about half [3,4,5,6]. However, the magnitude of the problem might be higher for various reasons. First, there is a high prevalence of vascular calcification in CKD patients, which results in a higher estimation of vertebral bone mass by DXA [7]. Second, CKD patients do not have a bone mass/quantity problem only, but a bone quality disorder as well [8]. Third, there is underutilization of osteoporosis diagnostic tools in CKD patients, despite the KDIGO recommendations. Up to 30–50% of fractured CKD patients had a T-score higher than ?2.5 [9,10]. Advanced CKD patients have up to an 8-fold higher fracture risk when compared to the general population [11]. Osteoporotic fractures lead to a deleterious effect on the quality of life in CKD patients. One-year mortality after having a hip fracture is 17–27% in the general population [12,13], while it is up to 64% in patients with end-stage kidney disease (ESKD) [14,15].

Renal osteodystrophy (ROD), medication usage, hypogonadism, systemic inflammation, acidosis, and concurrent systemic illnesses contribute to bone loss in patients with CKD. Metabolic acidosis stimulates osteoclasts and induces robust bone resorption. ROD develops with early stages of CKD and progresses with further loss of kidney function [16]. There are many co-players in the pathogenesis of ROD. FGF-23, an osteocyte-secreted phosphaturic hormone, rises in early stages of CKD to prevent hyperphosphatemia [17,18]. Hyperphosphatemia occurs in late CKD stages despite increasing levels of FGF-23 due to klotho deficiency/resistance [19]. FGF-23 inhibits vitamin D activation and increases its catabolism [20,21]. Vitamin D deficiency/insufficiency, and hyperphosphatemia, contribute to secondary hyperparathyroidism in CKD patients [22,23,24,25]. Levels of sclerostin, DKK-1, and WNT pathway inhibitors increase with deterioration of kidney function [26]. They inhibit bone formation and promote low turnover bone disease [27]. On the other hand, the imbalance between osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) levels in CKD patients increases osteoclastogenesis and induces high turnover bone disease [28,29]. Moreover, disturbed gonadal hormones could be a major reason for osteoporosis. Many drugs commonly used in CKD patients such as heparin, warfarin, glucocorticoids, proton pump inhibitors, and diuretics can negatively affect bone health [30,31].

Many tools can be used in the diagnosis of osteoporosis in CKD patients, although there is no consensus on the optimal tool. DXA is the most widely used method. The Fracture Risk Assessment Tool (FRAX) helps to estimate the 10-year fracture risk; however, it does not include CKD as a secondary cause of osteoporosis [32]. Quantitative computed tomography (QCT) is not affected by vascular calcifications and could be a better tool, compared to DXA, especially for longitudinal follow-up and in obese patients [33]. However, its use is less common due to higher costs and radiation exposure. Both tools help to assess bone mass/quantity. On the other hand, TBS, high-resolution imaging techniques, finite element analysis, and Fourier transform infrared spectroscopy can be used in the assessment of bone quality. Bone turnover markers provide dynamic assessment of bone formation and resorption and facilitate ROD management [34]. Bone-specific alkaline phosphatase (BSAP) and intact procollagen-1 N-terminal peptide (P1NP) as bone formation markers, and tartrate-resistant acid phosphatase 5b (TRAP 5b) as a bone resorption marker are reliable in CKD patients [35]. Bone turnover markers and parathyroid hormone (PTH) do not only help to understand bone turnover status [36], but also to predict fracture risk [37,38]. Bone biopsy remains the gold standard to identify the mechanism and severity of bone loss [39]. It also helps to choose the appropriate medication, but it is limited by its invasive nature and lack of expertise. Assessment of bone histology in CKD patients should include three elements: turnover, mineralization, and volume [16,40]. Nowadays, the most common pathological findings in CKD patients are low turnover bone disease (LTBD), high turnover bone disease (HTBD), mixed ROD, while osteomalacia is less frequently seen in adults [41]. Recently published reviews have described the bone quality assessment and management in patients with CKD [7,42].

The primary step in osteoporosis management is to control the CKD metabolic derangements. Vitamin D deficiency, hyperphosphatemia, and hyperparathyroidism are common findings in these patients and have detrimental effects on bones. Patients should be instructed about fall risk prevention and non-pharmacological interventions to improve bone health. Smoking cessation, alcohol limitation, personalized exercise protocols, and well-balanced nutrition have a positive impact on bone, but are underutilized in CKD patients [42]. Optimizing calcium intake and the proper use of phosphate-lowering therapies, vitamin D, and calcimimetics can reduce fracture risks by improving ROD [43].

Determining the type of ROD and including high versus low turnover help to choose the appropriate treatment with higher efficacy and lower adverse events. Patients with HTBD are expected to benefit more from antiresorptives, e.g., bisphosphonates and denosumab, while patients with LTBD may benefit from osteoanabolics to improve bone formation.

Despite being excreted by the kidneys, bisphosphonates can be used in mild to moderate CKD patients without major safety concerns [44]. Their use in advanced CKD patients should be cautious with a concern for CKD progression [45]. Moreover, prolonged use of bisphosphonates in patients with advanced CKD might induce LTBD and increase the risk of atypical femur fracture [46]. Denosumab has been shown to improve BMD and reduce bone turnover in CKD patients in observational studies and small randomized control trials (RCTs) [47,48]. As opposed to bisphosphonates, it is not excreted through the kidneys, however close monitoring of serum calcium and vitamin D should be conducted for the risk of hypocalcemia.

On the other hand, osteoanabolics (teriparatide, abaloparatide, and romosozumab) have a promising role in mitigating bone loss in patients with LTBD. Teriparatide has been used in advanced CKD patients in several studies [49,50,51,52]. Abaloparatide was safe and effective in the early stages of CKD [53]. Romosozumab increased BMD in patients with mild to moderate CKD [54] and in dialysis patients [55].

3. Endocrinological Causes

3.1. Diabetes Mellitus

Diabetes is a chronic metabolic disease associated with an increased risk of fragility fracture. Adults with Type 1 diabetes mellitus (T1DM) have a greater risk of fracture, especially non-vertebral fracture, than those with type 2 diabetes (T2DM) [56,57]. Nevertheless, vertebral fractures are not uncommon and associated with increased mortality, but they are often underdiagnosed because they could be asymptomatic [58]. Diabetes can compromise bone metabolism, impair cell function or damage the extracellular matrix. This results in bone loss, alteration of bone microarchitecture, reduction of bone turnover and predisposition to low trauma fracture. The pathogenesis and risk factors of brittle bone in diabetes consist of obesity, increased insulin resistance, blood sugar disturbances, production of advanced glycation end products, muscle dysfunction, macro- and microvascular complications, and medications. Moreover, the associated comorbidities, such as thyroid disorders, gonadal dysfunction, and malabsorption may contribute to bone loss [59,60]. Notably, T1DM has been associated with reduced osteoblast activity, lower or similar BMD, and a higher risk of fracture [56,61,62,63]. Whereas T2DM is associated with an increased rate of bone loss and fracture, even with normal or high BMD [56,64]. A T-score threshold of ?2.0 was suggested as a trigger for therapeutic intervention in T2DM [65]. However, the bone area at the total hip is a better surrogate for fragility fracture in elderly patients with T2DM compared to BMD [66].

Diabetes mainly affects bone quality, including disturbed bone material properties and increased cortical porosity, which are not measurable with BMD-DXA [59,67]. This emphasizes that bone density measurement by DXA underestimates the fracture risk in diabetic patients [68]. Trabecular bone score [69], peripheral quantitative computed tomography (pQCT), pQCT-based finite element analysis (pQCT-FEA) [70], and high resolution peripheral quantitative computed tomography (HR-pQCT) [71] are better tools to estimate fracture risk in diabetic patients. Invasive methods, such as microindentation and bone histomorphometry, are expensive and not widely available [68,72].

Diabetes causes skeletal fragility and applying strategies to reduce fracture is crucial. Furthermore, it seems there is a correlation between the degree of blood sugar control and the risk of fracture. [73,74]. In a large cohort study, there was a cubic relationship between HbA1c and risk of fracture [75]. Thiazolidinediones should be avoided in diabetic patients with increased bone fragility [76]. Moreover, there is growing evidence suggesting a negative outcome of sodium glucose cotransporter 2 (SGLT2) inhibitors on bone health. Alendronate use for 3 years resulted in an increase in BMD in diabetic patients with osteoporosis [77]. Anti-osteoporotic medications (mainly bisphosphonates) appear to prevent bone loss similarly in the spines of diabetic and non-diabetic individuals in a recent systematic review [78]. Use of daily subcutaneous injections of abaloparatide (80 mcg) was associated with improvement in BMD in diabetic patients [79].

3.2. Gonadal Disorders

Hypogonadism is a risk factor for osteoporosis. The peak bone mass and BMD are higher in men; however, if both a man and a woman have similar BMD, the man would have a higher risk of fracture. The incidence of osteoporosis in men under the age of 70 is significantly lower compared to women because the bone loss in women occurs earlier and at a higher rate [80,81]. Testosterone replacement therapy can improve BMD but results in hypogonadal older men were inconclusive. However, the volumetric BMD and bone strength significantly improved in hypogonadal older men who received testosterone treatment for one year [82,83].

3.3. Parathyroid Disorders (Hypoparathyroidism and Primary Hyperparathyroidism)

Hypoparathyroidism is a low bone turnover condition. The information regarding fracture risk is inconsistent [84,85,86], but patients with nonsurgical hypoparathyroidism seem to have a higher risk of vertebral fracture [86,87,88]. This could be potentially due to a longer period of bone changes in nonsurgical hypoparathyroidism compared to surgical hypoparathyroidism [86]. Therefore, we would speculate that the higher fracture risk is due to over-maturation and impaired quality of the bone. They have higher BMD by DXA at all skeletal sites, especially at the lumbar spine [89]. Furthermore, they typically have normal [89,90,91] or low [92] trabecular bone scores and are classified as degraded microarchitecture. Compared to the age and sex-matched controls, they often have higher volumetric BMD (trabecular and cortical), and higher cortical area and thickness by pQCT [89,93]. Nevertheless, HR-pQCT showed increased cortical volumetric BMD, but reduced cortical thickness and cortical porosity [89,94]. They also seem to have normal biomechanical strength determined by finite element modeling [94,95], but lower bone material strength index, measured by impact microindentation, than controls [86,96]. Calcium and vitamin D supplements are widely used. However, the long-term safety and efficacy of this practice are not very well studied. Donovan Tay et al. reported that long-term use of PTH (1-84) therapy reduced supplemental calcium and vitamin D requirements and increased lumbar spine and total hip BMD [97]. PTH (1-84) reduced urinary calcium and serum phosphorus levels and improved quality of life without increasing serious adverse events, compared to traditional management [98,99,100]. In a recent meta-analysis, compared to PTH, active vitamin D usage was associated with similar serum calcium levels but a trend toward lower urinary calcium levels [101]. Moreover, the long-term safety is not completely recognized, and dose-dependent increased risk of osteosarcoma is reported in rat studies [102,103]. This concern limited the long-term usage of PTH (1-84) as replacement therapy for hypoparathyroidism. Small studies reported heterogeneity regarding the efficacy of parathyroid tissue allotransplantation for treating hypoparathyroidism [104].

Primary hyperparathyroidism (PHPT) is associated with decreased BMD and increased fracture risk across various skeletal sites, especially at the lumbar spines [105,106]. BMD measurement by DXA is an acceptable predictor of fracture at hip and forearm but underdiagnoses vertebral fragility [107]. There are valuable tools, such as trabecular bone score, 3D-DXA [108], bone strain index (BSI) by finite element analysis of DXA [109], and HR-pQCT [110], to assess bone health and predict skeletal fragility [105]. HR-pQCT revealed altered microarchitecture of cortical and trabecular bone, including reduced cortical and trabecular volumetric densities, increased cortical porosity, and heterogeneity of trabecular distributions [110,111]. This is almost consistent with histomorphometric studies, except for preservation or even improvement of trabecular bone structure [112]. The assessment of bone material strength index at the tibia by using the impact microindentation technique showed impaired bone material properties in PHPT subjects, especially in those with fragility fracture [113]. Parathyroidectomy reduces calcium concentrations and increases BMD at different skeletal sites. It might reduce fracture risk better than active surveillance [114], but its advantages over medical therapy regarding risk of fracture, kidney stones and quality of life lack sufficient evidence [114,115]. Nevertheless, parathyroidectomy could improve bone strength assessed by HR-pQCT and finite element analysis [116]. In terms of medical therapy, optimization of calcium and vitamin D intake is suggested [117]. Calcium supplements can reduce PTH and increase femoral neck BMD in patients with asymptomatic PHPT [118]. There is no reason to restrict dietary calcium intake in the patients with mild PHPT, but close monitoring of calcium is necessary and calcium supplementation should be avoided in severe PHPT with elevated 1,25(OH)2D and higher serum PTH levels. Other medical therapies include bisphosphonates, cinacalcet, denosumab, and estrogen, which are appropriate for lowering calcium, increasing BMD or both [117].

3.4. Thyroid Disorders

Thyroid hormones play a pivotal role in bone metabolism. Hyperthyroidism, even subclinical, is a known risk factor for osteoporosis. It is associated with increased bone turnover, decreased bone mass, and increased fracture risk [119,120]. In addition, long-term TSH suppression in patients with differentiated thyroid cancer was associated with lower BMD in postmenopausal women [121]. Hyperthyroid women had impaired bone quality and quantity reported by HR-pQCT. Euthyroidism could improve volumetric BMD and cortical microarchitecture [119]. Overt hypothyroidism reduces bone formation. However, data on BMD and fracture risk are inconclusive [122].

3.5. Adrenal Disorders

Osteoporosis happens in 30–50% [123,124,125], and vertebral fractures in 30–70%, of patients with Cushing syndrome [126,127]. Cushing syndrome leads to excess glucocorticoid production, which negatively impacts bone metabolism through suppression of growth hormone and gonadal axis, besides altering the rhythmic production of parathyroid hormone [126]. Trabecular bone loss is more pronounced in patients with Cushing syndrome. Adrenal nodules with autonomous cortisol secretion [128], primary aldosteronism [129], pheochromocytoma [130,131], and congenital adrenal hyperplasia [132] are associated with deterioration of bone quality and quantity.

3.6. Growth Hormone

Despite acromegalic patients having a higher rate of bone formation, they have an increased risk of vertebral fractures because of increased bone turnover and poor bone quality. However, they may have increased, decreased, or similar BMD, compared to the general population [133,134]. They have higher cortical porosity and altered bone microarchitecture, which is attributed to altered bone remodeling and Wnt signaling.

Growth hormone deficiency is associated with low bone turnover osteoporosis, and loss of cortical greater than trabecular bone, which leads to increased fracture risks [135]. Growth hormone replacement initially increases bone turnover and reduces bone density. A maintenance treatment encourages improved bone mass, but its effects on fracture risk is not definite [136]. This could be due to increased DKK-1, a Wnt inhibitor, therefore increasing cortical porosity [137].

4. Gastrointestinal Causes

Malabsorption and chronic liver disease are well-known causes of osteoporosis, and they are included in the FRAX. Physiologic bone metabolism requires optimum amounts of nutrients, particularly minerals and vitamins. Vitamin D is a fat-soluble vitamin, so bone loss is remarkable in diseases associated with fat malabsorption [138,139,140,141,142,143]. Furthermore, in cases of steatorrhea, calcium absorption may be hindered by binding to excess fatty acids in the gastrointestinal (GI) lumen [144]. In this section, we will discuss the most common causes of GI-related osteoporosis.

4.1. Celiac Disease

Patients with celiac disease have a high prevalence of osteopenia and osteoporosis, 40% and 15%, respectively, even after excluding postmenopausal women [145]. It has been reported that 8% of patients with idiopathic low BMD have positive IgA anti-endomysial antibodies even though they are asymptomatic. Routine screening for celiac disease might be considered in idiopathic cases of osteoporosis [146,147]. A gluten-free diet can significantly improve BMD [148,149]. However, bone loss may persist due to the continuous inflammatory process leading to higher osteoclast activity and lower ability to generate bone matrix [150].

4.2. Chronic Pancreatitis

More than 50% of patients with chronic pancreatitis, particularly smokers and alcoholics, have low BMD. Pancreatic enzymes and vitamin D replacement significantly lowered the risk of fracture [151]. Cystic fibrosis can disturb bone health through mechanisms other than malabsorption. Cystic fibrosis transmembrane conductance regulator is expressed in bone cells, thus it might have a negative impact on bone metabolism. Additionally, bone resorption increases during pulmonary exacerbations as the proinflammatory cytokines stimulate osteoclast activity [152].

4.3. Short Bowel Syndrome

The prevalence of osteoporosis in patients with short bowel syndrome is 2-fold higher compared to matched controls [141]. Bone loss occurs because of micro and macronutrients’ malabsorption. Metabolic acidosis, either caused by chronic diarrhea or D-lactic acidosis by bacterial overgrowth, can also impair bone health [153].

4.4. Hepatic Osteodystrophy

Disturbed enterohepatic circulation of fat-soluble vitamins impairs bone metabolism. This is one of the main causes of bone loss in biliary disorders as primary biliary cholangitis (PBC) and sclerosing cholangitis. The prevalence of osteoporosis and fractures in PBC is up to 50% and 20%, respectively [154,155,156]. The etiology of chronic liver disease, alcohol, viral hepatitis, and autoimmune diseases, may contribute to the pathogenesis of hepatic osteodystrophy [154,157,158,159,160,161]. Cirrhosis complications such as malnutrition, impaired physical activity, and hypogonadism, along with disturbed vitamin D and K metabolism [162,163], can aggravate bone loss.

4.5. Peptic Ulcer Disease

Peptic ulcer disease is linked to osteoporosis, especially among males. Certain species of H-pylori infections may afflict bone metabolism by enhancing inflammatory status, reducing the circulatory ghrelin and estrogen levels, and increasing postprandial serotonin levels. Moreover, long-term use of PPIs can impair bone health [164,165].

4.6. Inflammatory Bowel Disease (IBD)

Patients with IBD have a higher risk of bone loss [166], poor bone quality [167,168], and fractures [169,170,171,172]. This can be explained by malnutrition, chronic inflammatory process, and immunosuppressive drugs [171,173,174]. Low turnover bone disease is the predominant underlying pathology in patients with osteoporosis and IBD [175,176]. The American College of Gastroenterology recommended using the conventional risk factors as indications for BMD screening in IBD patients using DXA scan [177]. The Cornerstone Health organization has expanded the indications for BMD screening to include maternal history of osteoporosis, malnourished or very thin patients, and amenorrheicor postmenopausal women [178]. Maldonado and colleagues highlighted the role of biomechanical CT to detect patients with an increased risk of fracture. 40% of those patients were not included in the Cornerstone checklist. Thus, IBD patients undergoing CT enterography may benefit from biomechanical CT screening for fracture risk [179]. Early suppression of the inflammatory process by anti-TNF is associated with better bone preservation [169,180]. In addition to calcium and vitamin D optimization, bisphosphonates are relatively safe and effective treatment options [181]. In an animal study, a natural compound (emodin) has been reported to inhibit osteoclast function and prevent IBD-related osteoporosis [182].

4.7. Irritable Bowel Syndrome

Patients with irritable bowel syndrome have a higher incidence of osteoporosis and fragility fractures [183]. This might be explained by chronic inflammation, overactivation of the hypothalamic-pituitary-adrenal axis, nutritional deficiency, and smoking. Further studies are needed to confirm the underlying mechanisms and to establish a treatment approach [184].

4.8. Dysbiosis

Microbiota is considered a hidden organ that has a bidirectional interaction with cellular responses. Certain species of microbiota are linked to osteoporosis and autoimmune diseases such as IBD, PBC, and sclerosing cholangitis [185,186]. The beneficial effects of probiotics were explained experimentally by manipulating the expression of OPG/RANKL, Wnt10b, and inflammatory cytokines [186,187].

Other GI disorders with increased risk of osteoporosis include post-gastrectomy [188], atrophic gastritis [189,190], and bariatric surgeries [191].

5. Nutritional Causes

Nutritional factors can potentially affect bone mass, metabolism, matrix, and microarchitecture. Insufficient nutrition leads to deficiency of protein, vitamins, and minerals, particularly calcium, phosphorus, and magnesium, which are essential for bone health [192]. The recommended daily calcium intake for adults is between 800–1200 mg daily [32,193], while it is 700 mg and 320–420 mg for phosphorus and magnesium, respectively [194]. The daily protein requirement is recommended to be 0.8 gm/kg for adults and 1–1.2 gm/kg for the elderly [195,196]. The vitamin D daily requirement ranges from 800 to 1000 IU [197].

Malnutrition can happen either because of poor nutrient intake, increased losses, and/or increased demand [198]. Bad dietary habits, anorexia nervosa, bulimia nervosa, prolonged total parental nutrition (TPN), bariatric interventions, and excess alcohol intake can cause secondary osteoporosis [199]. As osteoporosis and fractures are associated with many life-threatening events, their prevention is essential via balanced diet and physical exercise [200].

Starvation, the most severe form of malnutrition, can be caused by various socio-economic, environmental, and medical factors [201]. Starvation can negatively affect bone quantity and quality through minerals, vitamins, and collagen type I deficiency [201,202]. There is a positive relationship between malnutrition during early life, or even in utero, and early incidence of osteoporosis and fractures [203,204,205,206,207].

Vitamin D deficiency results in decreased calcium absorption and hypocalcemia leading to secondary hyperparathyroidism, consequently stimulating bone turnover and decreased BMD [208]. Treatment with vitamin D supplements has beneficial effects on bone health in patients with 25-hydroxy vitamin D levels less than 30 nmol/L [209,210]. On the other hand, prophylactic doses of vitamin D have a debatable role in the prevention of osteoporosis and fractures. [211,212,213,214,215,216].

Many observational studies reported a positive relationship between body mass index (BMI) and BMD [217]. Moreover, previous studies demonstrated that obesity could protect against fractures [218,219]. However, more recent studies did not show a positive impact of obesity on bone [220]. The Look AHEAD trial reported a modest increase in bone loss at the hip with intensive non-surgical weight loss interventions in obese type 2 diabetics [221,222]. Moreover, most bariatric surgeries were associated with bone loss and fragility [191,223]. This may be explained by mechanical unloading, secondary hyperparathyroidism due to malabsorption of calcium and vitamin D, decreased estrogen, leptin, and ghrelin, and increased adiponectin levels [191,224,225]. Therefore, it is recommended to receive adequate calcium and vitamin D and to monitor BMD after bariatric surgeries [226].

Patients with anorexia nervosa extremely limit their food intake because they are scared of weight gain [227]. This can lead to several medical complications including bone loss [228] with a 2–7-fold increased risk of fractures [229,230]. This is not only because of nutritional deficiencies but hormonal disturbances as well [231]. On the other hand, improving nutritional status corrects the endocrinological disorders and BMD in these patients [232]. Anti-osteoporotic medications may help to ameliorate bone loss in patients with persistently low BMI and amenorrhea [233]. Residronate use, either alone or combined with transdermal testosterone, resulted in improved spinal BMD [234,235]. Moreover, physiological doses of transdermal estrogen lead to increased spinal and hip BMD [236]. In a recent RCT, sequential therapy with recombinant human IGF-1 and risedronate was superior to risedronate alone in improving lumbar spine BMD in women with anorexia nervosa [237]. Furthermore, Fazeli et al. reported a significant increase in lumbar spine BMD after 6 months of teriparatide use [238].

Patients with prolonged TPN have an osteoporosis prevalence of 40 to 100% [239,240,241]. Despite TPN improving nutritional status, the prolonged need for TPN may induce dysbiosis [242], decreased gut calcium, and phosphorus absorption [239]. Moreover, it can induce hypercalciuria because of the hyperfiltration secondary to high amino acid infusion [243]. Routine vitamin D monitoring and management are necessary for patients with prolonged TPN because vitamin D deficiency is very prevalent among these patients [239]. Bisphosphonates improved BMD in patients with TPN-associated osteoporosis [244,245].

Bad dietary habits have been reported to be associated with osteoporosis. High dietary sugar may lead to osteoporosis [246] by glucose-induced hypercalciuria, hypermagnesuria [247,248], and decreasing vitamin D activation [249]. In addition, hyperglycemia can decrease osteoblast proliferation and increase osteoclast activation [250,251]. On the other hand, the effect of dietary salt on bone health is unclear [252].

Heavy alcohol intake has been associated with decreased BMD [253]. Mechanistically, it directly reduces osteoblast activity and increases osteoclastogenesis [254,255,256]. Indirectly, it can cause changes in body composition [257] and alterations in various hormones, including PTH, vitamin D, testosterone, and cortisol [258]. Alcohol abstinence may improve bone metabolism and increase BMD [259,260].

6. Drug-Induced

Drug-induced osteoporosis is the second most common cause of secondary osteoporosis. Despite their well-known adverse events, glucocorticoids are still one of the cornerstone immune-suppressive/modulator and anti-inflammatory therapies. Up to 40% of patients on long-term glucocorticoid therapy suffer from fractures during their lifetime [261,262].

Areas with high trabecular bone, such as lumbar spine and hip trochanter, are the classic sites for glucocorticoid-induced fractures [263]. Robust bone loss may reach up to 20% within the first year of therapy, and subsequently decline to 1 to 3% annually [264,265]. The fracture risk with glucocorticoid therapy is dose and time-dependent [262]. The impact of glucocorticoids on bone has been linked to their cumulative effect, which disturbs both bone quantity and quality. Glucocorticoids can induce bone loss irrespective of the route of administration. For instance, long-term inhaled glucocorticoids were associated with a 10% loss of BMD [266,267]. Even controlled-release budesonide and topical corticosteroid can negatively impact bone health [268,269].

Glucocorticoids initially decrease bone formation and increase RANKL/osteoprotegerin ratio, inducing high bone resorption [270,271]. The mechanism of bone loss with long-term usage is more attributed to suppressed bone formation rather than increased bone resorption. This could be due to the downregulation of the Wnt signaling pathway which impairs the osteoblast activity [272]. Additionally, glucocorticoids have an indirect impact on bone through their effects on calcium homeostasis, parathyroid gland activities, and vitamin D metabolism [273,274]. Furthermore, glucocorticoids lead to loss of muscle mass and strength which increases the risk of falls and fractures. They can also induce hypogonadism which decreases the anti-resorptive effect of testosterone and/or estrogen [275].

The use of a DXA scan and FRAX after 6 months of glucocorticoid therapy is recommended for those with a history of fragility fracture, patients of 40 years of age or older, and those with major osteoporotic risk factors [276].

For prevention of glucocorticoid-induced osteoporosis, daily intake of 1000–1200 mg calcium and 600–800 units of vitamin D, along with lifestyle modification, are highly recommended [275]. For adults with high risk of fracture, treatment with oral bisphosphonate is the preferred line of therapy [276]. Teriparatide is also effective in preventing and treating glucocorticoid-induced bone loss [277].

Antidepressants like selective serotonin reuptake inhibitors and monoamine oxidase inhibitors can induce low bone density and increase incidence of fracture [278,279,280,281]. It is not clear how these medications affect bone health, but it may be attributed to diminished osteoblast proliferation through the serotonin receptors and transporters [282].

Many studies showed significant bone loss with long-term use of antiepileptic drugs [283,284,285]. The pathogenesis is multifactorial, however accelerated vitamin D metabolism is a crucial co-player [286,287,288,289]. Bone loss occurs as a result of bone remodeling abnormalities rather than abnormal mineralization [290,291,292].

Aromatase inhibitors, adjuvant long-term therapies for breast cancer, lead to abrupt deprivation of estrogen and consequently, bone loss [293]. Moreover, concomitant use of gonadotropin-releasing hormone agonists induces up to 7% annual BMD loss [294]. The use of gonadotropin-releasing hormone agonists in prostate cancer patients is associated with increased fracture risk [295,296,297].

Antidiabetic medications can impact bone health either positively or negatively. Peroxisome proliferator-activated receptor gamma (PPARγ) plays an important role in the regulation of bone formation and energy metabolism, along with insulin sensitivity [298,299]. Its stimulation by thiazolidinediones induces bone resorption and inhibits bone formation [300]. Thiazolidinediones decreased the BMD and increased the risk of osteoporosis when compared to other anti-diabetic medications [301]. The effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on bone metabolism and fracture risk are receiving more attention because of their wide use. They may increase bone turnover, disturb bone microarchitecture, and reduce BMD [302]. In a recent study, Koshizaka and colleagues reported increased TRAP 5b with no change in BMD in a 24-week RCT [303].

In 2010, the FDA released a warning against long-term use of proton pump inhibitors (PPIs) as it may increase the incidence of osteoporosis and fracture risk [304]. The limited available evidence suggested that this might happen through histamine over-secretion [305], and affecting mineral homeostasis [306,307]. There is inconsistent data regarding the impact of PPIs on BMD.

Despite the negative effect of anticoagulants on bone metabolism having been studied for a long time, such effect is still debatable, and the underlying mechanisms are still poorly understood [308]. Unfractionated heparin was associated with significant bone loss compared to low molecular weight heparin [309,310,311]. Long-term use of warfarin was associated with decreased BMD and TBS [312]. In a recent study, this negative effect on bone was more pronounced in warfarin but was also found in direct oral anticoagulants [313].

7. Infection

Chronic active infections are not infrequent causes of bone loss, mainly due to cytokine release that stimulates osteoclastogenesis and suppresses osteoblast function. Human immunodeficiency virus (HIV)-infected patients have a three times higher prevalence of osteoporosis and up to four-fold increased risk of fractures compared to the general population [314,315]. This might be directly attributed to the HIV infection or secondary to the use of antiretroviral therapy (ART), concomitant alcohol use, smoking, associated hypogonadism, malnutrition, hepatitis B and/or C co-infection, and vitamin D insufficiency [316,317,318,319,320]. HIV infection promotes osteoblast apoptosis and osteoclast activation [321,322,323,324,325]. Furthermore, HIV infection induces a state of chronic inflammation in addition to immune system activation afflicting bone health [326,327,328]. Tenofovir disoproxil fumarate (TDF) is associated with osteoporosis and fractures more than the newer ART [329,330,331,332], as it induces multiple renal tubular defects and mineral losses [333,334]. The European AIDS Clinical Society (EACS) [335] guidelines recommend tenofovir alafenamide (TAF) as a first-line therapy instead of TDF in patients with progressive osteopenia or osteoporosis, as it is less toxic to the renal tubules [336,337]. Bisphosphonates are used effectively for the treatment of HIV-related bone disease [338]; however, bone anabolic drugs have not been adequately studied [315].

Hepatitis B and C viral (HBV; HCV) infections even without subsequent liver cirrhosis is associated with an increased risk of osteopenia and osteoporosis [158,339,340,341]. Furthermore, previous studies reported that the risk of osteoporosis was still higher in patients with HBV and HCV infections even after adjustment for other osteoporosis risk factors [158,342]. Of note, previous studies reported an increased risk of fractures in patients with HIV and HCV co-infection compared with HIV-infected patients [319]. Interestingly, HCV clearance led to a two-thirds reduction in fracture risk in postmenopausal women with osteoporosis [343].

Herpes zoster infection is associated with osteoporosis [344,345]. This negative effect on bone health may be due to the upregulation of inflammatory cytokines, especially in patients with post-herpetic neuralgia [346,347].

COVID-19 might predispose patients to osteoporosis [348]. This may be because of associated pro-inflammatory cytokine production and prolonged immobilization in severe cases [349]. Furthermore, there might be direct sequelae of infection on the skeleton [350]. The virus can decrease ACE2 expression in both osteoblasts and osteoclasts [351], leading to disordered bone formation and resorption. In addition, corticosteroids used in the treatment of COVID-19 have a negative impact on bone.

Osteomyelitis is commonly associated with significant bone loss and subsequent fragility fractures [352]. This is mainly attributed to the upregulation of inflammatory cytokines such as IL-1, IL-6, and TNFα with subsequent activation of RANKL and inhibition of osteoprotegerin [353,354].

Patients with active TB and TB survivors with pulmonary fibrosis have increased risk of osteoporosis [342,355]. Chronic systemic inflammation, concomitant malnutrition, and vitamin D deficiency are the main contributors to bone loss [354,356,357,358].

8. Hemato-Oncological Causes

Hematologic disorders are potentially able to damage bone through direct cellular effects or indirectly, mediated by several circulating factors [359]. The bone loss occurs mainly due to an imbalance between RANKL/RANK and WNT signaling pathways with subsequently increased bone resorption and decreased bone formation [360,361,362,363].

Anemia can lead to bone resorption and increases bone fragility [364,365]. Iron deficiency may negatively impact cytochromes’ P450 activity, which is essential for vitamin D metabolism and bone health [366]. β thalassemia causes ineffective erythropoiesis and bone marrow expansion that leads to medullary destruction and cortical thinning [367]. Moreover, pubertal delay, cytokine disturbances, growth hormone deficiency, iron bone deposition, deferoxamine-induced bone dysplasia, and vitamin D deficiency can further contribute to inadequate bone health in thalassemia patients [368,369,370,371,372,373]. Bisphosphonate may improve BMD [373,374], however its effect on fracture rate is uncertain in patients with thalassemia [375]. There is limited information but promising results observed by using denosumab or teriparatide to increase bone density in thalassemia patients [376,377].

The estimated prevalence of secondary osteoporosis in hemophilia patients is up to 58.7% [378]. The underlying mechanisms for low bone mass include vitamin D deficiency, limited physical activity secondary to hemophilic arthropathy, and the acquisition of osteoporosis-linked blood-born infections such as HIV [379,380,381]. In addition, Factor VIII deficiency is directly associated with increased bone resorption and decreased formation secondary to the imbalance in OPG/RANK/RANKL system [382,383]. Screening for osteoporosis should be implemented in the underweight, those with fragility fractures, HIV, and/or advanced hemophilic arthropathy [384]. Replacement of the deficient factor could minimize joint bleeding and hemoarthropathy and subsequently reduce the risk and progression of osteoporosis [385].

Both monoclonal gammopathy of undetermined significance and multiple myeloma patients are at increased hazard for osteoporosis and fragility fractures [386,387]. Myeloma cells stimulate the release of cytokines, IL-6, and IL-7, leading to activation of the RANKL/RANK pathway and enhanced bone resorption [361]. On the other hand, the expression of WNT inhibitors, Dkk-1, and secreted frizzled protein-2 is enhanced, leading to reduced bone formation [388,389]. Several guidelines recommend myeloma screening in elderly patients with osteoporosis and/or fragility fractures [390,391]. Bisphosphonate is recommended in myeloma patients as they have antineoplastic, immunomodulatory, and anticatabolic effects [392,393]. Nevertheless, renal impairment which is frequent in those patients is still an important hindrance [394] and may obligate the use of other safer drugs such as denosumab [395]. In addition, treatment of multiple myeloma, such as bortezomib, and monoclonal antibodies targeting DKK1 or sclerostin can reduce bone loss [396,397,398].

Osteoporosis is the most common skeletal pathology that occurs in 18 to 40% of systemic mastocytosis patients [399,400,401]. Bone involvement occurs due to bone marrow infiltration by mast cells, besides the release of circulating factors, such as histamine, prostaglandins, and interleukins (IL-1, IL-3, IL-6), which enhance osteoclast activity [402]. The manifestations consist of a wide clinical spectrum from asymptomatic condition to varying degrees of bone damage, such as osteopenia, osteoporosis, osteolytic lesions, and osteosclerosis [403]. Besides antiresorptive medications such as bisphosphonate and denosumab [404,405], interferon may improve bone pathology by controlling the disease activity [406]. Contrarily, safety concerns exist with the use of teriparatide as it may enhance the proliferation of malignant cells [407].

In patients with solid tumors, bone damage usually occurs either as a side effect of anticancer treatment or secondary to osteolytic metastasis, most commonly from breast cancer [408]. Moreover, cytotoxic chemotherapy and hormone deprivation therapies have detrimental effects on both bone quantity and quality [409,410,411]. Bone loss in patients receiving aromatase inhibitors or androgen deprivation therapy is up to ten times that in age-matched healthy controls [412,413]. Therefore, baseline and follow-up DXA scans are serially recommended based on the underlying diseases [414,415]. Bisphosphonate is advised in aromatase inhibitor receivers with higher fracture risk [416].

9. Rheumatological-Immunological Causes

The immune system plays an important role in bone homeostasis. Activated T cells affect bone health through the secretion of various cytokines [417]. Some experimental studies detected that Th17 cells are responsible for stimulating bone resorption, while T reg cells are peculiarly associated with inhibition of bone resorption [418]. Moreover, CD8+ T cells might have a protective function through the secretion of various factors, such as osteoprotegerin and interferon-γ which have an anti-osteoclastogenesis effect [419].

9.1. Inflammatory Arthritis

Inflammatory arthritis, including rheumatoid arthritis (RA), psoriatic arthritis, and spondyloarthropathy, is frequently associated with systemic skeletal complications, such as osteoporosis and fragility fractures [420].

Osteoporosis prevalence in patients with RA is about 30% and increases up to 50% in post-menopausal women [421,422]. Furthermore, a large meta-analysis revealed that patients with RA have a higher risk of fracture [423].

RA-related osteoporosis is described by two main features: local and systemic bone loss [424]. Several mechanisms are involved in the pathogenesis of bone loss including sustained inflammation, glucocorticoid use, decreased physical activity and increased secretion of proinflammatory cytokines such as IL-6, IL-1, and TNF-α [422,425]. Moreover, overexpression of RANKL promotes osteoclastogenesis [426]. There is enough evidence to support the role of autoantibodies in the pathogenesis of both local and systemic bone loss through osteoclast activation [427,428,429].

Disease-modifying anti-rheumatic drugs (DMARDs) don’t only control the inflammatory status but also help to avoid the long-term negative effects of corticosteroids on bone health [430]. The use of leflunomide was associated with a significant increase in lumbar spine BMD [431]. Moreover, TNF-inhibitors improved BMD and reduced the rate of fracture [432]. Other biological agents such as tocilizumab, rituximab, and abatacept significantly reduced bone resorption markers and RANKL expression [433,434]. On the other hand, the impact of methotrexate on bone loss is controversial [435].

Despite several studies demonstrating a significant association between psoriatic arthritis and bone loss/fragility fracture [436,437], others did not find such association [438]. Pro-inflammatory cytokines are involved in the mechanism of local bone loss [439].

On the other hand, patients with ankylosing spondylitis (AS) have lower BMD, even in the early stage of the disease [440]. The prevalence of osteopenia and osteoporosis is about 54% and 16%, respectively, within 10 years of the disease onset [440]. A large database showed a higher risk of vertebral and non-vertebral fractures among patients with AS [441]. The use of non-steroidal anti-inflammatory drugs was associated with decreased fracture risk [441]. TNF-inhibitors increased lumbar spine and total hip BMD, however they did not decrease the rate of vertebral fractures [442].

9.2. Systemic Lupus Erythematosus (SLE)

Osteoporosis and fragility fractures are well-known comorbidities in patients with SLE [443]. The incidence of fracture is up to 35% in this patient population [444]. Furthermore, asymptomatic vertebral, and non-vertebral fractures were associated with decreased quality of life and increased risk of mortality [445,446]. Pro-inflammatory cytokines directly affect bone mass [447]. Organ damage can indirectly cause bone mass loss. The disease duration and severity, besides the long-term glucocorticoid usage, are the main determinants of bone loss [448,449]. Lower levels of P1NP are predictive of bone loss and decrease BMD over 12 months in premenopausal SLE patients [450].

9.3. Multiple Sclerosis (MS)

Several studies showed that people with MS have lower BMD, higher rates of osteoporosis, and increased fracture risk compared to healthy controls [451,452,453]. Various risk factors contribute to bone loss in patients with MS, including disease duration and severity, vitamin D insufficiency, cumulative steroid dose, decreased ambulation, and inflammatory processes [453,454]. The pro-inflammatory osteopontin levels increase in patients with MS and correlate with femur neck BMD [455].

10. Others

10.1. Smoking

Smoking is incorporated within the FRAX score as a risk factor for osteoporosis [456]. It has direct harmful effects on osteogenesis and bone blood flow [457]. Indirectly, it afflicts serum levels of vitamin D, PTH [458,459], and sex hormones, particularly in females [460]. The effect of smoking cessation on BMD is unclear; however, it has been shown that it could increase BMD at femur and total hip [461] and reduce vertebral fractures [462].

10.2. Disuse Osteoporosis

Osteocytes have certain mechano-receptors that use weightbearing-induced signals to orchestrate bone turnover. Immobility leads to osteocyte dysfunction and subsequent inhibition of bone formation via downregulation of Wnt/β-catenin pathway [463]. This can be a systemic disorder with prolonged immobilization or a local disease among patients with hemiparesis, spinal cord injuries, or neuromuscular diseases. Physical exercise and rehabilitation programs are essential in preventing and treating this type of bone loss. The use of antiosteoporotic medications such as bisphosphonates, denosumab, teriparatide, and romosozumab might be indicated in refractory cases [463,464,465].

10.3. Genetic Causes of Osteoporosis

Genetics plays a crucial role in bone microarchitectural properties, skeletal strength, and the risk of osteoporosis. Rare, monogenic forms of osteoporosis start in childhood or young adulthood [466]. The most common one is osteogenesis imperfecta (OI), also known as ‘brittle bone disease’ [467]. Osteogenesis imperfecta is a genetic connective tissue disorder caused by defective bone formation, mainly due to impaired production and/or processing of type 1 collagen [468]. It is characterized by an abnormally high bone matrix mineralization. This is related to a larger number of crystals with the same volume of matrix [469,470]. Cortical porosity, thin trabeculae, abnormal bone quality, and low bone density with associated increased risk of fracture are common findings in OI [471,472,473]. There is limited evidence that bisphosphonates increase BMD and decrease the risk of fracture in patients with OI [474]. Moreover, denosumab had poor and inconclusive results [475]. Notably, romosuzumab increased BMD and improved turnover biomarkers in those patients [419]. Apart from OI, whole-genome sequencing studies were able to unmask new genetic variants that are associated with osteoporosis. The expression of these genetic variants is involved in different bone-protecting functions, such as vitamin D metabolism, mesenchymal stem cell osteogenic differentiation, and bone morphogenetic proteins. Some of these variants are population-specific and others are shared between patients with low BMD from different races [476,477].

Osteoporotic fractures are increasing exponentially [478] and are considered one of the major health care problems [479]. Osteoporosis is associated with a negative effect on fracture healing, especially in unstable and comminuted fractures, which indicate internal fixation [480,481]. The power of screw holding is decreased in the osteoporotic bone which, in turn, causes implant loosening, loss of fixation, and impaired healing. Antiosteoporotic medication should be considered to improve bone formation and the success rate of bone implants in osteoporotic fractures [482].

The current review is limited by the quantity and quality of the clinical studies in this field. Few RCTs demonstrated the impact of different anti-osteoporotic medications on bone.

11. Conclusions

Secondary osteoporosis is diagnosed when bone fragility is caused by a disease, drug, or nutritional deficiencies. It is an evolving, devastating health problem. Proper diagnosis and prevention are the cornerstones of preventing further bone loss and fragility fractures. Although causal treatment is essential, antiosteoporotic medications can further decrease the risk of fractures, as well as improve fracture healing. More RCTs are required to explore the safety and efficacy of antiosteoporotic drugs in various clinical settings.