髖部骨折是全球面臨的重要公共健康問(wèn)題和挑戰(zhàn)。1990年,全世界髖部骨折人數(shù)為131萬(wàn);預(yù)計(jì)到2025年,髖部骨折人數(shù)將達(dá)到394萬(wàn)(男性116萬(wàn),女性278萬(wàn));到2050年,髖部骨折人數(shù)將上升至626萬(wàn)(男性179萬(wàn),女性447萬(wàn))[1]。髖部骨折大大增加了社會(huì)經(jīng)濟(jì)負(fù)擔(dān),在美國(guó),髖部骨折病人所需費(fèi)用約占所有骨折病人總費(fèi)用的1/3[2]。在亞洲,髖部骨折病人每年花費(fèi)774～14 198.90美元不等,約占該國(guó)人均GDP的18.95%[3]。老年人骨質(zhì)疏松患病率明顯增加,髖部骨折發(fā)生率也隨之顯著增高[4]。老年髖部骨折更為復(fù)雜,并發(fā)癥多,預(yù)后差,死亡率高。據(jù)統(tǒng)計(jì),髖部骨折1個(gè)月死亡率約10%,1年死亡率上升至30%,8年死亡率高達(dá)80%[5]。

心血管疾病是老年人群最常見(jiàn)的疾病。有文獻(xiàn)報(bào)道,心血管疾病與髖部骨折存在共同的易患因素和潛在的病理生理機(jī)制,如高齡、脂質(zhì)代謝異常、氧化應(yīng)激、炎癥、糖尿病等[6]。與無(wú)心血管疾病的老年人相比,患心血管疾病的老年人髖部骨折發(fā)生率增加53%。髖部骨折者也更易發(fā)生心血管疾病,55～64歲人群心血管疾病發(fā)病率增加80%,65～79歲人群增加83%,≥80歲人群增加16%[7]。本文旨在討論心血管疾病與髖部骨折的相關(guān)性,為臨床治療提供幫助。

1 心房顫動(dòng)與髖部骨折

一項(xiàng)納入了113 600個(gè)體的大樣本隊(duì)列研究顯示,心房顫動(dòng)病人髖部骨折發(fā)生率為17.5/1000人年,而非心房顫動(dòng)病人髖部骨折發(fā)生率為7.4/1000人年[8]。在校正年齡、并發(fā)癥和藥物等差異后,男性心房顫動(dòng)發(fā)生髖部骨折的風(fēng)險(xiǎn)是非心房顫動(dòng)的1.97倍,女性為2.08倍。另一項(xiàng)研究表明心房顫動(dòng)是骨科手術(shù)術(shù)前預(yù)測(cè)死亡率的危險(xiǎn)因素之一,合并心房顫動(dòng)的骨科手術(shù)病人死亡率達(dá)3.45%[9]。心房顫動(dòng)與髖部骨折相關(guān)性的可能機(jī)制是兩種疾病有心力衰竭、高血壓、糖尿病等共同的臨床危險(xiǎn)因素,存在炎癥、氧化應(yīng)激、血管功能障礙、基因等相似的病理生理過(guò)程[8]。

2014年美國(guó)心臟協(xié)會(huì)、美國(guó)心臟病學(xué)學(xué)會(huì)和心律學(xué)會(huì)發(fā)布的《2014年心房顫動(dòng)病人診療指南》中指出CHA2DS2-VASc評(píng)分≥2分的病人血栓栓塞危險(xiǎn)因素較高,需要接受抗凝治療,包括維生素K拮抗劑和新型口服抗凝藥達(dá)比加群、利伐沙班等[10]?？诜鼓幣c骨質(zhì)疏松存在相關(guān)性[11]。有研究顯示口服維生素K拮抗劑可導(dǎo)致異常的非羧化的骨鈣蛋白生成,異常的骨鈣蛋白不能整合至骨質(zhì)中,而是完全釋放到循環(huán)中,增加了患骨質(zhì)疏松的風(fēng)險(xiǎn)[12]。利伐沙班不僅在骨質(zhì)形成的早期起抑制作用,而且影響骨調(diào)節(jié)激素刺激效應(yīng)[13]。但Namba等[14]報(bào)道服用華法林的心房顫動(dòng)病人改服用利伐沙班,骨形成的標(biāo)志物水平增加,骨吸收的標(biāo)志物水平減少。

2 動(dòng)脈粥樣硬化與髖部骨折

異常的脂質(zhì)代謝同時(shí)參與骨髂重構(gòu)和動(dòng)脈粥樣硬化過(guò)程,導(dǎo)致骨質(zhì)疏松和動(dòng)脈粥樣硬化并存。低密度脂蛋白(low density lipoprotein, LDL)與骨密度呈負(fù)相關(guān),高密度脂蛋白(high density lipoprotein, HDL)則與其呈正相關(guān)[15]。動(dòng)物研究表明對(duì)鼠進(jìn)行致動(dòng)脈粥樣硬化高脂飲食喂養(yǎng)7個(gè)月后,鼠的骨質(zhì)形成降低[16]。他汀類藥物通過(guò)抑制HMG-CoA還原酶,降低總膽固醇、LDL和甘油三酯,升高HDL,抑制動(dòng)脈粥樣硬化形成,降低心血管事件和死亡的發(fā)生。現(xiàn)研究也表明他汀類藥物可以增加骨密度,降低骨折發(fā)生的風(fēng)險(xiǎn)[17]。在體外和動(dòng)物研究中發(fā)現(xiàn),他汀類藥物可能通過(guò)促進(jìn)成骨細(xì)胞BMP-2的表達(dá)和產(chǎn)生來(lái)刺激骨形成和增強(qiáng)成骨細(xì)胞分化[18]。炎癥在動(dòng)脈粥樣硬化從脂紋形成到斑塊的破裂整個(gè)過(guò)程均起重要作用,現(xiàn)研究表明炎癥也參與了骨質(zhì)疏松的發(fā)生發(fā)展[19]。由此可見(jiàn),動(dòng)脈粥樣硬化與髖部骨折可能存在相關(guān)性。一項(xiàng)臨床隨訪調(diào)查研究發(fā)現(xiàn),缺血性心臟病和外周動(dòng)脈粥樣硬化癥分別增加髖部骨折風(fēng)險(xiǎn)2.32倍和3.2倍,如缺血性心臟病僅限于急性心肌梗死,髖部骨折風(fēng)險(xiǎn)增加2.42倍[20]。

3 心力衰竭與髖部骨折

心力衰竭很可能加速骨質(zhì)流失,導(dǎo)致骨折發(fā)生率增加。心力衰竭病人維生素D水平下降,甲狀旁腺水平升高[21]。心力衰竭病人醛固酮水平是升高的[22],而動(dòng)物研究表明高水平的醛固酮可促進(jìn)鈣排泄的增加和甲狀旁腺水平的升高[23]。此外,治療心力衰竭的藥物也會(huì)影響病人患骨質(zhì)疏松風(fēng)險(xiǎn)。噻嗪類利尿劑、安體舒通、血管緊張素抑制劑(ACEI)和β受體阻滯劑與骨質(zhì)代謝呈正相關(guān),相反,髓袢利尿劑與骨密度流失相關(guān)[24-25]。Van等[26]隨訪了16 294例年齡≥65歲的心血管疾病病人,發(fā)現(xiàn)心力衰竭組病人髖部骨折發(fā)生率要明顯高于非心力衰竭組(1.3%比0.1%,P<0.001)。心力衰竭病人髖部骨折風(fēng)險(xiǎn)增加6倍,骨折風(fēng)險(xiǎn)增加4倍。Carbone等[27]入選了年齡≥65歲5 613例個(gè)體,隨訪了11.5年,同樣發(fā)現(xiàn)心力衰竭組髖部骨折年發(fā)生率較非心力衰竭組高。在校正年齡、種族、吸煙、體質(zhì)量指數(shù)、藥物等多種變量后,心力衰竭仍是髖部骨折的危險(xiǎn)因素,合并髖部骨折的心力衰竭病人死亡率是單純心力衰竭病人的2倍。

4 高血壓與髖部骨折

動(dòng)物實(shí)驗(yàn)、臨床研究和流行病學(xué)調(diào)查均顯示高血壓與鈣代謝異常有相關(guān)性。高血壓可導(dǎo)致鈣流失、甲狀旁腺繼發(fā)性激活及促進(jìn)鈣從骨骼中遷移,增加患骨質(zhì)疏松的風(fēng)險(xiǎn),進(jìn)而促進(jìn)骨折的發(fā)生[28]。一項(xiàng)前瞻性研究納入9 704例年齡≥65歲的白人女性,在校正年齡、初始骨密度、體質(zhì)量、吸煙和激素替代治療多種變量后,發(fā)現(xiàn)股骨頸部骨流失比率隨血壓的升高而增加[29]。高血壓者患髖骨骨折風(fēng)險(xiǎn)是非高血壓者的1.6倍[20]。另外,高血壓可導(dǎo)致腦白質(zhì)損害,后者可增加髖部骨折風(fēng)險(xiǎn)3倍[30]。但Bhattacharyya等[9]研究發(fā)現(xiàn)高血壓病人骨科手術(shù)死亡率反而是降低的,考慮很可能高血壓病人術(shù)前得到正規(guī)藥物治療,而且高血壓病人常使用β受體阻滯劑,其對(duì)心臟有保護(hù)作用。

心血管疾病和髖部骨折之間的關(guān)系還遠(yuǎn)沒(méi)有定論,需要進(jìn)一步的研究來(lái)證實(shí)這兩種常見(jiàn)疾病之間的相關(guān)性。但提示我們老年髖部骨折絕不是單一的學(xué)科局部治療,需要多學(xué)科聯(lián)合全面救治。英國(guó)國(guó)家臨床優(yōu)化研究所(National Institute for Clinical Excellence, NICE)等多個(gè)國(guó)際指南均強(qiáng)調(diào)多學(xué)科綜合治療老年髖部骨折的重要性[5]。多學(xué)科綜合治療可以降低老年髖部骨折病人術(shù)后并發(fā)癥和死亡率的發(fā)生,縮短住院時(shí)間,獲得更好的功能恢復(fù)[31]。

[參考文獻(xiàn)]

[1] Fernandez MA, Griffin XL, Costa ML. Management of hip fracture[J]. Br Med Bull, 2015, 115(1):165-172.

[2] Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures[J]. Lancet, 2002, 359(9319): 1761-1767.

[3] Mohd-Tahir NA, Li SC. Economic burden of osteoporosis-related hip fracture in Asia: a systematic review[J]. Osteoporos Int, 2017, 28(7): 2035-2044.

[4] 中華醫(yī)學(xué)會(huì)骨質(zhì)疏松和骨礦鹽疾病分會(huì). 原發(fā)性骨質(zhì)疏松癥診療指南(2017)[J]. 中華骨質(zhì)疏松和骨礦鹽疾病雜志, 2017, 10(5):413-443.

[5] Riemen AH, Hutchison JD. The multidisciplinary management of hip fractures in older patients[J]. Orthop Trauma, 2016, 30(2):117-122.

[6] McFarlane SI, Muniyappa R, Shin JJ, et al. Osteoporosis and cardiovascular disease: brittle bones and boned arteries, is there a link? [J] Endocrine, 2004, 23(1): 1-10.

[7] Xu B, Han L, Liu H, et al. Cardiovascular disease and hip fracture among older inpatients in Beijing, China[J]. Biomed Res Int, 2013, 2013:493696.

[8] Wong CX, Gan SW, Lee SW, et al. Atrial fibrillation and risk of hip fracture: A population-based analysis of 1113,600 individuals [J]. Int J Cardiol, 2017, 243:229-232.

[9] Bhattacharyya T, Iorio R, Healy WL. Rate of and risk factors for acute inpatient mortality after orthopaedic surgery [J]. J Bone Joint Surg Am, 2002, 84-A(4):562-572.

[10] January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society[J]. Circulation, 2014, 130(23):2071-2104.

[11] Cerit L. Atrial fibrillation, hip fracture, and oral anticoagulant therapy[J]. Int J Cardiol, 2017, 249:259.

[12] Vermeer C. Vitamin K: the effect on health beyond coagulation-an overview[J]. Food Nutr Res, 2012, 56(2):77-81.

[13] Pearson DA. Bone health and osteoporosis: the role of vitamin K and potential antagonism by anticoagulants[J]. Nutr Clin Pract, 2007, 22(5):517-544.

[14] Namba S, Yamaoka-Tojo M, Kakizaki R, et al. Erratum to: Effects on bone metabolism markers and arterial stiffness by switching to rivaroxaban from warfarin in patients with atrial fibrillation [J]. Heart Vessel, 2017, 32 (8):977-982.

[15] Yamaguchi T, Sugimoto T, Yano S, et al. Plasma lipids and osteoporosis in postmenopausal women[J]. Endocr J, 2002, 49(2):211-217.

[16] Parhami F, Tintut Y, Beamer WG, et al. Atherogenic high-fat diet reduces bone mineralization in mice[J]. J Bone Miner Res, 2001,16(1):182-188.

[17] Bauer DC, Mundy GR, Jamal SA, et al. Use of statins and fracture. results of 4 prospective studies and cumulative meta-analysis of observational studies and controlled trials[J]. Arch Intern Med, 2004, 164(2):146-152.

[18] Mundy G, Garrett R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins[J]. Science, 1999, 286(5446):1946-1949.

[19] Farhat GN, Cauley JA. The link between osteoporosis and cardiovascular disease[J]. Clin Cases Miner Bone Metab, 2008, 5(1):19-34.

[20] Sennerby U, Melhus H, Gedeborg R, et al. Cardiovascular diseases and risk of hip fracture[J]. JAMA, 2009, 302(15):1666-1673.

[21] Ogino K, Ogura K, Kinugasa Y, et al. Parathyroid hormone-related protein is produced in the myocardium and increased in patients with congestive heart failure[J]. J Clin Endocrinol Metab. 2002, 87(10):4722-4727.

[22] Weber KT. Aldosterone in congestive heart failure[J]. N Engl J Med, 2001, 345(23):1689-1697.

[23] Chhokar VS, Sun Y, Bhattacharya SK, et al. Hyperparathyroidism and the calcium paradox of aldosteronism[J]. Circulation, 2005, 111(7):871-878.

[24] Wiens M, Etminan M, Gill SS, et al. Effects of antihypertensive drug treatments on fracture outcomes: a meta-analysis of observational studies[J]. J Intern Med, 2006, 260(4):350-362.

[25] Schlienger RG, Kraenzlin ME, Jick SS, et al. Use of beta-blockers and risk of fractures[J]. JAMA, 2004, 292(11):1326-1332.

[26] van Diepen S, Majumdar SR, Bakal JA, et al. Heart failure is a risk factor for orthopedic fracture: a population-based analysis of 16,294 patients[J]. Circulation, 2008, 118(19):1946-1952.

[27] Carbone L, Buzkova P, Fink HA, et al. Hip fractures and heart failure: findings from the Cardiovascular Health Study[J]. Eur Heart J, 2010, 31(1):77-84.

[28] McCarron DA, Pingree PA, Rubin RJ, et al. Enhanced parathyroid function in essential hypertension:a homeostatic response to a urinary calcium leak[J]. Hypertension, 1980, 2(2): 162-168.

[29] Cappuccio FP, Meilahn E, Zmuda JM, et al. High blood pressure and bone-mineral loss in elderly white women: a prospective study[J]. Lancet, 1999, 354(9183): 971-975.

[30] Corti MC, Baggio G, Sartori L, et al. White matter lesions and the risk of incident hip fracture in older persons: results from the Progetto Veneto Anziani Study[J]. Arch Intern Med, 2007, 167(16):1745-1751.

[31] Franch Parella J. Analysis of an integral care programme for hip fracture patients aged over 65 years[J]. Rev Esp Cir Ortop Traumatol, 2017,(9)：S1888-4415.