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Arthritis Care Res (Hoboken)。作者手稿；可在 PMC 2023 年 2 月 1 日查阅。
最终编辑版本为
pmcid: pmc8054264if：4.7 Q2
Is there an association of serum low density lipoprotein, high density lipoprotein or total cholesterol with development of knee osteoarthritis?
血清低密度脂蛋白、高密度脂蛋白或总胆固醇与膝关节骨性关节炎的发病是否有关？
本文的最终编辑版本可在 Arthritis Care Res (Hoboken) 上查阅。
Abstract 摘要
Objectives: 目标：
Studies suggest an association between elevated total serum cholesterol (TC), particularly low-density lipoprotein cholesterol (LDL), and osteoarthritis (OA). We evaluated the association between total cholesterol, LDL, and high-density lipoprotein (HDL) and risk of knee OA.
研究表明，血清总胆固醇（TC），尤其是低密度脂蛋白胆固醇（LDL）的升高与骨关节炎（OA）之间存在关联。我们评估了总胆固醇、低密度脂蛋白和高密度脂蛋白（HDL）与膝关节 OA 风险之间的关系。
Methods: 方法
We studied participants from the Multicenter Osteoarthritis study (MOST) cohort at risk of developing knee OA. From baseline through 7 years, repeated knee x-rays and MRIs were obtained and knee symptoms were queried. From baseline fasting blood samples, lipids and lipoproteins were analyzed using standard assays. After excluding participants with baseline OA, we defined two sets of cases: those developing radiographic OA and those developing symptomatic OA (knee pain and radiographic OA). Controls did not develop these outcomes. Additionally, we examined worsening of: cartilage loss and synovitis on MRI and of knee pain using the WOMAC scale. We carried out logistic regression adjusting for age, sex, BMI, education, baseline pain, and depressive symptoms, testing total cholesterol and lipoproteins as continuous measures and did sensitivity analyses examining whether commonly used thresholds for high cholesterol, LDL or low HDL increased risk.
我们研究了多中心骨关节炎研究（MOST）队列中的膝关节OA高危人群。从基线到 7 年期间，我们重复采集了膝关节 X 光片和核磁共振成像，并询问了膝关节症状。使用标准检测方法对基线空腹血样中的血脂和脂蛋白进行分析。在排除基线有 OA 的参与者后，我们定义了两组病例：出现影像学 OA 的病例和出现症状性 OA（膝关节疼痛和影像学 OA）的病例。对照组没有出现这些结果。此外，我们还检查了以下方面的恶化情况：核磁共振成像上的软骨损失和滑膜炎，以及使用 WOMAC 量表的膝关节疼痛。我们进行了逻辑回归，调整了年龄、性别、体重指数、教育程度、基线疼痛和抑郁症状，测试了作为连续测量指标的总胆固醇和脂蛋白，并对常用的高胆固醇、低密度脂蛋白或低高密度脂蛋白阈值是否会增加风险进行了敏感性分析。
Results: 结果
We studied 337 cases with incident symptomatic OA and 283 cases with incident radiographic OA. Mean age at baseline was 62 years (55% women). Neither total, LDL, nor HDL showed a significant association with radiographic or symptomatic OA. Additionally, we found no association of these lipid measures with cartilage loss, worsening synovitis or worsening knee pain.
我们研究了337例症状性OA和283例影像学OA病例。基线平均年龄为 62 岁（55% 为女性）。总胆固醇、低密度脂蛋白和高密度脂蛋白均与影像学或症状性 OA 无关。此外，我们还发现这些血脂指标与软骨损失、滑膜炎恶化或膝关节疼痛恶化均无关联。
Conclusion: 结论
Our data do not support an association between total cholesterol, LDL or HDL with OA outcomes.
我们的数据不支持总胆固醇、低密度脂蛋白或高密度脂蛋白与 OA 结果之间存在关联。
关键词身体成分 骨关节炎 疼痛 血脂
Osteoarthritis (OA) is the most common form of arthritis and is a leading cause of disability in the United States (1). Its prevalence is estimated at around 30 million in the U.S. and 240 million worldwide, with increasing disease burden attributed to the obesity epidemic and an aging population (1,2). Current treatment focuses on management of pain and improvement of function. Thus far, therapies aimed at delaying structural deterioration of the joint have been unsuccessful in both modifying the course of the disease and reducing pain.
骨关节炎（OA）是最常见的关节炎，也是美国致残的主要原因（1）。据估计，美国的发病率约为 3,000 万，全球的发病率约为 2.4 亿，肥胖症的流行和人口老龄化导致疾病负担日益加重 ( 1, 2)。目前的治疗重点是控制疼痛和改善功能。迄今为止，旨在延缓关节结构恶化的疗法在改变病程和减轻疼痛方面均不成功。
Osteoarthritis has been viewed traditionally as a disease caused by excessive mechanical loading, e.g. “wear and tear,” leading to degeneration of articular cartilage over time. Over the past decade, the understanding of processes underlying the pathology of osteoarthritis have, in addition to loading, increasingly included a model of synovial inflammation driven by a complex interplay of cytokines, metalloproteinases, and reactive oxygen species causing cartilage degeneration and bone loss (2). Studies evaluating OA have identified a link between obesity and OA of hand joints (3–5) suggesting that OA could be caused, in part, by factors unrelated to mechanical load. These findings support current research focusing on the hypothesis that OA is not only a localized joint disease, but an inflammatory disease involving both metabolic and mechanical factors.
骨关节炎传统上被认为是一种由过度机械负荷（如 "磨损"）引起的疾病，随着时间的推移导致关节软骨退化。在过去的十年中，人们对骨关节炎病理基础过程的认识，除了负荷外，还越来越多地包括由细胞因子、金属蛋白酶和活性氧的复杂相互作用导致软骨退化和骨质流失的滑膜炎症模型 ( 2)。对 OA 进行评估的研究发现，肥胖与手部关节 OA 之间存在联系（3-5），这表明 OA 部分可能是由与机械负荷无关的因素引起的。这些研究结果支持了当前的研究假设，即 OA 不仅是一种局部关节疾病，还是一种涉及代谢和机械因素的炎症性疾病。
Several experimental studies have suggested an association between dyslipidemia and OA. Proposed mechanisms by which this may occur include anti-inflammatory effects of elevated serum high density lipoprotein (HDL) and pro-inflammatory effects of elevated serum low density lipoprotein (LDL) and oxidized LDL. DeMunter et al showed that mice fed a cholesterol-rich diet had LDL accumulation in synovial cells, synovitis and increased ectopic bone formation; they propose a mechanism by which increased levels of oxidized LDL activate synovial macrophages, fibroblasts, and endothelial cells, leading to local inflammation, cartilage loss, and ectopic bone formation (5). (6, 7). Busso, et al showed that synovial fluid and plasma total cholesterol, HDL and LDL were highly correlated with synovial fluid levels of these lipoproteins suggesting that circulating serum lipids are able to freely move into the joint, further strengthening the hypothesis that altered lipid levels in the blood may have a direct effect on joint homeostasis (8).
一些实验研究表明，血脂异常与 OA 之间存在关联。所提出的发生机制包括血清高密度脂蛋白（HDL）升高的抗炎作用以及血清低密度脂蛋白（LDL）和氧化低密度脂蛋白（LDL）升高的促炎作用。DeMunter 等人发现，以富含胆固醇的饮食喂养的小鼠，其滑膜细胞中的低密度脂蛋白蓄积、滑膜炎和异位骨形成增加；他们提出了氧化低密度脂蛋白水平升高激活滑膜巨噬细胞、成纤维细胞和内皮细胞，导致局部炎症、软骨损失和异位骨形成的机制 ( 5)。( 6, 7).Busso 等人的研究表明，滑膜液和血浆中的总胆固醇、高密度脂蛋白和低密度脂蛋白与滑膜液中这些脂蛋白的水平高度相关，这表明循环血清中的脂质能够自由进入关节，进一步加强了血液中脂质水平的改变可能会直接影响关节稳态的假设 ( 8)。
Given the experimental evidence supporting an association between dyslipidemas and the development of OA, several authors have attempted to evaluate this relationship through observational studies. However, these studies have reported mixed results, highlighting the need for further research in this area (9, 10). Few of these reports have focused on serum HDL and LDL concentrations, and to our knowledge, only three studies reported longitudinal data. In one longitudinal study, results suggested an increased risk of hand OA with higher levels of HDL, but the sample size was small and confidence intervals wide. The other studies were not about painful OA per se, but focused on MRI bone marrow lesions (BML) and their relation to lipids (11, 12). While these data serve as a starting point in understanding the role that plasma lipids may play in the development of OA, there exists a paucity of literature directly evaluating the relationship between serum lipid and lipoprotein concentrations and incident osteoarthritis, particularly incidence of disease in the knee, the site of most disabling OA.
鉴于有实验证据支持血脂异常与 OA 的发生有关，一些学者试图通过观察性研究来评估这种关系。然而，这些研究的结果喜忧参半，凸显了在这一领域开展进一步研究的必要性 ( 9, 10)。这些报告很少关注血清高密度脂蛋白和低密度脂蛋白的浓度，据我们所知，只有三项研究报告了纵向数据。在一项纵向研究中，结果表明高密度脂蛋白水平越高，手部 OA 风险越大，但样本量较小，置信区间较宽。其他研究本身并不涉及疼痛性 OA，而是侧重于磁共振成像骨髓病变（BML）及其与血脂的关系（11、12）。虽然这些数据可作为了解血浆脂质在 OA 发病过程中可能扮演的角色的起点，但直接评估血清脂质和脂蛋白浓度与骨关节炎发病率，尤其是膝关节疾病发病率之间关系的文献还很少，而膝关节是致残性 OA 最严重的部位。
Using longitudinal data from the MOST cohort, the goal of this study was to comprehensively and longitudinally determine whether circulating total cholesterol, LDL, and HDL were associated with the risk of radiographic and symptomatic knee OA in the MOST cohort.
本研究的目的是利用社会变革管理计划队列的纵向数据，全面、纵向地确定循环总胆固醇、低密度脂蛋白和高密度脂蛋白是否与社会变革管理计划队列中膝关节放射学和症状性 OA 的风险相关。
Subjects and Methods 研究对象和方法
Study sample 研究样本
MOST is a large NIH-funded longitudinal observational study focused on symptomatic and radiographic knee OA in a cohort of community dwelling older adults with or at high risk for knee OA (13). The study enrolled 3026 participants age 50–79 years from 2003–2006 at two clinical sites (Iowa City, Iowa and Birmingham, Alabama). Participants’ demographic, medical, and lifestyle information as well as imaging were collected at baseline. Participants were followed with repeated examinations at 30, 60 and 84 months.
MOST是一项由美国国立卫生研究院（NIH）资助的大型纵向观察研究，主要针对患有膝关节OA或膝关节OA高危人群的症状和影像学膝关节OA（13）。该研究于 2003-2006 年期间在两个临床基地（爱荷华州爱荷华城和阿拉巴马州伯明翰）招募了 3026 名年龄在 50-79 岁之间的参与者。基线研究收集了参与者的人口统计学、医疗和生活方式信息以及影像学资料。参与者在 30、60 和 84 个月时接受重复检查。
Weight-bearing, semi-flexed posteroanterior (PA) and lateral views of the knees were obtained at baseline and at each exam according to the MOST radiograph protocol (14). Two readers interpreted and graded all radiographs according to Kellgren-Lawrence (KL) grade and if they disagreed, readings were adjudicated by a panel of three readers (15). MRIs of the knee were acquired at each visit using a 1.0 T magnet (OrthOne, ONI Inc., Wilmington, MA, USA) and a circumferential extremity coil. All images were acquired without contrast. As in previous work (16) we read one randomly selected knee MRI per person. This was done for budgetary reasons and because of the high rate of symmetry in knee MRIs. The MRIs were read by two experienced musculoskeletal radiologists using the Whole Organ MRI Score (WORMS) (17). Synovitis and cartilage morphology were scored in MRIs at baseline, 30, and 60 months. There was good interobserver agreement for each of the features reported (18). At each examination, participants completed the WOMAC questionnaire, reporting on the amount of pain experienced during activities in each knee.
在基线和每次检查时，根据 MOST X 光片检查方案（14）对膝关节进行负重、半屈曲后正位（PA）和侧位切面检查。两名读片员根据凯尔格伦-劳伦斯（Kellgren-Lawrence，KL）等级对所有X光片进行判读和分级，如果两人意见不一致，则由三名读片员组成的小组裁定读片结果（15）。每次就诊均使用 1.0 T 磁体（OrthOne，ONI 公司，美国马萨诸塞州威尔明顿市）和肢体环形线圈采集膝关节核磁共振成像。所有图像均在无对比度的情况下获得。与之前的研究（16）一样，我们为每人随机选取了一张膝关节 MRI 图像。这样做一方面是出于预算考虑，另一方面是因为膝关节核磁共振成像的对称率很高。核磁共振成像由两名经验丰富的肌肉骨骼放射科医生使用全器官核磁共振成像评分法（Whole Organ MRI Score，WORMS）（17）进行判读。在基线、30 个月和 60 个月的 MRI 中对滑膜炎和软骨形态进行评分。观察者之间对报告的每项特征都有很好的一致性（18）。每次检查时，参与者都要填写 WOMAC 问卷，报告每个膝关节在活动时的疼痛程度。
Anthropometric measurements—BMI
人体测量--体重指数
Weight was measured to the nearest 0.1 kg on a standard medical balance beam scale, and height was measured on full inspiration to the nearest 1 mm with a wall-mounted Harpenden stadiometer by certified MOST personnel following a written protocol. BMI was calculated as weight in kilograms divided by the height in meters squared.
体重用标准的医用平衡木秤测量到 0.1 千克，身高用壁挂式哈彭登测高计测量到 1 毫米，由获得认证的社会变革管理计划人员按照书面协议进行。体重指数的计算方法是体重（公斤）除以身高（米）的平方。
Assessment of OA structure and pain symptoms
评估 OA 结构和疼痛症状
We defined two primary knee outcomes: incident radiographic OA and incident symptomatic OA both up to 7 years after baseline and created two separate nested case control studies. In the first of these, outcome was incident radiographic knee OA among the subset of participants who had no radiographic OA in either knee (both knees with Kellgren and Lawrence grade <2) at baseline. Those participants who developed either radiographic knee OA (KL≥2) or had a knee arthroplasty in either knee by follow-up were defined as having incident radiographic knee OA. In the second case control study, we focused on symptomatic OA. It was defined in a person when they had the combination of frequent knee pain (saying yes to the question, Do you have pain, aching or stiffness in either knee on most days?) and had concurrent radiographic OA in that knee. Persons with symptomatic OA at baseline in either knee were excluded from both case control studies, and for each of these studies, we followed participants for 7 years to identify incident cases. For each of these case groups, we used risk set sampling to select controls randomly from eligible participants at baseline who did not become cases during follow-up. One risk set took 30-month follow-up and randomly selected controls who were not cases then, a second set of cases at 60 months and a third set of cases at 84 months. For incident x-ray OA, we selected 1 control per case. To increase the likelihood that we would detect an association for the clinically important outcome of symptomatic OA, we selected 2 controls per case.
我们定义了两个主要的膝关节结果：放射学 OA 事件和症状性 OA 事件，均在基线后 7 年内发生，并创建了两个独立的嵌套病例对照研究。在第一项研究中，结果是在基线时未出现任何膝关节放射学 OA（两个膝关节的 Kellgren 和 Lawrence 分级均小于 2 级）的参与者中出现膝关节放射学 OA。那些在随访中出现膝关节放射学 OA（KL≥2）或在任一膝关节中进行了膝关节置换术的参与者被定义为出现了膝关节放射学 OA。在第二项病例对照研究中，我们重点关注有症状的 OA。当一个人经常出现膝关节疼痛（对问题 "您的任一膝关节在大多数日子里是否有疼痛、酸痛或僵硬感？"回答 "是"），且该膝关节同时出现放射学上的 OA 时，即被定义为有症状的 OA。在这两项病例对照研究中，我们都排除了基线时任一膝关节有症状的 OA 患者，并对每项研究的参与者进行了长达 7 年的跟踪调查，以确定偶发病例。对于每个病例组，我们都采用风险组抽样法，从基线符合条件但在随访期间未成为病例的参与者中随机抽取对照组。其中一个风险组的随访时间为 30 个月，随机抽取当时不是病例的对照组，第二组病例的随访时间为 60 个月，第三组病例的随访时间为 84 个月。对于X光检查发现的OA病例，我们为每个病例选择了一名对照组。为了提高我们检测到无症状 OA 这一重要临床结果的相关性的可能性，我们为每个病例选择了 2 个对照组。
To further investigate potential associations of lipid and lipoprotein levels with outcomes, we assessed several secondary outcomes, including cartilage loss and change in synovitis based on MRI readings (17). These analyses were performed in the combined sample of all cases and controls. Within each of 14 subregions in each knee, cartilage morphology was scored 0–6 using the WORMS scale (17). We defined worsening cartilage morphology by analyzing each sub-region and characterizing each as worsening when the score increased by 1 point. Sub-regions with baseline scores of 6 were excluded. Second, we examined change in synovitis. Each region (infrapatellar, intercondylar and suprapatellar) was scored 0–3 based on volume at each timepoint, and the scores were then summed (0–9). We defined worsening synovitis as an increase in the summed score of one or more, excluding knees with synovitis scores of 9 at baseline (20). We assessed one knee pain outcome (change in WOMAC pain) and calculated changes in pain as the difference of WOMAC pain score from baseline to the end of follow-up in each knee.
为了进一步研究血脂和脂蛋白水平与结果的潜在关联，我们评估了几种次要结果，包括软骨损失和基于核磁共振成像读数的滑膜炎变化（17）。这些分析是在所有病例和对照组的合并样本中进行的。在每个膝关节的 14 个亚区域中，软骨形态采用 WORMS 量表（17）进行 0-6 级评分。我们通过分析每个亚区域来定义软骨形态的恶化，当每个亚区域的评分增加 1 分时，我们就将其定性为恶化。基线分值为 6 分的亚区域被排除在外。其次，我们检查了滑膜炎的变化。每个区域（髌下、髁间和髌上）根据每个时间点的体积分为 0-3 分，然后将分数相加（0-9）。我们将滑膜炎恶化定义为总分增加 1 分或 1 分以上，但不包括基线滑膜炎评分为 9 分的膝关节( 20)。我们评估了一项膝关节疼痛结果（WOMAC 疼痛的变化），并将疼痛的变化计算为每个膝关节从基线到随访结束时 WOMAC 疼痛评分的差异。
Lipid and Lipoprotein Profile
血脂和脂蛋白概况
Blood draws were performed at the time of the baseline visit following an overnight fast. Blood samples were allowed to clot at room temperature for 30 minutes, and serum was separated by centrifugation at 1,500 g at 4 °C for 20 minutes. Aliquots were stored at −80° C in the MOST repository. For the determination of lipid profiles, matched case-control samples (N=994) were shipped overnight on dry ice to the Cardiovascular Nutrition Laboratory at the Jean Mayer USDA Human Nutrition Research Center of Aging at Tufts University. Serum total cholesterol and HDL concentrations were measured on an AU400e automated analyzer (Beckman Coulter, Brea, CA; intra-assay CV< 3%; inter-assay CV <4%) using enzymatic reagents (Beckman-Coulter). LDL concentration was calculated using the Friedewald equation (19) except when triglycerides were above 400mg/dl. For those samples, a direct LDL method was used (AU400e automated analyzer, Beckman Coulter, Brea, CA; intra-assay CV< 2.4%; inter-assay CV <3.6%).
基线访问时，在一夜禁食后进行抽血。血液样本在室温下凝结 30 分钟，然后在 4 °C 下以 1,500 g 离心 20 分钟，分离血清。等分样品在零下 80 摄氏度保存在 MOST 储存库中。为了测定血脂谱，匹配的病例对照样本（N=994）被连夜用干冰运送到塔夫茨大学让-梅耶美国农业部人类老龄化营养研究中心的心血管营养实验室。使用酶试剂（Beckman-Coulter）在 AU400e 自动分析仪（Beckman Coulter, Brea, CA；测定内 CV< 3%；测定间 CV< 4%）上测量血清总胆固醇和高密度脂蛋白浓度。低密度脂蛋白浓度采用弗里德瓦尔德方程（19）计算，除非甘油三酯超过 400 毫克/分升。对于这些样本，采用直接低密度脂蛋白法（AU400e 自动分析仪，Beckman Coulter, Brea, CA；测定内 CV< 2.4%；测定间 CV <3.6%）。
Potential Confounders 潜在的混杂因素
As indicated for each analysis, the data were adjusted for participants’ demographic, lifestyle, and medical history reported on the baseline questionnaire, age, sex (men, women), education (college or above, yes vs. no), physical activity (Physical Activity Scale for the Elderly [PASE], continuous), smoking (never, past, current), BMI (kg/m2, continuous) and statin use (yes/no). We used an indicator variable to adjust for race (white vs. non-white) and clinic site. For all pain outcomes, we included depressive symptom score (Center for Epidemiologic Studies Depression [CES-D], scale score ≥16, yes vs. no as a covariate). For knee pain analyses, we adjusted for baseline WOMAC pain score (continuous).
如每项分析所示，数据已根据基线问卷中报告的参与者人口统计学、生活方式和病史、年龄、性别（男性、女性）、教育程度（大专或以上，是与否）、体力活动（老年人体力活动量表 [PASE]，连续性）、吸烟（从未、过去、现在）、体重指数（kg/m 2 ，连续性）和他汀类药物使用情况（是/否）进行了调整。我们使用指标变量来调整种族（白人与非白人）和就诊地点。对于所有疼痛结果，我们都将抑郁症状评分（流行病学研究中心抑郁症[CES-D]，评分≥16，是/否作为协变量）纳入其中。对于膝关节疼痛分析，我们对基线 WOMAC 疼痛评分（连续性）进行了调整。
Statistical Analyses 统计分析
Our analytic sample consisted of MOST participants who were either selected as cases or controls in one of our case control studies (incident x-ray OA or incident symptomatic OA) and who had an archived baseline fasting serum sample. They had to be followed until at least the second MOST exam at 30 months.
我们的分析样本包括在我们的病例对照研究中被选为病例或对照的MOST参与者（发生X光OA或发生症状性OA），他们都有存档的基线空腹血清样本。他们必须接受随访，直到至少在30个月后接受第二次MOST检查。
Our analyses looked at the range of lipids on OA outcomes, testing each on a continuous basis and examining risk per s.d. increase. To avoid not missing potential associations between total cholesterol, LDL or HDL on OA outcomes, we tested commonly used thresholds for high total cholesterol (≥200 mg/dL), high LDL (≥130 mg/dL), and low HDL (≤60 mg/dL).
我们的分析着眼于血脂对 OA 结果的影响范围，对每种血脂进行连续测试，并检查每 s.d. 增加的风险。为避免遗漏总胆固醇、低密度脂蛋白或高密度脂蛋白与 OA 结果之间的潜在关联，我们测试了常用的高总胆固醇（≥200 mg/dL）、高低密度脂蛋白（≥130 mg/dL）和低高密度脂蛋白（≤60 mg/dL）阈值。
Analyses of radiographic OA and incident symptomatic OA were at the level of the person. For each case control study, we used logistic regression to analyze the association of the lipid or lipoprotein level at baseline with the OA outcome. The dependent variable for each of these analyses was cumulative incidence of the OA outome over 7 years. For analyses of MRI findings and of WOMAC pain, we combined data from all cases and controls from the primary case control studies, creating one large sample. Analyses of MRI findings and of WOMAC pain were at the level of the knee, or knee subregion for cartilage loss; to adjust for the correlation between knees (or subregions of knees), we performed generalized estimating equations.
对放射学 OA 和偶发症状性 OA 的分析以个人为单位。在每项病例对照研究中，我们使用逻辑回归分析基线血脂或脂蛋白水平与 OA 结果之间的关系。每项分析的因变量都是 7 年内 OA 外显子的累积发病率。在对 MRI 结果和 WOMAC 疼痛进行分析时，我们将来自主要病例对照研究的所有病例和对照组的数据合并在一起，形成一个大样本。核磁共振成像结果和WOMAC疼痛的分析是在膝关节或膝关节软骨损失亚区的水平上进行的；为了调整膝关节（或膝关节亚区）之间的相关性，我们使用了广义估计方程。
We carried out several sensitivity analyses. First, because of concerns that baseline levels of lipids and lipoproteins might not accurately reflect levels up to 7 years later, we carried out analyses limiting incidence to 5 years. Second, some incident OA is caused by injury which would tend to cause unilateral disease. We wanted to focus on those with systemic factors affecting disease, so in another sensitivity analysis, we defined cases as those who during follow-up developed incidence in both knees, either contemporaneously (e.g both at 30 months) or sequentially (e.g. one knee at 30 months, the other at 60 months). In addition, we examined quartiles of cholesterol, HDL and LDL to see if high (or low) levels affected risk of disease. Lastly, we added visceral adiposity (21) as a covariate in our analysis to see if the relationships of lipids with OA outcomes were altered. Analyses were carried out using SAS version 9.4.
我们进行了几项敏感性分析。首先，由于担心血脂和脂蛋白的基线水平可能无法准确反映7年后的水平，我们进行了将发病时间限制在5年的分析。其次，有些OA事件是由损伤引起的，而损伤往往会导致单侧疾病。我们希望关注那些受全身因素影响的病例，因此在另一项敏感性分析中，我们将病例定义为在随访期间双膝同时（如双膝均在30个月时）或先后（如一个膝关节在30个月时，另一个膝关节在60个月时）发病的病例。此外，我们还检查了胆固醇、高密度脂蛋白和低密度脂蛋白的四分位数，以了解高（或低）水平是否会影响患病风险。最后，我们在分析中加入了内脏脂肪率（21）作为协变量，以观察血脂与 OA 结果之间的关系是否会发生改变。分析使用 SAS 9.4 版进行。
Institutional review board approvals were obtained from University of California, San Francisco, Boston University, University of Alabama at Birmingham and The University of Iowa. All participants provided written consent for study participation.
加州大学旧金山分校、波士顿大学、阿拉巴马大学伯明翰分校和爱荷华大学获得了机构审查委员会的批准。所有参与者都提供了参与研究的书面同意书。
Results 成果
Mean age at baseline was 62 years and 55% were women, more than 20% took statins (see Table 1 for description of study participants) with 614 participants in the case control study of radiographic OA and 898 in the study of symptomatic OA. There were no associations of incident radiographic OA and incident symptomatic OA with total cholesterol, LDL, and HDL cholesterol levels (see Table 2). We also found no association of total cholesterol, LDL and HDL with cartilage loss, worsening synovitis or worsening knee pain (see Table 3). Lastly, we examined whether persons with high cholesterol, LDL or low HDL had an increased risk of OA, and found no suggestive associations (see Figure 1).
基线时的平均年龄为 62 岁，55% 为女性，20% 以上的人服用他汀类药物（研究参与者的描述见表 1），其中 614 人参加了放射性 OA 病例对照研究，898 人参加了症状性 OA 研究。放射性 OA 和无症状 OA 的发病与总胆固醇、低密度脂蛋白和高密度脂蛋白胆固醇水平没有关联（见表 2）。我们也没有发现总胆固醇、低密度脂蛋白和高密度脂蛋白与软骨损失、滑膜炎恶化或膝关节疼痛恶化有关（见表 3）。最后，我们研究了高胆固醇、低密度脂蛋白或低高密度脂蛋白人群是否会增加罹患 OA 的风险，结果没有发现任何提示性关联（见图 1）。
Association of High Levels of Cholesterol and LDL and Low Levels of HDL with Incident OA Outcomes
高胆固醇和低密度脂蛋白水平以及低高密度脂蛋白水平与 OA 发病结果的关系
Table 1: 表 1：
Description of Study Participants according to Case Control study
根据病例对照研究对研究参与者的描述
| Incident Radiographic OA 放射 OA 事故 | Incident Symptomatic OA 出现症状的 OA | |||
|---|---|---|---|---|
| Cases (n=285) 病例（n=285） | Controls (n=329) 对照组（n=329） | Cases (n=338) 病例（人数=338） | Controls (n=560) 对照组（n=560） | |
|
Mean Age (years, s.d.) 平均年龄（岁，s.d.） | 60.8 (8.0) | 59.9 (7.5) | 62.4 (8.1) | 61.1 (7.8) |
| Female | 62% | 59% | 63% | 57% |
| Mean BMI (s.d.) 平均体重指数（s.d.） | 30.5 (5.3) | 28.7 (4.5) | 30.9 (5.6) | 29.3 (4.8) |
| Some college education 受过一些大学教育 | 79% | 77% | 74% | 78% |
| Mean Cholesterol (s.d.) 平均胆固醇（s.d.） | 229 (4.8) | 230 (51.2) | 225 (47.1) | 229 (48.9) |
| Mean LDL (s.d.) 平均低密度脂蛋白（s.d.） | 136 (38.6) | 138 (42.9) | 133 (38.2) | 138 (4.03) |
| Mean HDL (s.d.) 平均高密度脂蛋白（s.d.） | 62 (16.8) | 62 (16.7) | 62 (17.1) | 62 (16.5) |
| Statin Use | 22% | 23% | 27% | 24% |
Table 2: 表 2：
Association of Cholesterol, LDL and HDL with Incident Knee OA : Results of Logistic Regression Analyses*
胆固醇、低密度脂蛋白和高密度脂蛋白与膝关节 OA 发生率的关系：逻辑回归分析结果 *
| Mean (mg/dl) | Adj OR with 95% CI (per SD) Adj OR，95% CI（单位标差） | P value | ||
|---|---|---|---|---|
| Cases | Controls | |||
|
Incident Knee Radiographic OA(cases/controls=283/329) 发生膝关节放射学 OA（病例/对照=283/329） | ||||
| Total Chol | 229 | 229 | 1.00 (0.88,1.14) | 0.97 |
| LDL | 136 | 138 | 0.98 (0.87, 1.12) | 0.80 |
| HDL | 62 | 61 | 1.11 (0.96, 1.29) | 0.16 |
|
Incident Symptomatic Knee OA(cases/controls=336/559) 症状性膝关节 OA 发生率（病例/对照=336/559） | ||||
| Total Chol | 224 | 229 | 0.91 (0.80, 1.03) | 0.12 |
| LDL | 132 | 137 | 0.89 (0.79, 1.01) | 0.06 |
| HDL | 62 | 61 | 1.09 (0.95, 1.24) | 0.24 |
0# Logistic 回归调整了协变量：年龄、性别、体重指数、教育程度、种族、就诊地点和 WOMAC 疼痛结果，还调整了基线 WOMAC 疼痛评分和抑郁症状（是/否）。
Table 3: 表 3：
Associations of Cholesterol, HDL and LDL Levels with Change in Worseninig Synovitis or Pain and with Cartilage Loss*
胆固醇、高密度脂蛋白和低密度脂蛋白水平与滑膜炎恶化或疼痛的变化以及软骨损失的关系 *
| Worsening Synovitis 滑膜炎恶化 (218/711) | WOMAC Worsening WOMAC恶化 (300/1654) | Cartilage Loss 软骨损失 (4268/10297) | ||||
|---|---|---|---|---|---|---|
| adjOR (95% CI) 副OR (95% CI) | P value | adjOR (95% CI) 副OR (95% CI) | P value | adjOR (95% CI) 副OR (95% CI) | P value | |
| Total Chol | 1.03 (0.70–1.52) 1.03 (0.70-1.52) | 0.87 | 1.02 (0.88–1.20) 1.02 (0.88-1.20) | 0.78 | 1.02 (0.96–1.10) 1.02 (0.96-1.10) | 0.47 |
| HDL | 0.98 (0.81–1.18) 0.98 (0.81-1.18) | 0.81 | 0.97 (0.83–1.14) 0.97 (0.83-1.14) | 0.73 | 1.09 (1.02–1.17) 1.09 (1.02-1.17) | 0.02 |
| LDL | 0.97 (0.80–1.18) 0.97 (0.80-1.18) | 0.77 | 1.03 (0.88–1.21) 1.03 (0.88-1.21) | 0.69 | 1.02 (0.95–1.09) 1.02 (0.95-1.09) | 0.64 |
0# Logistic 回归调整了协变量：年龄、性别、体重指数、教育程度、种族、就诊地点和 WOMAC 疼痛结果，还调整了基线 WOMAC 疼痛评分和抑郁症状（是/否）。
In sensitivity analyses, we found no associations of cholesterol, LDL or HDL with incident OA if we limited incidence to the first 5 years after baseline and also found no association with lipids or lipoproteins when we restricted cases to those who developed bilateral disease. In analyses examining quartiles of cholesterol, HDL and LDL, we similarly found no associations with incident radiographic or symptomatic OA. Lastly adjusting for visceral adiposity in our main analyses shown in table 2 did not affect results of these analyses (data not shown).
在敏感性分析中，我们发现胆固醇、低密度脂蛋白或高密度脂蛋白与基线后最初 5 年的发病率没有关系，而当我们将病例限制在双侧发病者时，也发现胆固醇、低密度脂蛋白或高密度脂蛋白与血脂或脂蛋白没有关系。在对胆固醇、高密度脂蛋白和低密度脂蛋白的四分位数进行分析时，我们同样没有发现它们与放射学或症状性 OA 的发生有关。最后，在表 2 所示的主要分析中对内脏脂肪含量进行调整并未影响这些分析的结果（数据未显示）。
Discussion 讨论
In this longitudinal nested case control study, we examined the relationship between lipid and lipoprotein levels and OA within the Multicenter Osteoarthritis study (MOST) cohort. Although there is a growing body of experimental and epidemiologic evidence that suggest an association between elevated serum total cholesterol and LDL, and low HDL, with the development of OA, our data did not support such an association. We also did not find an association between serum lipid and lipoprotein levels with either cartilage loss, worsening synovitis or worsening knee pain.
在这项纵向巢式病例对照研究中，我们研究了多中心骨关节炎研究（MOST）队列中血脂和脂蛋白水平与 OA 之间的关系。尽管越来越多的实验和流行病学证据表明，血清总胆固醇和低密度脂蛋白升高以及高密度脂蛋白降低与 OA 的发生有关，但我们的数据并不支持这种关联。我们也没有发现血清脂质和脂蛋白水平与软骨损失、滑膜炎恶化或膝关节疼痛恶化之间存在关联。
Advances in the understanding of the pathogenesis of OA indicate that it involves not only “wear and tear” related to age and mechanical loading, but also synovial inflammation. This knowledge has led to a growing body of research evaluating the mechanisms by which metabolic factors that affect inflammation may contribute to OA. Several experimental studies evaluating the relationship of dyslipidemia and OA suggest that alterations in lipids play a role in the development of OA. De Munter et al showed that in mice with increased levels of LDL via cholesterol-rich diet or ApoE deficiency, there was increased synovial thickening and ectopic bone formation (6, 7). Additionally, Triantaphyllidou et al (23) showed that mice with low HDL levels and high LDL levels (based on a lecithin cholesterol acyltransferase (LCAT) knockout and apoA-I knockout) who were placed on a Western diet developed OA in their joints, whereas control mice did not. In these mice, the Western diet activated enzymes that break down cartilage (5). Busso et al showed that total cholesterol, LDL and HDL levels were all similar in plasma and synovial fluid, suggesting easy transit between compartments (22).
对 OA 发病机理的研究进展表明，OA 不仅涉及与年龄和机械负荷有关的 "磨损"，还涉及滑膜炎症。这些知识促使越来越多的研究对影响炎症的代谢因素可能导致 OA 的机制进行评估。一些评估血脂异常与 OA 关系的实验研究表明，血脂的改变在 OA 的发生中起着一定的作用。De Munter 等人的研究表明，通过富含胆固醇的饮食或载脂蛋白E缺乏症增加低密度脂蛋白水平的小鼠，滑膜增厚和异位骨形成增加（6，7）。此外，Triantaphyllidou 等人（23）的研究表明，高密度脂蛋白水平低、低密度脂蛋白水平高（基于卵磷脂胆固醇酰基转移酶（LCAT）基因敲除和载脂蛋白 A-I 基因敲除）的小鼠在摄入西式饮食后，其关节会出现 OA，而对照组小鼠则不会。在这些小鼠体内，西式饮食激活了分解软骨的酶（5）。Busso 等人的研究表明，血浆和滑膜液中的总胆固醇、低密度脂蛋白和高密度脂蛋白水平都很接近，这表明它们之间的转运非常容易（22）。
Another factor that has been implicated in leading to OA is oxidative stress and reactive oxygen species within the joint, particularly oxidized LDL. The complex mechanisms by which oxidative stress contribute to the pathogenesis of OA was recently reviewed by Lepetsos et al, and include overproduction of reactive oxygen species within chondrocytes leading to increased chondrocyte apoptosis and synovial inflammation, cartilage degradation, and subchondral bone dysfunction (24–27). Oxidized LDL, a lipid peroxidation product produced mainly by reactive oxygen species, has been shown to play a role in the pathogenesis of OA. Shen et al found increased levels of oxidized LDL in the synovial fluid as well as increased lectin-type oxLDL receptor (LOX-1) expression in the cartilage of OA patients in comparison to controls (28). Erturk et al investigated the relationship of Paraoxonase-1 (PON-1), an enzyme that protects LDL and HDL from oxidative damage, with oxLDL and oxidative stress in OA (29). They found increased levels of oxLDL, higher markers of oxidative stress, and significantly lower levels of PON-1 in the sera of participants with OA in comparison to controls. There was also a correlation between serum ox-LDL and knee OA grade utilizing the Kellgren-Lawrence scoring system and pain via WOMAC score.
导致 OA 的另一个因素是关节内的氧化应激和活性氧，尤其是氧化低密度脂蛋白。Lepetsos 等人最近对氧化应激导致 OA 发病的复杂机制进行了综述，其中包括软骨细胞内活性氧的过度产生导致软骨细胞凋亡增加和滑膜炎症、软骨降解以及软骨下骨功能障碍 ( 24- 27)。氧化低密度脂蛋白是一种主要由活性氧产生的脂质过氧化产物，已被证明在 OA 的发病机制中发挥作用。Shen等人发现，与对照组相比，OA患者滑液中氧化低密度脂蛋白水平升高，软骨中凝集素型氧化低密度脂蛋白受体（LOX-1）表达增加（28）。Erturk 等人研究了 Paraoxonase-1（PON-1）（一种保护低密度脂蛋白和高密度脂蛋白免受氧化损伤的酶）与氧化LDL 和 OA 中氧化应激的关系（29）。他们发现，与对照组相比，OA 患者血清中的 oxLDL 水平升高，氧化应激标记物升高，而 PON-1 水平明显降低。血清中的 ox-LDL 与使用 Kellgren-Lawrence 评分系统进行的膝关节 OA 分级以及通过 WOMAC 评分进行的疼痛之间也存在相关性。
The results of these experimental studies suggest that elevated levels of lipids and/or lipoproteins are major contributors to the pathogenesis of OA. Despite this strong experimental evidence, this study showed a null association with incident symptomatic and radiographic knee OA and elevated serum LDL levels.
这些实验研究结果表明，血脂和/或脂蛋白水平升高是导致 OA 发病的主要因素。尽管有这些有力的实验证据，但本研究显示，有症状和影像学表现的膝关节 OA 与血清低密度脂蛋白水平升高之间的关系为负相关。
Although there have been cross sectional studies reporting possible associations between lipid levels and OA as recently evaluated in the systematic review and meta-analysis by Baudart et al (10), caution must be used when drawing conclusions regarding causation based on the results of cross sectional studies. To date, only three longitudinal studies have specifically assessed the relationship between certain features of OA (cartilage loss) and lipid and lipoprotein profiles. The results have been mixed.
虽然有一些横断面研究报告了血脂水平与 OA 之间可能存在的联系，最近 Baudart 等人的系统回顾和荟萃分析（10）也对此进行了评估，但根据横断面研究的结果得出因果关系的结论时必须谨慎。迄今为止，只有三项纵向研究专门评估了 OA 的某些特征（软骨损失）与脂质和脂蛋白概况之间的关系。研究结果喜忧参半。
Garcia-Gil et al evaluated whether serum lipid levels were associated with incident radiographic hand OA in 277 participants without OA at baseline. Hand radiographs were repeated 11 years after baseline. No statistically significant associations between serum lipids and radiographic hand OA were observed, but a trend toward high HDL levels being associated with a lower risk of hand OA was reported. Despite the longitudinal nature of this study and the analysis of serum lipids as both continuous and categorical set of variables, a significant limitation of this study was that it was underpowered. Additionally, the patient population included only women who were younger (mean age 50) with lower levels of obesity than the average population.
Garcia-Gil 等人评估了 277 名基线时没有手部 OA 的参与者的血清脂质水平是否与手部放射性 OA 事件有关。在基线年后的11年重复进行了手部X光检查。没有观察到血清脂质与手部放射学 OA 之间有统计学意义的关联，但报告了高密度脂蛋白水平与较低的手部 OA 风险相关的趋势。尽管这项研究具有纵向性质，并将血清脂质作为连续和分类变量进行了分析，但这项研究的一个重要局限是研究力量不足。此外，研究对象仅包括较年轻（平均年龄 50 岁）且肥胖程度低于普通人群的女性。
Davies-Tuck et al evaluated 148 female participants without a history of OA for the development of bone marrow lesions (BML) of the knee; they obtained baseline lipids and followed up with knee MRI two years later (11). Results showed an association between BML incidence and higher total cholesterol levels, but no association with LDL or HDL. They did not find an association between presence of BMLs at baseline with any lipid parameter, nor with change in cartilage volume over two years. This study’s results were at odds with a longitudinal study published three years later by Dore, et al, who evaluated the development of BMLs of the knee in 394 male and female participants (12). Baseline lipids and knee MRI were evaluated at baseline, and BMLs were assessed by MRI 2.7 years later. They found no significant cross-sectional or longitudinal association between total cholesterol and BMLs but did report an inverse association of BML change and HDL.
Davies-Tuck 等人对 148 名没有 OA 病史的女性参与者进行了膝关节骨髓病变（BML）发展情况的评估；他们获得了基线血脂，并在两年后进行了膝关节核磁共振成像随访（11）。结果显示，骨髓病变发生率与总胆固醇水平升高有关，但与低密度脂蛋白或高密度脂蛋白无关。他们没有发现基线 BML 的存在与任何血脂参数或两年内软骨体积的变化之间存在关联。这项研究的结果与 Dore 等人三年后发表的一项纵向研究结果不一致，后者评估了 394 名男性和女性参与者膝关节 BMLs 的发展情况 ( 12)。他们在基线时对血脂和膝关节核磁共振成像进行了评估，并在 2.7 年后通过核磁共振成像对 BML 进行了评估。他们发现总胆固醇和 BML 之间没有明显的横向或纵向联系，但 BML 的变化与高密度脂蛋白呈反向关系。
In this study, we did not find any significant associations between incident symptomatic knee OA and lipid levels. It is unlikely that this null association was attributable to sample size, as our confidence bounds were narrow. For example, increasing levels of LDL were associated with a modest reduction in risk of OA, but the upper border of that confidence bound stretched only to 1.12, consistent with a 12% increase in the odds of disease. If an association does exist, there may be other factors which have not yet been identified contributing to the correlation between lipids and OA. Among these other factors may be metabolic syndrome and a component of it, visceral adioposity. A recent review has strongly suggested that metabolic syndrome is not associated with knee OA, especially after adjustment for BMI (30). We carried out additional analyses testing visceral adiposity as a confounder and it did not affect the associations we report, suggesting it does not account for a spurious null associations. Despite the strong evidence that lipids enter the joint freely and intraarticular oxLDL leads to joint damage, perhaps another mechanism exists within the joint which disturbs this relationship, making measured serum lipids unrelated to intraarticular oxLDL. Lastly, although our data showed a small protective association of elevated total cholesterol and elevated LDL on symptomatic OA, this was not statistically significant and was likely due to chance.
在这项研究中，我们没有发现有症状的膝关节 OA 发病与血脂水平之间有任何明显的关联。由于我们的置信区间较窄，这种无效关联不太可能是样本量造成的。例如，低密度脂蛋白水平的升高与 OA 风险的适度降低有关，但置信区间的上限仅为 1.12，与患病几率增加 12% 的情况一致。如果两者之间确实存在关联，那么可能还有其他尚未发现的因素导致了血脂与 OA 之间的关联。这些其他因素可能包括代谢综合征及其组成部分--内脏肥胖。最近的一篇综述强烈建议代谢综合征与膝关节 OA 无关，尤其是在调整体重指数后（30）。我们进行了额外的分析，将内脏脂肪含量作为混杂因素进行测试，结果并未影响我们报告的关联性，这表明内脏脂肪含量不会导致虚假的无效关联。尽管有确凿证据表明脂质可自由进入关节，而关节内的氧化低密度脂蛋白会导致关节损伤，但也许关节内存在另一种机制干扰了这种关系，从而使测量的血清脂质与关节内的氧化低密度脂蛋白无关。最后，虽然我们的数据显示总胆固醇升高和低密度脂蛋白升高对有症状的 OA 有轻微的保护作用，但这在统计学上并不显著，很可能是偶然因素造成的。
This study has several strengths. This is one of the few studies evaluating the temporal relationship between serum lipid levels and incident knee OA using a longitudinal design. We evaluated participants using indices which account for both symptoms (pain) and radiographic changes, whereas previous longitudinal studies have assessed only radiographic changes; therefore we are able to identify participants which meet ACR criteria for knee OA, which includes the presence of pain. The nested case control design of this study reduces selection bias, since cases and controls are selected from the same population. Finally, we tested cholesterol as both a continuous measure and did sensitivity analyses examining whether commonly used lipid thresholds for increased risk, thereby evaluating the data from several angles to ensure robustness.
这项研究有几个优点。这是少数采用纵向设计评估血清脂质水平与膝关节OA发病之间时间关系的研究之一。我们使用同时考虑症状（疼痛）和影像学变化的指数对参与者进行评估，而以往的纵向研究只评估影像学变化；因此，我们能够确定符合 ACR 膝关节 OA 标准的参与者，其中包括疼痛的存在。由于病例和对照组是从同一人群中挑选出来的，因此本研究的嵌套病例对照设计减少了选择偏差。最后，我们测试了作为连续测量指标的胆固醇，并进行了敏感性分析，研究了常用的血脂阈值是否会增加风险，从而从多个角度对数据进行评估，以确保数据的稳健性。
One limitation of this study is that participants within the MOST cohort are primarily older, Caucasian Americans, and therefore our results may not be generalizable to a more diverse population. Additionally, we focused on incident knee OA, and it is possible that the metabolic factors affecting non-weight bearing joints such as the hand may differ from those affecting large, weight-bearing joints such as the knee. Also, our analyses of secondary outcomes such as cartilage loss may be affected by selection bias in that these outcomes were correlated with case status. While we adjusted in analyses for statin use at baseline, statin use may take decades to influence the occurrence of OA and we did not know the duration of statin use in our participants. Further, we did not examine the effect of other lipid lowering agents which were rarely used by MOST participants. Finally, lipid levels were taken at at single point in time, and therefore we cannot rule out whether additional factors such as lifestyle modifications affected the lipid levels later, modifying OA risk.
这项研究的一个局限性是，美国社会变革管理计划队列中的参与者主要是年龄较大的白种美国人，因此我们的结果可能无法推广到更多样化的人群中。此外，我们关注的重点是膝关节OA，影响手部等非负重关节的代谢因素可能与影响膝关节等负重大关节的代谢因素不同。此外，我们对软骨损失等次要结果的分析可能会受到选择偏差的影响，因为这些结果与病例状态相关。虽然我们在分析中对基线时使用他汀类药物的情况进行了调整，但他汀类药物的使用可能需要数十年的时间才能对 OA 的发生产生影响，而我们并不清楚参与者使用他汀类药物的持续时间。此外，我们没有研究其他降脂药物的影响，因为社会变革管理计划的参与者很少使用其他降脂药物。最后，血脂水平是在单个时间点测定的，因此我们不能排除生活方式的改变等其他因素是否会影响以后的血脂水平，从而改变 OA 风险。
In conclusion, we did not find an association between total cholesterol, LDL, or HDL levels with incident OA or other OA outcomes. While LDL may have local deleterious effects on joint structure, elevated systemic levels probably do not confer risk of disease.
总之，我们没有发现总胆固醇、低密度脂蛋白或高密度脂蛋白水平与发生的 OA 或其他 OA 结果之间存在关联。虽然低密度脂蛋白可能会对关节结构产生局部有害影响，但全身水平的升高可能不会带来患病风险。
Grants and Financial Support:
赠款和资助：
The MOST study was supported by the National Institutes of Health (Felson, U01 AG18820; Lewis, U01 AG18947; Nevitt, U01 AG19069; Torner, U01 AG18832). This analysis was supported by R01 AR071950. This work was also supported by NIH AR P30 072571. Dr. Felson receives support from the National Institute for Health Research (NIHR), as part of the Manchester Musculoskeletal NIHR Biomedical Research Centre Grant.
MOST 研究得到了美国国立卫生研究院（Felson，U01 AG18820；Lewis，U01 AG18947；Nevitt，U01 AG19069；Torner，U01 AG18832）的支持。这项分析得到了 R01 AR071950 的支持。这项工作还得到了美国国立卫生研究院 AR P30 072571 的支持。费尔逊博士获得了美国国家健康研究所（NIHR）的支持，这是曼彻斯特肌肉骨骼 NIHR 生物医学研究中心资助的一部分。
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