Relation of Alignment and Other Risk Factors to Knee OA

描述（由申请人提供）：症状性膝关节骨关节炎影响6%的美国成年人群和12-13%的60岁及以上人群（Felson和Zhang，1998）。药物治疗往往不能完全缓解疼痛和残疾，也没有已知的治疗方法来防止疾病进展。骨关节炎倡议（OAI）是一项针对膝关节OA患者和疾病高风险患者的多中心5年观察性研究，对所有受试者进行重复膝关节MRI，代表了有史以来识别OA风险因素的最佳机会。尽管有丰富的测量方法，但最近发现了一个进展的风险因素，即全肢X线片上的对线不良，OAI没有对其进行全面评估。在基线时经常发生膝关节疼痛和X线OA的受试者中采集了评估对线的全肢片，但在其他受试者中未采集，并且没有对其进行阅读的计划。虽然已发表的数据表明，对线不良是膝关节OA患者结构进展的最有效的风险因素，但没有数据表明肢体对线是否会影响新发症状性膝关节OA或新发结构性疾病的风险。此外，有初步数据表明，肢体的对齐状态会影响其他已知的OA风险因素，如肥胖和肌无力是否会影响进展的风险，或者是否会影响。本项目解决了两个关于对线的关键未研究问题：1）对线是否影响基线时无症状OA的患者的疾病，2）肢体对线不良状态是否决定了其他已知和推定的膝关节OA风险因素对疾病的影响。我们假设，如果肢体对线不良，所有通过关节负荷作用的可改变的风险因素对膝关节OA的轨迹将产生不同的影响。在严重对线不良的肢体中，疾病的进展将是不可避免的，风险因素对恶化的影响很小。在绘制与通过对齐可改变的风险因素（例如肥胖）相关的疾病恶化风险时，我们假设一个倒U形曲线-当肢体中性对齐时肥胖风险低，当肢体严重对齐不良时，当肢体中度对齐不良时肥胖风险高。这一假说对OA预防的机会和OA治疗的发展具有深远的意义。该补助金的目的是：1.评估在基线时患和不患OA的患者中，全肢X线片上肢体的机械轴是否增加软骨丢失和膝关节疼痛恶化的风险; 2.测试是否存在严重对线不良的阈值，超过该阈值，软骨损失和膝关节疼痛的发展或进展是普遍的; 3.为了评估已知和假定的OA风险因素是否在肢体对线不良时与肢体中性对线时对OA的影响不同，a.测试肥胖的影响是否因排列而不同; B.检查肌力对膝关节骨性关节炎的影响是否因对线状态而异。C.评估习惯性体力活动是否对中性对线肢体OA的影响与对线不良肢体OA的影响不同;开发可用于其他研究的对齐代理措施。除了解决这些问题外，本项目还将完成对线片的阅读，并将这些数据纳入OAI数据集中，还将提供OAI受试者MRI上软骨体积损失的关键读数，否则这些数据将不受支持。

DESCRIPTION (provided by applicant): Symptomatic knee osteoarthritis affects 6% of the U.S. adult population and 12-13% of those age 60 and over (Felson and Zhang, 1998). Medical treatment often fails to provide full relief of pain and disability, and there are no known treatments to prevent disease progression. A multicenter 5 year observational study of those with knee OA and those at high risk of disease with repeated knee MRIs on all subjects, the Osteoarthritis Initiative (OAI) represents the best opportunity ever to identify risk factors for OA. Despite its richness of measurements, there is one recently identified risk factor for progression, malalignment on full limb x-rays that is not being comprehensively assessed in OAI. Full limb films to assess alignment are being acquired in those with frequent knee pain and x-ray OA at baseline but not in other subjects and there is no plan for their reading. While published data suggest that malalignment is the most potent yet identified risk factor for structural progression in those with knee OA, there are no data on whether alignment of the limb affects the risk of developing new symptomatic knee OA or new structural disease. Further, there are preliminary data that the limb's alignment status affects whether other known risk factors for OA such as obesity and muscle weakness affect the risk of progression, or whether it affects. There are two critical unstudied issues regarding alignment that are addressed by this project: 1) whether alignment affects disease in those without symptomatic OA at baseline and 2) whether the malalignment status of a limb determines the effect on disease of other known and putative risk factors for knee OA. We hypothesize that all modifiable risk factors that act through joint loading will have different effects on the trajectory of knee OA if the limb is malaligned than if the limb is neutrally aligned. In limbs with severe malalignment, progression of disease will be inevitable, and risk factors will have little effect on worsening. In graphing the risk of disease worsening associated with a modifiable risk factor (e.g. obesity) by alignment, we postulate an inverted U shaped curve -- low risks for obesity when limbs are neutrally aligned and when limbs are severely malaligned, high risks associated with obesity when limbs are moderately malaligned. This hypothesis has profound implications on opportunities for OA prevention and on the development of treatments for OA. The aims of this grant are: 1. To evaluate whether the limb's mechanical axis on full limb films increases the risk of cartilage loss and worsening knee pain in those with and without OA at baseline; 2. To test whether there is a threshold of severe malalignment above which cartilage loss and knee pain development or progression are universal; 3. To evaluate whether known and putative risk factors for OA affect OA differently when limbs are malaligned than when limbs are neutrally aligned, a. To test whether the effect of obesity differs by alignment; b. To examine whether effects of muscle strength on knee OA differ by alignment status. c. To evaluate whether habitual physical activity affects OA differently in limbs with neutral alignment than in those with malalignment; 4. To develop proxy measures for alignment that can be used in other studies. In addition to addressing these questions, this project will complete the reading of alignment films and make these data available in the OAI data set and will provide also critical readings of cartilage volume loss on MRI in OAI subjects, data that would otherwise not be supported.