Relation of Alignment and Other Risk Factors to Knee OA

描述（由申请人提供）：症状性膝骨关节炎影响6%的美国成年人和12-13%的60岁及以上人群（Felson和Zhang， 1998）。医学治疗往往不能完全缓解疼痛和残疾，也没有已知的预防疾病进展的治疗方法。骨关节炎倡议（OAI）是一项为期5年的多中心观察性研究，对膝关节OA患者和高风险患者进行了反复的膝关节mri检查，为识别OA的危险因素提供了最好的机会。尽管测量方法丰富，但最近发现了一个进展的危险因素，即在OAI中未全面评估的全肢x线排列失调。在基线时有频繁膝关节疼痛和x线骨性关节炎的患者中，可获得用于评估关节对齐的全肢片，但在其他受试者中没有，也没有计划对他们进行阅读。虽然已发表的数据表明，不对齐是膝关节OA患者结构进展的最有效的危险因素，但没有数据表明肢体对齐是否会影响发生新的症状性膝OA或新的结构性疾病的风险。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（如肥胖和肌肉无力）是否会影响进展风险，或者是否会影响。关于关节对齐有两个关键的未研究的问题，本项目将解决：1)关节对齐是否会影响基线时无症状性骨关节炎患者的疾病，2)肢体的不对齐状态是否决定了其他已知和假定的膝骨关节炎危险因素对疾病的影响。我们假设通过关节负荷作用的所有可改变的危险因素对膝关节骨性关节炎的发展轨迹有不同的影响，如果肢体错位，与肢体中立对齐。对于严重畸形的肢体，疾病的进展是不可避免的，而危险因素对病情的恶化几乎没有影响。在绘制与可改变的风险因素（如肥胖）相关的疾病恶化风险时，我们假设了一个倒U形曲线——当四肢中等对齐和严重对齐时，肥胖风险较低，当四肢中度对齐时，肥胖风险较高。这一假设对OA预防的机会和OA治疗的发展具有深远的影响。这项资助的目的是：1。评估全肢片上的肢体机械轴是否会增加基线时有或无OA患者软骨丢失和膝关节疼痛加重的风险；2. 为了测试是否存在一个严重错位的阈值，超过这个阈值，软骨丢失和膝关节疼痛的发展或进展是普遍的；3. 为了评估已知的和假定的OA危险因素是否会在肢体不对齐时与肢体中立对齐时对OA产生不同的影响，a.测试肥胖的影响是否因肢体对齐而不同；b.检查肌肉力量对膝关节OA的影响是否因排列状态而异。c.评估习惯性体育活动对中立位肢体与畸形位肢体OA的影响是否不同；4. 开发可用于其他研究的校准代理措施。除了解决这些问题外，该项目还将完成对齐片的阅读，并将这些数据纳入OAI数据集，并提供OAI受试者MRI上软骨体积损失的关键读数，否则这些数据将不被支持。

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.