骨密度丢失与膝关节骨关节炎进展相关

一项观察性队列研究表明，股骨颈骨密度(BMD)纵向丢失与膝关节骨关节炎(OA)再发相关，表明有必要进一步研究骨质疏松症治疗药物对骨关节炎进展的预防作用。

这项由美国波士顿Tufts医学中心风湿病科Ji Y. Lee博士领导开展的研究，以先前BMD丢失与摄片示关节间隙变窄加重相关的研究结果为依据。目前这是首个通过MRI提示的软骨体积和厚度来评估BMD与膝关节OA进展之间相关性的研究，这是反映膝关节软骨改变的更为敏感的指标(Arthritis Rheum. 2013 March 12 [doi:10.1002/art.37926])。

研究者对127例再发性膝关节OA患者进行了分析，所有患者的Kellgren-Lawrence分级均≥2级。患者2年内至少接受了2次MRI扫描，多数接受了3次扫描，时间分别在基线时、第1年和第2年。患者的平均年龄为63岁，男性占41%，平均体重指数(BMI)为30 kg/m2。双侧股骨颈的基线BMD平均为0.95 g/cm2。

校正基线年龄、性别、BMI、关节排列情况、维生素D治疗等因素之后，多因素线性回归模型分析显示，BMD丢失0.1 g/cm2与软骨体积每年丢失1.25%相关。对于BMD明显丢失(研究者定义为较之基线至少丢失了4.7%)的患者，每年软骨体积丢失比没有BMD丢失的患者多1.02%。

模型分析还表明，BMD丢失0.1 g/cm2与胫骨软骨厚度显著丢失相关(每年0.028 mm)。与没有丢失BMD的患者相比，BMD至少丢失了4.7%的患者其胫骨软骨厚度每年平均丢失0.021 mm。不过，基线BMD与所有软骨结局之间都没有明显的相关性。

Lee博士及其同事称，这项研究表明BMD与初发性或再发性经放射学检查确定的膝关节OA相关，但这与过去的其他研究结果不相吻合，其他研究没有发现BMD与OA放射学进展相关。这可能是因为既往研究纳入的是已经患有OA的患者而可能导致选择偏倚。Lee博士及其同事希望通过研究发病后发生了改变的危险因素的效应，即BMD的变化，来避免这种选择偏倚。

Lee博士及其同事写道，膝关节OA患者的全身性BMD与软骨丢失有关的生物学机制之一可能是，“BMD健康的环境可能有助于机体在应对OA应激因素时很好地完成软骨下骨转换和骨重建，从而提高关节的稳定性”，而最佳骨健康状态对于软骨健康的有利影响可能是通过“体液机制”来实现的。“全身性BMD也是各种可能影响或混杂这种相关性的协变量的一个标志物，比如全身性炎症、循环生长因子或激素、体力活动或虚弱。”

这项观察性队列研究所依据的原始研究，即维生素D用于膝关节OA患者的随机对照试验，由美国国立关节肌肉骨骼及皮肤病研究所资助。所有作者均声明无相关利益冲突。

随刊述评：OA与BMD之间的相关性有待进一步研究

英国牛津大学的M. Kassim Javaid博士和Nigel K. Arden博士评论指出，要了解OA与骨质疏松症之间的相关性是有一定难度的，因为判断BMD对OA的影响很难，反之要判断OA对BMD和骨折风险的影响也很难(Arthritis Rheum. 2013 March 12 [doi:10.1002/art.37924])。

他们认为有可能在讨论局部软骨下骨骼体积和BMD特点对OA进展的影响时找到答案。外周定量CT研究表明，OA患者的骨骼体积更大，但其体积BMD(vBMD)并不高。另一项采用CT测定软骨下骨骼vBMD的研究显示，膝关节OA患者的vBMD更高。而这些因素可能与无法通过测定BMD来衡量的骨表型特征相混淆，包括骨髓病灶、代谢活性和骨转换标志物。

就这个问题而言，Lee博士及其同事所开展研究的创新点在于考虑到了股骨颈BMD随时间的变化，这有助于发现BMD对OA进展的真实影响。但值得注意的是，这项研究“并没有明确[面积]BMD的变化是导致软骨丢失的原因还是软骨丢失所产生的影响。不过这种相关性很可能是双向的，骨骼会改变软骨细胞和基质的特性，反之亦然。”

他们还指出，这项研究的局限性包括只有13%的患者达到了BMD明显丢失的标准，而且也不清楚Kellgren-Lawrence分级达到4级的膝关节OA患者是否出现了病情进展。

Javaid博士和Arden博士指出，还需要开展进一步的研究，建议将症状进展而非软骨体积变化作为主要结局。一项重要的随机对照试验似乎提示双膦酸盐类药物治疗对OA没有作用，而一项Ⅲ期试验却从膝关节OA患者的症状和结构性终点等方面证实了雷尼酸锶保护软骨的效应。

Javaid博士和Arden博士均声明无相关利益冲突。

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By: JEFF EVANS, Clinical Endocrinology News Digital Network

Longitudinal loss of bone mineral density from the femoral neck was associated with prevalent knee osteoarthritis in an observational cohort study, lending support to the notion that osteoporosis treatments are worth further investigation for the prevention of osteoarthritis progression.

The study, led by Dr. Ji Y. Lee of the division of rheumatology at Tufts Medical Center, Boston, builds on previous research that loss of bone mineral density (BMD) is associated with the progression of radiographic joint space narrowing. The current study is the first to examine the relationship between BMD and knee osteoarthritis (OA) progression as measured by cartilage volume and thickness on MRI, providing a more sensitive measure of changes in knee cartilage (Arthritis Rheum. 2013 March 12 [doi:10.1002/art.37926]).

The study contrasts with previous research, which has shown a positive relationship between BMD and incident or prevalent radiographically measured knee OA. Other past studies have found no relationship between BMD and radiographic progression of OA or a paradoxical opposite relationship in which low BMD predicted radiographic progression, according to Dr. Lee and associates.

Because previous studies included patients who already had OA, there may have been selection bias (collider confounding) in which the variables of interest – BMD and cartilage volume and thickness – were affected by the same factors. Dr. Lee and colleagues hoped to avoid this selection bias by studying the effect of risk factors that change after disease onset – in this case, change in BMD.

The investigators analyzed a cohort of 127 patients with prevalent knee OA, defined as a Kellgren-Lawrence grade of 2 or more. The patients had at least two MRI scans over a 2-year period, but most had three scans: at baseline and at 1 and 2 years. The patients (41% men) had a mean age of 63 years and mean body mass index (BMI) of 30 kg/m2. Baseline BMD averaged across two femoral neck measurements was 0.95 g/cm2.

In multivariate linear regression models – adjusted for baseline values of age, gender, BMI, alignment status, and vitamin D treatment – BMD loss of 0.1 g/cm2 was associated with a 1.25% per year loss of cartilage volume. For patients who lost BMD at a rate considered to be significant (calculated by the investigators to be a loss of at least 4.7% from baseline), cartilage volume loss was 1.02% per year greater than for patients without BMD loss.

The models also showed that a BMD loss of 0.1 g/cm2 was associated with a significant loss of cartilage thickness at the tibia (0.028 mm/year). Those who lost at least 4.7% of BMD lost a mean of 0.021 mm in tibial cartilage thickness per year, compared with those who did not lose BMD, the investigators reported.

Baseline BMD, however, was not significantly associated with any cartilage outcomes in the study.

The biological mechanisms conjectured to link systemic BMD to cartilage loss in knee OA include the possibility that "BMD health might provide an environment that supports optimal subchondral bone turnover and remodeling in response to OA stressors, thus favoring joint stabilization" and the beneficial effect that optimal bone health might have on cartilage health via "humoral mechanisms," Dr. Lee and colleagues wrote. "Systemic BMD could also be a marker for a range of covariates that mediate or confound the relationship, such as systemic inflammation, circulating growth factors or hormones, physical activity, or frailty."

The original trial from which the observational cohort was derived, the Randomized Controlled Trial of Vitamin D for Knee OA, was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. None of the authors had financial disclosures to report.

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OA, BMD relationship needs further study

Dr. M. Kassim Javaid and Dr. Nigel K. Arden commented: Understanding the association between OA and osteoporosis has proven to be challenging because of the difficulty in disentangling the effects of BMD on OA, and, conversely, the effects of OA on BMD and fracture risk.

The answer might be found in the effects of bone size and the BMD properties of local subchondral bone on progression of OA. Patients with OA have been found to have larger bone size but not higher volumetric BMD (vBMD), as measured by peripheral quantitative CT. Another study that used CT to measure vBMD of the subchondral bone found higher vBMD among patients with knee OA, Dr. Javaid and Dr. Arden wrote.

These factors may be intertwined by characteristics of bone phenotype that cannot be assessed by measuring BMD, including bone marrow lesions, metabolic activity, and bone turnover markers.

The novelty of Dr. Lee and colleagues getting around this problem by accounting for changes in femoral neck BMD over time helps to shed light on the true contribution of BMD to OA progression, but it should be noted that the study "does not address whether changes in [areal] BMD are a cause vs. effect of cartilage loss. However it is likely the relationship is bi-directional with bone altering chondrocyte and matrix properties and vice versa," Dr. Javaid and Dr. Arden said.

They also noted that the study by Dr. Lee and colleagues is limited by the fact that only 13% of patients lost enough BMD to be deemed significant and by the question of whether the knee OA of patients with a Kellgren-Lawrence grade of 4 could progress.

Further studies will need to focus on symptomatic progression as a primary outcome rather than change in cartilage volume. A key randomized controlled trial appeared to indicate that bisphosphonate treatment had no effect on OA, but a cartilage-sparing effect of strontium ranelate has been confirmed in a phase III trial on both symptoms and a structural end point for knee OA (Ann. Rheum. Dis. 2013;72:179-86), Dr. Javaid and Dr. Arden noted.

Dr. Javaid and Dr. Arden, both with the University of Oxford (England), did not report having any conflicts of interest. Their remarks were taken from an editorial accompanying Dr. Lee’s study (Arthritis Rheum. 2013 March 12 [doi:10.1002/art.37924]).