Contribution of Circulatory Disturbances in Subchondral Bone to the Pathophysiology of Osteoarthritis.

PURPOSE OF REVIEW: This review describes the contributions of abnormal bone circulation to the pathophysiology of osteoarthritis. Combining dynamic imaging with MRI and PET with previous observations reveals that venous stasis and a venous outlet syndrome is most likely the key circulatory pathology associated with the initiation or progression of osteoarthritis. RECENT FINDINGS: MRI and PET have revealed that venous outflow obstruction results in physicochemical changes in subchondral bone to which osteoblasts are responsive. The osteoblasts express an altered pattern of cytokines, many of which can serve as structural or signaling molecules contributing to both bone remodeling and cartilage degeneration. The patterns of circulatory changes are associated with alterations in the physicochemical environment of subchondral bone, including hypoxia. Osteoblast cytokines can transit the subchondral bone plate and calcified cartilage and communicate with chondrocytes.

Controversial role of arthroscopic meniscectomy of the knee: A review.

The role of arthroscopic partial meniscectomy (APM) in reducing pain and improving function in patients with meniscal tears remains controversial. Five recent high-quality randomized controlled trials (RCTs) compared non-operative management of meniscal tears to APM, with four showing no difference and one demonstrating superiority of APM. In this review, we examined the strengths and weaknesses of each of these RCTs, with particular attention to the occurrence of inadvertent biases. We also completed a quantitative analysis that compares treatment successes in each treatment arm, considering crossovers as treatment failures. Our analysis revealed that each study was an excellent attempt to compare APM with non-surgical treatment but suffered from selection, performance, detection, and/or transfer biases that reduce confidence in its conclusions. While the RCT remains the methodological gold standard for establishing treatment efficacy, the use of an RCT design does not in itself ensure internal or external validity. Furthermore, under our alternative analysis of treatment successes, two studies had significantly more treatment successes in the APM arm than the non-operative arm although original intention-to-treat analyses showed no difference between these two groups. Crossovers remain an important problem in surgical trials with no perfect analytical solution. With the studies available at present, no conclusion can be drawn concerning the optimal treatment modality for meniscal tears. Further work that minimizes significant biases and crossovers and incorporates sub-group and cost-benefit analyses may clarify therapeutic indications.

Pathophysiology and risk factors for osteonecrosis.

Osteonecrosis, also known as avascular necrosis or AVN, is characterized by a stereotypical pattern of cell death and a complex repair process of bone resorption and formation. It is not the necrosis itself but rather the resorptive component of the repair process that results in loss of structural integrity and subchondral fracture. Most likely, a common pathophysiological pathway exists involving compromised subchondral microcirculation. Decreased femoral head blood flow can occur through three mechanisms: vascular interruption by fractures or dislocation, intravascular occlusion from thrombi or embolic fat, or intraosseous extravascular compression from lipocyte hypertrophy or Gaucher cells. In this review, we emphasize etiologic relationships derived mostly from longitudinal cohort studies or meta-analyses whose causal relationships to osteonecrosis can be estimated with confidence. Understanding risk factors and pathophysiology has therapeutic implications since several treatment regimens are available to optimize femoral head circulation, interrupt bone resorption, and preserve the subchondral bone.

Characterization of bone perfusion by dynamic contrast-enhanced magnetic resonance imaging and positron emission tomography in the Dunkin-Hartley guinea pig model of advanced osteoarthritis.

This study characterizes changes in subchondral bone circulation in OA and examines relationships to bone structure and cartilage degeneration in Dunkin-Hartley guinea pigs. We have used dynamic contrast-enhanced MRI (DCE-MRI) and PET, with pharmacokinetic modeling, to characterize subchondral bone perfusion. Assessments are made of perfusion kinetics and vascular permeability by MRI, and blood volume and flow, and radionuclide incorporation into bone, by PET. These parameters are compared to cartilage lesion severity and bone histomorphometry. Assessments of intraosseous thrombi are made morphologically. Prolonged signal enhancement during the clearance phase of MRI correlated with OA severity and suggested venous stasis. Vascular permeability was not increased indicating that transvascular migration of contrast agent was not responsible for signal enhancement. Intraosseous thrombi were not observed. Decreased perfusion associated with severe OA was confirmed by PET and was associated with reduced radionuclide incorporation and osteoporosis. MRI and PET can be used to characterize kinetic parameters of circulation in OA and correlate them with subchondral bone metabolism of interest to the pathophysiology of OA. The significance of these observations may lie in alterations induced in the expression of cytokines by OA osteoblasts that are related to bone remodeling and cartilage breakdown.

Post-traumatic osteoarthritis after ACL injury.

Post-traumatic osteoarthritis (PTOA) occurs as a consequence of joint trauma or occupations or sports that subject joints to excessive loading stresses. Ligament injuries to the knee, particularly tears of the anterior cruciate ligament (ACL), often result in PTOA. Approximately half of the individuals with an ACL injury develop PTOA regardless of the reconstruction of the torn ligament. This observation has raised the possibility that other injuries occur to the knee in association with ACL tears that may involve ligamentous capsular structures, articular cartilage, or subchondral bone. Many ACL injuries occur in noncontact sports and are the result of biomechanical abnormalities. Female athletes are more likely than their male counterparts to suffer ACL injuries. This review outlines the epidemiology of ACL tears, its pathology in cartilage and bone, some of the demographic, biomechanical, and neuromuscular factors involved in ACL tears, and PTOA and important information gained from preclinical injury models.

Orthopedic medical devices: ethical questions, implant recalls and responsibility.

The hip replacement is a surgical procedure to replace the femoral head and acetabulum with prosthetic implants to improve function, increase mobility, and relieve pain caused by damage from disorders such as osteoarthritis and fractures. In recent years, we have seen several recalls of poorly functioning implant systems, most recently, the Johnson and Johnson (J&J) Articular Surface Replacement device. Product recalls are often the results of premature failure of implants requiring additional surgery to exchange the failed device. This raises many questions - technical, medical, regulatory, ethical, and legal - that ultimately put patients at risk, compromise confidence in medicine and regulatory agencies, and important relationships including those between the physician-patient and physician-industry. Where do the responsibilities lie for the patients' suffering, morbidity, and costs of removing the failed device? This article discusses the current recall of the J&J implant, the responsibilities of the manufacturer, surgeons, and the regulatory agency.

Pathogenesis and epidemiology of osteoarthritis.

Osteoarthritis (OA) is a disease of high prevalence that produces substantial morbidity and is a leading cause of physical and psychological disability and expense, including time lost from work, medical care, and disability support. Until recently, the focus of research into the pathophysiology of OA has been on articular cartilage and has not resulted in either biomarkers of OA activity or effective targets for disease-modifying therapy. The contemporary paradigm of OA considers involvement of all joint tissues. It has been shown that, in later-stage OA, bone blood flow and oxygen content are markedly reduced and have a deleterious effect on bone cells, inducing them to release proteins (cytokines) that contribute to the bone remodeling and cartilage breakdown seen in OA.

Corticosteroid-associated avascular necrosis: dose relationships and early diagnosis.

Corticosteroids are the most common etiological factor in nontraumatic avascular necrosis (AVN) of bone, accounting for about 10% of arthroplasties performed annually in the United States. Evidence is conflicting on the relative importance of peak dose, daily dose, or cumulative dose, and most likely all three represent "high dose" corticosteroid administration and play a role in AVN. The etiology may be multifactorial with corticosteroids superimposed on genetic or pathological predispositions. Joint preservation depends upon early diagnosis and treatment before fracture of the subchondral trabeculae and joint incongruity. Early intervention depends upon identifying at-risk patients and quantifying their risk by understanding clinical and pathophysiological contributions to that risk. Our data and that of others suggest that a screening MRI of at-risk populations will permit detection of AVN at a prefracture stage when preservation of the joint is possible.

Scaffold hopping in the rational design of novel HIV-1 non-nucleoside reverse transcriptase inhibitors.

High-throughput screening hit 1 was identified as a potent, broad-spectrum, non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 replication. Analysis of the bound conformation of analogs of this inhibitor via molecular modeling and NMR contributed to the design of novel tertiary amide, carbamate, and thiocarbamate based NNRTIs.