Use of colchicine associated with reduced risk of hip and knee replacement

8th June 2023

In an exploratory analysis of low-dose colchicine use to reduce the occurrence of cardiovascular events, researchers have found that the drug lowers the incidence of hip and knee replacements for osteoarthritis (OA).

Published in the Annals of Internal Medicine, researchers examined the effect of colchicine on the incidence of hip and knee replacements in participants within the LoDoCo2 trial. This randomised, double-blind, placebo-controlled trial was designed to explore the effects of colchicine on the risk of cardiovascular events in patients with a recent myocardial infarction. Patients with coronary artery disease received either colchicine 0.5 mg daily or matching placebo.

In the exploratory analysis of data from LoDoCo2, the primary outcome of interest was the time to the first knee or hip replacement.

Effect of colchicine on knee and hip replacements

A total of 5,478 participants with a mean age of 66 years (15.3% female), were randomised to either colchicine (2,762) or placebo and followed for a median of 28.6 months.

Overall, the use of colchicine reduce the risk of knee or hip replacements by 31% (hazard ratio, HR = 0.69, 95% CI 0.51 – 0.95).

During a sensitivity analysis, this finding remained significant when excluding patients with gout (HR = 0.68, 95% CI 0.49 – 0.94) and those with a knee or hip replacement within the first three (HR = 0.61) or six (HR = 0.58) months after randomisation.

Whilst the trial did not specifically collect data on the incidence of OA, or any information on joint pain or physical functioning, it clearly had some effect on the course of the disease. The authors called for further studies to investigate colchicine therapy in slowing disease progression in OA.

Joint replacements in context

OA is a condition associated with cartilage destruction, subchondral bone remodelling and inflammation of the synovial membrane which is thought to be due to an increased release of pro-inflammatory cytokines. In fact, use of canakinumab, an anti-interleukin-1β inhibitor and which is a pro-inflammatory cytokine, has been shown to reduce the incidence of both knee and hip replacement in patients with OA.

Colchicine works through tubulin disruption and this action down regulates multiple inflammatory pathways, suggesting that the drug may be of value as an anti-inflammatory agent.

Osteoarthritis risk lower in type 2 diabetics taking metformin

2nd May 2023

The risk of developing osteoarthritis is lower in type 2 diabetic patients taking metformin than among those taking sulfonylureas

Osteoarthritis (OA) is a common form of arthritis which globally affects 528 million people. Treatment focuses on drug therapy, self-management and exercise. In addition, there are currently no preventative therapies available. Metformin is an oral hypoglycaemic agent for the treatment of type 2 diabetes. The drug also appears to have other actions including the ability to suppress inflammation. In fact, there appears to be a beneficial effect on long-term knee joint outcomes in those with osteoarthritis and obesity. However, whether metformin can prevent the development OA is less clear.

In the current study, US researchers explored if metformin was able to lower the risk of developing OA as well as the need for joint replacement in type 2 diabetics. The team undertook a retrospective analysis using sulfonylureas as a comparator anti-diabetic therapy. Individuals with a prior diagnosis of OA were not included in their analysis. Researchers propensity-matched metformin and sulfonylurea patients 1:1. The primary outcome of interest was the time to an incident diagnosis of OA, 90 days after starting either medication.

Osteoarthritis development and anti-diabetic therapy

There were 41,874 individuals with a mean age of 62 years (41.8% female) with usable data for analysis. Among this total, 20,937 were receiving metformin.

The risk of developing osteoarthritis was 24% lower in those using metformin than a sulfonylurea (Hazard ratio, HR = 0.76, 95% CI 0.68 – 0.85, p < 0.001). However, there was no significant difference between the two groups in the risk for joint replacement (HR = 0.80, 95% CI 0.50 – 1.27, p = 0.34). Similar findings were obtained in a sensitivity analysis (HR = 0.77, 95% CI 0.65 – 0.90, p < 0.001) for OA.

These findings led the authors to suggest that metformin may have a protective effect against the development of OA.

Osteoarthritis progression identifiable using plasma proteomics signature

7th February 2023

Progression of osteoarthritis based on a marker of cartilage degeneration and pain can be predicted using a plasma proteomic signature

US researchers have identified a plasma proteomic signature that is able to distinguish between patients with osteoarthritis whose disease is progressive or non-progressive and which is superior to currently used methods.

In a global analysis from 2017, it was found that the annual incidence rate of osteoarthritis was 181.2 per 100,000 patients and the authors noted that the burden of disease is increasing in most countries. Currently, there is a need to develop OA prognostic markers and in 2016, researchers identified a method for diagnosing radiographic OA based on a series of serum biomarkers. More recently, a number of systemic biomarkers were identified and deemed to have promise as predictors of both pain and structural worsening of OA. To date, measurement of urinary carboxyl-terminal cross-linked telopeptide of type II collagen (uCTXII) appears to be the strongest predictor of clinically relevant osteoarthritis progression. In the current study, the US team used uCTXII as the ‘best-in-class’ biomarker to evaluate the performance of the proteomic signature they had identified back in 2016, for predicting clinically relevant knee OA progression, defined in terms of both joint structure and pain worsening, over a period of 48 months.

Using a cohort of 596 individuals with OA, the US team set out to measure the effectiveness of their proteomic signature (based on the area under the receiver operating curve, AUC) at distinguishing between progressors and non-progressors.

Osteoarthritis proteomic signature and identification of disease progressors

Data were available for 596 individuals with knee OA with a mean age of 61.6 years (58.7% female) and who at baseline, had moderate to severe radiographic knee OA.

Based on the proteomic signature, containing 13 distinct proteins, the AUC was 73% for differentiating between progressors (based on a measure of both radiographic joint space loss and pain scores). In contrast, the uCTXII model only had an AUC of 58% which was comparable to a model based only on baseline structural OA and the severity of pain (59%).

The researchers went a step further and assessed their proteomic model (but with only 11 proteins) in a second OA cohort and determined an AUC of 70% for distinguishing progressors from non-progressors.

They concluded that their plasma biomarker signature was able to effectively identify clinically relevant knee OA progressors from non-progressors, adding that the proteomic signature may be of value during clinical trials to identify those with the greatest need for treatment.

Citation
Zhou K et al. A “best-in-class” systemic biomarker predictor of clinically relevant knee osteoarthritis structural and pain progression. Sci Adv 2023

Walking for exercise significantly reduces in new frequent knee pain in osteoarthritis

28th June 2022

Walking for exercise in patients with knee osteoarthritis is associated with a lower of odds of developing new frequent knee pain

Individuals aged 50 and older with knee osteoarthritis and who report walking for exercise are significantly less likely to develop new frequent knee pain, compared to those who do not walk for exercise, according to finding of a study by US researchers.

Osteoarthritis (OA) is a leading cause of disability and societal cost in older adults. Globally, the incidence of OA has increased since 1990 and in 2019, there were estimated to be 527.81 million cases. Moreover, knee osteoarthritis is the most common presentation, accounting for approximately 85% of the worldwide burden of OA.

Although pharmacological interventions for OA are known to be effective, non-pharmacological interventions such as exercise, are also recommended for all patients.

However, while there is evidence that supervised fitness walking can improve functional status without worsening pain or exacerbating arthritis-related symptoms in patients with knee OA, the study was short-term and only lasted for 8 weeks.

For the present study, the researchers wanted to examine the impact of walking over a much longer period of time. They used data collected as part of the Osteoarthritis initiative, a prospective longitudinal observational study that recruited patients both with and without symptomatic knee OA from 2004 – 2006.

Individuals undertook annual evaluations, starting when they were first recruited and which continued until month 48 and then every two years to month 96.

The researchers included participants aged over 50 with data on knee-specific pain and radiographs at baseline and at months 36 or 48, which provided evidence of OA.

As part of their assessment, patients were asked about their level of walking, the time spent walking and for how many years. Individuals reporting walking for exercise at least 10 times (which was the question asked in assessment), were categorised as walkers and those who answered no, were deemed to be ‘non-walkers’.

Three primary outcome measure were employed: new frequent knee pain, medial joint space narrowing (which is a marker for worsening OA) and the Kellgren-Lawrence grade, which assess OA severity.

Walking and OA outcomes

A total of 1212 participants with a mean age of 63.2 years (45% male) were included in the final analysis, of whom, 73% were defined as walkers.

Among those who reported walking for exercise, there was a 40% lower odds of new frequent knee pain compared to non-walkers (odds ratio, OR = 0.60, 95% CI 0.40 – 0.80). There was also a significantly reduced odds of medial joint space narrowing among walkers compared to non-walkers (OR = 0.8, 95% CI 0.6 – 1.0). However, there was no significant difference in Kellgren-Lawrence score worsening between the two groups.

The authors concluded that their findings offered a glimmer of hope that walking might improve OA symptoms and provide a structural benefit (based on lower medial joint space narrowing).

Citation
Lo GH et al. Association Between Walking for Exercise and Symptomatic and Structural Progression in Individuals with Knee Osteoarthritis: Data from the Osteoarthritis Initiative Cohort Arthritis Rheumatol 2022