Researchers looked at four studies involving 416 people with osteoarthritis to see if methotrexate—a medication commonly used for rheumatoid arthritis—could help reduce pain and stiffness. They found that methotrexate did reduce pain and stiffness in people with osteoarthritis, though the benefits were modest. However, because this drug can affect how your body uses certain nutrients, especially folate (a B vitamin), doctors recommend taking folate supplements if you use methotrexate. The research suggests this medication might be helpful for some osteoarthritis patients, but more studies are needed to fully understand its long-term effects.
The Quick Take
- What they studied: Whether methotrexate, a drug used to treat rheumatoid arthritis, could help reduce pain and stiffness in people with osteoarthritis (wear-and-tear arthritis).
- Who participated: 416 people across four different research studies who had osteoarthritis. These were high-quality studies where some people received methotrexate and others received a placebo (fake pill).
- Key finding: Methotrexate reduced pain by about one-third at 3 months and by about half at 6 months compared to placebo. It also reduced stiffness at 6 months. However, it didn’t clearly improve how well people could move and function in their daily lives, though some evidence suggests it might help in certain cases.
- What it means for you: If you have osteoarthritis, methotrexate might be worth discussing with your doctor as a possible treatment option to reduce pain and stiffness. However, you would need to take folate supplements while using it, and your doctor would need to monitor your health regularly. This isn’t a cure, but it may help manage symptoms.
The Research Details
Researchers conducted a systematic review and meta-analysis, which means they carefully searched scientific databases for all high-quality studies comparing methotrexate to placebo in osteoarthritis patients. They found four studies that met their strict quality standards, involving a total of 416 people. They used a special tool to check if each study was done properly and then combined the results to see the overall effect of the medication.
This approach is like gathering all the best evidence on a topic and looking at it together, rather than relying on just one study. By combining results from multiple studies, researchers can get a clearer picture of whether a treatment actually works. The researchers followed strict international guidelines (called PRISMA) to make sure their review was done correctly and registered their plan in advance so there wouldn’t be any hidden bias.
A systematic review and meta-analysis is one of the strongest types of research because it combines evidence from multiple studies. This approach reduces the chance that one study’s unusual results will mislead us. By looking at all the best available evidence together, we get a more reliable answer about whether methotrexate actually helps with osteoarthritis. This type of research is especially important for deciding whether doctors should recommend a medication to their patients.
The researchers used a well-respected tool (Cochrane RoB 2) to check the quality of each study they included. They only included randomized controlled trials, which are considered the gold standard in medical research because they reduce bias. The fact that they registered their review plan in advance (PROSPERO) before doing the analysis is also a good sign—it means they couldn’t change their methods based on what they found. However, only four studies were included, which is a relatively small number, and the studies involved only 416 people total, so the results should be considered preliminary.
What the Results Show
Methotrexate showed clear benefits for pain relief. At 3 months, people taking methotrexate had about one-third less pain than those taking placebo. By 6 months, the pain reduction was even better—about 50% more improvement than placebo. These differences were statistically significant, meaning they’re unlikely to be due to chance.
For stiffness, methotrexate also showed benefits at 6 months, reducing stiffness by about half compared to placebo. This is important because morning stiffness and ongoing stiffness are major complaints from people with osteoarthritis.
Regarding physical function (how well people could move and do daily activities), the results were less clear. The main analysis didn’t show a clear benefit, but when researchers removed one study that had quality concerns, they found a modest improvement in function. This suggests methotrexate might help some people move better, but the evidence isn’t as strong as it is for pain relief.
The side effects reported were consistent with what doctors expect from low-dose methotrexate use, meaning the medication appeared to be reasonably well-tolerated in these studies.
An important finding was that none of the four studies measured folate levels in participants, even though methotrexate is known to interfere with how the body uses folate (a B vitamin). This is a significant gap because folate is essential for many body functions. The researchers emphasized that people taking methotrexate should receive folate supplementation to prevent nutritional deficiencies. This highlights that if methotrexate is used for osteoarthritis, it would need to be paired with careful nutritional monitoring and supplementation.
Methotrexate has been used for decades to treat rheumatoid arthritis, where it reduces inflammation and pain. This research suggests it might work similarly in osteoarthritis, though osteoarthritis is a different type of joint disease. The pain relief seen in this analysis is consistent with what we know about methotrexate’s anti-inflammatory effects. However, the modest benefit for physical function is somewhat surprising and suggests that methotrexate may work better for symptom relief than for actually improving how well people can function day-to-day.
The biggest limitation is that only four studies were included, involving just 416 people total. This is a relatively small amount of evidence. Additionally, the studies were relatively short (3-6 months), so we don’t know if the benefits continue over years of use or if side effects become more common with longer use. None of the studies measured nutritional markers like folate levels, which is a major gap given that methotrexate affects nutrition. The studies also didn’t look at different doses of methotrexate or compare it to other osteoarthritis treatments. Finally, we don’t know if the benefits apply equally to all types of osteoarthritis or all types of people.
The Bottom Line
Based on this research, methotrexate may be considered as a treatment option for osteoarthritis pain and stiffness, particularly for people who haven’t responded well to other treatments. However, this should only be done under close medical supervision. If methotrexate is used, folate supplementation is essential and should be discussed with your doctor. Regular blood tests would be needed to monitor for any nutritional deficiencies or other side effects. The confidence level for pain relief is moderate (fairly good evidence), but the confidence level for improving physical function is lower (weaker evidence).
This research is most relevant for people with osteoarthritis who have significant pain and stiffness that isn’t controlled by other treatments. It may be particularly interesting for people who also have inflammatory markers in their blood tests. However, this research is preliminary, and methotrexate is not yet a standard treatment for osteoarthritis. People who are pregnant, planning to become pregnant, or breastfeeding should not use methotrexate. People with certain liver or kidney conditions may also not be suitable candidates. Anyone considering this treatment should have a detailed conversation with their rheumatologist or doctor.
Based on the studies reviewed, pain relief may begin to appear within 3 months of starting methotrexate, with greater improvement by 6 months. However, individual responses vary, and some people may see benefits sooner or later. It’s important to understand that this is symptom relief, not a cure for osteoarthritis. The benefits would likely continue only as long as you take the medication. Long-term effects beyond 6 months are not yet well-studied.
Want to Apply This Research?
- If using methotrexate for osteoarthritis, track daily pain levels (0-10 scale) and morning stiffness duration (in minutes) three times per week. Also log any side effects, folate supplement intake, and dates of blood tests for nutritional monitoring.
- Set reminders to take folate supplements on the same days as methotrexate doses. Create a simple pain and stiffness log each morning to identify patterns and share with your doctor at appointments. Schedule regular check-ins with your healthcare provider for blood work and symptom assessment.
- Maintain a 12-week tracking period to assess if methotrexate is working for your pain and stiffness. Share your tracked data with your doctor at each visit. Monitor for any new side effects and track folate supplement compliance. After 6 months, review whether the benefits justify continuing the medication and whether nutritional markers remain healthy.
This research summary is for educational purposes only and should not be used to make medical decisions. Methotrexate is a prescription medication with potential side effects and requires medical supervision. If you have osteoarthritis or are considering methotrexate treatment, please consult with your doctor, rheumatologist, or healthcare provider before making any changes to your treatment plan. This summary represents preliminary research findings and should not be considered definitive medical advice. Individual responses to treatment vary, and what works for one person may not work for another.
This research translation is published by Gram Research, the science division of Gram, an AI-powered nutrition tracking app.