Reference: JAMA Intern Med. 2024 Dec 1;184(12):1443-1447
Practice Point: Vitamin K2 might work for nocturnal leg cramps. Or, it might not. Don’t change your practice yet.
EBM Pearl: Researchers—please don’t cramp study validity with unclear published methods or irreproducible results. When the validity of study data is in question, going ahead with the intervention because it seems "benign" might be exposing people to the harms of a treatment without the possibility of benefit.
Have you ever woken up in the middle of the night with a sudden, painful, leg-thrashing cramp? People who experience frequent nocturnal leg cramps would do just about anything to prevent them, and massage and stretching usually don’t cut it. Unfortunately, there are few treatments that are both effective and safe.
A highly publicized randomized trial published in JAMA Internal Medicine suggested new hope for avoiding nocturnal leg cramps. The study, performed in China, evaluated vitamin K2 (menaquinone) in adult volunteers ≥ 65 years old with at least 2 episodes of unexplained nocturnal leg cramps (average was 2-3) in the last 2 weeks. Side note: Vitamin K2 is not found in standard vitamin K tablets or foods such as spinach that are conventionally considered to be high in vitamin K (which are usually high in K1) but can be found in a variety of probiotic-containing and fermented foods. Back to study details: Cramps associated with specific metabolic diseases and neuropathies were excluded. The participants, who importantly were recruited by volunteering for the study, were on average 72 years old and weighed about 52 kg, and a majority had hypertension and diabetes. Vitamin K2 was prescribed as 180 mcg orally once nightly for 8 weeks. Patients recorded the number, severity, and duration of cramps by diary, with investigators checking in regularly by phone. The authors reported that after 8 weeks, vitamin K2 was found to reduce the number of cramps per week (mean 0.96 vs. 3.63 in placebo group), severity of cramps, and duration of cramps. No adverse effects were reported.
Don’t get too excited, though. We might sound like a broken record, but we’re going to go there again with this study: Trustworthy results require trustworthy (valid) methodology. When study methods are not clearly reported or inconsistently reported, we lose confidence in the results. In this case, there were some noteworthy discrepancies noted in how randomization and data collection methods were reported in a public peer review from April 2025. These concerns were presented by Professor Alison Avenell and organized according to the REAPPRAISED checklist. We agree there should be more details about how data was collected.
The authors performed an intention-to-treat analysis, and although the published protocol states that the reasons why patients are excluded or drop out from protocol would be reported, they failed to clearly do so. If patients drop out of a study because bad things happen to them (even things that don’t initially seem related to the research), readers should know that. In addition, concerns were raised related to the impossibility of the outcome data due to the precision of confidence intervals (CIs) for between-group differences (-2.67 cramps/week, 95% CI -2.86 to -2.49). When we calculate CIs from the data provided in the supplement, we get CIs that are wider than this, similar to what is presented in the peer review. All of these questions raise concerns. However, while writing this EBM Focus, a notice of retraction and replacement was published in which the authors clarified some discrepancies and committed to resubmit their publication with errors and corrections highlighted. While some might question whether these concerns should have been raised via the original peer review process, we’re going to go with better late than never.
This all leads to the bigger issue of the pressure to publish, which inevitably contributes to the growing problem of untrustworthy data. In 2023 alone, more than 10,000 research papers were retracted from medical literature. Astounding, right? And how many more are floating out there in circulation yet to be discovered? Online publishing and AI make the critical appraisal of medical literature simultaneously more important and more difficult. It is essential that clinicians 1) know this problem exists and 2) either perform critical analysis themselves—a Herculean task—or find trusted tools (such as DynaMed) to do it for them. The stakes are too high to believe everything you read. As in so many things in our world, we suspect the original paper will have far more views than any retraction published by the authors. So, for now, you can trust that the evidence is unclear about the use of Vitamin K2 for nocturnal leg cramps.
For more information, see the topic Nocturnal Leg Cramps in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by McKenzie Ferguson, PharmD, BCPS, Senior Clinical Writer at DynaMed. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Dan Randall, MD, MPH, FACP, Senior Deputy Editor at DynaMed; Rich Lamkin, MPH, MPAS, PA-C, Clinical Writer at DynaMed; Matthew Lavoie, BA, Senior Medical Copyeditor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor II at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.