Vitamin K2 in Nocturnal Leg Cramps: What Did the Randomized Trial Show?

Detailed evaluation

Why are nocturnal leg cramps important?

Nocturnal leg cramps are common, particularly in older age. They usually present as sudden, involuntary, and painful contractions in the calf or foot muscles; they can disrupt sleep and impair quality of life. Although magnesium is frequently recommended in clinical practice, randomized trials and systematic reviews show that the effect of short-term magnesium use, particularly in idiopathic nocturnal cramps, is not consistent.

Study design

• Design: Multicenter, double-blind, placebo-controlled randomized clinical trial.
• Center: Two clinical centers in China.
• Period: 2022-2023.
• Participants: Individuals aged 65 years and older who recorded at least 2 nocturnal cramp episodes during a two-week screening.
• Number of individuals analyzed: 199.
• Mean age: 72.3 years.
• Proportion of women: 54.3%.
• Intervention: Vitamin K2, menaquinone-7 (MK-7), 180 µg/day.
• Control: Identical-appearing placebo.
• Duration: 8 weeks.

Primary outcome: Cramp frequency

At baseline, weekly cramp frequency was close between the groups: a mean of 2.60 episodes/week in the K2 group and 2.71 episodes/week in the placebo group.

During the 8-week intervention period, the mean weekly cramp frequency decreased to 0.96 in the K2 group. In the placebo group, the mean frequency during the same period was reported as 3.63. The mean difference between groups was -2.67 cramps/week (95% confidence interval -2.86 to -2.49; p<0.001).

The researchers reported that the difference between the groups became apparent from the first week onward. However, the increase seen in the placebo group compared to baseline may be related to natural fluctuation or a measurement effect due to more detailed record-keeping during the follow-up period; the authors explicitly discussed this in the corrected version.

Cramp severity and duration

In the vitamin K2 group, a mean change of -2.55 points in cramp severity was reported, compared to -1.24 points in the placebo group. The mean reduction in cramp duration was -0.90 minutes in the K2 group and -0.32 minutes in the placebo group.

These two outcomes were secondary endpoints; they should not be interpreted as strongly as the primary endpoint, but the fact that they are in the same direction as the main finding supports the consistency of the clinical signal.

Why is the form of K2 used important?

The form used in the study was menaquinone-7 (MK-7). This detail is important; “vitamin K2” is not a single molecule, and different menaquinones such as MK-4 and MK-7 are not pharmacokinetically identical. Therefore, it is not appropriate to automatically generalize the result of this study to all K2 forms.

Is the mechanism known?

Strictly speaking, no. The study aimed to demonstrate a clinical effect; it did not include biomarkers or muscle physiology measurements to confirm the mechanism of action. Hypotheses can be put forward that vitamin K may act through muscle cell physiology, calcium regulation, or neuromuscular function, but this study did not prove any of these mechanisms.

Considering it comparatively with magnesium

Although magnesium is one of the most frequently used supplements in daily life for nocturnal cramps, the available data are not convincing, especially for short-term use. In the 2020 Cochrane review, no significant difference was demonstrated between magnesium and placebo in terms of cramp frequency in patients with idiopathic cramps, most of whom were older adults. For this reason, the effect size demonstrated by the K2 study is noteworthy; however, because no study has been conducted directly comparing K2 with magnesium, the conclusion that “K2 is superior to magnesium” cannot be drawn.

Safety

No adverse events attributed to vitamin K2 use were identified in the study. However, this result is limited to 199 individuals and an 8-week follow-up; it does not rule out rare or long-term adverse effects.

Important clinical note: In individuals using vitamin K antagonist anticoagulants such as warfarin, changes in vitamin K intake can affect anticoagulation control. Therefore, K2 supplementation should not be initiated in this group without a physician’s evaluation.

Why was the article retracted and republished?

This is one of the most critical methodological details regarding this study. The editors of JAMA Internal Medicine and the authors reported that after initial publication, there were discrepancies in intention-to-treat sample numbers and protocol and analysis descriptions. The article underwent a retracted and replaced process on May 2, 2025: the initial version was retracted, and a new version containing corrected analyses and explanations was published under the same article record.

The authors explained that 210 individuals were initially randomized 105 to 105; due to 11 individuals dropping out before receiving the intervention, the analyzed groups were 103 and 96 individuals. In the corrected analysis, the primary outcome continued to remain in favor of K2. This process does not automatically invalidate the result; however, it increases the importance of independent replication and is one of the main reasons limiting the Confidence Index.

Strengths of the study

• Randomized design.
• Double-blind implementation.
• Placebo control.
• Conducted across two centers.
• Primary endpoint was prespecified.
• Cramp frequency, severity, and duration changed in the same direction.

Limitations of the study

• Population limited to a single country and older age group.
• 199 individuals is a small sample size to evaluate rare adverse effects.
• Cramp records are based on participant diaries.
• Follow-up is only 8 weeks.
• No robust long-term data for quality of life and sleep quality.
• The mechanism of action was not directly tested.
• There is no independent validation study yet.
• Inconsistencies requiring correction in the protocol and analysis descriptions were identified after the initial publication.

How should it be interpreted clinically?

This study shows that vitamin K2 may carry a genuine therapeutic signal for nocturnal leg cramps in older individuals. Especially considering that the evidence for magnesium is weak, the result is clinically noteworthy.

However, nocturnal leg cramps are not attributable to a single cause. Peripheral vascular diseases, neuropathies, lumbar spinal pathologies, certain medications, fluid-electrolyte disturbances, and other metabolic conditions can lead to similar complaints. Therefore, vitamin K2 should not replace the evaluation of underlying causes.

Conclusion

Daily 180 µg MK-7 was found to be associated with a significant reduction in cramp frequency, severity, and duration over 8 weeks in individuals aged 65 and older with nocturnal cramps. The findings provide a strong initial clinical signal; however, they need to be confirmed in different populations with longer follow-up and independent randomized trials before turning into a routine clinical recommendation.

References

1. Tan J, Zhu R, Li Y, et al. Vitamin K2 in Managing Nocturnal Leg Cramps: A Randomized Clinical Trial. JAMA Intern Med. 2024;184(12):1443-1448. DOI: 10.1001/jamainternmed.2024.5726.
2. Tan J, Zhu R. Notice of Retraction and Replacement. JAMA Intern Med. 2025;185(7):904. DOI: 10.1001/jamainternmed.2025.2160.
3. Garrison SR, et al. Magnesium for skeletal muscle cramps. Cochrane Database of Systematic Reviews. 2020.

Medical review note: This content has been prepared to interpret scientific research; it is not a personalized diagnosis or treatment recommendation.