{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T16:18:46Z","timestamp":1792167526376,"version":"4.4.0"},"reference-count":17,"publisher":"American Medical Association (AMA)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Intern Med"],"published-print":{"date-parts":[[2024,12,1]]},"abstract":"<jats:sec><jats:title>Importance<\/jats:title><jats:p>Currently, there are no treatments for nocturnal leg cramps (NLCs) that have been proven to be both safe and effective. Seeking safe and effective approaches for managing NLCs is of crucial importance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To determine whether vitamin K<jats:sub>2<\/jats:sub> is better than placebo in managing NLCs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted in China between September 2022 and December 2023. This study used a volunteer sample comprising community-dwelling individuals 65 years and older with 2 or more documented episodes of NLCs during 2 weeks of screening. Researchers performed a history and physical screening of candidates recruited from the community through advertisements, and eligible participants were randomized in a 1:1 ratio to receive vitamin K<jats:sub>2<\/jats:sub> or a placebo for 8\u2009weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interventions<\/jats:title><jats:p>Patients orally took capsules containing either vitamin K<jats:sub>2<\/jats:sub> (menaquinone 7), 180 \u03bcg, or a similar-looking placebo every day for 8\u2009weeks. The study products were custom manufactured to have identical packaging and for the capsules to have matching appearance and identical excipients that shared similar taste and weight.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>The primary outcome was the mean number of NLCs per week between the vitamin K<jats:sub>2<\/jats:sub> and the placebo group over 8 weeks according to modified intention-to-treat analysis. Secondary outcomes included the duration of muscle cramps measured in minutes and the severity of muscle cramps assessed using an analog scale ranging from 1 to 10.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among the 310 participants, 111 participants were excluded. Of the 199 enrolled individuals, 108 (54.3%) were female, and the mean (SD) age was 72.3 (5.5) years. A total of 103 patients (51.8%) were randomly assigned to receive vitamin K<jats:sub>2<\/jats:sub> and 96 (48.2%) were assigned to placebo. The mean (SD) baseline weekly frequency of cramps was comparable in both the vitamin K<jats:sub>2<\/jats:sub> group (2.60 [0.81]) and the placebo group (2.71 [0.80]). During the 8-week intervention, the vitamin K<jats:sub>2<\/jats:sub> group experienced a reduction in the mean (SD) weekly frequency of cramps to 0.96 (1.41). Meanwhile, the placebo group maintained mean (SD) weekly frequency of cramps at 3.63 (2.20). The between-group difference was statistically significant (difference, \u22122.67; 95% CI, \u22122.86 to \u22122.49; <jats:italic>P<\/jats:italic>\u2009&amp;amp;lt;\u2009.001). The vitamin K<jats:sub>2<\/jats:sub> group had a more significant mean (SD) reduction in NLC severity (\u22122.55 [2.12] points) compared with the placebo group (\u22121.24 [1.16] points). The vitamin K<jats:sub>2<\/jats:sub> group exhibited a more pronounced mean (SD) decrease in the duration of NLCs (\u22120.90 [0.88] minutes) than the placebo group (\u22120.32 [0.78] minutes). No adverse events related to vitamin K<jats:sub>2<\/jats:sub> use were identified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Relevance<\/jats:title><jats:p>This randomized clinical trial showed that vitamin K<jats:sub>2<\/jats:sub> supplementation significantly reduced the frequency, intensity, and duration of NLCs in an older population with good safety.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p>ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT05547750\">NCT05547750<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jamainternmed.2024.5726","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T15:32:14Z","timestamp":1730129534000},"page":"1443","source":"Crossref","is-referenced-by-count":16,"title":["Vitamin K<sub>2<\/sub> in Managing Nocturnal Leg Cramps"],"prefix":"10.1001","volume":"184","author":[{"given":"Jing","family":"Tan","sequence":"first","affiliation":[{"name":"The Third People\u2019s Hospital of Chengdu, Chengdu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zhu","sequence":"additional","affiliation":[{"name":"The Third People\u2019s Hospital of Chengdu, Chengdu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medicine, North Sichuan Medical College, Nanchong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeng","family":"Liao","sequence":"additional","affiliation":[{"name":"School of Medicine, North Sichuan Medical College, Nanchong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Cheng","sequence":"additional","affiliation":[{"name":"School of Medicine, North Sichuan Medical College, Nanchong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"LingXiu","family":"Mao","sequence":"additional","affiliation":[{"name":"School of Medicine, North Sichuan Medical College, Nanchong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Jing","sequence":"additional","affiliation":[{"name":"School of Medicine, North Sichuan Medical College, Nanchong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"4","key":"ioi240069r1","first-page":"350","article-title":"Nocturnal leg cramps.","volume":"86","author":"Allen","year":"2012","journal-title":"Am Fam Physician"},{"issue":"5","key":"ioi240069r2","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1001\/jamainternmed.2016.9261","article-title":"Effect of magnesium oxide supplementation on nocturnal leg cramps: a randomized clinical trial.","volume":"177","author":"Roguin Maor","year":"2017","journal-title":"JAMA Intern Med"},{"issue":"7","key":"ioi240069r3","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1111\/j.1742-1241.1999.tb11786.x","article-title":"Leg cramps in the elderly: prevalence, drug and disease associations.","volume":"53","author":"Abdulla","year":"1999","journal-title":"Int J Clin Pract"},{"issue":"1","key":"ioi240069r4","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1093\/fampra\/cmx062","article-title":"Treatment of nocturnal leg cramps by primary care patients over the age of 60.","volume":"35","author":"Lorenzo","year":"2018","journal-title":"Fam Pract"},{"key":"ioi240069r5","doi-asserted-by":"publisher","DOI":"10.1016\/j.nut.2022.111608","article-title":"Vitamin K2 as a potential therapeutic candidate for the prevention of muscle cramps in hemodialysis patients: a prospective multicenter, randomized, controlled, crossover pilot trial.","volume":"97","author":"Xu","year":"2022","journal-title":"Nutrition"},{"key":"ioi240069r6","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2023.1119233","article-title":"Effect of vitamin K2 in the treatment of nocturnal leg cramps in the older population: study protocol of a randomized, double-blind, controlled trial.","volume":"10","author":"Li","year":"2023","journal-title":"Front Nutr"},{"issue":"1","key":"ioi240069r7","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s12875-017-0600-x","article-title":"Criteria in diagnosing nocturnal leg cramps: a systematic review.","volume":"18","author":"Hallegraeff","year":"2017","journal-title":"BMC Fam Pract"},{"issue":"1","key":"ioi240069r8","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1186\/s12937-021-00747-9","article-title":"A randomized, double-blind, placebo-controlled, multicenter study assessing the efficacy of magnesium oxide monohydrate in the treatment of nocturnal leg cramps.","volume":"20","author":"Barna","year":"2021","journal-title":"Nutr J"},{"issue":"18","key":"ioi240069r9","doi-asserted-by":"publisher","first-page":"3959","DOI":"10.1080\/10408398.2016.1211616","article-title":"Effect of vitamin K in bone metabolism and vascular calcification: a review of mechanisms of action and evidences.","volume":"57","author":"Villa","year":"2017","journal-title":"Crit Rev Food Sci Nutr"},{"issue":"4","key":"ioi240069r10","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1093\/nutrit\/nuab061","article-title":"Vitamin K - sources, physiological role, kinetics, deficiency, detection, therapeutic use, and toxicity.","volume":"80","author":"Mladenka","year":"2022","journal-title":"Nutr Rev"},{"issue":"4","key":"ioi240069r11","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.3390\/nu13041222","article-title":"The dual role of vitamin K2 in \u201cbone-vascular crosstalk\u201d: opposite effects on bone loss and vascular calcification.","volume":"13","author":"Mandatori","year":"2021","journal-title":"Nutrients"},{"issue":"2","key":"ioi240069r12","doi-asserted-by":"publisher","first-page":"691","DOI":"10.3390\/nu13020691","article-title":"The medical benefits of vitamin K2 on calcium-related disorders.","volume":"13","author":"Khalil","year":"2021","journal-title":"Nutrients"},{"issue":"1","key":"ioi240069r13","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2015-008166","article-title":"Acupuncture point injection treatment of primary dysmenorrhoea: a randomised, double blind, controlled study.","volume":"6","author":"Wade","year":"2016","journal-title":"BMJ Open"},{"issue":"4","key":"ioi240069r14","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1016\/j.bbrc.2016.05.132","article-title":"Vitamin K3 inhibits mouse uterine contraction in vitro via interference with the calcium transfer and the potassium channels.","volume":"476","author":"Zhang","year":"2016","journal-title":"Biochem Biophys Res Commun"},{"issue":"7","key":"ioi240069r15","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1093\/nutrit\/nux022","article-title":"US Pharmacopeial Convention safety evaluation of menaquinone-7, a form of vitamin K.","volume":"75","author":"Marles","year":"2017","journal-title":"Nutr Rev"},{"issue":"6","key":"ioi240069r16","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.3390\/nu15061505","article-title":"Associations between body mass index and probable sarcopenia in community-dwelling older adults.","volume":"15","author":"Curtis","year":"2023","journal-title":"Nutrients"},{"key":"ioi240069r17","doi-asserted-by":"publisher","DOI":"10.1016\/j.nut.2019.110581","article-title":"Epidemiology of weight loss, malnutrition and sarcopenia: a transatlantic view.","volume":"69","author":"Schneider","year":"2020","journal-title":"Nutrition"}],"container-title":["JAMA Internal Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamainternalmedicine\/articlepdf\/2825457\/jamainternal_tan_2024_oi_240069_8928_1745939683.53546.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T15:00:31Z","timestamp":1746198031000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamainternalmedicine\/fullarticle\/2825457"}},"subtitle":["A Randomized Clinical Trial"],"short-title":[],"issued":{"date-parts":[[2024,12,1]]},"references-count":17,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024,12,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamainternmed.2024.5726","relation":{},"ISSN":["2168-6106"],"issn-type":[{"value":"2168-6106","type":"print"}],"subject":[],"published":{"date-parts":[[2024,12,1]]}}}