nocturnal leg cramps: vitamin K2 helps

 A recent study found that vitamin K2 decreased nocturnal leg cramps in older patients (see nocturnal cramps vit K2 helps JAMAintmed2024 in dropbox, or doi:10.1001/jamainternmed.2024.5726)

 

Details:

--199 community-dwelling individuals 65 years and older participated in this multicenter, double-blind, placebo-controlled randomized clinical trial conducted in China between September 2022 and December 2023

    -- all had 2 or more documented episodes of nocturnal leg cramps (NLCs) during 2 weeks of screening

-- 103 participants were randomly assigned to 180 μg vitamin K2 (menaquinone 7) capsules or a similar-looking placebo every day for 8 weeks, 96 patients were randomized to placebo

-- 108 (54%) were female, mean age 72 years

-- hypertension 68%, diabetes 51%, serum creatinine 0.89 mg/dL

-- baseline weekly frequency of cramps was 2.60 in the vitamin K2 group and 2.71 in the placebo group

-- patients with other relevant conditions (restless leg syndrome, claudication, myositis, peripheral neuropathy) were excluded by history and physical exam

-- other exclusions included patients with hypothyroidism, hemodialysis, hypoglycemia, alcoholism, amyotrophic lateral sclerosis, poliomyelitis complications, lumbar spinal stenosis, Parkinson disease, radiculopathies, motor neuron diseases, malignant tumors, use of diuretics, taking either vitamin K antagonists or vitamin K2 supplements within the 2 months before enrollment.

-- the primary outcome was the mean number of NLCs per week between the vitamin K2 and the placebo group

-- 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

 

Results:

-- treatment adherence:

    -- vitamin K2 group: 92%

    -- placebo group: 87%

 

-- mean frequency of cramps during the 8-week intervention:

    -- vitamin K2 group: 0.96

    -- placebo group: 3.63

        -- between-group difference −2.67 (−2.86 to −2.49), P < .001

            -- the between-group difference became significant beginning the first week of the intervention

 

-- NLC severity, on analog scale of 1-10:

    -- vitamin K2 group: 1.12

    -- placebo group: 2.08

        -- between-group difference -0.97 (-1.14 to -0.79)

-- NLC duration:

    -- vitamin K2 group: 0.25minutes

    -- placebo group: 0.98 minutes

         -- between-group difference -0.73 (-0.80 to -0.65)

 

-- Adverse events: none identified

 

Commentary:

-- vitamin K2, also called K2-7 or menaquinone-7 (MK-7 was the one studied though there is also MK-4), is a form of the fat-soluble vitamin K; K2-7 is absorbed more readily and is more bioavailable than vitamin K1 (phylloquinone): https://pmc.ncbi.nlm.nih.gov/articles/PMC9237441/

-- vitamin K1 is a product present in all photosynthetic plants, is responsible for clotting factors, and can be converted to K2 in humans by bacterial production or conversion from dietary K1: https://pmc.ncbi.nlm.nih.gov/articles/PMC3321250/ and https://www.ncbi.nlm.nih.gov/books/NBK551578/

-- there is some evidence that K2 has a longer half-life

-- vitamin K2 has health-beneficial effects in the following diseases (much info on the following diseases that seem to be related in part to vitamin K deficiency are elaborated in https://link.springer.com/article/10.1007/s11154-019-09517-9 and the associated references):

       -- osteoporosis: there are some studies suggesting that bone mineral density improved by vitamin K2; eg, finding decreased loss of vertebral height in the lower thoracic region, and reduction in bone fractures (https://pmc.ncbi.nlm.nih.gov/articles/PMC7760385/)

            -- however, BMD is a surrogate marker with incomplete association with clinical bone disease: https://gmodestmedblogs.blogspot.com/2024/06/using-surrogate-markers-for-disease-are.html

            -- and, of note, the vitamin K antagonist warfarin is associated with osteoporosis in men and women: https://pmc.ncbi.nlm.nih.gov/articles/PMC7053309/

       -- cardiovascular disease: benefit is unclear, though vitamin K-dependent proteins are associated with  preventing calcification within the vascular wall,  including in the cardiovascular system, and protection of endothelial cells: https://www.spandidos-publications.com/10.3892/mmr.2018.8940

       -- diabetes: osteocalcin (which is decreased by vitamin K) is associated with increased adiponectin, increased systolic blood pressure and LDL concentrations, and increased hemoglobin A1c, and may well be associated with the development of diabetes:  https://academic.oup.com/jcem/article-abstract/94/1/45/2597641?redirectedFrom=fulltext

    -- inflammation: vitamin K supplementation has been found to decrease C-reactive protein levels: https://pubmed.ncbi.nlm.nih.gov/29968548/

    -- cancer: though studies are a bit mixed, observational studies have found that vitamin K deficiency is associated with hepatocellular carcinoma, with vitamin K found to inhibit growth of HCC cells as well as their invasiveness, and it induces apoptosis: https://pmc.ncbi.nlm.nih.gov/articles/PMC4568524/

    -- Alzheimer’s disease: in older individuals, higher intake of vitamin K is associated with better cognitive function, and higher levels of Menaquinone-4  in brain tissue is associated with a 17-20% lower odds of dementia or mild cognitive impairment, a 14-16% lower odds of Braak stage ≥IV (a semiquantitative measure of the severity of neurofibrillary tangle pathology), and lower Alzheimer's disease global pathology scores:  https://pmc.ncbi.nlm.nih.gov/articles/PMC9019903/

    -- peripheral neuropathy: a study of MK7 decreased the symptoms of peripheral neuropathy in a study of 100 patients with diabetic or B12 associated neuropathy, at a dose of 100 mcg twice a day: https://pmc.ncbi.nlm.nih.gov/articles/PMC8483258/

-- a prior study by the same researchers as the current one found effectiveness of K2 in a small group of patients on hemodialysis: https://www.sciencedirect.com/science/article/pii/S0899900722000211?via%3Dihub#tbl0002

-- this current randomized clinical trial showed that vitamin K2 supplementation significantly reduced the frequency, intensity, and duration of NLCs in an older population, and with good safety

-- the Food and Nutrition Board at the Institute of Medicine provided input on what the adequate intake of vitamin K should be by ages, noting that the "maximum daily intake was unlikley to cause adverse health effects": https://ods.od.nih.gov/factsheets/VitaminK-HealthProfessional/, and no known toxicity for high amounts of either vitamin K1 or K2 from food or supplements

 

Limitations 

-- this study was done in single country (China) and the results may not be generalizable to other areas with different cultures including different diets and exercise. for example, stretching exercises are often helpful for prevention of recurrent NLCs, and it is likely that these are done more often in older people in China with the many doing regular taichi. there may also be additional benefit from increased regular exercise, shoes with more hindfood support, and avoiding drugs, alcohol, caffeine, exercise in extreme heat or on concrete floors

-- there was little background information that might be important, such as levels of baseline magnesium, calcium, phosphorus, cystatin C, A1c, CK, LFTs, and TSH, limiting the generalizability of the results (they did exclude patients with many of the associated conditions as noted above, but details were not published; it is not clear how much of a workup was done to assess these electrolyte abnormalities etc.) Also no comment on the amount of liquid consumption and types/level of hydration (since dehydration is a common cause of NLCs)

-- unclear if these results are generalizable to a younger group of patients, since this study only included those >65yo

--  there was pretty clear benefit of vitamin K2 for improving nocturnal cramps, so one might assume that there would therefore be K2 benefit for sleep quality and quantity, but this should be measured (and was not in this study)

-- this study was also done on community-based elderly who had only moderate cramps (2.7 on a scale to 10), and one cannot assume it would equally apply to those with more severe cramps; however, in the quite small hemodialysis study done by these same authors, the baseline cramp severity was 7 and decreased 2.7 with vitamin K2

So, vitamin K2 might be a very useful intervention for people >65yo who have recurrent and severe night cramps (though not in those on warfarin):

    -- It appears to be quite effective in decreasing the number of nocturnal leg cramps, as well as their severity and their duration

    -- zero adverse effects were found (and the FDA does not even list an upper limit on how much should be taken because of this...)

    -- and it appears to works within one week of starting it

geoff

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