Evidence Review
Nattokinase and Cardiovascular Endpoints
The primary clinical trial base for nattokinase comes from small-to-medium RCTs focused on hypertension and thrombosis markers.
Kim et al. (2008) conducted an 8-week double-blind RCT in 86 participants with prehypertension or stage 1 hypertension randomized to nattokinase (2,000 FU/day) or placebo. The nattokinase group showed significant reductions: systolic BP −5.55 mmHg (p=0.04), diastolic BP −2.84 mmHg (p=0.02), and plasma renin activity −1.17 ng/mL/h (p=0.03) [1]. The renin finding suggests that nattokinase may act partly through the renin-angiotensin-aldosterone system, not only through direct fibrinolytic activity.
Jensen et al. (2016) replicated and extended these findings in a multicenter North American RCT with 79 hypertensive subjects receiving 100mg nattokinase daily for 8 weeks. Diastolic BP fell from 87 to 84 mmHg in the treatment group (statistically significant vs. placebo). In female participants specifically, von Willebrand factor — a recognized independent predictor of cardiovascular events — was significantly reduced, pointing to an antithrombotic effect beyond blood pressure alone [2].
A mechanistic review by Weng et al. (2017) compiled evidence for nattokinase's antithrombotic mechanisms: direct fibrin degradation (nattokinase cleaves fibrin chains at multiple sites), degradation of PAI-1 (which normally inhibits endogenous tissue plasminogen activator), and conversion of prourokinase to active urokinase. The review notes that nattokinase was in Phase II clinical trials in the US for atherothrombotic prevention as of 2017 [3]. A 2024 systematic review and meta-analysis of RCTs (PMID 39076715) pooled data finding nattokinase reduces systolic BP by −3.45 mmHg and diastolic BP by −2.32 mmHg across multiple trials.
Limitations: Most cardiovascular trials are short-duration (8–12 weeks) and small (n<100). Long-term endpoint data (myocardial infarction, stroke) are lacking. Most nattokinase trials use isolated supplements, not the whole food — it is unclear whether digestion alters activity compared to supplement formulations.
Natto and Bone Mineral Density
The most compelling bone evidence comes from two large Japanese epidemiological studies measuring BMD.
Ikeda et al. (2006) followed 944 women from the Japanese Population-Based Osteoporosis Study for 3 years, assessing habitual natto consumption via food frequency questionnaire and measuring BMD at the femoral neck, distal radius, and lumbar spine. Higher natto intake was significantly associated with less femoral neck and radius bone loss in postmenopausal — but not premenopausal — women. Crucially, this association was not present for tofu or isoflavone intake alone, isolating the fermentation-derived products (nattokinase and MK-7) as the relevant factors [4].
Fujita et al. (2012) examined 1,662 elderly men in the FORMEN cohort, finding that habitual natto consumers had significantly higher total hip BMD (p<0.05) and femoral neck BMD (p<0.05). After adjustment for undercarboxylated osteocalcin — a serum biomarker that rises when K2 is insufficient — the BMD association became non-significant, providing strong mediation evidence that MK-7 is the operative mechanism [5].
The MK-7 RCT by Knapen et al. (2013) provides the highest-level evidence: 244 postmenopausal women randomized to 180 mcg MK-7 daily or placebo for 3 years. The MK-7 group showed significantly less decline in bone mineral content at L1–L4 (p=0.014) and BMD at L1–L4 (p=0.004), along with significantly reduced vertebral height loss at thoracic vertebrae T3 and T10. The dose used (180 mcg MK-7) is readily achievable from two to three weekly servings of natto [6].
Nutritional Composition and Broader Properties
A 2022 critical review in Biochemistry Research International catalogued natto's full nutritional and bioactive profile: nattokinase (≥2,000 FU/g), MK-7 (~800–1,100 mcg/100g), isoflavones (genistein, daidzein), gamma-polyglutamic acid (a prebiotic fiber), B. subtilis probiotics, and high protein content (~18g/100g) [7]. The review notes antibacterial activity of natto extracts against H. pylori, Staphylococcus aureus, and antibiotic-resistant strains, though these effects are based primarily on in vitro work.
Warfarin interaction: The high MK-7 content in natto is clinically significant for anticoagulant users. Even a single serving of natto can substantially elevate INR variability in warfarin patients. This is a well-documented drug-food interaction that warrants medical guidance.
Overall evidence quality: The bone evidence is strong — consistent across population studies and supported by a mechanistic RCT using the same MK-7 compound. The cardiovascular evidence is promising but limited by short trial durations and small sample sizes. Gut microbiome effects are plausible given B. subtilis content but require direct clinical investigation.