Vitamin B12 Deficiency Linked to Higher Fracture Hazard

Key Takeaways

• Among adults aged at least 50 years who underwent vitamin B12 testing in a multicenter electronic-record cohort, deficiency was associated with higher subsequent incident fracture hazard than normal concentrations.
• The association persisted in a later sensitivity window after a statistical assumption was violated in the full-period comparison.
• Exploratory fracture-, fall-, and osteoporosis-related associations pointed in a similar direction, without establishing causation or predictive performance.

Earlier evidence linking vitamin B12 status to fracture risk has been inconsistent. For older adults undergoing vitamin B12 testing, it remains unclear whether laboratory-defined deficiency, compared with a normal concentration, is associated with subsequent incident fracture.

Yang and colleagues used TriNetX Global Collaborative Network electronic health records for a retrospective multicenter cohort in their Scientific Reports study of vitamin B12 status and fracture risk. The cohort included adults aged ≥50 years who had undergone vitamin B12 testing. Investigators applied a 1-year landmark design and compared deficiency, defined as ≤199 picograms per milliliter (pg/mL), with normal concentrations of 300–900 pg/mL. After 1:1 propensity score matching, each group contained 115,735 people. The endpoint was subsequent incident fracture.

Across the full analytic period, vitamin B12 deficiency was associated with an incident fracture hazard ratio (HR) of 1.33 (95% confidence interval (CI), 1.29–1.38) relative to normal concentrations. The estimate compares relative fracture hazard, not the proportion of people who sustained a fracture.

The full-period analysis violated the proportional hazards assumption, prompting a sensitivity analysis focused on years 1–5. In that window, the fracture HR was 1.37 (95% CI, 1.32–1.42), with no evidence of non-proportionality. Exploratory secondary analyses showed directionally similar associations for fracture-, fall-, and osteoporosis-related outcomes. The accompanying study report also describes weaker, exploratory fracture-hazard associations at borderline and high B12 concentrations; these findings do not establish a simple deficiency-specific or dose-response pattern.

These associations apply to people who underwent vitamin B12 testing and remained event-free through the landmark period, rather than to all older adults. Abnormal vitamin B12 concentrations may partly reflect broader nutritional status, comorbidity, or healthcare utilization. Matching and the sensitivity analysis do not resolve those possible explanations or establish that deficiency causes fractures or predicts individual fracture risk.

Yang and colleagues concluded that deficiency was associated with subsequent fracture hazard in this matched, tested population, without establishing a causal relationship or an independently predictive fracture marker.

Clinician Questions

Do vitamin B12–fracture hazard ratios show an individual patient's absolute fracture risk?

No. The estimates compare subsequent fracture hazard between tested groups defined by vitamin B12 concentrations; they cannot tell a clinician an individual patient's probability of fracture.

Do the vitamin B12–fracture estimates characterize borderline or above-normal B12 levels?

No. The reported comparison covers deficiency and normal concentrations; it does not characterize fracture associations for concentrations between or above those ranges.