An analysis published in the Nutrition Journal suggests that an increased consumption of riboflavin, vitamin B2, is associated with a lower risk of developing osteoporosis. Data was collected from over 4,000 women participating in the National Health and Nutrition Examination Survey (NHANES), a cross-sectional representative study of the U.S. population, including estimates of riboflavin intake as well as dual-energy X-ray absorptiometry (DXA) measurements of femur bone mineral density (BMD). Riboflavin intake was estimated by an average of two 24-hour dietary recall interviews conducted within 10 days of each other. Multiple other covariates were included in the assessment, ranging from behavioral factors such as smoking and physical activity, to medical conditions (e.g., diabetes, prednisone use) and vitamin D supplementation. Finally, a network pharmacological analysis was performed, identifying potential targets and mechanisms via which riboflavin may have related effects.
In a model that adjusted for all covariates, a higher riboflavin intake was linked to a lower risk for osteoporosis. In this model, women in the highest quartile of riboflavin intake had a 39% lower incidence of osteoporosis compared to the lowest quartile, as well as a greater BMD in each region of the femur (total, femoral neck, trochanter, and intertrochanter BMD). Unfortunately, the authors did not provide the absolute amount of riboflavin consumed in each quartile, only the mean intake by osteoporosis diagnosis (ranging from 1.69 to 1.92 mg). Yet for each 1 mg increment of increasing riboflavin intake, there was also an elevation in BMD in each region of the femur. It does not appear that riboflavin supplementation was considered, such as would be expected in women taking a multivitamin, another limitation of this study (in addition to the use of 24-hour recalls). There was no significant association between riboflavin and hip fracture, which was self-reported, though a cross-sectional study like this may not capture long-term effects.
A mediation analysis found that serum alkaline phosphatase (ALP) mediated a significant portion of the association between riboflavin and BMD, around 12% of the connection with osteoporosis. Dietary riboflavin levels were negatively associated with ALP, and in turn, ALP levels were negatively associated with BMD. This finding of a negative association between ALP and BMD (i.e., higher levels of ALP are associated with a lower BMD) is not new; it has been observed in both a younger population as well as among postmenopausal women with osteoporosis. The authors note that a compromise in bone mineralization leads to excessive production of ALP by osteoblasts, and thus serum ALP (especially the bone-specific isozyme) is a marker for high bone turnover. It’s plausible that higher riboflavin intakes successfully promoted healthy bone formation, marked by a decline in ALP levels.
The network pharmacological analysis points to a number of pathways by which riboflavin may do just that. For example, a total of 37 overlapping genetic targets between riboflavin, osteogenic, and osteoclastic processes were found, i.e., pathways that riboflavin can influence bone health. The top 10 genetic candidates were established (HIF1A, HDAC4, HDAC3, HDAC2, BCL2, TP53, MYC, NFKB1, PPARG, and PPARGC1A), with functions related to inflammation and other well-established signaling pathways (HIF-1, p53, AGE-RAGE, longevity regulating, etc.). Lastly, the apparent protective effect of riboflavin was most pronounced among women with insufficient physical activity.
This study is not the first to find a BMD-promoting association with riboflavin, one which may depend on intraindividual factors (such as limited physical activity). One large study with over 5600 Chinese adult men and women found that the prevalence of osteoporosis decreased with increasing riboflavin intake, but only among women. In another large cohort that included more than 5,000 men and women over the age of 55, the Rotterdam study, riboflavin intake did not correlate with BMD in the overall study population. However, in the lowest quartile of riboflavin intake, women homozygous for a single-nucleotide polymorphism in the MTHFR gene (C677T, TT genotype) had a nearly 2-fold increase in risk for osteoporotic fracture and a 2.6-fold increase in fragility fractures compared to the CC genotype.
This riboflavin-MTHFR interaction has been observed in other studies and other health conditions; for example, in an observational study with more than 6,000 adults, among people with the TT genotype not only is the risk for incident hypertension elevated (42% higher) compared to the CC genotype, but hypertension risk is dependent on riboflavin intake. Indeed, this study found a 3-fold risk for hypertension when comparing low riboflavin intake and a TT genotype compared to normal intake and the CC genotype. On the other hand, treatment with even a low dose of riboflavin (1.6 mg per day) was found to decrease blood pressure “more effectively than treatment with current antihypertensive drugs only” among people with hypertension and the TT genotype in a randomized clinical trial.
A number of other mechanisms were proposed in this recent analysis. Riboflavin is also needed for the conversion of oxidized glutathione (GSSG) back to its reduced form (GSH) by the enzyme glutathione reductase. An increase in oxidative stress with low riboflavin intake (and a consequent low GSH status) may also impair the osteogenic capacity of bone-producing cells, and may help explain the association with low physical activity (e.g., increased oxidative burden). While there were multiple limitations to this study and it was not a clinical trial, it does suggest that riboflavin may play an important role in maintaining bone health and should be an important component of a healthy bone-promoting diet.
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