*Geek Box: Bertrand’s Rule
The French biological scientist and biochemist, Gabriel Bertrand, first published what became known as ‘Bertrand’s Rule’ in 1912. In effect, Bertrand’s Rule describes the dose-response bell-curve of biological activity for micronutrients and trace minerals. The rule states that if a nutrient is required for a specific function, this function [effect] will be be low or absent in a deficiency state, and the function will increase with increasing levels of the nutrient from a deficiency. This increase in function is followed by a plateau in the range of adequate intake, then impairment of function if the mechanisms regulating that nutrient are overwhelmed from excessive intake.
For each nutrient, therefore, there is a range of intake that is adequate; differences in effect are not likely to be observed comparing levels within this range. An important point in this respect is that the biological activity of nutrients are absolutely specific: deficiency can only be prevented by that element, not by another, even if they are chemically related. E.g., iron and zinc may be metal minerals, but zinc can’t prevent/reverse anaemia. Calcium may be crucial for bone health, but only vitamin D adequacy will prevent rickets. Unfortunately, very little heed is given to this fundamental rule of nutrient action outside of the field of nutrition. This tends to manifest as an issue primarily in randomised controlled trials, because the implication of Bertrand’s rule is that if nutrient status is within the adequacy range, then relatively optimal biological function will be maintained.
Thus, many ’null’ effects in RCTs are null by design, not null because there is no effect of the nutrient; it is a biological fact that there is an effect of a nutrient. As the null hypothesis of an RCT on a nutrient supplement is, “Nutrient A has no effect on health outcome B”, this is inconsistent with the biological fact that all nutrients have biological activity and influence health status. It is the nutritional status of the participants being compared that may explain the lack of difference between comparison groups.