Reading the diagram — the five systems in plain language
The diagram above maps five interdependent systems. Each one is a point of potential failure. Inadequate function at any point in this chain can produce functional vitamin D insufficiency even in the presence of a "normal" 25-OH-D blood result.
1 — The source: skin synthesis and dietary intake
Vitamin D enters the body either through UVB-driven skin synthesis or through dietary consumption — food sources (fatty fish, liver, eggs) or supplementation. At Scottish latitudes from October to March, skin synthesis is essentially unavailable regardless of outdoor time. The dietary and supplemental pathway carries the entire burden during this period. The body makes no distinction between the two sources — both produce D3 that enters the liver for processing.
2 — Liver hydroxylation: producing the storage form
The liver converts D3 to 25-hydroxyvitamin D — calcidiol — via the enzyme 25-hydroxylase. This is the storage form measured by standard blood tests. Liver disease and severe hepatic dysfunction can impair this step, but it is generally the most robust part of the pathway and rarely the rate-limiting factor in insufficiency. The more important point is what this measurement does not tell you: calcidiol is biologically inactive. It is a precursor. Storage is not function.
3 — Kidney hydroxylation: the rate-limiting step
The kidney converts 25-OH-D to 1,25-dihydroxyvitamin D — calcitriol — via the enzyme 1-alpha-hydroxylase. This is the active hormonal form that produces biological effects by binding to the vitamin D receptor. This conversion is the rate-limiting step in the entire pathway and is tightly regulated by several signals:
| Regulatory Signal | Effect on Kidney Conversion | Clinical Implication |
|---|---|---|
| PTH (low calcium → PTH rises) | Strongly stimulates 1α-hydroxylase — increases calcitriol production | PTH is the primary driver of kidney vitamin D activation. When calcium falls, PTH rises to activate more vitamin D, which increases calcium absorption. The system is designed to maintain calcium homeostasis, not to optimise immune or neurological function. |
| Low phosphate (PO4) | Stimulates 1α-hydroxylase | Phosphate-restricted diets or malabsorption can drive excess calcitriol production independently of vitamin D status. |
| FGF23 (fibroblast growth factor 23) | Inhibits 1α-hydroxylase | Produced by bone in response to high phosphate and high calcitriol. Acts as a brake on conversion. Chronically elevated in chronic kidney disease. |
| Chronic kidney disease | Severely impairs 1α-hydroxylase activity | CKD patients can have normal or even high 25-OH-D while being severely deficient in active calcitriol. Standard vitamin D testing alone is inadequate for this population. |
| Inflammation (elevated cytokines) | Diverts calcitriol production toward local immune use | In chronic inflammatory states, locally produced calcitriol is consumed by the immune response rather than contributing to systemic calcium regulation. Systemic 25-OH-D looks normal; functional availability is reduced. |
4 — Magnesium: the cofactor at every step
Magnesium is required for the activity of 25-hydroxylase (liver step), 1-alpha-hydroxylase (kidney step), and for the vitamin D receptor to function correctly in target tissues. It is also required for PTH secretion and action. A person who is magnesium-insufficient — which, as we have established in the food-as-foundation post, is the majority of people on a Western diet — has reduced efficiency at every stage of this pathway simultaneously.
This is why supplementing vitamin D without addressing magnesium status produces sub-optimal results in many people, and why some individuals experience adverse effects from vitamin D supplementation (including increased calcium-related symptoms) that resolve when magnesium is added. The cofactor was missing. The system was running on one wheel.
5 — Vitamin K2: directing where calcium goes
Calcitriol increases intestinal calcium absorption. If adequate vitamin K2 is not present, this calcium is less efficiently directed to bone and teeth via the K2-dependent proteins osteocalcin and matrix Gla protein (MGP). In the absence of K2, increased calcium absorption from vitamin D supplementation can contribute to arterial calcification — the calcium deposits that are associated with cardiovascular risk rather than with bone strength. This is the mechanistic argument for always supplementing D3 and K2 together, which is the clinical standard in functional medicine and increasingly recognised in conventional cardiology research.
When the ratio matters more than the number — a clinical note on autoimmune contexts
What can go wrong — and what it looks like clinically
What this means clinically — the panel that tells the story
The clinical picture of the vitamin D mineral axis requires more than a 25-OH-D measurement. The markers that complete the picture include: PTH (to assess parathyroid response and functional calcium status), calcium (serum and ideally ionised), magnesium (serum as a minimum, though intracellular is more accurate), phosphate, and where kidney function is a concern, eGFR and creatinine. On the comprehensive Randox blood chemistry panel used in the TDG programme, all of these are included — and are interpreted together, not in isolation.
"Vitamin D is not a vitamin. It is a hormone precursor that operates within a mineral regulatory system. A single number — even an optimal one — cannot tell you how that system is functioning. The system is what requires assessment."
The full mineral axis — part of every TDG blood chemistry panel
25-OH-D, PTH, calcium, magnesium, phosphate, and the full metabolic picture — interpreted together by a practitioner with 37 years of clinical experience, at functional optimal ranges rather than population reference ranges.
See the TDG Programme →