Vitamin D and Bone Formation
Let us now further explore the key factors involved in bone formation—Vitamin D and Vitamin K. In the previous text, we discussed how Vitamin C plays an essential role as a cofactor in collagen synthesis, and we will cover Vitamin K in the following article. In the final article in this series on bones we will discusses antiresorptive agents and anabolic agents, and most of them are prescribed when osteoporosis has already progressed to a certain degree. Bone density reduction due to aging may be an unavoidable part of life. However, even so, this opportunity to delve into the intricate mechanisms of bone remodeling offers meaningful value if we take a closer look at the vital nutrients associated with bone formation.
Vitamin D and Bone Health
Vitamin D is an essential nutrient for maintaining healthy bones. Calcium is one of the most critical components in forming hydroxyapatite crystals, the mineral substance of bone. The human body must maintain stable calcium levels in the blood to function normally. If calcium is not well absorbed from the diet and blood calcium levels drop, the parathyroid hormone will instruct bone to break down to regulate calcium levels, as previously discussed. Vitamin D is the nutrient that aids the intestines in efficiently absorbing calcium. It also plays a role in preventing calcium from being excreted via the kidneys and promotes its reabsorption into the bloodstream. This means that no matter how much calcium is consumed, without the help of Vitamin D, strong bones cannot be assured. While the saying "You are what you eat" was once popular, a more accurate expression might be "You are what you absorb." Ultimately, the gut matters more than the mouth. Thus, "You are not what you eat, but what you absorb" is the more appropriate saying.
Vitamin D Biosynthesis
Vitamin D can be consumed through foods like salmon, mackerel, and egg yolks or supplements, but fortunately, the human body can also synthesize it on its own. This synthesis begins in a very cheap and simple way—by exposing the skin to sunlight. Let’s examine this process in detail. Vitamin D is one of the fat-soluble vitamins, part of the ADEK group. Being fat-soluble means it is not water-friendly and requires assistance from other substances to circulate in the bloodstream. However, it can pass through lipid membranes of cells and nuclei with ease. Let’s follow the biosynthesis of Vitamin D, starting from the skin and passing through the liver and kidneys to form its active form.
Vitamin D is closely related to cholesterol. 7-Dehydrocholesterol, the precursor of Vitamin D3, is produced in the final steps of the cholesterol biosynthesis pathway. When exposed to UVB (ultraviolet B) rays, it converts into pre-vitamin D3 in the skin. Without UVB, 7-Dehydrocholesterol is reduced to 100% cholesterol by the enzyme 7-Dehydrocholesterol Reductase (DHCR7). In other words, without sunlight, it becomes cholesterol; with sunlight, it becomes Vitamin D3.
The pre-vitamin D3 produced in keratinocytes in the epidermis is converted by body heat into stable Vitamin D3, or cholecalciferol. However, this form of Vitamin D3 is inactive and must undergo two additional activation steps to perform physiological functions. First, it travels to the liver. Since it is fat-soluble, it moves with the help of Vitamin D Binding Protein (DBP). In the liver, a hydroxyl group is added to the 25th carbon, converting it into calcidiol. Then, it moves to the kidneys, where another hydroxyl group is added to the 1st carbon. This second hydroxylation increases its binding affinity to the Vitamin D Receptor (VDR) by more than a thousandfold. Once both hydroxylations are completed, it becomes calcitriol—the active form—which acts like a steroid hormone, entering the nucleus and regulating gene expression. This hormone-like function is why Vitamin D is often regarded as a hormone. The genes transcribed under the influence of calcitriol include the TRPV6 calcium channel protein in the intestines for early calcium absorption, the TRPV5 channel protein in the kidneys for calcium reabsorption, and RANKL and OPG involved in osteoclast activation. Therefore, Vitamin D plays a crucial role in maintaining blood calcium homeostasis.
Vitamin D and the Cholesterol Synthesis Pathway
Cholesterol, one of the most important biomolecules synthesized by the human body, is not based on fatty acids but on a hydrocarbon compound called isoprene. These are synthesized from two molecules of acetyl-CoA, which are derived from pyruvate (from glucose breakdown) and from the beta-oxidation of fatty acids. Inside the mitochondria, acetyl-CoA enters the TCA cycle, producing NADH and FADH2, which are used to generate ATP through the electron transport chain. Some acetyl-CoA exits the mitochondria in the form of citrate and moves into the cytosol, where two molecules combine and proceed through the mevalonate pathway to form isoprenoid units (IPP, DMAPP). These compounds polymerize to form squalene and undergo more than 30 steps to finally become cholesterol. The fact that just two acetyl-CoA molecules undergo so many steps to synthesize cholesterol indicates how crucial this molecule is for human survival, requiring precise and cautious regulation. A proper understanding of cholesterol is often lacking. Statin drugs, which inhibit cholesterol synthesis, act early in the 30-step pathway and thereby block all downstream pathways. Hence, attention and necessary measures are required. Inhibiting cholesterol synthesis also suppresses the production of Vitamin D precursors. Therefore, those taking statins might consider supplementing with Vitamin D.
Recommended Intake of Vitamin D
Vitamin D daily intake recommendations vary slightly among organizations, but typically range from 600 IU to a maximum of 2,000 IU. While individual needs may vary based on age and health status, 800–1,000 IU is considered an appropriate amount for most, and 1,500–2,000 IU is recommended for the elderly or those at risk of osteoporosis.
For those relying on sunlight rather than food or supplements for Vitamin D, it helps to understand the types and properties of ultraviolet rays. Ultraviolet (UV) rays are classified by wavelength into UVA, UVB, and UVC. UVC (100–280 nm) is almost entirely absorbed by the ozone layer and has minimal relevance to humans. UVA (320–400 nm) makes up about 95% of UV rays reaching the earth’s surface and penetrates the dermis, contributing to aging, pigmentation, oxidative stress, DNA damage, and skin cancer—but it does not aid in Vitamin D synthesis. Excessive UVA exposure may even impair Vitamin D biosynthesis. UVA is also difficult to fully block with most SPF products. UVB (280–320 nm), which constitutes about 5% of UV rays, reaches the epidermis, potentially causing erythema or burns, but is key to Vitamin D synthesis. Note that typical window glass blocks or reflects most UVB, making effective synthesis through indoor sunlight exposure impossible.
The internationally standardized Ultraviolet (UV) Index, which was jointly developed by global organizations and is used in most countries around the world, quantifies the intensity of ultraviolet exposure on a scale from 0 to 11+. It is said that vitamin D synthesis begins when the UVB index reaches at least 3. As latitude increases, the amount of UVB (290–315 nm) reaching the earth's surface decreases, so Vitamin D synthesis varies seasonally above 35° latitude. In summer, about 15 minutes of sun exposure during high sun can yield about 1,000 IU, while other times or in winter, about 20 minutes of full-body exposure is needed. In high latitudes or darker skin (with more melanin), only about 200 IU may be produced, requiring longer exposure. Adults over 70 synthesize up to four times less 7-dehydrocholesterol than people in their 20s. [1] These factors indicate that relying solely on sunlight may not suffice for Vitamin D synthesis.
Other Effects of Vitamin D
Insulin Sensitivity
We’ve examined how Vitamin D affects calcium absorption and bone health, but its influence doesn’t end there. Despite conflicting study results, many researchers suggest that Vitamin D deficiency increases the risk of insulin resistance (IR)—a central pathology in type 2 diabetes, metabolic syndrome, impaired fasting glucose, non-alcoholic fatty liver disease, and polycystic ovary syndrome. Vitamin D may enhance insulin sensitivity by increasing insulin receptor expression in muscles, liver, and adipose tissues, while also supporting pancreatic function and reducing inflammation. As we’ve seen, Vitamin D becomes active after a second hydroxylation step, and this hydroxylase enzyme (CYP27B1) exists not only in the kidneys but also in the pancreas, muscles, and liver.[2] This means Vitamin D can be activated locally in these tissues. The promoter region of the insulin receptor gene contains a Vitamin D response element, allowing Vitamin D to promote gene transcription. Skeletal muscle, critical for postprandial glucose uptake, may have its glucose utilization capacity improved by Vitamin D, thereby improving insulin sensitivity. Some suggest that Vitamin D supplementation may help improve HbA1c and insulin levels and could be used as adjunct therapy in diabetes treatment. [3]
Immune Function, Antioxidant Activity, and Obesity
Vitamin D also relates to immune function. Various immune cells—macrophages/monocytes, antigen-presenting cells (APCs), T cells, and B cells—express CYP27B1 and can activate Vitamin D locally. Active Vitamin D (calcitriol) reduces inflammatory cytokine production in dendritic cells and promotes a shift in macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. In T cells, Vitamin D induces anti-inflammatory cytokines like Treg and IL-10 to suppress excessive immune responses. Thus, Vitamin D may help prevent autoimmune diseases. It is thought to regulate immune system development during early years of life, promoting tolerance toward self-cells. A deficiency in this period may increase the risk of autoimmune conditions, such as type 1 diabetes, where the immune system attacks β-cells in the pancreas.
Though not a direct antioxidant, Vitamin D contributes to antioxidant defense by promoting the expression of intracellular antioxidants like glutathione (GSH), glutathione peroxidase (Gpx), and superoxide dismutase (SOD), thereby reducing oxidative stress.
In obese individuals, inactive Vitamin D (cholecalciferol), whether synthesized in the skin or absorbed through food, may be sequestered in adipose tissue due to its fat-soluble nature, impeding its transport to the liver for activation. As a result, blood levels of Vitamin D may be lower in obese individuals, negatively affecting immune and metabolic function.
[References]
[1] Vitamin D and Bone Health; Potential Mechanisms
https://pmc.ncbi.nlm.nih.gov/articles/PMC3257679/
[2] The Role of Vitamin D and Its Molecular Bases in Insulin Resistance, Diabetes, Metabolic Syndrome, and Cardiovascular Disease: State of the Art
doi: 10.3390/ijms242015485
[3] Efficacy of vitamin D supplementation on glycemic control in type 2 diabetes patients
doi: 10.1097/MD.0000000000014970
