Calcium

Calcium is an essential element that needs to be ingested in adequate amounts. It turns out that the uptake of calcium from the intestine and its transfer into the blood is relatively inefficient in the absence of Calcitriol Vitamin D. Adequate levels of Calcitriol facilitate the uptake. This is important because hypocalcemia (too little calcium) and hypercalcemia (too much calcium) are problematic and lead to severe health problems (see below).

Calcium has the atomic number of 20, which means it contains 20 protons and 20 electrons. Since the atomic weight is around 40, it also contains 20 neutrons. Calcium has two outer electrons that are highly reactive. As one of the Alkaline earth metals, it readily gives up these electrons and often exists as $Ca^{2+}$ in solution. Due to this high reactivity, elemental calcium is not found. It is most often found in compounds such as $CaCO_{3}$ (calcium carbonate), a crystal that has a good solubility in water ($Ca^{2+}$, $CaCO_{3}^{2-}$).

Hypocalcemia (low calcium levels) can lead to neuromuscular symptoms that may include muscle spasms, cramps, tingling, or numbness, particularly around the mouth and in the extremities. The most characteristic symptom (tetany), involves involuntary contraction of muscles, leading to painful spasms. Sudden drops in calcium levels can also lead to seizures. Cardiac issues can also occur due to low calcium levels can cause changes in the heart’s rhythm, leading to arrhythmias or cardiac arrest in severe cases. Psychological effects such as mood changes, irritability, depression, and mental confusion should not be underestimated.

Hypercalcemia (high calcium levels) can lead to the formation of kidney stones which can cause severe pain and lead to other kidney complications. Digestive problems such as constipation, nausea, vomiting, and abdominal pain are common. Pancreatitis and peptic ulcers have also been associated with hypercalcemia. Similar to hypocalcemia, cardiac arrhythmias such as irregular heartbeats and other cardiovascular complications are associated with hypercalcemia. Neurological symptoms. such as confusion, lethargy, fatigue, and in severe cases, coma, can occur due to high calcium levels and should immediately be treated.

The bone as Calcium Storage Chronic hypocalcemia leads to rickets in children (a condition that affects bone development) and osteomalacia in adults (softening of the bones), increasing the risk of fractures. Interestingly, hypercalcemia also leads to bone conditions such as bone pain and osteoporosis. This might seem counterintuitive, but high blood calcium often results from calcium being leached from the bones.
Bones are not build once and then forgotten about by the body. Instead, they are metabolically active and they are constantly deconstructed and reconstructed. Bones consist mostly of collagen fibers but by themselves, they would not provide enough stability. Calcium in form of hydroxyapatite crystals (Ca10(PO4)6(OH)2) are instrumental in conveying stability together with collagen. In order to be metabolically active, anabolic (constructing) and catabolic (deconstructing) functions need to exist. Two different cell types exist in bones that convey these functionalities (Osteoblasts and Osteoclasts).
Osteoblasts are anabolically active and build new bone tissue while Osteoclasts do the opposite. Similar processes exist for all tissues. Otherwise, stresses on these tissues would lead to a slow deterioration. Most of the calcium in the body (99%) is stored in the bones. In case the blood calcium level drops (hypocalcemia), the parathyroid hormone (PTH) increases Calcitriol levels which in turn leads to a stronger absorption of calcium from the intestines. At the same time, osteoclasts are activated and calcium is released from the bones. There is nothing wrong with this process and bones are intended as calcium storage alongside providing skeletal stability. A problem occurs if either not enough calcium is absorbed or not enough Calcitriol can be formed (e.g., Calcifediol storage is depleted).

parathyroid hormone (low calcium) —activates—> 1α-hydroxylase [1]

parathyroid hormone (low calcium) —activates—> osteoclasts [2]

Remember, PTH activates the enzyme that converts Calcifediol to Calcitriol (1). Therefore, with low calcium and the release of PTH, two mechanisms that increase blood calcium are activated (reactions 1,2).

Calcitonin is a hormone that is released by the thyroid gland in response to high calcium levels. Calcitonin has the opposite effect of PTH. It inhibites osteoclast activity (3) and activates osteoblast activity (4). This should lead to more deposition of calcium in the bones.

calcitonin (high calcium) —inhibits—| osteoclasts [3]

calcitonin (high calcium) —activates—> osteoblasts [4]

Calcitriol —inhibits—| PTH production [5]

The feedback loop of high calcitriol that inhibits PTH production (5) also leads to the lowering of calcium in the blood. The activation of osteoblasts (4) which leads to bone formation is dependent on an osteocalcin, a protein synthesized by osteoblasts that binds calcium (6). The activity of osteocalcin (7) in turn depends on the activation via vitamin K. Without sufficient osteocalcin, or if osteocalcin is not properly activated (due to a deficiency in vitamin K), bone mineralization can be impaired, leading to weaker bones and an increased risk of fractures.

osteoblasts —synthesize—> osteocalcin [6]

vitamin K —activates—> osteocalcin [7]

In summary, low calcium levels trigger PTH, which increases calcitriol and activates osteoclasts to release calcium from bones. High calcium levels trigger calcitonin, which inhibits osteoclasts and activates osteoblasts to deposit calcium into bones. Calcitriol inhibits PTH, reducing calcium release.
Osteocalcin, produced by osteoblasts, binds calcium and depends on vitamin K for activation, ensuring proper bone mineralization.

Calcium levels in the blood

As we saw above, the bones are responisble for calcium storage and release. Therefore they are important for calcium homeostasis (keeping calcium levels in a certain range). In the blood, there are two forms of calcium, one is bound to proteins (typically albumin) and one that is unbound and dissolved in the blood in its ionic Ca2+ form. The total calcium is than the sum of these two calcium forms.

Typical calcium levls in the blood. Two forms are considered (bound to albumin and ionized). The sum provides the total calcium level in the blood.

As pointed out above, the calcium levels in the blood are tightly regulated (e.g., reactions 1-7 and D reguation) and a dysregulation (reaching levels outside the typical range) may lead to bad health outcomes.

With such a complex system, it is not easy to assess whether the calcium levels are optimal. Perhaps bones are being demineralized because too little calcium is absorbed from food. Therefore, a number of tests might need to be taken in conjunction to provide a better picture.
BMD Testing (DXA) assesses the amount of calcium and minerals in bones, indicating overall bone strength. Serum Calcium and Ionized Calcium checks how well the body regulates calcium levels, reflecting bone calcium release. PTH and vitamin D evaluates hormonal regulation of calcium and bone health. Bone turnover markers measure rates of bone formation and resorption. Imaging (X-rays/CT scans) provides visual evidence of bone health. Urine calcium assesses how well the body is retaining calcium. Hence, when in doubt, a simple measure of total serum calcium is not enough and many other tests should be made.

Calcium uptake

Calcium is in many foods (see below), so the ingestion of calcium should not typically pose a problem. Whether the calcium you eat actually ends up in your blood also depends on the levels of Calcitriol (8).

calcitriol —activates—> calbindin [8]

Calcitriol activates calcium binding proteins in the small intestine (e.g., reaction 8). The difference between calcitriol deficiency and sufficiency can have a substantial impact on the absorption of calcium into the blood. In severe vitamin D deficiency, only 10-15% of the dietary calcium is absorbed. With sufficient Calcitriol levels, this rises to 30-40% absorption, a 2 to 4 fold increase of calcium absorption. If you ingest huge amounts of calcium and even supplement large amounts, and have high Calcitriol levels, chronically, this could load your system with calcium which may lead to hypercalcemia in the long run. However, we rather see bone mineralization problems in the world today which implies that either Calcitriol levels are low or calcium uptake is inadequate (unlikely).

Calcium-rich foods

Most any real food you eat contains calcium so it is unlikely, that you do not get enough calcium from food unless you follow a very strict diet, perhaps to deprive yourself of calcium. Which is important in certain conditions, for example, if you have abnormally high Calcitriol due to disesases where for example your macrophages also convert Calcifediol to Calcitriol. In this disease, sarcoidosis, you should limit your calcium intake deliberately.

List of calcium in some foods.

This is just one list, but there are many foods and it might be useful if you check the foods you eat most to get a feal for your dietary uptake of calcium. Some may recommend things like Okinawa coral calcium, but whether that is really needed, should be investigated more closely, since calcium homeostasis is very important and because its dysregulation leads to catastrophic outcomes.

• Calcium
• Ca
• Element
• Mineral