Your skeleton holds about a kilogram of calcium. All the fluid outside your cells holds only about a gram, and your blood plasma about a quarter of that, yet that small pool is the calcium your nerves, muscles and heart depend on from second to second. This page explains calcium homeostasis and bone: the normal blood calcium range, why the level must be held so tightly, what happens when it falls or rises, the negative feedback loop that uses bone, the kidneys and the intestine to control it, and the nutrients that keep the whole system supplied.
A patient whose bones are emptying into her blood
Mrs. Chen, 66, is being treated for breast cancer. Over two weeks she has become weak, thirsty, sleepy and confused, and her bowels have almost stopped. Her blood test shows a calcium of 14.2 mg/dL, far above normal. The cancer has spread to her bones, and the tumor cells there are driving osteoclasts to dissolve bone faster than her body can clear the calcium. Her kidneys and brain are now struggling with the excess. To make sense of her symptoms, you need to know what the normal level is, why calcium matters so much, and how your body normally holds it steady.
The normal blood calcium range
Blood calcium is the concentration of calcium in the plasma, the liquid part of the blood. In a healthy adult, the total is held between about 8.5 and 10.5 mg/dL (about 2.1 to 2.6 mmol/L). That is the normal blood calcium range, and your body holds each person's level within a much narrower band inside it, often within a few percent of its set point from one day to the next.
Not all of that calcium is equally active. Plasma calcium comes in three forms:
- Free calcium ions (Ca2+), about half. This is the form that cells sense and use, and the form the feedback loop controls.
- Calcium bound to proteins in the plasma, about 40%. Bound calcium is a reserve that trades with the free pool.
- Calcium bound to small ions such as phosphate and citrate, about 10%.
Where is the rest of your calcium? About 99% is in bone and teeth, as calcium phosphate crystals. About 1% is inside cells, where it is kept very low in the cytosol, about 10,000 times lower than outside, and stored in organelles. Only about 0.1% is in the extracellular fluid, including the blood. So the blood is a tiny pool sitting next to a huge store, and the flow between the two is what keeps the blood level steady.
Why the calcium level matters
Calcium ions do several jobs that depend on their concentration:
- Excitability of nerve and muscle. Calcium ions outside the cell sit on the outer face of the plasma membrane, near voltage-gated sodium channels. There they make it harder for the channels to open. So the calcium level outside sets how easily nerve and muscle cells, the excitable cells you met with electrical signals, fire action potentials.
- Muscle contraction. A rise in calcium inside a muscle cell triggers contraction in skeletal, cardiac and smooth muscle. Heart muscle depends especially on calcium entering from the extracellular fluid with each beat.
- Neurotransmitter release. When an action potential reaches the end of a neuron, calcium enters, and that triggers exocytosis of neurotransmitter at the synapse.
- Blood clotting. Several steps in forming a blood clot need calcium ions.
- Signaling inside cells. Calcium acts as a second messenger in many cells, including hormone-secreting cells.
- Bone mineral. New osteoid can mineralize only if enough calcium and phosphate are available.
Because excitability is so sensitive to extracellular calcium, both a low and a high level cause trouble, and the troubles are opposites.
Hypocalcemia
Hypocalcemia (hypo- = under, calc- = calcium, -emia = blood condition) is a blood calcium below the normal range. With fewer calcium ions on the outside of the membrane, voltage-gated sodium channels open more easily, so neurons and muscle fibers fire with little or no stimulus. The result is overexcitability:
- tingling around the mouth and in the fingers and toes;
- muscle cramps and spasms (tetany). A classic sign: inflating a blood pressure cuff on the arm makes the hand cramp into a claw;
- in severe cases, spasm of the muscles of the voice box that narrows the airway, seizures, and heart rhythm problems.
Hypercalcemia
Hypercalcemia (hyper- = over) is a blood calcium above the normal range. Extra calcium makes the sodium channels harder to open, so nerves and muscles become less excitable:
- muscle weakness and tiredness;
- a slowed gut, with poor appetite, nausea and hard stools;
- low mood, drowsiness, confusion and, if very high, coma;
- heart rhythm problems;
- thirst and large volumes of urine, because high calcium stops the kidneys from concentrating urine, and stones of calcium salts in the kidneys.
| Hypocalcemia | Hypercalcemia | |
|---|---|---|
| Blood calcium | Below about 8.5 mg/dL | Above about 10.5 mg/dL |
| Voltage-gated sodium channels | Open more easily | Harder to open |
| Nerves and muscles | Overexcitable | Less excitable |
| Typical signs | Tingling, cramps, tetany, seizures | Weakness, tiredness, confusion, slow gut |
| Kidneys | Usually no direct problem | Large volumes of urine, thirst, stones |
| Common causes | Too little of the calcium-raising hormone (often after neck surgery), severe vitamin D deficiency | Too much of the calcium-raising hormone, cancer in bone |
A memory trick: calcium outside the cell acts like a brake on the sodium channels. Too little calcium, too little brake: everything fires. Too much calcium, too much brake: everything slows.
That is exactly what Mrs. Chen shows. Her weakness, confusion and stalled bowels are the "too much brake" of hypercalcemia, and her thirst comes from her kidneys losing water.
The blood calcium feedback loop
Blood calcium is held steady by the blood calcium feedback loop, a negative feedback loop like those you met in Homeostasis and feedback loops (Figure 1). Its parts:
- Regulated variable: the free calcium ion concentration in the blood.
- Sensory receptor and control center: the cells of four tiny glands on the back of the thyroid gland. Their membranes carry a receptor protein that binds calcium ions. When calcium falls, fewer ions bind, and the cells release more of a calcium-raising hormone within seconds. When calcium rises, they release less. The same cells both sense the change and decide the response.
- Effectors: three organs that can move calcium into or out of the blood: bone, the kidneys and the intestine.
When calcium falls
- Fewer calcium ions bind the receptor protein on the gland cells, and they release more calcium-raising hormone.
- Bone: the hormone acts on osteoblasts, which respond by signaling more osteoclasts to form and to work harder. Osteoclasts resorb bone, releasing calcium and phosphate into the blood. Existing osteoclasts speed up within hours; forming new ones takes days.
- Kidneys: the hormone makes the kidney tubules return more calcium from the forming urine to the blood, so less is lost. It also makes them keep less phosphate, so more phosphate leaves in the urine. That matters: the phosphate released from bone would otherwise combine with calcium and lower the free calcium again.
- Kidneys, activating vitamin D: the hormone switches on the kidney step that completes the activation of vitamin D, which you met with the skin.
- Intestine: the activated vitamin D makes the intestinal lining absorb much more calcium, and phosphate, from food. This effect takes a day or more, because it works by making new transport proteins.
- Calcium rises back toward its set point, more ions bind the gland cells' receptor protein, and hormone release falls. That is the negative feedback.
When calcium rises
- More calcium binds the gland cells, and they release less calcium-raising hormone.
- Osteoclast activity falls and bone takes up more calcium than it releases.
- The kidneys return less calcium to the blood, so more is lost in the urine.
- Less vitamin D is activated, so the intestine absorbs less calcium.
- Calcium falls back toward its set point.
A second hormone adds a small extra brake when calcium rises:
Two time scales
The effectors work at different speeds. Bone and the kidneys respond within minutes to hours, so they handle quick changes. The intestine responds over a day or more, so it handles the long run: over weeks, the calcium you absorb must match the calcium you lose, or bone makes up the difference.
Calcium mass balance
Calcium in the blood follows the rule of mass balance: over time, what comes in must equal what goes out. The only way into the body is absorption from the gut. The ways out are the urine and the feces. Bone is a store in between: it can lend calcium to the blood or take it back, but it cannot create any.
Worked example: a day of calcium
Problem. An adult eats 1,000 mg of calcium in a day. Her intestine absorbs 30% of it. Her intestine also releases 150 mg of calcium from the body back into the gut in its secretions, and her kidneys excrete 150 mg in the urine. Is she in calcium balance, and if not, where does the difference come from?
- Calcium absorbed. 30% of 1,000 mg = 0.30 × 1,000 = 300 mg into the blood.
- Net absorption. 300 mg absorbed − 150 mg released back into the gut = 150 mg net gain from the gut.
- Calcium in the feces. 1,000 mg eaten − 300 mg absorbed + 150 mg released back = 850 mg lost in the feces.
- Total output. 850 mg in feces + 150 mg in urine = 1,000 mg.
- Compare. Input 1,000 mg; output 1,000 mg. Net absorption (150 mg) equals urine loss (150 mg).
Answer. She is in balance: bone neither gains nor loses calcium overall. If she ate only 600 mg with the same absorption and losses, she would absorb 180 mg, net 30 mg, and still lose 150 mg in urine. The missing 120 mg a day would come out of her bones, and the loop would hold her blood calcium normal while her skeleton slowly paid for it.
That is the key point. The feedback loop protects blood calcium first, because nerves and the heart cannot wait. Bone is spent to do it. A long-term shortfall in calcium intake or absorption shows up as a normal blood test and a thinning skeleton.
Nutrients for bone health
Bone is built from what you eat. The main nutrients for bone health:
- Calcium. Dietary calcium is the calcium in food. Adults need about 1,000 mg a day; teenagers, who are building bone fastest, about 1,300 mg; and women over 50 and everyone over 70, about 1,200 mg. Good sources are milk, yogurt and cheese, calcium-fortified plant milks and juices, tofu set with calcium, canned fish eaten with its bones, and some leafy greens such as kale. Spinach contains calcium but also compounds that bind it, so little is absorbed.
- Vitamin D. Without it, the intestine absorbs only a small fraction of the calcium you eat. You make it in your skin in sunlight and get some from oily fish, egg yolks and fortified foods. Adults are advised about 600 IU (15 micrograms) a day, 800 IU over age 70; people with little sun exposure often need a supplement. In children, severe deficiency causes rickets, the soft, bowed bones you met with the skin.
- Protein. Collagen is protein, and it makes up most of the organic matrix. Too little protein weakens bone and slows fracture healing.
- Phosphorus. Bone mineral is calcium phosphate. Phosphorus is plentiful in most diets, so shortage is rare.
- Magnesium and several vitamins are also needed to build matrix and mineralize it. You will meet them in the nutrition chapter.
Nutrients are only half of it. Bone also needs load: through Wolff's law, weight-bearing and resistance exercise tell osteocytes to keep bone. Calcium without exercise builds less bone than calcium with it, and heavy drinking and smoking both work against bone however well you eat.
Back to Mrs. Chen
Tumor cells in Mrs. Chen's bones release signals that switch on her osteoclasts, bypassing the feedback loop. Calcium pours out of bone faster than her kidneys can excrete it. Her gland cells sense the high calcium and shut off their calcium-raising hormone, which is exactly the right response, but it cannot stop osteoclasts that are being driven by the tumor. Treatment follows from the loop: fluids through a vein to help the kidneys excrete calcium, and drugs that switch off osteoclasts.