Bones and Calcium Balance

Bone Growth
Bone growth requires the proper hormones and adequate amounts of protein and
calcium.

Anatomy of Bones
Bone is composed largely of an extensive calcified extracellular matrix = calcium
phosphate (hydroxyapatite) crystals + a collagenous lattice support.

Skeletal bones have two layers: an outer layer of dense compact bone and an inner layer
of spongy or trabecular bone.

- Compact bone provides strength and is thickest where support is needed (such as
in the long bones of the legs) or where muscles attach.
- Trabecular bone is less sturdy and has open, cell-filled spaces between struts of
calcified lattice.
- In some bones, a central cavity is filled with marrow.

Linear Bone Growth Occurs in Adolescence

Bone is a dynamic tissue, constantly being formed and broken down.

Bone formation occurs when osteoblasts synthesize and deposit matrix (osteoBlasts
Build bone)

- Bone diameter increases when matrix is deposited on the surface of the bone
- When matrix is added at the ends of long bones, the bone shaft lengthens.
 - When matrix is added on the surface of the bone, bone diameter increases.

Bone breakdown (resorption) occurs when osteoclasts secrete acid that dissolves
calcified matrix (osteoClasts Chew bone)

Linear growth of long bones in children/adolescents occurs along the epiphyseal plate.

- Closer to the epiphysis (end of the bone), chondrocytes continuously divide,

laying down new cartilage and lengthening the bone.
o Chondrocytes = the collagen-producing cells of cartilage.
- Closer to the diaphysis, older chondrocytes die, leaving spaces that
osteoblasts invade to create new bone.
o The osteoblasts secrete calcium phosphate and osteoid (a protein mixture)
on top of the cartilage base. The combination of calcium phosphate and
osteoid creates new bone.
 When osteoblasts complete their work, they revert to a less active form
known as osteocytes.

This bone growth continues as long as the epiphyseal plate is active. In adolescents, sex
hormones eventually inactivate the epiphyseal plate. Because the epiphyseal plates of
various bones close in a regular, ordered sequence, X-rays that show which plates are
open and which have closed can be used to calculate a child’s “bone age.”

Bo
ne Remodeling Occurs Throughout Life
Linear bone growth ceases after adolescence, but bones undergo continual remodeling
throughout life. Most bone turnover in adults takes place in spongy bone, such as that
found in vertebra of the spine.

- The vertebral body has a thin outer layer of compact bone and a large central area
of spongy bone, making it one of the most active regions of bone remodeling.

Bone mass in the body is an example of mass balance.

- Children: bone deposition > bone resorption, and bone mass increases.
 - Young adults up to about age 30: deposition = resorption, bone mass stable
- Age 30 on: resorption > deposition, and bone mass decreases.

Control of Bone Growth

Growth of long bone is under the influence of growth hormone and the insulin-like
growth factors. In the absence of these hormones, normal bone growth does not occur.

Long bone growth is also influenced by steroid sex hormones. The growth spurt of
adolescent boys used to be attributed solely to increased androgen production but it now
appears that estrogens play a significant role in pubertal bone growth in both sexes.

One nonendocrine factor that plays an important role in bone mass is mechanical stress
on the bone.

- High-impact exercise, such as running, helps build bone, but non-weight-bearing

exercise such as swimming will not.
o Osteocytes and chondrocytes act as mechanosensors and are able to
transduce mechanical stimuli into intracellular signals to lay down new bone

Calcium Balance
Physiological Functions of Ca2+
Most calcium in the body—99%, or nearly 2.5 pounds—is found in the bones. This pool is
relatively stable, however, so it is the body’s small fraction of non-bone calcium
that is most critical to physiological functioning. Ca2+ has several physiological
functions:
 1. Signal molecule
2. “cement” in tight junctions, holding cells together
3. Cofactor in the coagulation cascade
o Although Ca2+ is essential for blood coagulation, body Ca2+ concentrations
never decrease to the point at which coagulation is inhibited. However,
removal of Ca2+ from a blood sample will prevent the specimen from
clotting in the test tube.
4. Influences the excitability of neurons
o this function that is most obvious in Ca2+ related disorders.
 plasma Ca2+ too low / hypocalcemia  neuronal permeability to Na+
increases  neurons depolarize, and the nervous system becomes
hyperexcitable.
 In its most extreme form, hypocalcemia causes sustained
contraction (tetany) of the respiratory muscles, resulting in
asphyxiation.
 Plasma Ca2+ too high / hypercalcemia depresses neuromuscular
activity.

Plasma Calcium is Closely Regulated

Because calcium is critical to so many physiological functions, the body’s plasma Ca2+
concentration is very closely regulated.
Calcium homeostasis follows the principle of mass balance:

1. Total body Ca2+ is all the calcium in the body, distributed among three
compartments:
o Extracellular fluid
 Ionized Ca2+ is concentrated in the ECF
 In the plasma, nearly half the Ca2+ is bound to plasma proteins and
other molecules. The unbound Ca2+ is free to diffuse across
membranes through open Ca2+ channels. Total plasma Ca2+
concentration is about 2.5 mM.
o Intracellular Ca2+
 Very small amounts (intracellular [Ca2+] << extracellular [Ca2+])
 Tends to be inside mitochondria and the sarcoplasmic reticulu
o Extracellular matrix (bone)
 Bone is the largest Ca2+ reservoir in the body, with most bone Ca2+ in
the form of calcium phosphate crystals called hydroxyapatite,
Ca10(PO4)6(OH)2.
 Reservoir that can be tapped to maintain plasma Ca2+ homeostasis.
 Usually only a small fraction of bone Ca2+ is ionized and readily
exchangeable, and this pool remains in equilibrium with Ca2+ in the
interstitial fluid.
 2. Intake is the Ca2+ ingested in the diet and absorbed in the small intestine.
o Only about one-third of ingested Ca2+ is absorbed, and unlike organic
nutrients, Ca2+ absorption is hormonally regulated.
 Transcellular Ca2+ absorption is hormonally regulated; paracellular
absorption is unregulated.
 Intestinal calcium absorption takes place both between the cells
(paracellular transport) and through the cells.
 Once inside the cell, Ca2+ binds to a protein called calbindin that helps
keep free intracellular [Ca2+] low. This is necessary because of the role
of free Ca2+ as an intracellular signal molecule.
3. Output, or Ca2+ loss from the body, occurs primarily through the kidneys, with a
small amount excreted in feces.
o Ionized Ca2+ is freely filtered at the glomerulus. Most (90%) of the filtered
Ca2+ is reabsorbed through paracellular pathways in the proximal tubule
and ascending limb of the loop of Henle.
o Hormonally regulated reabsorption takes place in the distal nephron and
uses the same transporters found in the intestine

Three Hormones Control Calcium Balance

Three hormones regulate the movement of Ca2+ between bone, kidney, and intestine:
parathyroid hormone, calcitriol (vitamin D3), and calcitonin. Of these,
parathyroid hormone and calcitriol are the most important in adult humans.

Parathyroid Hormone

Four small parathyroid glands lie on the dorsal surface of the thyroid gland. They secrete
PTH peptide whose main function is to increase plasma Ca2+ concentrations.

- PTH is essential for life.

o No PTH  hypocalcemia  hypocalcemic tetany and respiratory paralysis
o You can survive without a thyroid gland, but NOT without the parathyroid
glands
- PTH release is stimulated by a decrease in plasma Ca2+
o monitored by a GPCR, the Ca2+ sensing receptor (CaSR).
 Fun fact: CaSR was the first membrane receptor identified whose
ligand was an ion rather than an organic molecule
- PTH raises plasma Ca2+ in three ways by acting in three places: the bone,
kidney, and intestine:
1. Bone: PTH mobilizes calcium from bone
2. Kidney: PTH enhances renal reabsorption of calcium
o Simultaneously, PTH enhances renal excretion of phosphate by reducing its
reabsorption.
o The opposing effects of PTH on calcium and phosphate are needed to keep
their combined concentrations below a critical level. If the concentrations
exceed that level, calcium phosphate crystals form and precipitate out of
solution. High concentrations of calcium phosphate in the urine are one
cause of kidney stones.
3. Intestines: PTH indirectly increases intestinal absorption of calcium
through its influence on vitamin D3 / calcitriol.
o The production of vitamin D3 / calcitriol is regulated at the kidney by the
action of PTH.
o plasma Ca2+ decreases  PTH secretion increases  D3/calcitriol synthesis
increases  intestinal absorption of calcium increases
Calcitriol
Calcitriol is the primary hormone responsible for enhancing Ca2+ uptake from the small
intestine.

- The body makes calcitriol from vitamin D that has been obtained through diet or
made in the skin by the action of sunlight on precursors made from acetyl CoA.
- Vitamin D is modified in two steps—first in the liver, then in the kidneys—to make
vitamin D3 or calcitriol.
- Calcitriol synthesis is stimulated by:
1. PTH (increases calcitriol synthesis in kidneys)
2. Prolactin, the hormone responsible for milk production in breast-feeding
(lactating) women.
o This ensures maximal absorption of Ca2+ from the diet at a time when
metabolic demands for calcium are high.

Calcitonin
Calcitonin decreases plasma Ca2+ (calcitonin tones down plasma Ca2+)

- Produced by the C cells of the thyroid gland.

- released when plasma Ca2+ increases
- actions are opposite to those of parathyroid hormone
o decreases bone resorption
o increases renal calcium excretion.
 - Calcitonin apparently plays only a minor role in daily calcium balance in adult
humans.
o Patients whose thyroid glands have been removed show no disturbance in
calcium balance, and people with thyroid tumors that secrete large amounts
of calcitonin also show no ill effects

Multiple Factors Control Bone Remodeling

Bone mass in adults is determined by the relative activity of boneforming osteoblasts
and bone-dissolving osteoclasts, which in turn is controlled by an alphabet soup of
hormones, cytokines, and their receptors.

- Resorption > deposition  bone mass lost  osteopenia {penia, poverty} 

osteoporosis

We now example how normal adult bone mass is maintained.

Osteoblasts
- responsible for production of the calcified matrix of bone.
o PTH and vitamin D3 cause osteoblasts to
 secrete osteoid = collagen, enzymes and other proteins
 release calcium and phosphate compounds
 free Ca2+ and PO4 - from those compounds using their secreted
enzymes
o The Ca2+/PO4- precipitate into hydroxyapatite crystals, which interact with
osteoid to become the mineralized matrix of bone.

Osteoclasts
- Osteoclasts resorb bone.
- They are large, mobile, multinucleate cells derived from the same hematopoietic
stem cells as macrophages.
o Mature osteoclasts attach to a section of matrix with tight junctions around
their edges, much like a suction cup.
o They then secrete
 hydrochloric acid
 protease enzymes that work at low pH
o The combination of acid and enzymes dissolves the bone matrix
o Ca2+ from hydroxyapatite becomes part of the ionized Ca2+ pool and can
enter the blood
Control of Bone Remodeling
Curiously, although osteoclasts are responsible for dissolving the calcified matrix and
would be logical targets for PTH trying to raise plasma Ca2+, they do not have PTH
receptors. Instead, PTH effects are mediated through a collection of paracrine molecules.

- In bone, PTH receptors are found on the osteoblasts.

- When PTH activates osteoblasts, they secrete factors that regulate differentiation
and activity of osteoclasts. Modulating the ratios of these factors enables
osteoblasts to control osteoclast activity.

Calcium and Phosphate Homeostasis Are Linked

Phosphate homeostasis is closely linked to calcium homeostasis.

- Phosphate is the second key ingredient in the hydroxyapatite of bone,

Ca10(PO4)6(OH)2, and most phosphate in the body is found in bone
- Also involved in energy transfer and storage in high-energy phosphate bonds, and
phosphorylation/dephosphorylation control mechanisms, needed for DNA/RNA
backbones
- Phosphate homeostasis parallels that of Ca2+.
o Phosphate is absorbed in the intestines, filtered and reabsorbed in the
kidneys, and divided between bone, ECF, and intracellular compartments.
o Vitamin D3 enhances intestinal absorption of phosphate.
o Renal excretion is affected by both PTH (which promotes phosphate
excretion) and vitamin D3 (which promotes phosphate reabsorption).