Calcium Homeostasis and Bone Health

Question 1

Calcium Is Essential For Biological Functions

Answer 1

Important for current flow across excitable membranes
Important for muscle contraction and fusion and release of storage vesicles
Important as a second messenger in signal transduction
Promotes blood coagulation and formation/remodeling of bone

Three forms of calcium: Ionized (Ca2+, 50%), Protein bound (40%), complexed (10%)

Question 2

Phosphate

Answer 2

Present in plasma, extracellular fluid, cell membrane phospholipids, intracellular fluids, collagen, and bone
Dynamic constituent of intermediary and energy metabolism
Distribution
80% in bone
15% in soft tissue

Question 3

Calcium and Phosphate Homeostasis

Answer 3

Hydroxyapatite (Ca10(PO4)6(OH)2) is the primary mineral form in bone
Regulated by the same hormones - parathyroid hormone, 1,23-dihydroxyvitamin D (calcitriol), and calcitonin
Control is at the levels of the gastrointestinal system (entry into the body), kidneys (exit from the body), and bone (storage)

Question 4

Osteoid

Answer 4

90% is Type 1 collagen made of a triple helix with a tight helical structure
Provides site of nucleation of hydroxyapatite crystals with alignment along the long axis of collagen fibers for tensile strength
Osteocalcin (bound Ca) synthesized by osteoblasts is induced by 1,25-dihydroxyvitamin D and likely promotes nucleation
Osteonectin synthesized by osteoblasts binds hydroxyapatite and collagen to promote mineralization of collagen.
Both free Ca and hydroxyapatite are found bound to collagen

Osteoblasts also secrete Ca and PO4 from intracellular vesicles to promote nucleation.

Question 5

Bone reabsorption

Answer 5

Osteoclasts attaches to bone matrix when integrins attach to vitronectin on bone matrix
Osteoclasts secrete acids and proteases into the resorption space (lacunae) to demineralize the bone and hydrolyze the matrix proteins
Osteoblasts replace osteoclasts to build new bone matrix and promote mineralization
Osteoprotegerin (RANK) ligand stimulates differentiation of preosteoclasts to osteoclasts and the activity of mature osteoclasts (glucocorticoids increase production of RANK)

Question 6

Cortical Bone (compact)

Answer 6

Dense tissue composed of bone mineral and extracellular matrix elements. Osteocytes are interconnected to each other and osteoblasts by canaliculi (canaliculi allow transfer of Ca2+ from interior of bone to surface (osteocytic osteolysis))

Question 7

Trabecular (cancellous or medullary)

Answer 7

Composed of thin spicules of bone that extend from cortex into medullary cavity
Spicules may be lined with osteoblasts and osteoclasts

Trabecular bone is in constant resorption and deposition at a rate much greater than cortical bone

Question 8

Parathyroid Hormone

Answer 8

Regulates extracellular calcium levels through a G-protein coupled receptor to:

• Stimulate adenylyl cyclase (increases cAMP and protein kinase A activity)
• Stimulate phospholipase C (generates IP3 and DAG)

In the bone:

Question 9

Parathyroid Hormone in the kidney

Answer 9

(BH) promotes calcium reabsorption, and stimulates conversion of vitamin D to 1,25-dihydroxyvitamin D (calcitriol) (increase Ca)
but also inhibits phosphate reabsorption.

Question 10

Parathyroid Hormone in the bone

Answer 10

Persistent release (normal) stimulates bone resorption by osteoclasts - indirect action mediated through osteoblasts and osteoclast precursors to trigger release of agents that promote the development and activation of osteoclasts. Inhibits collagen synthesis by osteoblasts and promotes the production of proteases that digest bone matrix.

Give intermittent release promotes bone synthesis (pulse dose of PTH) Directly activates calcium channels in osteocytes to promote calcium transfer ultimately to the osteoblasts at the bone surface where they pump calcium into the extracellular matrix. Indirectly stimulates osteoclasts to secrete growth factors.

Question 11

Vitamin D (1,25-dihydroxyvitamin D)

Answer 11

Vitamin D3 is synthesized from 7-dehydrocholesterol, present in the skin, provided adequate ultraviolet light is absorbed. Both require conversion to 1,25-dihydroxyvitamin D.
Vitamin D acts through Vitamin D Receptors (VDRs), a member of the family of nuclear receptors

Question 12

Vitamin D (1,25-dihydroxyvitamin D In small intestine

Answer 12

Stimulates calcium absorption by increasing production of proteins that are important to this process:
Calcium channels and energy-dependent extrusion proteins
May also enhance diffusion by increasing overall permeability factors
Stimulates phosphate absorption by increasing transporter protein levels

(increase Ca also increase PO4 absorption)

Question 13

Vitamin D (1,25-dihydroxyvitamin D) in kidney

Answer 13

Acts synergistically with parathyroid hormone to enhance calcium reabsorption

Question 14

Calcitonin

Answer 14

32-amino acid peptide made by C (clear or parafollicular) cells of thyroid
Stored in vesicles in C cells, release is triggered by mid-physiological levels of extracellular calcium
Release inhibited by low extracellular calcium levels

G-protein coupled receptor that may activate adenylyl cyclase or phospholipase C.
Binding to osteoclasts inhibits the resorptive activity and slows the rate of bone turnover.
Reduces osteocytic osteolysis (canaliculi allow transfer of Ca2+ from interior of bone to surface).

In the kidney, calcitonin promotes mild phosphaturia (phosphate in urine), natriuresis (sodium in urine) and calciurias (calcium in urine).

Question 15

Testosterone & Estradiol (Sex Hormones) and Glucocorticoids

Answer 15

Testosterone and estradiol promote bone deposition. Bone formation is greater than bone resorption. Thicker bones in men, however, women are better at retaining Ca.

Glucocorticoid excess may lead to osteoporosis through effects on osteoprotegerin and osteoprotegerin ligand