Calcium, Vitamin D, and Bone Metabolism
complexed with calmodulin participates in numerous enzymatic reactions, is vital for the mechanisms of hormone secretion and action, intimately involved in muscle contraction, mitosis, fertilization and blood clotting, as well as the major cation in bone and teeth.
The equilibrium between active (ionized) Ca2+ and protein bound calcium is pH dependent. ß pH = less bound (more active)
Daily turnover of Calcium – dietary Ca2+ may vary, the % absorbed µ 1/ intake (less in = more absorbed).
At daily intake of 1000mg, 35% absorbed, 350mg excreted
- extracellular calcium – 10-3 molar
- intracellular calcium – 10-7 molar (range 5 x 10-8 to 3 x 10-7)
- intracellular compartments – 10-2 molar
200mg excreted in urine
Extracellular pool is ~ 1000mg. One kilogram is stored in the skeleton. 4000 mg of this is available for buffering of plasma calcium. At steady state, Ca2+ is removed, exchanged, and replaced from the bone every day.
When plasma or extracellular levels are too high or too low, intracellular function can be seriously affected. Abnormalities in neurotransmission and in the growth and renewal of skeleton result.
- 150 mg secreted into intestinal juices
the major intracellular anion, important in ATP, NADP, as a modifier of enzymes and lipids, as well as a component of intermediates in glucose and amino acids metabolism. Also forms part of the crystalline structure of bone.
nL plasma conc. is 2.4- 4.5 mg/dL (0.81- 1.45 x 10-3 M).
The % of phosphate absorbed is constant (more ingested = more absorbed)
Urinary excretion regulates phosphate balance. Daily filtered load ~6000mg but renal reabsorption varies from 70 –100%
Soft tissue stores in muscle are a source of rapid regulation of plasma concentration. Approximately 250 mg of phosphate enters and leaves the extracellular pool daily in the course of bone turnover.
Severe depletion of phosphate Þ muscle dysfunction (cardiac) as well as abnormal bone growth.
a major intracellular cation, essential in neuromuscular transmission and a co-factor for many reactions.
nL plasma = 1.8- 2.4 mg/dL (0.75 –1.0 x 10-3 M). 1/3rd of plasma Mg2+ is bound to protein. Average daily intake ~300mg, 40% absorbed, and in steady state, excreted in the urine. 50% of body Mg2+ is present in the skeleton.
Severe depletion of magnesium Þ abnormal neuromuscular transmission and arrhythmias.
Fundamentals of Bone Turnover – bone is a dynamic structure.
Þ the 5 fold greater surface area of trabecular bone gives it disproportionate significance in the regulation of calcium metabolism, despite its lesser mass
Bone is constantly being formed and broken down. Formation of bone occurs on the outer surface (or cortical bone) while resorption occurs on its inner surface. Both bone formation and resorption occur in specialized canals within cortical bone and on the surface of trabecular bone.
Linear growth occurs between the heads and the shafts of long bones in areas known as epiphyseal plates. These close off at the end of puberty. Total bone mass peaks between 20 –30 years old. Steady state formation/resorption continues for 40-50 years, until resorption begins to exceed formation and total bone mass slowly decreases. Women are more affected because of smaller peak bone mass, earlier onset, and more rapid rate of senescent loss than men.
Osteoblasts – arise from primitive mesenchymal cells (osteoprogenitor cells within connective tissue). Osteoblasts synthesize and secrete collagen type I producing a matrix for mineral deposition (the osteoid). After hydroxyapatite crystals (Ca + HCO3 + OH) surround the osteoblast it loses its synthetic activity and becomes an OSTEOCYTE.
Þ Alkaline phosphatase and osteocalcin are circulating proteins whose levels correlate well with osetoblastic activity.
Osteolysis – osteocytes remove Ca from newly formed bone to return it to the circulation. Does not decrease bone mass.
Osteoclasts – a giant multinucleated cell derived from the fusion of monocyte/macrophage precursors. This cell attaches to bone and digests it with enzymes, tunneling its way through mineralized bone. Ca, Mg, Phos, and Hydroxyproline (due to collagen) are released into the blood. Decreases bone mass.
Þ the level of hydroxyproline in the urine is a quantitative index of bone resorption.
Þ it is currently thought that bone reabsorption triggers bone formation.
- cortical bone – compact bone, 80% of total bone, typified by the thick shafts of the appendicular skeleton (arms/legs)
- trabecular bone – spongy bone, makes up the axial skeleton (vertebra, skull, and ribs)
Regulation of Bone Turnover – many cytokines influence (TGF, SGF, IL-1, interferons)
µ 1/ serum [Ca] (hypercalcemia decreases PTH synthesis). Overall effect of PTH is to increase the plasma Ca conc. and lower the plasma phosphate conc. By acting directly on the bone (Ý resorption) and kidney (stimulates renal reabsorption of Ca but not phosphate), and indirectly on the GI tract (Ý intestinal mineral absorption).
- Vit D – facilitates bone formation by providing Ca and phosphate. Increases Ca absorption from gut and bone resorption, thereby raising or sustaining plasma Ca levels.
- Parathyroid Hormone PTH – secretion of PTH