6. BONE’S ROLE IN CALCIUM HOMEOSTASIS

6. BONE’S ROLE IN CALCIUM HOMEOSTASIS

• Bone is the body’s major calcium reservoir, storing 99% of total body calcium. 

• One way to maintain the level of calcium in the blood 

1. is to control the rates of calcium resorption from bone into blood and of calcium deposition from blood into bone. 

•  Both nerve and muscle cells depend on a stable level of calcium ions (Ca²⁺ ) in extracellular fluid to function properly. 
• Blood clotting also requires Ca²⁺. 
• Also, many enzymes require Ca²⁺ as a cofactor (an additional substance needed for an enzymatic reaction to occur). 
• For this reason, the blood plasma level of Ca²⁺  is very closely regulated between 9 and 11 mg/100 mL. 

Even small changes in Ca²⁺ concentration outside this range may prove fatal—

• the heart may stop (cardiac arrest) if the concentration goes too high,
•  or breathing may cease (respiratory arrest) if the level falls too low. 

The role of bone in calcium homeostasis is to help “buffer” the blood Ca²⁺ level, 

• releasing Ca²⁺ into blood plasma (using osteoclasts) when the level decreases, 
• and absorbing Ca²⁺ (using osteoblasts) when the level rises.

1. Parathyroid hormone (PTH)

• Ca²⁺ exchange is regulated by hormones, the most important of which is parathyroid hormone (PTH) secreted by the parathyroid glands . 
• This hormone increases blood Ca²⁺ level.

• PTH secretion operates via a negative feedback system .
•  If some stimulus causes the blood Ca²⁺ level to decrease, parathyroid gland cells (receptors) detect this change and increase their production of a molecule known as cyclic adenosine monophosphate (cyclic AMP). 
• The gene for PTH within the nucleus of a parathyroid gland cell (the control center) detects the intracellular increase in cyclic AMP (the input). 
• As a result, PTH synthesis speeds up, and more PTH (the output) is released into the blood. 
• The presence of higher levels of PTH increases the number and activity of osteoclasts (effectors), which step up the pace of bone resorption.
• The resulting release of  Ca²⁺  from bone into blood returns the blood Ca²⁺ level to normal.

• PTH also acts on the kidneys (effectors) to decrease loss of Ca²⁺ in the urine, so more is retained in the blood. 
• And PTH stimulates formation of calcitriol (the active form of vitamin D), a hormone that promotes absorption of calcium from foods in the gastrointestinal tract into the blood. 
• Both of these actions also help elevate blood Ca²⁺level.

2. Calcitonin (CT)

• Another hormone works to decrease blood Ca²⁺ level. 
• When blood  Ca²⁺ rises above normal, parafollicular cells in the thyroid gland secrete calcitonin (CT). 
• CT inhibits activity of osteoclasts, speeds blood Ca²⁺ uptake by bone, and accelerates Ca²⁺ deposition into bones. 

• The net result is that CT promotes- bone formation and decreases blood Ca²⁺ level. 
• Despite these effects, the role of CT in normal calcium homeostasis is uncertain because it can be completely absent without causing- symptoms. 

• Nevertheless, calcitonin harvested from salmon ( Miacalcin®) is an effective drug for treating osteoporosis because it slows bone resorption.

EXERCISE AND BONE TISSUE

• Within limits, bone tissue has the ability to alter its strength in response to changes in mechanical stress. 
• When placed under stress, bone tissue becomes stronger through increased deposition of mineral salts and production of collagen fibers by osteoblasts. 
• Without mechanical stress, bone does not remodel normally because bone resorption occurs more quickly than bone formation.

• The main mechanical stresses on bone are those that result from 

1. the pull of skeletal muscles and 
2. the pull of gravity. 

• If a person is bedridden or has a fractured bone in a cast, the strength of the unstressed bones diminishes because of the loss of bone minerals and decreased numbers of collagen fibers. 
• Astronauts subjected to the microgravity of space also lose bone mass. 
• In both cases, bone loss can be dramatic—as much as 1% per week.

•  In contrast, the bones of athletes, which are repetitively and highly stressed, become notably thicker and stronger than those of astronauts or nonathletes. 
• Weight-bearing activities, such as walking or moderate weight lifting, help build and retain bone mass. 
• Adolescents and young adults should engage in regular weight-bearing exercise prior to the closure of the epiphyseal -plates to help build total mass prior to its inevitable reduction with aging. 
• However, people of all ages can and should strengthen their bones by engaging in weight-bearing exercise.

AGING AND BONE TISSUE-

• From birth through adolescence, more bone tissue is produced than is lost during bone remodeling. 
• In young adults the rates of bone deposition and resorption are about the same. 
• As the level of sex hormones diminishes during middle age, especially in women after menopause, a decrease in bone mass occurs because bone resorption by osteoclasts outpaces bone deposition by osteoblasts. 

• In old age, loss of bone through resorption occurs more rapidly than bone gain. 
• Because women’s bones generally are smaller and less massive than men’s bones to begin with, loss of bone mass in old age typically has a greater adverse effect in females. 
• These factors contribute to the higher incidence of osteoporosis in females.

• There are two principal effects of aging on bone tissue: 

1. loss of bone mass and
2.  brittleness. 

1. Loss of bone mass results from -

• demineralization , the loss of calcium and other minerals from bone extracellular matrix. 
• This loss usually begins after age 30 in females, -
• accelerates greatly around age 45 as levels of estrogens decrease, 
• and continues until as much as 30% of the calcium in bones is lost by age 70.

• Once bone loss begins in females, about 8% of bone mass is lost every 10 years.

•  In males, calcium loss typically does not begin until after age 60, 
• and about 3% of bone mass is lost every 10 years. 

• The loss of calcium from bones is one of the problems in osteoporosis 

2. The second principal effect of aging on the skeletal system, brittleness, 

• results from a decreased rate of protein synthesis.
• the organic part of bone extracellular matrix, mainly collagen fibers, gives bone its tensile strength. 
• The loss of tensile strength causes the bones to become very brittle and susceptible to fracture. 

• In some elderly people, collagen fiber synthesis slows, in part, due to diminished production of human growth hormone. 
• In addition to increasing the susceptibility to fractures, loss of bone mass also leads to deformity, pain, loss of height, and loss of teeth.

Factors That Influence Bone Metabolism
FACTOR	COMMENT
MINERALS
Calcium and phosphorus	Make bone extracellular matrix hard
Magnesium	Helps form bone extracellular matrix.
Fluoride	Helps strengthen bone extracellular matrix.
Manganese	Activates enzymes involved in synthesis of bone extracellular matrix.
VITAMINS
Vitamin A	Needed for the activity of osteoblasts during remodeling of bone; deficiency stunts bone growth; toxic in high doses.
Vitamin C	Needed for synthesis of collagen, the main bone protein; deficiency leads to decreased collagen production, which slows down bone growth and delays repair of broken bones.
Vitamin D Active form (calcitriol)	is produced by the kidneys; helps build bone by increasing absorption of calcium from gastrointestinal tract into blood; deficiency causes faulty calcification and slows down bone growth; may reduce the risk of osteoporosis but is toxic if taken in high doses.
Vitamins K and B12 .	Needed for synthesis of bone proteins; deficiency leads to abnormal protein production in bone extracellular matrix and decreased bone density
HORMONES
Human growth hormone (hGH)	Secreted by the anterior lobe of the pituitary gland; promotes general growth of all body tissues, including bone, mainly by stimulating production of insulinlike growth factors.
Insulinlike growth factors (IGFs) .	Secreted by the liver, bones, and other tissues upon stimulation by human growth hormone; promotes normal bone growth by stimulating osteoblasts and by increasing the synthesis of proteins needed to build new bone
Thyroid hormones  (thyroxine and triiodothyronine)	Secreted by thyroid gland; promote normal bone growth by stimulating osteoblasts.
Insulin	Secreted by the pancreas; promotes normal bone growth by increasing the synthesis of bone proteins.
Sex hormones (estrogens and testosterone)	Secreted by the ovaries in women (estrogens) and by the testes in men (testosterone); stimulate osteoblasts and promote the sudden “growth spurt” that occurs during the teenage years; shut down growth at the epiphyseal plates around age 18–21, causing lengthwise growth of bone to end; contribute to bone remodeling during adulthood by slowing bone resorption by osteoclasts and promoting bone deposition by osteoblasts
Parathyroid hormone (PTH)	Secreted by the parathyroid glands; promotes bone resorption by osteoclasts; enhances recovery of calcium ions from urine; promotes formation of the active form of vitamin D (calcitriol).
Calcitonin (CT)	Secreted by the thyroid gland; inhibits bone resorption by osteoclast
EXERCISE
	Weight-bearing activities stimulate osteoblasts and, consequently, help build thicker, stronger bones and retard loss of bone mass that occurs as people age.
AGING
	As the level of sex hormones diminishes during middle age to older adultood, especially in women after menopause, bone resorption by osteoclasts outpaces bone deposition by osteoblasts, which leads to a decrease in bone mass and an increased risk of osteoporosis