Normal Bone Metabolism

Evan Watts
Introduction
 Normal bone metabolism is the complex sequence of bone turnover (osteoclastogenesis
formation (osteoblastogenesis)
o Physiology of bone metabolism
 bone has structural and metabolic functions
 metabolic functions of bone largely involve the homeostasis of calcium and phosphate
 release of calcium, or absorption of calcium, by bone is largely regulated by hormones a
steroids
o Regulators of bone metabolism
 Hormones
 PTH
 Calcitonin
 Sex Hormones (eg. estrogen, androgens)
 Growth Hormone
 Thyroid Hormones
 Steroids
 Vitamin D
 Glucocorticosteroids
o Properties of bone metabolism
 Bone mass
 bone mass is the measure of bone tissue present at the end of skeletal maturity
 represents both its volume and size, as well as the density of the mineralized tissue
 peak bone mass occurs between ages 16 and 25
 greater in men and African Americans
 Bone loss
 bone mass decreases by 0.3 to 0.5% per year after skeletal maturity
 further decreases by 2-3% per year for untreated women during the 6th-10th years after
 rate of bone loss can be modulated by structural and metabolic factors
Calcium
 Location
o bone (99%)
o blood and extracellular fluid (0.1%)
o intracellular (1%)
 Function
o calcium has a wide range of function including
 muscle cell contraction
 nerve conduction
 clotting mechanisms
 Forms of calcium
o bone
 majority is hydroxyapatite
o serum
 Ca++ bound to protein (45%)
 free-ionized Ca++ (45%)
 bound to various anions, eg. citrate, bicarbonate (10%)
 Regulation
o absorption from the digestive tract
o resorption from bone
o resorption in the kidneys
 Dietary requirements
o 2000 mg/day for lactating women
o 1500 mg/day for pregnant women, postmenopausal woman, and patients with a healing
o 1300 mg/day for adolescents and young adults
o 750 mg/day for adults
o 600 mg/day for children
 Dysfunction
o hypercalcemia

o hypocalcemia
Phosphate
 Location
o bone (86%)
o blood and extracelluar fluid (0.08%)
o intracellular (14%)
 Function
o key component of bone mineral
o important in enzyme systems and molecular interactions
 Forms of phosphate
o bone
 majority is hydroxyapatite
o serum
 mostly inorganic phosphate (H2PO4-)
 Regulation
o plasma phosphate is mostly unbound and reabsorbed by the kidney
o may be excreted in urine
o elevated serum phosphate can lead to increased release of PTH and bone resorption
 Dietary intake
o 1000-1500 mg/day
PTH
 Structure
o 84 amino acid peptide
 Origin
o synthesized and secreted from chief cells in the four parathyroid glands
 Net effect
o increases serum calcium
o decreases serum phosphate
 Mechanism
o bone
 PTH stimulates osteoblasts to secrete IL-1, IL-6 and other cytokines to activate osteocla
increase resorption of bone
 Increases osteoblast production of M-CSF (macrophage colony-stimulating factor) and R
increases number of osteoclasts.
 Paradoxically, osteoclasts do not express receptor for PTH
o kidney
 stimulates enzymatic conversion of 25-(OH)-vitamin D3 converted to 1,25-(OH)2-vitamin
hormone form) which:
 increases resorption of Ca++ in kidney (increasing serum Ca++)
 increases excretion of PO4- from kidney (decreasing serum phosphate)
o intestine
 no direct action
 indirectly increase Ca++ absorption by activating 1,25-(OH)2-vitamin D3
 Dysfunction
o PTH-related protein and its receptor have been implicated in metaphyseal dysplasia
 Parathyroid hormone-related protein (PTHrP) has related effects to PTH as it binds to th
receptors on osteoblasts and renal cells to increase serum calcium
Calcitonin
 Structure
o 32 amino-acid peptide hormone
 Origin
o produced by clear cells in the parafollicles of the thyroid gland (C cells)
 Net effect
o limited role in calcium homeostasis
o inhibit number and activity of osteoclasts
 Function
o bone
 inhibits osteoclastic bone resorption by decreasing number and activity of
osteoclasts
 osteoclast have receptor for calcitonin
 Inc. serum Ca > secretion of calcitonin > inhibition of osteoclasts > dec. Ca
(transiently)
 Dysfunction
o secreted by medullary thyroid tumors and mulitple endocrine neoplasia type II
tumors
o Recombinant calcitonin used to treat Paget disease, osteoporosis, and
hypercalcemia in malignancy
Vitamin D
 Structure
o fat soluble secosteroid (steroid with a 'broken ring')
 Origin
o produced by skin when exposed to sunlight (UV B-generated Vitamin D)
o dietary intake (lipid-soluble vitamin D3)
o active metabolite 1,25-(OH)2-vitamin D3 formed by two hydroxylations in the liver and kid
respectively
 Net effect
o maintains normal serum calcium levels by activating osteoclasts for bone resorption and
intestinal absorption of calcium (increase serum Ca++)
o promotes the mineralization of osteoid matrix
 Function
o liver
 activated-vitamin D3 converted to 25-(OH)-vitamin D3
o kidney
 25-(OH)-vitamin D3 converted to 1,25-(OH)2-vitamin D3 (active hormone form)
 activated by
 increased levels of PTH
 decreased levels of serum Ca++, P
 1,25-(OH)2-vitamin D3 (active hormone form)can be inactivated to 24,25-(OH)2-vitamin D
 inactivity occurs with:
 decreased levels of PTH
 increased levels of serum Ca++, P
 vitamin D parallels that of PTH by increasing reabsorption of Ca in the kidneys
o bone
 1,25-(OH)2-vitamin D3 stimulates terminal differentiation of osteoclasts
 when osteoclasts mature they do not respond to 1,25-(OH)2-vitamin D3 and respond mo
cytokines released by osteoblasts
 1,25-(OH)2-vitamin D3 promotes the mineralization of osteoid matrix produced by osteob
 Dysfunction
o Vitamin D deficiency causes osteomalacia and rickets
o phenytoin (dilantin) causes impaired metabolism of vitamin D
Estrogen
 Structure
o D ring steroid hormone
 Origin
o predominantly in the ovaries
o synthetic forms available
 Net effect
o prevents bone loss by decreasing the frequency of bone resorption and remodeling
 Function
o alone, because bone formation and resorption are coupled, it also indirectly decreases b
o leads to an increase in bone density of the femoral neck and reduces the risk of hip fract
o most important sex-steroid for peak bone mass attainment in both men and women
 Therapeutic estrogen
o outcomes
 decreases bone loss if started within 5-10 years after onset of menopause
 significant side effects so risk/benefit ratio must be evaluated
 gains in bone mass usually limited to an annual increase of 2-4% for the first 2 years of t
o secondary effects
 increases risk of
 heart disease
 breast cancer
 decreases risk of
 hip fracture
 endometrial cancer (if combined with cyclic progestin)
o laboratory
 will see a decreases in
 urinary pyridoline
 serum alkaline phosphatase
Thyroid Hormone
 Function
o regulates skeletal growth at the physis by stimulating
 chondrocyte growth
 type X collagen synthesis
 alkaline phosphatase activity
o thyroid hormones increase bone resorption and can lead to osteoporosis
 large doses of therapeutic thyroxine can mimic this process and cause
osteoporosis
Growth Hormone
 Function
o increases serum calcium by
 increased absorption in intestine
 decreasing urinary excretion
o function is interdependent with insulin, somatomedins, and growth factors (TGF-
B, PDGF, mono/lyphokines)
 Gigantism
o oversecretion or increased response to growth hormone effecting the proliferative

zone of the growth plate

Steroids
 Function
o increase bone loss by
 decreasing Ca++ absorption in intestine through a decrease in binding proteins
 decreasing bone formation (cancellous more so than cortical bone) by
 decreasing collagen synthesis
 inhibiting osteoblast activity
 Bone Matrix
Tracy Jones

Introduction
 Bone is made up of
o organic component
 40% of dry weight
o inorganic component
 60% of dry weight
Organic component
 Components include
o collagen
 90% of organic component
 primarily type I collagen
 provides tensile strength
 it is a triple helix composed of one alpha-2 and two alpha-1 chains
o proteoglycans

 responsible for compressive strength

 inhibit mineralization
 composed of glycosaminoglycan-protein complexes
o matrix proteins
 includes noncollagenous proteins
 function to promote mineralization and bone formation
 three main types of proteins involved in bone matrix
 osteocalcin
 most abundant non-collagenous protein in the matrix (10%-20% of total)
 produced by mature osteoblasts
 function
 promotes mineralization and formation of bone
 directly involved in regulation of bone density
 attracts osteoclasts
 signaling
 stimulated by 1,25 dihydroxyvitamin D3
 inhibited by PTH
 clinical application
 marker of bone turnover
 can be measured in urine or serum
 osteonectin
 secreted by platelets and osteoblasts
 function
 believed to have a role in regulating calcium or organizing mineral in matrix
 osteopontin
 function
 cell-binding protein
o cytokine and growth factors
 small amounts present in matrix
 aid in bone cell differentiation, activation, growth, and turnover
 include
 IL-1, IL-6, IGF, TGF-beta, BMPs
Inorganic component
