Biochem 38 – Bone Metabolism and Calcium Homeostasis

 Introduction
o Bone serves as a reservoir of Calcium
o Skeleton contains 99% of calcium in body in the form of hydroxyapatite
 Cellular Role of Calcium
o Entry of calcium into cytoplasm is an important biological signal
 10,000-fold difference between cytoplasm and ECF Ca2+ concentration
 Opening of Ca2+ channels is regulated by pholpholipase C
 PLC turns PIP2 -> IP3+DAG
 Gq subunit
 Bone structure and Bone remodeling
o Bone is a specialized connective tissue that along with cartilage forms the skeletal
system
 2 types of bone
 Cortical bone
 Trabecular bone
 Components of bone matrix
 Collagen and hydroxyapatite
o Most collagen in bone is type 1 collagen
o Hydroxyapitate is in crystals between collagen fibers
 Deprivation of calcium or phosphate leads to Osteomalacia in adults or rickets
in children
 Bone growth
o Chondrocytes synthesize type II collagen -> cartilage
 Chondrocytes undergo apoptosis, and matrix is colonized by osteoblasts which
lay down bone
o Several signaling pathways are relevant to bone growth
 SHH pathway – chondrocyte maturation
 Wnt/B-catenin pathway
 Bone remodeling
o Bone constantly changes its structure through remodeling
o Osteoblasts are bone-forming cells
 Osteoblasts are derived from mesenchyme
 Synthesize type 1 collagen
o Osteoclasts are bone resorbing cells
 Derived from pluripotent hematopoietic cells in bone marrow
 Stimulated by M-CSF (monocyte colony stimulating factor)
o RANK prepares the osteoclast to resorb bone
 Osteoblasts secrete RANKL
 RANKL binds to RANK (on osteoclasts) (or to the decoy receptor OPG)
o Local factors and PTH contribute to osteoclast activation
 IL-1, TNF, TGF-B, INF-a control osteoclasts through RANKL and OPG
 PTH activated osteoclasts indirectly via calcitonin
 Bone Markers
o Bone resorption generates collagen fragments
o PINP and P1CP, and osteocalcin are markers of bone formation
o NTX, CTX and pyridinium crosslinks serve as markers of bone resorption
 Calcium homeostasis – calcium in plasma
o Calcium is present in the circulation in three forms
 Ionized calcium Ca2+ is physiologically active form (50% of Ca in body)
 Remaining is bound to Albumin or complexed to citrate and phosphate
 Parathyroid hormone (PTH)
o PTH is the main regulator of Calcium homeostasis
 PTH secreted by parathyroid glands
o PTH binds to a specific receptor and acts through cyclic adenosine monophosphate
(cAMP)
 PTH secretion stimulated by decreased in Ca2+ or by increased Phosphate
 PTH mobalizes Ca2+
 Stimulates osteoclasts, renal reabsorption and calcitriol in the small
intestine
 Calcitonin
o Calcitonin inhibits bone resorption (tones down Ca2+)
 Secreted by parafollicular cells
 Regulated by plasma calcium concentration
 increase in Ca2+ -> increase in calcitonin
 Vitamin D
o Vitamin D is synthesized in the skin by UV radiation
 Vit D2 is syntheized in skin by radiation of ergosterol
 Vit D3 is synthesized in skin by radiation of 7-dehydrocholesterol
o Calcidiol is the storage form of vitamin D
o Calcitriol is the most potent form of vitamin D
o Calcitriol increases the absorption of calcium and phosphate from the gut
 Calcitriol and PTH stimulate bone resorption by osteoclasts
 Deficiency of calcitriol leads to less mineralization of newly formed bone
 Leads to rickets in children and osteomalacia in adults
 Intestinal absorption and renal excretion of calcium
o Calcium is absorbed in the small intestine and is excreted in urine and feces
 Absorbed in proximal small intestine
 Children has a positive calcium balance (less excreted than taken in)
 Elderly (osteoporosis) are in negative calcium balance (more excreted than
taken in)
o Calcium is excreted through the kidney
 PTH promotes calcium reabsorption in the proximal renal tubules
o Several other hormones effect bone metabolism and calcium homeostasis
 TH stimulates bone resorption
 Estrogen and Testosterone stimulate osteoblasts/inhibit osteoclasts
  GH promotes skeletal growth
 Disorders of calcium metabolism
o Hypercalcemia is most commonly caused by primary hyperparathyroidism or by
malignancy
 Measuring PTH allows discrimination between hyperparathyroidism vs other
causes
 Increased PTH = parathyroid cause
 Undetectable PTH = other cause
o Primary hyperparathyroidism is common
 Hypercalcemia with increased PTH
 In secondary hyperparathyroidism (kidney and liver disease), PTH increases in
response to vitamin D disruption
 Calcidiol is made in the liver
 Calcitriol is made in the kidney
o Hypercalcemia occurs in advanced malignant diseases and is usually a poor prognostic
sign
 Results from tumor causing hypercalcemia of malignancy
o Hypercalcemia can also be caused by overtreatment with Vitamin D
 Vitamin D toxicity is 3rd most common cause of hyperclcemia
 Causes increased Ca2+ absorption and bone reabsorption ->
hypercalcemia
 Hyopcalcemia
o Hypocalcemia is common in clinical practice
 Chvostek’s sign = twitching around mouth when tapping facial nerve
 Trousseau’s sign = contraction of hand w/ reduced blood flow to arm from
blood pressure cuff
 Can be caused by low PTH or PTH resistance
 Pseudohypoparathyroidism
 Hypocalcemia, hypophosphatemia and increased PTH
 Can confirm diagnosis by demonstrating lack of cAMP in response to
PTH infusion
o Hypocalcemia may result from abnormal Vitamin D metabolism
 Rickets
o Abnormal bone formation develops before closing of growth plate due to vitamin D
deficiency
o Rickets can also develop as a result of phosphate deficiency
 From X-linked inhibition of Na/P cotransporter in kidney
o Enhanced phosphate reabsorption may result in ectopic calcification
 Hyperphosphatism may lead to calcification of organs
 Osteoporosis
o Osteoporosis is a common age-related disease of bone
 Reduction of bone density with increased chance of fracture
 Peak bone density is at age 30
 Bone loss accelerates in women after menopause b/c less estrogen
o Paget’s disease of bone is characterized by areas of accelerated bone turnover
 Characterized by increased osteoclast activity due to increased sensitivity to
calcitriol and RANKL
 Treat with bisphosphonates (they have antiosteoclast activity)