Introduction Normal bone metabolism is the complex sequence of bone turnover (osteoclastogenesis) and bone formation (osteoblastogenesis) 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 and, less so, by steroids Regulators of bone metabolism Hormones login to view 5 more bullets Steroids login to view 2 more bullets Properties of bone metabolism Bone mass login to view 4 more bullets Bone loss login to view 3 more bullets Calcium Location bone (99%) blood and extracellular fluid (0.1%) intracellular (1%) Function calcium has a wide range of function including muscle cell contraction nerve conduction clotting mechanisms Forms of calcium bone majority is hydroxyapatite serum Ca++ bound to protein (45%) free-ionized Ca++ (45%) bound to various anions, eg. citrate, bicarbonate (10%) Regulation absorption from the digestive tract resorption from bone resorption in the kidneys Dietary requirements 2000 mg/day for lactating women 1500 mg/day for pregnant women, postmenopausal woman, and patients with a healing bone fracture 1300 mg/day for adolescents and young adults 750 mg/day for adults 600 mg/day for children Dysfunction hypercalcemia hypocalcemia Phosphate Location bone (86%) blood and extracelluar fluid (0.08%) intracellular (14%) Function key component of bone mineral important in enzyme systems and molecular interactions Forms of phosphate bone majority is hydroxyapatite serum mostly inorganic phosphate (H2PO4-) Regulation plasma phosphate is mostly unbound and reabsorbed by the kidney may be excreted in urine elevated serum phosphate can lead to increased release of PTH and bone resorption Dietary intake 1000-1500 mg/day PTH Structure 84 amino acid peptide Origin synthesized and secreted from chief cells in the four parathyroid glands Net effect increases serum calcium decreases serum phosphate Mechanism bone PTH stimulates osteoblasts to secrete IL-1, IL-6 and other cytokines to activate osteoclasts and increase resorption of bone Increases osteoblast production of M-CSF (macrophage colony-stimulating factor) and RANKL, which increases number of osteoclasts. Paradoxically, osteoclasts do not express receptor for PTH kidney stimulates enzymatic conversion of 25-(OH)-vitamin D3 converted to 1,25-(OH)2-vitamin D3 (active hormone form) which: login to view 2 more bullets intestine no direct action indirectly increase Ca++ absorption by activating 1,25-(OH)2-vitamin D3 Dysfunction 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 the same receptors on osteoblasts and renal cells to increase serum calcium Calcitonin Structure 32 amino-acid peptide hormone Origin produced by clear cells in the parafollicles of the thyroid gland (C cells) Net effect limited role in calcium homeostasis inhibit number and activity of osteoclasts Function 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 secreted by medullary thyroid tumors and mulitple endocrine neoplasia type II tumors Recombinant calcitonin used to treat Paget disease, osteoporosis, and hypercalcemia in malignancy Vitamin D Structure fat soluble secosteroid (steroid with a 'broken ring') Origin produced by skin when exposed to sunlight (UV B-generated Vitamin D) dietary intake (lipid-soluble vitamin D3) active metabolite 1,25-(OH)2-vitamin D3 formed by two hydroxylations in the liver and kidney, respectively Net effect maintains normal serum calcium levels by activating osteoclasts for bone resorption and increasing intestinal absorption of calcium (increase serum Ca++) promotes the mineralization of osteoid matrix Function liver activated-vitamin D3 converted to 25-(OH)-vitamin D3 kidney 25-(OH)-vitamin D3 converted to 1,25-(OH)2-vitamin D3 (active hormone form) login to view 3 more bullets 1,25-(OH)2-vitamin D3 (active hormone form)can be inactivated to 24,25-(OH)2-vitamin D3 login to view 3 more bullets vitamin D parallels that of PTH by increasing reabsorption of Ca in the kidneys 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 mostly to cytokines released by osteoblasts 1,25-(OH)2-vitamin D3 promotes the mineralization of osteoid matrix produced by osteoblasts Dysfunction Vitamin D deficiency causes osteomalacia and rickets phenytoin (dilantin) causes impaired metabolism of vitamin D Estrogen Structure D ring steroid hormone Origin predominantly in the ovaries synthetic forms available Net effect prevents bone loss by decreasing the frequency of bone resorption and remodeling Function alone, because bone formation and resorption are coupled, it also indirectly decreases bone formation leads to an increase in bone density of the femoral neck and reduces the risk of hip fracture most important sex-steroid for peak bone mass attainment in both men and women Therapeutic estrogen 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 therapy secondary effects increases risk of login to view 2 more bullets decreases risk of login to view 2 more bullets laboratory will see a decreases in login to view 2 more bullets Growth Hormone Function increases serum calcium by increased absorption in intestine decreasing urinary excretion function is interdependent with insulin, somatomedins, and growth factors (TGF-B, PDGF, mono/lyphokines) Gigantism oversecretion or increased response to growth hormone effecting the proliferative zone of the growth plate Thyroid Hormone Function regulates skeletal growth at the physis by stimulating chondrocyte growth type X collagen synthesis alkaline phosphatase activity thyroid hormones increase bone resorption and can lead to osteoporosis large doses of therapeutic thyroxine can mimic this process and cause osteoporosis Steroids Function 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 login to view 2 more bullets