Bone Metabolism

Calcium levels tightly controlled by complex endocrine system: Parathyroid hormone (PTH) Vitamin D (see Nutrition slides) Calcitonin? (probably non-physiologic)

Bone Resevoir

Four parathyroid glands, near or w/in thyroid Not related to thyroid gland except by proximity Possess Ca-sensing receptors that: Inc. PTH secretion with low (free, ionized) calcium Dec. PTH secretion with high calcium 1,25-diOH vit. D suppresses PTH secretion Complex effects by Mg2+, esp. hypomagnesemia Ectopic parathyroid glands are not uncommon (thoracic)

84 amino acid protein Plasma half-life ~4 minutes Bone —–Stimulates osteoclasts which break down bone ——–Raises serum calcium raises phosph Kidney • –Increases tubular reabsorption of calcium • –Decreases tubular reabsorption of phosphate • –Induces 1α-hydroxylase which forms 1,25 diOH D lowers phosph Intestine —–Increases calcium absorption via 1,25-diOH vit. D increas phosph OVERALL PTH inc Ca and dec P

Measured by sandwich immunoassay Reference interval: 10-65 pg/mL Assays should measure “intact” PTH —One Ab vs N-terminal epitope, other vs C-terminal —1-34 aa (N-terminus) req’d for biological activity —7-84 commonly measured in commercial assays —“Bio-active” – measures 1-84 (limited availability) —Controversial necessity EDTA protects PTH from protease breakdown

32 aa peptide produced in parafollicular (C) cells of the thyroid gland Secretion stimulated by Ca2+, (penta)gastrin Actual physiological role in human calcium regulation unclear Measured more as a tumor marker for medullary thyroid cancer Measure by immunoassay

Counteracts effects of PTH • –Inhibits intestinal calcium absorption • –Inhibits osteoclast activity in bone • –Stimulates osteoblast activity in bone • –Inhibits tubular reabsorption of Ca2+ in kidney • –Inhibits tubular reabsorption of PO4 in kidney (= PTH) Used therapeutically in treatment of: • –Postmenopausal osteoporosis • –Paget’s disease • –Bone metastases

Disorder of the parathyroid Primary Hyperparathyroidism (“hyperpara”) Hyperplasia or adenoma of one or more glands Elevated serum PTH Hypercalcemia, hypophosphatemia, hypomagnesemia Decalcification of bone Occurs independently or as component of inherited disease (multiple endocrine neoplasia) Treat by parathyroidectomy of affected gland(s)

PTH testing done during surgery to verify removal of hyperplastic gland(s) Baseline PTH sample before suspect gland(s) removed Samples at 5 and/or 10 min post removal Send to lab for “super-stat” testing (or in OR) >50% PTH decline indicates successful removal of hyperplastic gland(s)

Secondary hyperparathyroidism Increased PTH due to refractory hypocalcemia Vitamin D deficiency Malabsorption (of Ca or vitamin D) Renal dz (reduced 1,25-diOH D production) Characterized by High PTH Low or normal Ca High phosphorus if not an absorption problem

Significant sequence homology to PTH Secreted by some tumors, but no negative feedback by calcium “Paraneoplastic” – from tumor secretion, not mass Typified by unexplained hypercalcemia with suppressed PTH Measure by specific immunoassay Does not identify tumor type or source

Much less common than hyperparathyroidism Characterized by hypocalcemia with low PTH —–Hyperphosphatemia common Pseudohypoparathyroidism: —Hypocalcemia with elevated PTH —Target organ PTH receptor deficiency/defect

Bone consists of collagen and hydroxyapatite (Ca10(PO4)6(OH)2) Constant “re-modeling” Osteoclasts – cells that induce bone resorption Osteoblasts – cells that induce bone formation Bone mineral density (BMD) Determined by special X-ray

Osteoporosis – loss of bone mass Usually asymptomatic until fracture (inappropriate) Osteopenia – loss of bone mass

Decreased mineralization of bone (formation) Rickets – occurring in childhood —Skeletal deformities common (e.g., bowed legs) Osteomalacia – occurring in adults —-Skeletal deformities uncommon Usually result from vitamin D deficiency –Formation (skin, hepatic, renal) or intake/absorption –Inherited defect of metabolism or action –Anticonvulsants – forms inactive vitamin D metabolites Alkaline phosphatase(marker of ostoblastic activity) commonly elevated, but not diagnostic due to many origins.

Paget’s disease • –Increased osteoclastic bone resorption plus disordered osteoblastic bone formation • —–May result from paramyxovirus in genetically susceptible • —-Results in weak, thickened and painful bones • —May result in pathological fractures Diagnosed by X-ray plus bone-specific alkaline phosphatase Treat with bisphosphonates and analgesia

Osteocalcin (plasma) Bone-specific-ALP (serum) – 15% x-rxn w/ liver ALP Procollagen I terminal peptides (serum)*–preferred

Pyridinium cross-links (urine) Collagen telopeptides (N- in urine, C- in serum*) preferred Tartarate-resistant acid phosphatase (TRAP 5b)

Most commonly use to monitor Rx in osteoporosis (* = preferred)