Bone Metabolism Regulation

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Bone Metabolism Regulation
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Bone and Mineral Metabolism

• Laboratories have expanded role
• From just total calcium, phosphate and magnesium
• Improvements in technology
• Free (ionized) calcium
• PTH, PTHrP
• Vitamin D metabolites
• Calcitonin
• Aging population trend
• Markers of bone formation or resorption
• Formation - Bone Alkaline phosphate, Osteocalcin
• Resorption - Collagen cross-links

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Mineral Regulators of Bone Metabolism

• Calcium.
• Adult body contains 900 to 1,500 grams of calcium
• Bone contains 99 of the bodys Calcium.
• Phosphate.
• Bone contains 85 of the bodys Phosphate,
• binds with Calcium to form hydroxyapatite
• Magnesium.
• 55 of the bodys magnesium is found in bone.

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Hormone Regulators of Bone Metabolism

• Parathyroid hormone (PTH)
• Stimulates bone metabolism.
• Vitamin D
• Stimulates intestinal calcium absorption.
• Estrogen
• May alter local regulating factors of bone
  remodeling.
• Calcitonin
• Inhibits bone resorption.

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Clinical Significance

• Hypocalcemia low total serum calcium
• Reduction in either free or protein-bound calcium
• Hypoalbuminemia most common cause
• Chronic renal failure
• Hypoproteinemia,hyperphosphatemia
• Low Vitamin D
• Hypoparathyroidism
• neck surgery
• Presentation
• Neuromuscular hyperexcitability
• Tetany
• Paresthesia
• Seisures

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Clinical Significance

• Hypercalcemia high total serum calcium
• Primary hyperparathyroidism
• Most common cause in outpatient clinics
• Malignancy
• Most common cause in hospitalized patients
• Occurs in 10-20 of cancer patients
• Caused by production of PTHrP
• Presentation
• Rapid rise in serum calcium
• Lethargy
• Nausea
• Vomiting

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Parathyroid Hormone (PTH) Introduction
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Introduction toParathyroid Hormone (PTH)

• PTH is secreted by the parathyroid glands in
  response to low blood calcium levels
  (hypocalcemia).
• Plays a crucial role in calcium homeostasis
• Measured during the workup of calcium and bone
  disorders.
• Monitor dialysis patients

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PTH Synthesis

• Polypeptide produced by the parathyroid glands
• lie posterior to the thyroid gland

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PTH Synthesis

• Synthesized as pre-pro-PTH (115 amino acids)
• Cleaved to pro-PTH
• Then to the mature 84-aa polypeptide PTH(1-84)
  which is secreted into blood

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PTH Metabolism

• PTH(1-84) undergoes rapid cleavage and
  proteolysis to generate
• Amino-terminal fragments (PTH-N)
• Mid-molecule fragments (PTH-M)
• Carboxyl-terminal fragments (PTH-C)

From Mayo Communiqué Feb. 2004
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PTH Metabolism

• PTH active forms
• Physiological activity is confined to the first
  34 residues of the N-terminal end
• PTH(1-84)
• PTH-N fragments
• Very short half-lives
• about 5 min

From Mayo Communiqué Feb. 2004
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PTH Metabolism

• Inactive PTH-C and PTH-M
• Much longer half-lives
• 24-36 hrs
• gt90 of total circulating PTH
• Primarily cleared by the kidneys
• can accumulate in severe renal failure.

From Mayo Communiqué Feb. 2004
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PTH Regulation

• The dominant regulator of PTH is plasma calcium
  concentration (plasma Ca2 ).
• Secretion of PTH is inversely related to plasma
  Ca2

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Calcium Regulation Feedback
Calcium levels
PTH levels
Calcium levels
PTH levels
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Actions of PTH

• On intestine
• Increases Ca2 absorption
• On kidney
• Promotes Ca2 re-absorption
• On bone
• Increases Ca2 mobilization from bone

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Parathyroid Hormone (PTH) Testing
Clinical Utility
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Clinical Utility of PTH

• Primary importance in the assessment of
• Hypocalcemia
• Hypercalcemia
• Metabolic bone diseases
• Two different aspects of diagnostic information
  are expected from a PTH measurement
• Direct information about parathyroid gland
  activity
• Indirect information about bone turnover

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Clinical Indications1. Differential Diagnosis of
Hypercalcemia (? Ca2)

• ? PTH Primary hyperparathyroidism
• Adenoma of parathyroid glands
• Hyperplasia of parathyroid glands
• ? or normal PTH Hypercalcemia of malignancy
• PTHrP secreting tumors

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Clinical Indications2. Differential Diagnosis of
Hypocalcemia (? Ca2)

• ? PTH
• True hypoparathyroidism (most common cause
  parathyroidectomy)
• ? PTH
• Secondary hyperparathyroidism (renal failure)
• Pseudohypoparathyroidism (defects in the PTH
  receptor complex)

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Clinical Indications3. Renal Failure (? or
induced- ? Ca2)

• Measurement of PTH to assess the degree of
  parathyroid function and bone turnover
• PTH and bone diseases in renal failure
• Renal osteodystrophy (ROD)
• major complication of end-stage renal disease
• Classified as low turnover, high turnover or
  mixed bone diseases
• Exact diagnosis is essential
• Bone biopsy is the gold standard.
• PTH has been the major laboratory determinant

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Serum Ca2 and PTH Concentrations vs.
Diseases
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Parathyroid Hormone (PTH) Intra-operative Testing
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Parathyroidectomy

• Primary hyperparathyroidism due to adenoma or
  hyperplastic tissue in one or more parathyroid
  glands.
• Surgical goals
• Remove all abnormal tissue
• Leave normal parathyroid glands in place
• Be as minimally invasive as possible to reduce
  scaring and shorten recovery time
• Decrease time under anesthesia

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Parathyroidectomy

• Traditional surgery
• General anesthesia, 5-6 cm incision
• Often difficult to locate all 4 parathyroid
  glands for examination

Tumor localization using technecium (Tc)-99m
sestamibi scintigraphy
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Minimally Invasive Parathyroidectomy
Local anesthesia, smaller
incision Complete removal of all abnormal tissue
confirmed by intra-operative PTH testing
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Intra-operative PTH Testing

• Rationale
• PTH is produced only by parathyroid glands
• PTH has a half-life of about 5 min.
• PTH secretion is suppressed in normal glands
• PTH level declines rapidly after removal of
  hyperfunctioning gland
• Intra-operative PTH testing can be performed
  using a simple protocol for performing testing
  and interpreting the results using peripheral
  blood sampling

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Intra-operative PTH Testing

• Result interpretation
• A drop in PTH of 50 or more, 10 minutes
  post-resection, signals success in removing the
  abnormally secreting parathyroid tissue.

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Intra-operative PTH Testing

• The National Academy of Clinical Biochemistry
  (NACB) makes the following recommendations
• based on evidence for improved patient/health,
  operational and economic outcomes, we recommend
  routine use of intra-operative PTH for patients
  undergoing surgery for primary hyperparathyroidism
  and strongly recommend routine use in minimally
  invasive or directed procedures.

From Evidence Based Practice for
POCT-intraoperative PTHNACB Laboratory Medicine
Practice Guidelines Final version 3/05
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Thank you

• David Schaffner Ph.D., MT(ASCP)
• Scientific Affairs Manager
• Beckman Coulter, Inc.
• dfschaffner_at_beckman.com