endocrinology review thyroid, pituitary, adrenal & bone
DESCRIPTION
Endocrinology Review Thyroid, pituitary, adrenal & bone. Dora Liu, MD FRCPC. Basic thyroid physiology. Hypothalamic-Pituitary- Thyroid Axis. Thyroid hormones. From UpToDate. Thyroid hormone transport. Three major transport proteins: Thyroxine-binding globulin (TBG) - PowerPoint PPT PresentationTRANSCRIPT
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Endocrinology Review
Thyroid, pituitary, adrenal & bone
Dora Liu, MD FRCPC
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Basic thyroid physiology
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Hypothalamic-Pituitary-Thyroid Axis
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Thyroid hormones
From UpToDate
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Thyroid hormone transport
• Three major transport proteins:– Thyroxine-binding globulin (TBG)– Thyroxine-binding prealbumin (TBPA)– Albumin
• Free (unbound) hormones are active• Proportion of “free” hormones:
– 0.04% of T4
– 0.4% of T3
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Thyrotoxicosis
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Clinical features of thyrotoxicosis
• Weight loss• Increased appetite• Heat intolerance• Anxiety, irritability• Fine tremor• Fatigue• Thyroid stare• Systolic HTN
• Tachycardia• Palpitations• Atrial fibrillation• Frequent BM’s• Proximal weakness• Diaphoresis• Moist skin• Fine hair
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Thyrotoxicosis - Investigations
• Primary:– Low TSH– Increased fT3 and/or fT4
– Thyroid uptake and scan to determine etiology of 1o hyperthyroidism
• Secondary:– TSH elevated or not suppressed– Increased fT3 and/or fT4
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Causes of 1o thyrotoxicosis
• Graves’ disease• Toxic adenoma or toxic multinodular goitre• Thyroiditis• Jod-Basedow (iodine-induced)• Exogenous thyroid hormone• Gestational hyperthyroidism (hCG-induced)
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Graves’ disease
• Autoimmune disorder• Thyroid stimulating immunoglobulin
binds TSH receptor• F > M• Any age with peak in 3rd-4th decade• Diffusely enlarged “meaty” goitre
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Graves Hyperthyroidism
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Graves ophthalmopathy
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Pretibial myxedema
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Graves diseaseIncreased homogeneous uptake
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Treatment of Graves disease
• Methimazole or propylthiouracil (PTU)• Radioactive iodine therapy• Thyroidectomy• Temporary measures:
-blockade– Steroids (decrease T4 to T3 conversion)– Iodine (Wolff-Chaikoff effect)
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Toxic adenoma
• Solitary thyroid nodule produces excess hormone
• Accounts for < 5% of hyperthyroidism• Frequency increases with age• F > M• Treatment of choice: radioactive iodine
therapy
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Toxic adenoma
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Toxic multinodular goitre
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Toxic multinodular goitre
2 nodules producing excess hormone• In Canada, most patients are > 50 yrs
old• Younger patients in areas of iodine
deficiency• Compressive symptoms can occur• Treatment of choice: I-131
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Toxic multinodular goitre
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Thyroiditis
• Destruction of thyroid cells causes release of hormones
• Autoimmune, infectious and toxic causes
• Can occur in post-partum period• Can be associated with fever, painful &
tender gland
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Diagnosis & treatment of thyroiditis
• Low uptake on thyroid scan• NSAIDs for painful inflammation• -blockers to control symptoms• Steroids for severe cases• Often followed by hypothyroid phase
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Gestational hyperthyroidism
• hCG mimics TSH and stimulates thyroid hormone production
• Associated with hyperemesis gravidarum, multiple gestation
• Improves by 2nd trimester• Must differentiate from Graves disease-blocker & PTU can be used during
pregnancy
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Extrathyroidal sources of thyroid hormone
• Exogenous sources:– Exogenous thyroid hormone– Hamburger thyrotoxicosis
• Endogenous sources:– Struma ovarii– Functioning thyroid cancer
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Other causes of hyperthyroidism
• TSH-secreting tumour• Iodine load (Jod-Basedow phenomenon)• Pituitary resistance to thyroid hormone
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Hypothyroidism
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Hypothyroidism
• 2-3% of population• F:M = 10:1• 1o hypothyroidism (90%)
– Autoimmune (e.g., Hashimoto’s)– Iatrogenic (surgery, RAI, drugs, iodine)– Congenital, intrinsic defect of hormone synthesis– Infiltrative (amyloid, progressive systemic sclerosis)
• 2o hypothyroidism - TSH deficiency• 3o hypothyroidism - TRH deficiency
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Clinical features of hypothyroidism
• Fatigue• Cold intolerance• Slow mental & physical
performance• Hoarse voice• Bradycardia• Diastolic hypertension• Edema
• Weight gain• Constipation• Menorrhagia• Dry skin• Macroglossia• Muscle cramps• Delayed DTR• Dyslipidemia
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Hypothyroidism - Lab tests
• 1o hypothyroidism– Elevated TSH– Low fT4 and/or fT3
• Central hypothyroidism– Low fT4 and/or fT3– TSH not reliable
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Treatment of hypothyroidism
• Typical levothyroxine (LT4) dose 50 - 200 mcg• Start low dose (25 mcg) and titrate up slowly
in elderly• R/O adrenal insufficiency• Check TSH 6-8 wk after dose change & titrate
to normalize TSH for 1o hypothyroidism• Titrate to normalize fT3 for central
hypothyroidism
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Myxedema coma• Severe hypothyroidism• Precipitating event (e.g., trauma, sepsis, cold
exposure, MI, narcotics)• Clinical features: Hypothermia, hypoglycemia,
hypotension, bradycardia, hypoventilation• Mortality up to 60%• Treatment:
– ABCs– Stress-dose steroids– L-T4 0.2-0.5 mg IV then 0.1 mg daily
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Non-thyroidal illness“Sick euthyroid syndrome”
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Non-thyroidal illness• Change in thyroid hormone levels related to
serious illness• Abnormalities in TSH secretion, hormone
binding & metabolism• Decreased T4 to T3 conversion• Typically see low fT3 & high rT3
• More severe illness: fT3, fT4 & TSH can all be low
• Rx: Treat underlying illness
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Thyroid nodules and malignancies
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Thyroid nodules
• ~ 4% prevalence• ~ 5% malignant• If nodule is identified, check TSH
– Low TSH Thyroid scan• Low probability of malignancy with hot nodules• FNAB if cold nodule is present (15-20% malignant)
– Normal or high TSH FNAB if palpable or > 1 cm in diameter
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Thyroid malignancies
• Well-differentiated thyroid carcinomas:– Papillary– Follicular
• Medullary thyroid carcinoma– Familial forms: MEN IIa & IIb, familial medullary
carcinoma– Calcitonin is a tumour marker
• Anaplastic thyroid carcinoma– Very poor prognosis
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Well-differentiated thyroid carcinoma
• Total thyroidectomy• I-131 therapy if higher risk
– Multifocal– Large tumour– Capsular invasion– Lymph node or distant metastases
• TSH suppression• Follow thyroglobulin level
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Medullary thyroid CA• Look for other features of MEN IIa & IIb
– R/O pheochromocytoma– R/O 1o hyperparathyroidism– RET protooncogene mutation
• Treatment– Surgical resection for cure– Some respond to MIBG or octreotide
• Prophylactic thyroidectomy in affected relatives
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MEN syndromes
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Medullary thyroid CA
• Look for other features of MEN IIa & IIb– R/O pheochromocytoma– R/O 1o hyperparathyroidism– RET proto-oncogene mutation
• Treatment– Surgical resection for cure– Some respond to MIBG or octreotide
• Prophylactic thyroidectomy in affected relatives
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Pituitary - Adrenal Disorders
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Basic pituitary & adrenal physiology
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Hypothalamic & anterior pituitary hormones
• GHRH Growth hormone (GH)• TRH TSH• Somatostatin GH & TSH• TRH & Prolactin-releasing factors Prolactin• Dopamine Prolactin• CRH ACTH• GnRH LH & FSH
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Pituitary hormones
• Anterior– Growth hormone– ACTH– LH– FSH– TSH– Prolactin
• Posterior– ADH (arginine
vasopressin)– Oxytocin
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Hyperprolactinemia
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Causes of hyperprolactinemia
Physiologic Medications Pathologic
Pregnancy
Nipple stimulation
Sleep
Stress
Exercise
EstrogenAnti-psychoticsMAOIOpioidsCimetidineLicorice
Pituitary tumours
Stalk compression
Chest wall lesions
Hypothyroidism
Renal failure
Severe liver disease
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Hyperprolactinemia
• Clinical features:– Galactorrhea, gynecomastia, infertility, low bone
density– Headaches, bitemporal hemianopsia (if
macroadenoma affects optic chiasm)
• Treat underlying cause, if present• 1o Rx for prolactinoma:
– Dopamine agonist (e.g., bromocriptine or cabergoline)
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Acromegaly
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Clinical features of acromegaly
• Coarse facial features• Acral enlargement• Hyperhidrosis• Heat intolerance• Oily skin• Fatigue• Weight gain• HTN
• Goitre• Cardiomegaly• Insulin resistance• Arthralgias• Parasthesias• Hypogonadism• Headaches
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Acromegaly
• Diagnostic tests:– Glucose suppression test– IGF-1 level
• Treatment:– Surgery– Somatostatin analogues (Octreotide)– Radiotherapy– GH receptor antagonist (Pegvisomant)
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Posterior pituitary disorders
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SIADH Diagnostic criteria
• Plasma osmolality < 275 mOsm/kg H2O, excluding pseudohyponatremia or hyperglycemia
• Inappropriate urine concentration (UOsm > 100 with normal renal function)
• Clinical euvolemia• Elevated urine sodium excretion with normal salt
and water intake• Absence of other potential causes of euvolemic
hypo-osmolality (hypothyroidism, adrenal insufficiency, diuretic use)
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Treating SIADH
• Fluid restriction• Loop diuretics• Hypertonic saline if urgent correction
needed• Demeclocycline, lithium (rarely used)• Do not correct Na+ too quickly• Treat underlying cause
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Diabetes insipidus
• Clinical features:– Polyuria, polydispsia– Hypernatremia, dehydration– Low urine Na+ & osmolality
• Treatments:– Oral & IV fluids– dDAVP– For nephrogenic DI:
• Na+ restriction, thiazides & PG inhibitors
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Hypothalamic Pituitary
Adrenal Axis
From Williams Textbook of Endocrinology
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POMC synthesis and cleavage
From Williams Textbook of Endocrinology
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Microscopic anatomy
Zone Hormone
Glomerulosa Aldosterone
Fasciculata Cortisol
Reticularis Androgens
Medulla Catecholamines
From Williams Textbook of Endocrinology
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Adrenal steroid function
• Glucocorticoids– Affects fuel metabolism, responses to
injury and general cell function• Mineralocorticoids
– Control body Na+ and K+ content• Androgens
– Similar function to male gonadal hormones
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Adrenal steroidogenesis
From Williams Textbook of Endocrinology
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Sites of glucocorticoid
action
From Williams Textbook of Endocrinology
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Cushing’s syndrome
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Features of Cushing’s
• Moon facies• Facial plethora• Dorsal &
supraclavicular fat pads
• Mental status change• HTN• Visceral adiposity
• Muscle wasting• Ecchymoses• Thin skin• Purple striae• Osteoporosis• Avascular necrosis• Insulin resistance
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Screening tests for Cushing’s syndrome
• 24 hr urinary free cortisol• Low-dose dexamethasone suppression
test• Evening cortisol• Salivary cortisol (23:00)
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Working up CushingsDiagnose Cushings
ACTH < 2 ACTH > 2
Adrenal Imaging
Adrenalectomy
High-dose DST
Cushings disease Ectopic Cushingsor Cushings disease
Inferior petrosal sinus sampling
MRI Pituitary
Pituitary surgeryCushings disease Ectopic Cushings
MRI Pituitary
Pituitary surgery
CT Chest/abdoOctreotide scan
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Adrenal insufficiency
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Clinical features of adrenal insufficiency
• Weight loss• Fatigue• Weakness• Hypoglycemia• Hyponatremia• Anemia
• Addison’s– Hyperpigmentation– Volume depletion– N/V, abdo pain– Hyperkalemia
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Adrenal insufficiency
• Treatment– IV fluids– Glucocorticoid therapy– Mineralocorticoid therapy for Addison’s
• Diagnosis– ACTH stimulation test– Insulin tolerance test for central disease
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Primary hyperaldosteronism
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Aldosterone secretion & actionHypotension Low Na+
Renin
Angiotensinogen Angiotensin I
Angiotensin II
ACE
Blood pressure
Aldosterone
Na+ reabsorption
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Assessment of renin-angiotensin-aldosterone axis• Random plasma renin activity not reliable• Plasma aldosterone > 695 pmol/L• Aldosterone:renin ratio • 24 hr urinary aldosterone
– Normal 14-56 nmol– Aldosterone-producing adenoma 125 9 nmol– Idiopathic hyperaldosteronism 75 5 nmol
• Adrenal vein sampling
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From UpToDate
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Adrenal androgens
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Adrenal androgen secretion
• > 50% of circulating androgens in premenopausal females
• Relative contribution smaller in males• Stimulated by ACTH• DHEA and androstenedione levels
demonstrate circadian rhythm (but not DHEAS)
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Congenital adrenal hyperplasia
XX
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Congenital adrenal hyperplasia
• Autosomal recessive disorder• Presentations of CAH:
– Female neonates: Ambiguous genitalia– Male neonates: Adrenal crisis– Non-classic: Hirsutism & infertility in females
• Treatment:– Glucocorticoid therapy– Mineralocorticoid for salt-wasting varieties
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Pheochromocytoma
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Clinical features of pheochromocytoma
• Paroxysmal or sustained HTN• Triad: H/A, palpitations/tachycardia,
diaphoresis• Postural drop in BP• Dilated cardiomyopathy• Tremor, anxiety• Chest pain• Papilledema, blurry vision
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Pheochromocytoma
• Diagnosis– Urine metanephrines or plasma
catecholamines– MIBG, octreotide scan
• Treatment -blockade or CCB (not -blocker 1st!)– Volume restoration– Adrenalectomy
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Bone & calcium disorders
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PTH-Ca2+ feedback loopParathyroid
glands
GI Tract
PTH
ECF Ca2+
1,25 D
-
PTH
-
Ca2+Ca2+ Ca2+
-
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Vitamin D
7-dehydrocholesterol Cholecalciferol
25-OH vitamin D
Calcitriol
PTH
24,25(OH)2 - D
IntestinalCa & PO4
absorption
PTHsecretion
Multiple effectsin bone
Effectsin muscle
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Hypercalcemia
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Clinical manifestations of hypercalcemia
• General: Weakness• CVS: HTN, valve & arterial calcification• GI: Constipation, anorexia, N/V, pancreatitis• Renal: Stones, DI (polyuria), renal
insufficiency• MSK: Bone pain• CNS: Altered mental status
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Mechanisms for hypercalcemia
• Increased bone resorption
• Increased gastrointestinal absorption of calcium
• Decreased renal excretion of calcium
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Increased bone resorption• Hyperparathyroidism (usually 1o)• Malignancies
– PTHrP (solid tumours, leukemia)– 1,25(OH)2D (lymphomas)– Ectopic PTH (rare)– Osteolytic lesions
• Hyperthyroidism• Immobilization• Paget’s disease (usually with immobilization)• Estrogen, tamoxifen• Hypervitaminosis A
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More causes of hypercalcemia• Increased calcium absorption
– Increased calcium intake– Hypervitaminosis D
• Lithium• Thiazide diuretics• Pheochromocytoma• Adrenal insufficiency• Rhabdomyolysis• Theophylline• Familial hypocalciuric hypercalcemia
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Ways to lower calcium
• IV fluids• Furosemide• Calcitonin• Steroids• Bisphosphonates• Dialysis
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Hypocalcemia
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Clinical features of hypocalcemia• Paresthesia• Laryngospasm• Seizures• Carpopedal spasm• Chvostek’s sign (CN VII)• Trousseau’s sign (carpal spasm)• Hyperreflexia• Mental status changes
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Causes of hypocalcemia• Low PTH
– Hypoparathyroidism– Hypomagnesemia
• Vitamin D related– Vitamin D deficiency– 1-hydroxylase activity (renal failure, vit D
dependent rickets)– Vitamin D resistant rickets
• Pseudohypoparathyroidism (PTH resistance)• Drugs (calcitonin, furosemide)
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Treatment of hypocalcemia
• ABC’s• Replace calcium
– Calcium gluconate IV– Oral calcium
• Treat hypomagnesemia, if present• May require vitamin D• Correct underlying cause
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Osteoporosis
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What is osteoporosis?
• Systemic skeletal disorder
• Characterized by compromised bone strength
• Leads to enhanced bone fragility and a consequent increase in fracture risk
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What determines bone strength?
• Bone density– Expressed in grams of bone mass over area or
volume of bone– Determined by peak bone mass & amount of
bone loss
• Bone quality– Refers to architecture, damage accumulation
(e.g., microfractures) & mineralization
NIH Consensus Statement 2000
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Bone density & quality determine bone strength
Bone volume Tissue volume 22% 13% 22%
Normal bone Low BMD Poor quality
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Osteoporosis & fractures
• Osteoporosis is a significant risk factor for fractures
• Fractures occur when a failure-inducing force is applied to osteoporotic bone
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Indications for BMD ≥ 50 yrs
• Age ≥ 65 yrs• Fragility fracture after age 40 yr• Prolonged glucocorticoid use• Use of other high-risk medications• Parental hip fracture• Vertebral # or osteopenia on X-ray• Current smoking or high EtOH intake• Low weight (< 60kg) or wt loss (>10% of weight at age 25 yr)• Rheumatoid arthritis• Other disorder strongly associated with osteoporosis
CMAJ 2010
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Indications for BMD < 50 yrs
• Fragility fracture• Prolonged use of glucocorticoid• Use of other high-risk medication• Hypogonadism or premature ovarian failure• Malabsorption syndrome• Primary hyperparathyroidism• Disorder strongly associated with rapid bone loss
and/or fracture
CMAJ 2010
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DEXA is used to measure BMD
• The PROS of DEXA scanning– Quick, non-invasive– 1/10 radiation of CXR (background radiation exposure
over 1 day)– Most accurate estimator of fracture risk
• The CONS of DEXA scanning– Not a measure of bone strength (only accounts for ~70%
of strength)– Inter-operator variability, lack of standardization
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Who should be screened?
• Indications for BMD scan:– Patients with 1 major or 2 minor risk factors for
osteoporosis– Age ≥ 65 years regardless of risk factors
• Contraindications for BMD scan:– Pregnancy– Recent GI study or nuclear medicine test (wait at
least 72 hr; up to 7 d for long-lived isotopes like gallium)
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Interpretation of BMD measurements
• T-score: # of SD’s from average person of same gender at peak bone mass
• Z-score: # of SD’s compared to average person of same gender, age & race
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WHO diagnostic categories
Classification Criterion
Normal T-score ≥ - 1.0
Osteopenia T-score between -1.0 and -2.5
Osteoporosis T-score < -2.5
Severe osteoporosisT-score < -2.5 with
Hx of fragility fracture(s)
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Secondary causes of osteoporosis
Endocrine & Metabolic
Nutritional DrugsCollagen disorders
Other
HypogonadismCushingsThyrotoxicosisAnorexia nervosaHyperprolactinemiaPorphyriaHypophosphatemiaDiabetesPregnancyHyperparathyroidismAcromegaly
MalabsorptionMalnutritionChronic cholestatic
liver disease
Gastric operationsVitamin D deficiencyCalcium deficiencyAlcoholism
GlucocorticoidsExcessive thyroid
hormoneHeparinGnRH agonistsPhenytoinPhenobarbitalVitamin D toxicity
Osteogenesis imperfecta
HomocystinuriaEhlers-Danlos
syndromeMarfan
syndrome
Rheumatoid arthritisMyeloma & some
cancersImmobilizationRenal tubular acidosisHypercalciuriaCOPDOrgan transplantationMastocytosisThalassemia
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Calcium & vitamin D intake Calcium
Children (4-8) 800 mg
Adolescents (9-18) 1300 mg
Premenopausal women 1000 mg
Men <50 1000 mg
Menopausal women 1500 mg
Men > 50 1500 mg
Pregnant or lactating women 1000 mg
Vitamin DAge < 50 400 IU
Age > 50 800 IU
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Fall Prevention
• Risk Factors– Sedatives– Previous fall– Cognitive impairment– Visual impairment– Foot problems– Gait abnormalities– Lower extremity
disability
• Prevention measures– Bathroom lights on– Install grab bars– Avoid loose rugs– Remove clutter– Keep wires behind
furniture
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Who should receive pharmacotherapy?
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10-yr fracture probability
Age (yrs)
T-score
Prob
abili
ty (%
)
Osteoporos Int 2001; 12: 989
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FRAX™ Calculation tool
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FRAX™ Calculation tool
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Treat high risk patients
• > 20% 10-yr fracture risk• Prior fragility # of hip• Fragility # of spine• > 1 fragility #
CMAJ 2010
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Moderate risk (10-20% 10-yr risk)
Consider treatment if:• Prior wrist # and age > 65 yr• L-spine T-score << femoral neck• Rapid bone loss• Androgen deprivation therapy or aromatase inhibitor• Long-term or repeated glucocorticoid use• Recurrent falls (> 2 in 12 mos)• Disorder strongly associated with osteoporosis or
rapid bone loss
CMAJ 2010
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Bisphosphonates
• Similar in structure to pyrophosphate in bone• Attaches to bone surface and inhibits
osteoclastic resorption• PO: Alendronate, risedronate• IV: Pamidronate, zoledronic acid• Possible adverse effects: Reflux, ONJ, atrial
fibrillation, low-energy subtrochanteric fractures
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Denosumab (Prolia)
• Human monoclonal RANKL antibody• Inhibits osteoclastic activity• Pros:
– Convenient, 60 mg SC q6 mos– Reduces vertebral & non-vertebral #’s– Well-tolerated
• Cons:– Lack of long-term data– Dermatologic side effects
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Calcitonin
• Inhibits bone resorption• Analgesic effect• No drug-drug interactions• Well-tolerated• Evidence for reduction in vertebral
fractures, but not non-vertebral fractures
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Hormone replacement therapy
• The benefits:– Decreases osteoclastic activity– Increases BMD & lowers fracture risk– Treats symptoms of estrogen deficiency– Decreases colon cancer risk
• The down side:– Increased CVD, VTE & PE risk– Increased breast cancer risk– Adverse effect on cognition
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Selective Estrogen Receptor Modulator (SERM)
• Binds to estrogen receptors• Produces an estrogen agonist effect in
some tissues• Produces an estrogen antagonist effect
in others• Examples: Tamoxifen, raloxifene
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Guidelines for Teriparatide• 1st line Rx for women ≥ 65 yrs with T < -2.5 and Hx
of vertebral fracture• Preferable to treat bisphosphonate naïve patients• Consider treating post-menopausal women with T <
-3.5 who continue to fracture despite adequate (2 yr) trial of therapy
• Discontinue bisphosphonate prior to PTH• Limit PTH Rx to maximum 24 mos• Administer bisphosphonate therapy after PTH
course
CMAJ 2006; 175:48
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Hip protectors
NEJM 2000; 343: 1506
• 1801 frail but ambulatory elderly adults, mean age 82 yrs
• Hip protector : control = 1 : 2• 1 month F/U• Relative hazard of hip fracture = 0.4;
P=0.008
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Vertebroplasty & kyphoplasty
• Vertebroplasty = minimally invasive surgical procedure to relieve the pain of compression fractures
• Kyphoplasty = proprietary derivative procedure using polymethylmethacrylate (PMMA) to fix a vertebral body in place after balloon inflation of the body
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Good luck!