2017 ENDOCRINOLOGY

CALCIUM AND BONE MINERAL METABOLISM

HARRISON’S PRINCIPLES OF INTERNAL MEDICINE 19E
o Promotes osteoclast differentiation and increases
CALCIUM METABOLISM osteoclast activity  bone resorption
- 99% resides in the skeleton 25-hydroxyvitamin D (25[OH]D
o Reservoir for calcium needed to maintain ECF - Major circulating and storage form of Vitamin D
calcium concentration
Functions:
- Mediate neurotransmitter release
- Maintain potential differences
- Cofactor in coagulation
- Activates metabolic enzymes
Total calcium concentration: [2.2-2.6Mm (8.5-10.5 mg/dl)]
- Almost 50% of which is ionized
- Others are bound to proteins (predominantly albumin) or
loosely complexed with phosphate, citrate, sulfate, other
anions
- Alterations in serum protein concentrations directly affect
the total blood calcium concentration even if ionized
calcium is normal
Ionized calcium [4.65-5.25mg/dl (1.16-1.31 nmol/L]
- Active form
- Directly suppresses PTH secretion by activating by activating
Calcium-sensing Receptors (CaSR) in parathyroid cells
Effect of Acid-Base Disorder:
- Alkalosis: enhances Albumin-calcium binding
- Acidosis: reduces albumin-calcium binding
- Adjustments are not accurate during acute illness and post- FIBROBLAST GROWTH FACTOR 23 (FGF23)
operative period - Key regulator of phosphorus metabolism
Regulation - Increased by phosphate and calcitriol
- Accomplished by adjusting the rates of calcium movement - Impair phosphate reabsorption and Induces urine
across intestinal and renal epithelia phosphate excretion
Intestinal Absorption - Suppresses calcitriol
- Active calcium transport occurs mainly in the proximal small - Potent inhibitor of renal 1-aalpha hydroxylase  Reduce
bowel (duodenum and proximal jejunum) synthesis of 1,259OH)2D
Renal reabsorption
- Phosphaturic hormone
- Most filtered calcium is reabsorbed in the proximal tubules
PARATHYROID HORMONE
PSEUDOHYPOCALCEMIA
- Primary regulator of calcium physiology
- Decreased total Calcium but ionized calcium is normal
- Seen in: - Primary Function: maintain ECF calcium concentration
o Volume Overload within a narrow normal range
PSEUDOHYPERCALCEMIA - 12mmol (500mg) of calcium is transferred between the ECF
- Increased total calcium but ionized calcium is normal and bone each day
- Seen in: Acts on:
o Dehydration - Bone (direct): induces calcium release
o Fluid movement out of vascular space - Kidney (direct):
o High protein diet (athletes) o Proximal Tubule: inhibition of phosphate transport
o Multiple Myeloma o Distal tubule: augmentation of calcium
 Monoclonal CHON binds to calcium with reabsorption
high affinity o Stimulates renal 25(OH)D-1alpha-hydroxylase
 (-) hypercalcemic SSx
- Intestine (indirect)
 Need to differentiate from true
Function:
hypercalcemia w/c can also occur in
MM - Increases the rate of dissolution of bone mineral
PHOSPHATE - Reduces renal clearance of calcium
- Stored in the bone as hydroxyapatite - Increases efficacy of calcium absorption in the ntestine by
VITAMIN D stimulating production of Vit D
Main actions: Chronic Effects on bone:
- Regulates intestinal Ca transport - Increase number of bone cells
- Stimulates bone formation o Osteoblast (stromal cell precursors)
- Promotes Ca and PO4 reabsorption in the kidneys  Have PTH/PTHrP receptors
1,25-Dihydroxyvitamin D (1,25[OH]2D)  Crucial for bone-forming effect of PTH
- Major steroid hormone involved in mineral ion homeostasis o Osteoclast
regulation  Lack PTH receptors
- Major source: Dermal Synthesis  Mediate bone breakdown
- Increases the efficiency of intestinal calcium absorption - Increases remodeling of bone
- Induces the expression of RANK ligand Regulation
- Calcium via the calcium-sensing receptor (CaSR)

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 - Vitamin D
- FGF23
PARATHYROID HORMONE-RELATED PROTEIN
- Responsible for humoral hypercalcemia of malignancy
(normal PTH levels)
- Essential role in endochondral bone formation and in
branching morphogenesis of the breast, and uterine
contraction
CALCITONIN
- Hypocalcemic peptide hormone
- Indirect antagonist to the calcemic actions of PTH
- Source: Thyroid Gland
Actions:
- Inhibits osteoclast-mediated bone resorption
- Stimulates renal calcium clearance
- Other Function:
o Analgesic effects directly on cells in the
hypothalamus and related structures
Medical Significance:
- Tumor marker in sporadic and hereditary cases of
medullary carcinoma
- Adjunctive treatment in severe hypercalcemia and in
Pagets’s disease of the bone
HYPERPARATHYROIDISM
- Common cause of hypercalcemia
- Continuous exposure to elevated PTH leads to increased
osteoclast-mediated bone resorption
Etiology
- Autonomous adenoma or hyperplasia - MC
- Humoral Hypercalcemia of malignancy
o Overproduction of PTHrP
HYPERCALCEMIA
Cause:
- Hyperparathyroidism - MC
- Malignancy
- Excessive Vit D action
- Impaired Metabolism of Vit D
- High bone turn-over
- Renal failure
False-positive Diagnosis:
- Inadvertent hemoconcentration
during blood collection
- Elevation of serum proteins
(albumin)
Clinical Features:
- Sx common at calcium level
>2.9-3.0mmol/L (11.6-12mg/dl)
o Fatigue, depression,
mental confusion
o Anorexia, N&V,
constipation,
o increase urine output,
reversal of renal
tubular defects
o short QT intervals in ECG PRIMARY HYPERPARATHYROIDISM
- >3.2 mmol/L (12.8mg/dl) - Generalized disorder of calcium, phosphate, and bone
o Calcifications in kidney, skin, vessels, lung, heart, metabolism
and stomach - Peak incidence: between 30-50s
o Renal insufficiency - inc PTH  hypercalcemia, hypophosphatemia
- Severe hypercalcemia ≥3.7-4.5mmol/L (14.8-18mg/dl) Etiology:
o Coma - Isolated adenoma -MC
o Cardiac arrest o most often located in the inferior parathyroid
****Asymptomatic in primary HPTH glands
****Symptomatic in malignancy: Death if no Tx within 6months o usually 0.5-5g in size
****If hypercalcemia or some Sx (kidney stones) for >1-2 years = - hereditary Sx
malignancy is unlikely o MEN 1 (wermer’s Syndrome)
 Pituitary tumor

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  Parathyroid Tumor FAMILIAL HYPOCALCIURIC HYPERCALCEMIA
 Pancreatic tumor  Zollinger-Ellsion Sx - AKA: familial benign hypercalcemia
o MEN 2A - Autosomal dominant
 Pheochromocytoma - Caused by inactivating mutation in CaSR
 Medullary thyroid CA - Abnormal sensing of blood calcium by the parathyroid
 Hyperparathyroidism gland and renal tubule causing:
*** all MEN sx are autosomal dominant o Inappropriate secretion of PTH
o Hyperparathyroidism Jaw Tumor (HPT-JT) o Excessive reabsorption of calcium in the distal
 AKA: nonsyndromic familial isolated HPT renal tubules
 Mutation in CDC73 (HRPT2) Diagnosis:
SSx: - leading to inappropriately normal or even increased
- Involve primarily kidneys and skeletal system secretion of PTH
- Recurrent nephrolithiasis Treatment:
o Either calcium oxalate or calcium phosphate - NO surgery except in severe cases
stones - Calcimetics
- Osteitis Fibrosa cystica – pathognomonic features: JANSEN’S DISEASE
o Increase in giant multinucleated osteoclasts in - Activating mutations in the PTH/PTHrP receptor
scalloped ares on the surface of the bone - Autosomal dominant
o Replacement off the normal cellular and marrow - Constitutive activation of receptor function
elements by fibrous tissue SSx:
- peptic ulcers - Short-limbed dwarfism
- mental changes Diagnosis:
- extensive bone resorption - Hypercalcemia
o cortical bone density reduced while cancellous - Hypophosphatemia
bone density is relatively preserved - Undetectable/ low PTH
- Hypercalcemic Parathyroid crisis MALIGNANCY-RELATED HYPERCALCEMIA
o Marked dehydration Mechanism
o Coma - In Solid tumors (squamous cell and renal tumors)
Diagnosis: o Local invasion and destruction of bone by tumor
- PTH assay cells
o 1st gen assay: displacement of radiolabeled PTH - Hematologic Malignancy:
from Ab o Elaboration by the malignant cells of humoral
o 2nd gen assay: double Ab assay mediators (PTHrP) of hypercalcemia
- S. phosphate either low or normal Diagnosis:
- Elevated urinary nephrogenous cAMP excretion
- Hypophosphatemia
- Increased urinary phosphate clearance
- PTH is undetectable or suppressed
- Low or normal 1,25(OH)2D
VITAMIN D-RELATED HYPERCALCEMIA
- Due to excessive or abnormal metabolism of vitamin D
- Usually acquired in association with a widespread
granulomatous disorder
Vitamin D Intoxication
Treatment: - Chronic ingestion of 40-100x the normal physiologic
- Surgical Excision requirement
- Calcimimetics - Dx:
o 25(OH)D >100mg/ml
- Tx:
o Restriction of dietary calcium intake
o Hydration
o Glucocorticoids
Sarcoidosis and Other Granulomatous Diseases:
- Excess 1,25(OH)2D synthesized by macrophages
- Tx:
o Avoid excess sunlight exposure
o Limit calcium and Vit D intake
LITHIUM THERAPY AND HYPERCALCEMIA o Glucocorticoids
-Used in the management of bipolar depression and other Idiopathic Hypercalcemia of Infancy (Williams’ Syndrome)
psychiatric disorder - Autosomal dominant
- Long standing stimulation of the parathyroid cell - Multiple congenital defects:
replication by lithium predispose to development of o Supravalvular aortic stenosis
adenoma o Mental retardation
Treatment: o Elfin Facies
- Withdrawal
- Surgery not recommended unless hypercalcemia and
elevated PTH persists after discontinuation

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 HYPERCALCEMIA ASSOCIATED WITH HIGH BONE Risk Factors for fractures:
TURNOVER - Age
Hyperthyroidism - Prior fractures
- Increased bone turnover, resorption > formation - Family history of osteoporosis-related fractures
Immobilization - Low body weight
- Disproportion between bone formation and resorption - Smoking
Thiazides - Excessive alcohol use
- Reduction in urinary calcium (enhance proximal tubular
resorption of sodium and calcium in response to sodium
depletion)
Vitamin A Intoxication
HYPERCALCEMIA RELATED WITH RENAL FAILURE
Secondary Hyperparathyroidsim in CKD
- Resistance to the normal level of PTH  parathyroid gland
enlargement
- Increase FGF23 by osteocytes  reduction in 1,25(OH)2D
 secondary hyperparathyroidism
SSx:
- Bone pain (renal osteodystrophy)
- Ectopic calcification
- Pruritus Pathophysiology
Treatment: - Age-related changes in bone remodeling
- Restriction of dietary phosphate - Inadequate calcium intake during growth among other
- Calcitriol (IV) nutritional factors
ALUMINUM INTOXICATION - Contributes to relative secondary hyperparathyroidism and
- Occur in patients on chronic dialysis an increase in the rate of bone remodeling
SSx: - Recommended daily intake: 1000-1200mg for adults
- Acute dementia Vitamin D insufficiency
- Multiple nonhealing fractures - Leads to compensatory secondary hyperparathyroidism
- Severe osteomalacia Estrogen Deficiency
MILK ALKALI SYNDROME - Mechanism:
- d/t excessive ingestion of calcium and absorbable
o Activation of new bone remodeling sites
antacids (milk or calcium carbonate)
o Exaggeration of the imbalance between bone
SSx:
formation and resorption
- Hypercalcemia
- MC cause: cessation of ovarian function at menopause
- Alkalosis
(ave 51yo)
- Burnett’s Syndrome (chronic form): associated with
o Cigarette smokers reach menopause 1-2 years
irreversible renal damage
earlier
SUMMARY Physical Inactivity
- Prolonged bed rest or paralysis
Clinical Presentation PTH Calcium Phosphate Vit Chronic Disease
D
- r/t nutrition, reduced physical activity levels, and factors
Primary High High Low
that affect rates of bone remodeling
Hyperparathyroidism
Medications:
Familial Normal/ High Low
Hypocalciuric High - Glucocorticoids - MC
Hypercalcemia - Thyroid Hormone administration
Granulomatous Low High High High - Anticonvulsants
Disease - Immunosupressants
Vit D deficiency High Low Low Low o Cyclosporine
Chronic Renal High Normal/ High o Tacrolimus
Disease Low - Aromatase inhibitors
Hypoparathyroidism Low Low High - SSRI
- PPI
OSTEOPOROSIS - Thiazolidinediones
- Decreased bone strength that leads to an increased risk of Cigarette Consumption
fractures - Mediated by directly by toxic effects on osteoblast; or
- Bone density falls 2.5 SD below the mean for young healthy - Indirectly by modifying estrogen metabolism
adults of the same sex (T-score of -2.5) MEASUREMENT OF BONE MASS
o T Score: comparing individual results to those Dual-energy x-ray absorptiometry (DXA)
young population that is matched for race and - Highly accurate
sex - Standard for measuring bone density
o Z score: compare individual results to those of an - Usually lumbar spine and hip
age-matched papulation that is also matched - Can also be used to measure body composition
for race and sex Single-energy x-ray absorptiometry
- Prevalent among postmenopausal women Quantitative CT
SSx: Ultrasound
- Vertebral and hip fractures

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 Dx:
- X-ray:
o lytic wedge, or blade of grass lesion
o expansion of an entire bone or area of a long
bone, cortical thickening, coarsening of
trabecular markings
- Skull X-ray: cotton-wool or osteoporosis circumscripta
- Vertebra: picture frame vertebra/ Ivory vertebra

WHEN TO TREAT
- Treatment when BMD is >2.5 SD T-score in either spine, total
hip, or femoral neck
- Postmenopausal women with fracture risk factors even
BMD is not in the osteoporosis range
TREATMENT
Management of Underlying Disease
- Risk Factor Reduction
- Nutritional Recommendations
o Calcium
 Supplements ≤600mg at a time
o Vitamin D
 200IU for adults <50yo
 400IU for 50-70yo
 600IU for >70yo
o Other Nutrients:
 Salt
 High protein
 Vit K
- Exercise
Pharmacologic Therapies
- Estrogen
- Progestins
- SERMs
o Raloxifen: approved for prevention and tx of
osteoporosis and prevention n of breast CA
o Tamoxifen: prevention and tx of Breast CA
o Bazedoxifene: prevention of osteoporosis
- Bisphosphonates
o Alendronate
o Risedronate
o Etidronate
o Ibandronate
o Zoledronic Acid
- Calcitonin
o Approved for Paget’s disease, hypercalcemia,
and osteoporosis in women >5yrs past
menopause
- Denosumab
- Parathyroid Hormone
- Fluoride
- Strontium Ranelate
Nonpharmacologic Approaches:
- Kyphoplasty
- Vertebroplasty
PAGET’S DISEASE
- Localized bone-remodeling disorder that affects
widespread, noncontiguous areas of the skeleton
- Initiated by overactive osteoclastic bone resorption
followed by a compensatory increase in osteoblastic bone
formation
- Structurally disorganized mosaic of woven and lamellar
bone
SSx
- Elevated ALP levels
- Pain -MC

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