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Learning Objectives• Understand the role of calcium in intracellular, extracellular and
skeletal physiology.
• Define what is meant by the terms of positive and negative calcium balance.
• Understand the integrated control of calcium and phosphate homeostasis through the interactions between parathyroid hormoneand vitamin D.
• Understand the clinical features of hypocalcemia and hypercalcemia
• Know the major etiologies of hypocalcemia and hypercalcemia
• Understand the risks and benefits of the various therapeutic approaches to hypocalcemia and hypercalcemia
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1000 gm
Physiologic Role of CalciumIntracellular
Extracellular
free - action potentials, motility & rearrangements, division, secretion
bound - storage
membrane potentials, contraction, exocytosis, blood clotting, enzyme modulation
Skeletal
structure, protection of organs, locomotion, storage
9 gm
2 gm
.
2 mg
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Composition of Calcium in Serum
Protein BoundFree (Ionized)
Complexed
45%45%10%
InertTightly Regulated
??
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Distribution of Ca & Fe
0.0001
0.001
0.01
0.1
1
10
100
1000
10000Free Bound Free Bound Free Bound
Free Bound
Fe
Intracellular
Free Bound
Ca
Extracellular
Free Bound
Ca
Ca/Fe, gm
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Physiologic Role of Phosphorus• Integral molecular component
• DNA, RNA
• ATP
• cAMP
• Glycolytic intermediates
• Covalent modifier of numerous enzymes
• Acid-base balance
• Crystalline structure of bone and teeth
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Mineral Absorption
• Fractional absorption depends on the H2O solubility of the mineral
High solubility - Na, K, P, Cl, I, F (80-100%)• Mechanism of absorption - diffusion
Low solubility - Ca, Mg, Fe, Zn, Cu (< 50%)• Mechanism of absorption - active or facilitated transport
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Parathyroid Hormone
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Parathyroid hormone
Skeletal release of Ca and P
Renal calcium reabsorption
Renal phosphate reabsorption
Renal synthesis of 1,25(OH)2 D
Hormonal Regulation of Mineral Homeostasis
PTH
Ca
Parathyroid Glands
++
PO4
1,25 D3
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Calcitonin• 32 amino acid protein secreted by the perifollicular or “C” cells of the thyroid
in response to hypercalcemia• potent inhibitor of osteoclast function
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Parathyroid hormone
Skeletal release of Ca and P
Renal calcium reabsorption
Renal phosphate reabsorption
Renal synthesis of 1,25(OH)2 D
Calcitonin
Skeletal release of Ca and P
Hormonal Regulation of Mineral Homeostasis
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Vitamin D
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Vitamin D Physiology
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Active Vitamin D Precursors
Vitamin D3Cholecalciferol
Vitamin D2Ergocalciferol
HO HO
Courtesy of Joanna Hudson, PharmD.
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Vitamin D
DietSkin
Liver 25-OH D
1,25(OH)2 DBone
IntestinePTH
Phosphate
Ca++
1,25(OH)2 D
Kidney
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Vitamin D
DietSkin
Liver 25-OH D
24,25(OH)2 DPTH
Phosphate
Ca++
1,25(OH)2 D
Kidney
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Regulation of Vitamin D Synthesis
25-OH D
1,25(OH)2 Dactive
24,25(OH)2 Dinactive
PTH
Ca++
PO4-
PTH
Ca++
PO4-} 1,25(OH)2D3
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Vitamin D Response to Sunlight
8765432100
20
40
60
80
100
Days
Vitamin D
(nmol/L) Young
Elderly
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Parathyroid hormone
Skeletal release of Ca and P
Renal calcium reabsorption
Renal phosphate reabsorption
Renal synthesis of 1,25(OH)2 D
Calcitonin
Skeletal release of Ca and P
1,25-dihydroxyvitamin D3 (1,25(OH)2 D)
GI Absorption of Ca and P
Skeletal release of Ca and P
Hormonal Regulation of Mineral Homeostasis
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Pathophysiology of Hypocalcemia
PTH
PTH
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Causes of Hypocalcemia
• Hypoparathyroidism - High Serum Phosphorus– Idiopathic (a)– Post-surgical (a)– Hypomagnesemia (a)– PTH resistance (b)
• Secondary hyperparathyroidism - Low Serum Phosphorus– Vitamin D deficiency (c & d)– Vitamin D resistance (e)– Miscellaneous (radiographic contrast agents, citrate-containing
transfusions, anticonvulsants, etc.) (f)
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Signs and Symptoms of Hypocalcemia
• Acute setting (neuromuscular)• Symptoms
– minor - paresthesias, numbness, tingling of the extremities– major - carpal-pedal spasm, laryngospasm, seizures
• Signs– Chvostek's sign - twitching of the ipsilateral facial muscle when
the facial nerve is gently tapped– Trousseau's sign - carpal spasm after the blood pressure cuff is
inflated above the systolic pressure for 2 minutes.– Prolonged QT interval on ECG
• Chronic settingCalcifications - soft tissue, lens, basal gangliaIntestinal malabsorption, diarrheaPapilledema
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Therapy of Hypocalcemia
A. Acute setting -symptomatic hypocalcemia or asymptomatic patient with seizure risk
1. Parenteral calcium(10 ml of 10% calcium gluconate [93mg elemental calcium]
infused over10 minutes.
2. Eliminate intake of calcium-binding anions (carbonate, phosphate)
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Therapy of HypocalcemiaChronic setting
1. Calcium supplementation ~15mg/kg/day of elemental calcium
2. Vitamin D supplementationa. Replete the earliest vitamin D metabolite that is deficientb. Consider features of cost, rapidity of onset and offset of
action and the potential to allow for endogenous responses to variations in mineral metabolism
c. Dose adjustments1) With change in interacting drugs - estrogens,
glucocorticoids, bile acid resins and anticonvulsants all increase dose requirements
2) With change in the underlying disease - adrenal insufficiency, hypogonadism, malabsorption and cirrhosis can all alter bone and mineral homeostasis.
3. Thiazides - increase renal calcium reabsorption
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Daily Calcium Intake for Males and Females
Mean Calcium Intake
1500
1000
500
2412 60 2412 60
MDR for Calcium
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Calcium Content of Selected FoodsFood
Vanilla Shake (Burger King)
Ca, mg479
Parmesan Cheese (1oz)Vanilla Shake (McDonalds)Collard Greens (1 cup)Sardines (8)Yogurt (1 cup)Skim Milk (1 cup)Whole Milk (1 cup)Molasses (2 tbsp)Turnip Greens (1 cup)Tofu (4 oz)Kale (1 cup)Broccoli (1 cup)
3903613573543453032882742491509472
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Calcium SupplementsDrugCalcium carbonate
CalBurstCaltrate+DOs-Cal+DTums 500Viactiv
Calcium citrateCitracal+DCalcium citrate+D
Calcium complexCalcet
Calcium phosphatePosture-D
Elem Ca/tab
500600500500500
315315
150
600
Tabs/day
22222
33
7
2
Cost/mo
$6.99$5.99$5.25$4.49$6.99
$8.24$8.99
$14.68
$5.99
Medical Letter 42:29, 2000
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Vitamin D Replacement TherapyVitamin D Analog Time (days) Dosage (µg) Cost ($/d) Organ Needed
D2 - ergocalciferol 10-30 1200 0.03 Liver & Kidney
D3 - cholecalciferol 20-60 1200 0.03 Liver & Kidney
25(OH)D3 - calcifediol 7-30 20 1.15 Kidney
DC - doxercalciferol 3-14 2.5 11.30 Liver
1,25(OH)2D3 - calcitriol 2-7 0.25 1.20 None
19-nor-1,25(OH)2D3 - paricalcitol 2-7 2 3.70 None
(Time=persistence of effect in the toxic state; Dosage=average starting dose in moderate osteomalacia;
in vitamin D resistant syndromes or severe cases of vitamin D deficiency substantially larger dosesmay be required to ameliorate symptoms and improve skeletal mineralization)
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Vitamin D Analogs
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Therapy of Hypocalcemic Disorders
Pre Na Restriction HCTZ0
100
200
300
400
Prevention of hypercalciuria
Calcium Excretion (mg/day)
Adams J, et al.Metabolism 30:217, 1981
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Hypercalcemia
Clinical Definition
Total serum calcium above the normal rangeConsider the use of ionized calcium measures:
• when protein binding abnormalities may exist (e.g., with a total Ca++ level of 10 mg/dL and an albumin level of 2.0 gm/dL; a total serum Ca++ level of 12 mg/dL in a patient with multiple myeloma)
• when total serum levels are borderline
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Symptoms of HypercalcemiaNeurological
Cognitive impairment, depression, confusion, coma
GastrointestinalConstipation, anorexia, N&V
RenalPolyuria, polydipsia, stones
CardiacShortened QT interval
Dehydration
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Differential Diagnosis ofHypercalcemia
Common Causes
Primary hyperparathyroidism
Malignant disease
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Clinical Clues• >90% due to hyperparathyroidism or cancer• If asymptomatic or chronic, hyperparathyroidism most likely
Use of PTH Assays• If PTH levels inappropriately high, hyperparathyroidism confirmed.
Caution: may be only part of the etiology.
• If PTH levels suppressed,– Acute, with or without symptoms, screen for CA– Chronic - CA unlikely, consider rarer causes
Differential Diagnosis of Hypercalcemia
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Differential Diagnosis of Hypercalcemia
Uncommon Causes
Bone KidneyThyrotoxicosis Thiazide diureticsImmobilization Renal failureVitamin A intoxication
AdrenalGut Pheochromocytoma
Vitamin D intoxication Adrenal insufficiencyGranulomatous disease
1,25(OH)2D Calcium SensorMilk alkali syndrome Familial hypocalciuric
hypocalcemia
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PTH assay results in patients with:
Hypoparathyroidism
Malignancy et al
1º hyperparathyroidism
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HyperparathyroidismPresentation
Kidney StonesHypercalciuria, mainly as a result of high 1,25(OH)2D levels and increased GI Ca++
absorption. Nephrocalcinosis.
Broken BonesIncreased bone resorption, primarily cortical, leading to fxs. In early disease, trabecular BMD may be enhanced.
Abdominal GroansAnorexia, dyspepsia, constipation. Ca++ effect on gastric acid secretion?
Psychic MoansNeuropsychiatric/cognitive disturbances, fatigue, muscle weakness/myopathy. Direct muscle/nerve effect of PTH?
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Adenoma 85%Hyperplasia 15%
sporadicfamilialMEN, isolated
Carcinoma <1%
Primary hyperparathyroidism
Differential Diagnosis ofHypercalcemia
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Hyperparathyroidism - Therapy
Confirmed Diagnosis
Adverse Effects?(low bone mass, renal stones/hypercalciuria, symptoms, Ca>11.5mg/dl)
Treat
Parathyroidectomy Medical therapy
Follow
Yes No
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Differential Diagnosis of Hypercalcemia
Important Etiologies to Consider
Primary hyperparathyroidism
Malignant disease• Parathyroid hormone related peptide -
PTHrP (e.g., squamous cell, renal, transitional)
• Ectopic 1,25(OH)2D
• Bone mets
• Cytokines
Familial hypocalciuric hypercalcemia
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Differential Diagnosis of Hypercalcemia
Parathyroid hormone related protein (PTHrP)
• Synthesized in small amounts in many normal tissues (e.g., breast, growth plate, skin)
• Essential for growth and differentiation
• Similar enough in structure to bind/activate PTH receptor, but with a distinct amino acid sequence
• Unregulated in many malignancies
Hyperparathyroid-like hypercalcemic syndrome
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PTHrP levels in a variety of clinical situations
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Treatment of Hypercalcemia
• Address the underlying cause
• Extracellular volume expansion
• Increase renal calcium excretion
• Decrease osteoclastic bone resorption
• Decrease intestinal calcium absorption
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Severe Hypercalcemia - Acute Therapy
Stage 1 (24 - 48 hr.)• saline 200-300 mL/hr (± furosemide)• calcitonin 8-12 U/kg/d IV/SQ in 3-4 divided doses
Stage 2 (24 - hr.)• saline 200-300 mL/hr (± furosemide)• bisphosphonate I.V.
Principle - increase ECV, reduce bone resorption
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R2
Bisphosphonates: General Molecular Structure
OH
OH OH
OH
C
R1
PPO O
When R1 is an OH group, binding to
hydroxyapatite is enhanced
The P-C-P group is essentialfor biological activity
R2 = -CH3 = etidronateR2 = -CH2CH2CH2NH2 = alendronate
R2 = -CH2CH2NH2 = pamidronateR2 = -CH2-3-pyridine = risedronate
The R2 side chain determines potency
P-C-P acts as“bone hook”
and is essentialfor binding tohydroxyapatite
Reprinted with permission from Russell RGG, et al. Osteoporosis Int. 1999;(suppl 2):66-80.
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Generations of Bisphosphonates
Generation Chemical modification Examples
Antiresorptivepotency
Short alkyl or halide side chain
First EtidronateClodronate
110
Cyclic side chainAmino-terminal group
Second TiludronatePamidronateAlendronate
10100100-1000
Cyclic side chainThird RisedronateIbandronateZoledronate
1000-10,0001000-10,00010,000+
Reprinted with permission from Watts NB. Endocrinol Metab Clin North Am. 1998;27:419-439.
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Response to intravenous etidronate in patients with hypercalcemia of malignancy
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Hypercalcemia - Chronic Therapy
Principle - eliminate causes
Treat malignancy, granulomatous disorder, etc.
If not curable:• maintain ECV, mobility
• intermittent bisphosphonate
• for 1,25(OH)2D mediated processes, glucocorticoids to reduce GI Ca++ absorption
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Hypercalcemia
Diagnosis
• hypercalcemia, chronic
• low urine calcium:creatinine clearance
• asymptomatic
• positive family history of hypercalcemia
Familial Hypocalciuric Hypercalcemia
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Calcium Sensing Receptor (CaSR)
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Consequence of CaSR Mutations
Inactivating mutation• Increased calcium pool• Decreased calcium excretion• Familial hypocalciuric
hypercalcemia
Activating mutation• Decreased calcium pool• Increased calcium excretion• Familial hypercalciuric
hypocalcemia
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Familial Hypocalciuric Hypercalcemiainactivating CaSR mutation
Hypercalcemia (usually mild)PTH levels are normal or slightly increased (instead of low) because of low calcium receptor activity
Low urinary calcium excretionrelatively inactive renal tubular calcium receptor results in avid calcium reabsorption
Asymptomatic; normal bone mass
Evidence of family involvementsevere neonatal hypercalcemia (homozygosity)
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Hypercalcemia
Therapy - noneParathyroidectomy ineffective or results in hypoparathyroidism
Familial Hypocalciuric Hypercalcemia
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Calcimimetic - Cinacalcet
$20/tablet (60 mg)$1,800/mo
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Calcimimetic Rx - 2º HPT
QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.
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Calcimimetic Rx - 2º HPT
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Calcimimetic Rx - Parathyroid Ca