Pathophysiology ofCalcium Metabolism Disorders

Robert F. Klein, M.D.kleinro@ohsu.edu

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

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

Composition of Calcium in Serum

Protein BoundFree (Ionized)

Complexed

45%45%10%

InertTightly Regulated

??

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

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

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

Parathyroid Hormone

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

Calcitonin• 32 amino acid protein secreted by the perifollicular or “C” cells of the thyroid

in response to hypercalcemia• potent inhibitor of osteoclast function

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

Vitamin D

Vitamin D Physiology

Active Vitamin D Precursors

Vitamin D3Cholecalciferol

Vitamin D2Ergocalciferol

HO HO

Courtesy of Joanna Hudson, PharmD.

Vitamin D

DietSkin

Liver 25-OH D

1,25(OH)2 DBone

IntestinePTH

Phosphate

Ca++

1,25(OH)2 D

Kidney

Vitamin D

DietSkin

Liver 25-OH D

24,25(OH)2 DPTH

Phosphate

Ca++

1,25(OH)2 D

Kidney

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

Vitamin D Response to Sunlight

8765432100

20

40

60

80

100

Days

Vitamin D

(nmol/L) Young

Elderly

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

Pathophysiology of Hypocalcemia

PTH

PTH

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)

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

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)

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

Daily Calcium Intake for Males and Females

Mean Calcium Intake

1500

1000

500

2412 60 2412 60

MDR for Calcium

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

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

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)

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

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

Symptoms of HypercalcemiaNeurological

Cognitive impairment, depression, confusion, coma

GastrointestinalConstipation, anorexia, N&V

RenalPolyuria, polydipsia, stones

CardiacShortened QT interval

Dehydration

Differential Diagnosis ofHypercalcemia

Common Causes

Primary hyperparathyroidism

Malignant disease

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

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

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?

Adenoma 85%Hyperplasia 15%

sporadicfamilialMEN, isolated

Carcinoma <1%

Primary hyperparathyroidism

Differential Diagnosis ofHypercalcemia

Hyperparathyroidism - Therapy

Confirmed Diagnosis

Adverse Effects?(low bone mass, renal stones/hypercalciuria, symptoms, Ca>11.5mg/dl)

Treat

Parathyroidectomy Medical therapy

Follow

Yes No

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

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

PTHrP levels in a variety of clinical situations

Treatment of Hypercalcemia

• Address the underlying cause

• Extracellular volume expansion

• Increase renal calcium excretion

• Decrease osteoclastic bone resorption

• Decrease intestinal calcium absorption

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

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.

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.

Response to intravenous etidronate in patients with hypercalcemia of malignancy

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

Hypercalcemia

Diagnosis

• hypercalcemia, chronic

• low urine calcium:creatinine clearance

• asymptomatic

• positive family history of hypercalcemia

Familial Hypocalciuric Hypercalcemia

Calcium Sensing Receptor (CaSR)

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

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)

Hypercalcemia

Therapy - noneParathyroidectomy ineffective or results in hypoparathyroidism

Familial Hypocalciuric Hypercalcemia

Calcimimetic - Cinacalcet

$20/tablet (60 mg)$1,800/mo

Calcimimetic Rx - 2º HPT

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Calcimimetic Rx - 2º HPT

Calcimimetic Rx - Parathyroid Ca