Lecture 20 - PTH, Vitamin D, Bone Turnover

what are the major players of calcium physiology

calcium

phosphate

calcium sensing receptor 

parathyroid hormone 

vitamin D (pro-hormone)

kidneys/intestines/bone

other hormones: calcitonin, estrogen, FGF23, Klotho

what is the major mineral of bone

calcium phosphate

what is the distribution of calcium in the body

99% in bone

1% extracellular

what are the functions of extracellular calcium

co-factor for enzymatic reactions

coagulation

muscle contraction

neurotransmitter release

endocrine/exocrine secretion

what is the distribution of phosphate in the body

85% in bone

15% as organic form

what is the function of organic phosphate

part of biological molecules 

nucleic acids, phospholipids, CHO, enzymes, cofactors, ATP 

how much of calcium is protein bound in the blood

50%

what is the biologically active form of calcium

the ionized form (Ca2+)

what do the kidneys do to calcium

reabsorbed by renal filtration

how is organic phosphate found in the body

almost completely ionized (H2PO4 or HPO4)

minimal protein binding and minimal complex with other cations 

what do the kidneys do to phosphate

readily cleared by renal filtration

what is the function of parathyroid hormone

raise serum calcium levels, tight control

2.10-2.55 mmol/L

what kind of hormone is PTH

peptide hormone

what kind of cells synthesize PTH

chief cells in parathyroid gland 

where are the superior pair of parathyroid glands from

4th brachial pouch

where are the inferior pair of parathyroid glands from

3rd brachial pouch (same as thymus)

what are the actions of PTH at the kidneys 

acts within minutes 

increases renal calcium reabsorption 

increases renal production of active vitamin D (→ increases intestinal calcium and phosphate absorption)

what are the actions of PTH in bone

increases resorption

acts on PTH receptors on osteoblasts to upregulate RANK-ligand → promotes osteoclasts

increases bone formation → osteoblasts form new bone

bone resorption and formation are coupled

what is the calcium sensing receptor (CaSR)

GPCR on chief cells in PT glands

senses extracellular calcium using CaSR

low levels → increases PTH secretion

what is the effect of low serum calcium on PTH secretion

increases secretion

primary stimulus

what is the effect of high serum phosphate on PTH secretion 

direct effect to increase PTH mRNA in Chief cells

indirect effect by decreased serum calcium

PTH will promote phosphate excretion in urine 

what is the effect of high vitamin D on PTH secretion

direct effect on gland - decrease PTH synthesis

what happens to bone when there is too much PTH around for a long time

excessive bone resorption, leading to osteoporosis/osteopenia

bone fracture may be first indicator of PTH disorders

where are type 1 PTH receptors found and what do they recognize

bone, kidney

recognizes PTH and PTHrP - PTH related protein, often associated with tumors

where are type 2 PTH receptors found and what do they recognize

brain, pancreas, testis, placenta

recognizes PTH only

what is a Whole PTH immunoassay 

sandwich assay

uses 2 antibodies - one for the amino terminus, one for the carboxyl terminus 

differentiates between 1-84 PTH (intact) and 7-84 PTH (cleaved)

what does 1-84 PTH do

triggers receptor to raise bone turnover - increase plasma calcium levels (triggers RANKL expression)

what does 7-84 PTH do

lowers bone turnover

functions as receptor antagonist

what is the therapeutic dosage form of PTH

recombinant human 1-34 PTH (teriparatide)

has amino acid residues 1-6 that are responsible for triggering PTH receptor activity

not detected by sandwich immunoassay 

what and the characteristics of PTH related protein 

homologous with PTH at the amino terminus 

similar effects to PTH on bone and kidney 

• increased bone resorption 

• increased phosphaturia 

• decreased renal calcium excretion 

can cause hypercalcemia of malignancy 

what kind of cells produce calcitonin

thyroid C cells

what are the functions of calcitonin

opposite of PTH

blocks osteoclast activity via calcitonin receptor

reduces blood calcium by:

• reducing intestinal absorption

• osteoclast inhibition (calcitonin receptors)

• promoting renal clearance

what are the functions of FGF23 and co-receptor Klotho

fibroblast growth factor 23

produced by osteoblasts and osteocytes in bone

induced by active vitamin D → inhibit further synthesis of active vitamin D

what is vitamin D2

ergocalciferol 

produced by UV radiation of plant steroid ergosterol 

what is vitamin D3

cholecalciferol

formed in skin (epidermis) under action of UV light on 7-dehydrocholesterol

how is vitamin D converted to active form

vitamin D2 and D3 are metabolized in liver to 25-dihydroxyvitamin D - calcidiol (major circulating form)

further hydroxylation in kidney to form highly biologically active 1,25-dihydroxyvitamin D - calcitriol

how are vitamin D2 and D3 converted to calcidiol

they are lipophilic

transported to liver bound to albumin to vitamin D binding protein

liver enzyme vitamin D-25 hydroxylase converts to 25-OH-VitD → continue to circulate free in serum and bound to vitamin D binding protein

how is calcidiol converted to calcitriol 

takes place in kidney 

kidney enzyme 25-vitaminD-1a-hydroxylase converts to 1,25-[OH]2-VitD

PTH increases synthesis of kidney enzyme → links formation of active vitamin D with feedback inhibiton of PTH and calcium homeostasis  

what are the effects of calcitriol

absorption of calcium and phosphate from small intestine

acts on nuclear vitamin D receptors in osteoblasts to upregulate RANKL → promotes osteoclasts

extracellular calcium homeostasis → directly and indirectly through decreasing PTH

mineralization of the skeleton

what is a major factor that influences vitamin D formation

drugs metabolized by CYP3A4

CYP3A4 has a shared metabolic pathway in calcidiol formation and xenobiotic drug metabolism

these patients may be at risk of vitamin D deficiency (regardless of supplementation)

what is primary hyperparathyroidism

most common parathyroid disorder 

excessive PTH production due to Chief cell adenoma (cancer)

treatment: excision surgery of PT gland

what is secondary hyperparathyroidism 

due to hyperplasia - response to events outside glands 

• severe Ca/Vit D deficiency (absorption issues)

• kidney reabsorption/conversion issues 

• offending drugs (e.g. block vitamin D conversion)

what are symptoms of hyperparathyroidism

usually asymptomatic until severe

skeletal complications - osteopenia, fracture

nephrolithiasis - kidney stones

what are the treatments for hyperparathyroidism 

calcimimetics - e.g. cinacalcet

bisphosphonates - prevent bone calcium loss (do not lower calcium)

hormone replacement therapy - help bone density in postmenopausal women (does not address PTH regulation directly)

other: SERMs (raloxifene), calcitonin - limited or temporary effects on calcium levels

what is hypoparathyroidism

less common, hypocalcemia from inadequate PTH

often result of surgical trauma to PTH glands, autoimmune diseases

what are the symptoms of hypoparathyroidism

neuromuscular s/s due to hypocalcemia

hyperphosphatemia contributes to ectopic calcifications in the kidney, brain, eye, or vasculature, risk of seizures

decreased bone turnover, increased bone mass

reduced quality of life, high risk of renal stone, renal calcifications, renal failure

what are the treatments of hypoparathyroidism

calcium supplements and active vitamin D - maintain calcium levels

PTH replacement therapy

• teriparatide (PTH 1-34) - short half-life, used off label

• recombinant human PTH (rhPTH 1-84) with longer half life

what is the focus of hyperparathyroidism drugs 

reducing PTH secretion or mitigating bone loss 

what is the focus of hypoparathyroidism treatments

calcium and PTH replacement to restore physiological balance

what is hypercalcemia of malignancy

if tumour secretes large amounts of PTHrP

• increases bone resorption/formation and calcium resorption from kidney

if tumour metastasizes to bone → focal bone resorption, calcium and phosphate liberated from bone (osteolysis), cytokine-mediated promotion of bone resorption

what are s/s of hypercalcemia of malignancy 

patients usually very ill, 6 week survival if not corrected

N/V, dehydration 

high serum calcium 

decreased serum phosphate

low PTH (suppressed)

usually high PTHrP levels 

what are s/s of hypocalcemia 

tetany - spontaneous tonic muscular contractions (carpal spasm)

Chvostek’s sign - twitching of facial muscles (tap facial nerve anterior to ear)

Trousseau sign - painful carpal tunnel muscle contractions after sphygmomanometer inflation for 3 minutes

what are causes of hypocalcemia related to inadequate PTH

surgical truma to PT glands

failure to secrete PTH

resistance to PTH action (pseudo-hypoparathyroidism)

what are causes of hypocalcemia related to inadequate vitamin D

malabsorption pathology

failure to produce sufficient calcitrol

resistance to calcitriol action

what are causes of hypocalcemia related to acute homeostatic changes 

drug induced - EDTA, citrate, plicamycin, bisphosphonates, phosphate

volume over-expansion 

magnesium depletion (diarrhea, loop duiretics, aminoglycosides, chronic alcoholism)

• Mg lowers PTH levels → lowers plasma Ca

what are causes of hypocalcemia related to hungry bone syndrome

bone avidly incorporates calcium and phosphate after surgical correction of hyperPTH (get secondary hypocalcemia)

can be seen post-anorexia nervosa

what are the goals of therapy for hypercalcemia

restoration of normocalcemia

treat underlying cause (pathology, offending drugs)

prevention of long-term consequences (renal insufficiency, kidney stones, vascular complications)

what are pharmacological treatments for hypercalcemia 

volume expansion to increase urinary excretion 

• saline/electrolytes, loop diuretics after hydration

potassium chloride administration to maintain normokalemia 

calcitonin - patients with renal deficiency (stop osteoclasts, increased excretion in urine)

bisphosphonates (block bone resorption)

what are non-pharmacological treatments for hypercalcemia in severe situations

hemodialysis against zero- or low-calcium dialysate (esp patients with low renal function)

address underlying disorder, correct fluid/electrolytes

what are the goals of therapy for hypocalcemia

restoration of normocalcemia

treat underlying cause (PTH disorders, vit D)

treat chronic renal insufficiency patients differently

• kidney disease = low calcium, secondary to hyperphosphatemia → complexation

• need to restore normo-phosphatemia first

what are pharmacological treatments for hypocalcemia

IV calcium bolus (acute cases)

• 100-300mg elemental Ca over 5-10 minutes

• avoid bicarbonate or phosphate IV solutions to avoid crystallization

• good for only 1-2 hours

treat underlying disorder

• oral calcium (1-3g/day elemental calcium)

• vitamin D malabsorption/diet deficiency → oral calcitriol 0.5-3 ug daily, oral ergocalciferol 50,000 IU daily, dose adjusted every 4 weeks

what is the management of hypocalcemia in chronic renal failure 

administer active vitamin D (calcitrol)

• vitamin D analogues (paricalcitol, doxercalciferol) - suppress PTH, bone sparing

calcium supplementation (at low normal range)

overtreatment side effects: hypercalcemia and hypercalciuria