Parathyroid Gland & Calcium Parathyroid Gland & Calcium MetabolismMetabolism

Munir Gharaibeh, MD, PhD, Munir Gharaibeh, MD, PhD, MHPEMHPE

Faculty of MedicineFaculty of Medicine

The Jordan UniversityThe Jordan University

April 2014April 2014

CalciumCalciumNormal Ca++ blood level is around 9-10 Normal Ca++ blood level is around 9-10

mg/dl mg/dl

CaCa++ ++ excess cause weakness excess cause weakness

Ca++ causes tetany.Ca++ causes tetany.

3 factors are involved in Ca++ blood level:3 factors are involved in Ca++ blood level:

PTHPTH

Vitamin DVitamin D

CalcitoninCalcitonin

3 tissues are also involved:3 tissues are also involved:

BoneBone

IntestineIntestine

KidneysKidneys

Parathyroid Hormone Parathyroid Hormone (PTH)(PTH)

84 a.a peptide translated as a pre-84 a.a peptide translated as a pre-prohormoneprohormone

Regulation of synthesis & release:Regulation of synthesis & release:

↓ ↓ [Ca[Ca++++] → ↑ PTH; ↑ [Ca] → ↑ PTH; ↑ [Ca++++] → ↓ ] → ↓ PTHPTH

Little if any regulation by POLittle if any regulation by PO44 ––

Parathyroid Hormone Parathyroid Hormone (PTH)(PTH)

Maximum secretion of PTH Maximum secretion of PTH occurs at plasma Caoccurs at plasma Ca++++ below 3.5 below 3.5 mg/dl mg/dl

At CaAt Ca++++ above 5.5 mg/dl, PTH above 5.5 mg/dl, PTH secretion is maximally inhibitedsecretion is maximally inhibited

Effects of PTHEffects of PTH On bone (1º target tissue):On bone (1º target tissue):

↑ ↑ resorption of Caresorption of Ca++++& PO& PO44----

(cAMP) mediated effect(cAMP) mediated effect On intestine:On intestine:

↑ ↑ absorption of Caabsorption of Ca++++& PO& PO44----

An indirect effect through ↑ vitamin D An indirect effect through ↑ vitamin D synthesissynthesis

On kidneys:On kidneys:↑ ↑ reabsorption of Careabsorption of Ca++++, ↑↑↑ excretion , ↑↑↑ excretion

of POof PO44----

(cAMP mediated effect) (cAMP mediated effect)

Vitamin DVitamin D Synthesis of vitamin DSynthesis of vitamin D Skin, UV lightSkin, UV light

7- 7- dehydrocholesterol Cholecalciferol dehydrocholesterol Cholecalciferol (D(D33))

LiverLiver

25(OH) cholecalciferol 25(OH) cholecalciferol KidneyKidney 1, 25(OH) 1, 25(OH)22 cholecalciferolcholecalciferol

(Calcifediol; Calcidiol) (Calcifediol; Calcidiol) (Calcitriol)(Calcitriol)

PTHPTH

DietDiet

Vitamin DVitamin D Normal daily requirementNormal daily requirement 400 IU/day.400 IU/day. On intestine (1º target tissue):On intestine (1º target tissue):

↑ ↑ absorption of Caabsorption of Ca++++& PO& PO44----

On bone:On bone:↑ ↑ bone resorptionbone resorption On kidney:On kidney:

↑ ↑ reabsorption of Careabsorption of Ca++++& PO& PO44----

CalcitoninCalcitonin 32 a.a peptide.32 a.a peptide.

Synthesized and released from Synthesized and released from parafollicular cells of the thyroid gland.parafollicular cells of the thyroid gland.

Regulation of synthesis & release:Regulation of synthesis & release:

↑ ↑ [Ca[Ca++++] → ↑ calcitonin; ↓ [Ca] → ↑ calcitonin; ↓ [Ca++++] → ↓ ] → ↓ calcitonincalcitonin

Effects:Effects:

On bone: On bone: ↓ bone resorption (↓Ca↓ bone resorption (↓Ca++++&PO&PO44----

movement)movement)

On kidneys: On kidneys: ↑ Ca↑ Ca++++& PO& PO44-- -- excretionexcretion

? ? On intestine: On intestine: ↓ Ca↓ Ca++++& PO& PO44-- -- absorptionabsorption

CalcitoninCalcitonin May be more important in May be more important in

regulating bone remodeling than regulating bone remodeling than in Cain Ca++++ homeostasis: homeostasis:

Evidence:Evidence: Chronic excess of Chronic excess of calcitonin does not produce calcitonin does not produce hypocalcemia and removal of hypocalcemia and removal of parafollicular cells does not parafollicular cells does not cause hypercalcemia. cause hypercalcemia.

PTH and Vitamin DPTH and Vitamin D33 regulation regulation dominates Ca++ homeostasis. dominates Ca++ homeostasis.

SummarySummary

PTHPTH Vit. DVit. D CalcitoninCalcitonin

[ Ca[ Ca++++] ↑ ↑ ] ↑ ↑ ↓ ↓

[PO[PO44----] ↓ ↑ ] ↓ ↑

↓ ↓

PTHPTH

Disorders affecting the parathyroids:Disorders affecting the parathyroids:

Hyposecretion (hypoparathyroidism):Hyposecretion (hypoparathyroidism): Causes:Causes:- Thyroidectomy (most common cause)Thyroidectomy (most common cause)- IdiopathicIdiopathic- ↓ ↓ sensitivity of target tissues to PTH sensitivity of target tissues to PTH

(pseudohypoparathyroidism)(pseudohypoparathyroidism)

Symptoms of Symptoms of

hypoparathyroidismhypoparathyroidism::Are those of hypocalcemia:Are those of hypocalcemia:Parasthesia, tingling lips, fingers, Parasthesia, tingling lips, fingers,

and toes, and toes, carpopedal spasm, muscle cramps, carpopedal spasm, muscle cramps,

tetanic contractions, convulsions tetanic contractions, convulsions (seizures) (seizures)

BronchospasmBronchospasmDepression, anxiety, abdominal Depression, anxiety, abdominal

pain pain CataractCataract

Lab. Tests of Lab. Tests of hypoparathyroidismhypoparathyroidism

- ↓ ↓ blood [Cablood [Ca++++]]- ↑ ↑ blood [POblood [PO44

----]]- ↓ ↓ urinary [cAMP] urinary [cAMP] - ↓ ↓ urinary [PTH]urinary [PTH]- ↓ ↓ urinary [Caurinary [Ca++++]]- ↓ ↓ urinary [POurinary [PO44

----]]

Treatment of Treatment of hypoparathyroidismhypoparathyroidism

- Vitamin D Vitamin D Calcifediol, Calcitriol, Ergocalciferol, Calcifediol, Calcitriol, Ergocalciferol, αα--

Calcidol, Dihydrotachysterol…Calcidol, Dihydrotachysterol…Drug of choice for chronic casesDrug of choice for chronic cases- CaCa++++ supplement supplementCaCa++ ++ rich dietrich dietCaCa++ ++ salts (chloride, salts (chloride, gluconate, carbonate...)gluconate, carbonate...)Drug of choice in acute casesDrug of choice in acute cases- Teriparatide Teriparatide (synthetic rPTH)-recently (synthetic rPTH)-recently

approved in the management of approved in the management of osteoporosisosteoporosis

HyperparathyroidismHyperparathyroidism- 1º hyperparathyroidism (adenomas)1º hyperparathyroidism (adenomas)- 2º hyperparathyroidism2º hyperparathyroidism

2º to any cause of hypocalcemia2º to any cause of hypocalcemia e.g. malabsorption syndrome, renal e.g. malabsorption syndrome, renal

disease…disease…- 3º hyperparathyroidism3º hyperparathyroidismResults from hyperplasia of the Results from hyperplasia of the

parathyroid glands and a loss of parathyroid glands and a loss of response to serum calcium levels.response to serum calcium levels.

Most often seen in patients with Most often seen in patients with chronic renal failurechronic renal failure

Symptoms of Symptoms of hyperparathyroidismhyperparathyroidism

Are those of hypercalcemia:Are those of hypercalcemia:

Generalized weakness and fatigueGeneralized weakness and fatigue

depression, bone pain, muscle depression, bone pain, muscle pain (myalgias), decreased pain (myalgias), decreased appetite, feelings of nausea and appetite, feelings of nausea and vomiting, constipation, polyuria, vomiting, constipation, polyuria, polydipsia, cognitive impairment, polydipsia, cognitive impairment, kidney stones and osteoporosiskidney stones and osteoporosis..

Lab. Tests of Lab. Tests of hyperparathyroidismhyperparathyroidism

- ↑ ↑ blood [Cablood [Ca++++]]- ↓ ↓ blood [POblood [PO44

----]]- ↑ ↑ urinary [cAMP] urinary [cAMP] - ↑ ↑ urinary [PTH]urinary [PTH]- ↑ ↑ urinary [Caurinary [Ca++++]]- ↑ ↑ urinary [POurinary [PO44

----]]

Bone x-ray → bone decalcificationBone x-ray → bone decalcification

Treatment of Treatment of hyperparathyroidismhyperparathyroidism- Low CaLow Ca++++ diet diet

- NaNa++ phosphate phosphate- Steroids e.g. Prednisolone... ↓ CaSteroids e.g. Prednisolone... ↓ Ca++++

absorptionabsorption- CalcitoninCalcitonin- Surgery (best Rx)Surgery (best Rx)- Cinacalcet (calcimimetic), Cinacalcet (calcimimetic), oral tabs oral tabs

used to treat patients with chronic used to treat patients with chronic kidney disease who are on dialysis & kidney disease who are on dialysis & also used to treat patients with 1º & also used to treat patients with 1º & 2º hyperparatyroidism & cancer of 2º hyperparatyroidism & cancer of parathyroid gland parathyroid gland

Treatment of Treatment of hyperparathyroidismhyperparathyroidism

- Diuretics, Diuretics, e.g. Furosemide (↑ Cae.g. Furosemide (↑ Ca++++ excretion)excretion)

- PlicamycinPlicamycin- BiophosphonatesBiophosphonates

Etidronate, Etidronate, Pamidronate…Pamidronate…↑ ↑ bone formation and ↓ bone bone formation and ↓ bone resorption resorption

PagetPaget’’s diseases diseaseRare bone disorder characterized by Rare bone disorder characterized by

deminaralization of bone, deminaralization of bone, disorganized bone formation, ↑ bone disorganized bone formation, ↑ bone resorption, fractures, spinal cord resorption, fractures, spinal cord injuries, deafness…injuries, deafness…

RRxx::

- Salmon calcitonin (drug of choice), - Salmon calcitonin (drug of choice), S.C, I.MS.C, I.M

- Biophosphanates, orally- Biophosphanates, orally

Etidronate, alendronate, residronate, Etidronate, alendronate, residronate, pamidronate…pamidronate…

OsteoporosisOsteoporosis Definitions:- Osteoblasts: fibroblasts, essential for

bone formation and mineralization of bone matrix

- Osteoclasts: cells that break down bone and are responsible for bone resorption

- Bone matrix: the intercellular substance of bone formed by osteoblasts, consisting of collagenous fibers, ground substance, and inorganic salts

- Bone resorption: a process by which osteoclasts break down bone and release minerals resulting in transfer of Ca++ from bone to blood

OsteoporosisOsteoporosis -Bone turnover or Bone remodeling:

removal of old bone and its replacement by new bone. Bone is constantly remodeled throughout adult life, and in general, the processes of bone resorption and formation are "coupled" so that there is no net change in bone mass.

During growth, osteoblast activity is more than that of osteoclsts (bone formation), but in diseases such as osteoporosis, bone resorption is greater than bone formation, leading

to a net decrease in bone mass

OsteoporosisOsteoporosisA reduction in bone mass per unit A reduction in bone mass per unit

volume leading to fractures volume leading to fractures particularly the spine, distal radius particularly the spine, distal radius and proximal femurand proximal femur

Often known as Often known as ““ the silent thief the silent thief ””because bone loss occurs without because bone loss occurs without symptomssymptoms

Etiology:Etiology:- Hormone deficienciesHormone deficienciesEstrogen deficiency in ♀’s; androgen Estrogen deficiency in ♀’s; androgen

deficiency in ♂’sdeficiency in ♂’s

Causes of OsteoporosisCauses of OsteoporosisPostmenopausal osteoporosis is the Postmenopausal osteoporosis is the

most common form of osteoporosismost common form of osteoporosisThe greatest amount of bone density The greatest amount of bone density is lost during the first 5 years after is lost during the first 5 years after the onset of menopause, so it is the onset of menopause, so it is important to start therapy early.important to start therapy early.

ThyrotoxicosisThyrotoxicosisHyperparathyroidismHyperparathyroidismAlcohol consumptionAlcohol consumptionSmokingSmoking

Causes of OsteoporosisCauses of OsteoporosisLow CaLow Ca++ ++ intake: intake:

Dietary Dietary

Malabsorption syndromeMalabsorption syndrome

Drug-induced osteoporosis:Drug-induced osteoporosis:Glucocorticoids (CushingGlucocorticoids (Cushing’’s syndrome)s syndrome)

GnRH agonistsGnRH agonists

AnticonvulsantsAnticonvulsants

Heparin...Heparin...

Osteoporosis Risk FactorsOsteoporosis Risk Factors- Female, menopause (early Female, menopause (early

menopause → high incidence)menopause → high incidence)- Family history of osteoporosisFamily history of osteoporosis- Limited physical activityLimited physical activity- Low CaLow Ca++++ diet diet- Low Vit. D diet or limited exposure Low Vit. D diet or limited exposure

to sunlightto sunlight

Osteoporosis Risk FactorsOsteoporosis Risk Factors

Caffeine consumptionCaffeine consumption

SmokingSmoking

Alcohol intakeAlcohol intake

Chronic use of glucocorticoids or Chronic use of glucocorticoids or anticonvulsantsanticonvulsants

Diagnosis of osteoporosisDiagnosis of osteoporosis- Symptoms and signs:Symptoms and signs:No symptoms in early stageNo symptoms in early stageFractures of vertebrae, hips, or wristFractures of vertebrae, hips, or wristLow back painLow back painNeck pain...Neck pain...- lab. Tests:lab. Tests:X-ray, bone mineral density (BMD; X-ray, bone mineral density (BMD;

densitometry), blood biochemistry, densitometry), blood biochemistry, bone biopsy if necessary...bone biopsy if necessary...

Treatment of osteoporosisTreatment of osteoporosisGood outcome if started early.Good outcome if started early.Late osteoporosis or patients with fracture Late osteoporosis or patients with fracture

2º to osteoporosis resist R2º to osteoporosis resist Rxx but therapy but therapy could limit further fracturescould limit further fractures

Effective drugs:Effective drugs:- Estrogen + progesterone (to ↓ incidence Estrogen + progesterone (to ↓ incidence

of uterine cancer)of uterine cancer)- Androgen therapyAndrogen therapy

Treatment of osteoporosisTreatment of osteoporosis- Selective estrogen receptor modulators Selective estrogen receptor modulators

(SERM) e.g. (SERM) e.g. Raloxifene Raloxifene (has estrogenic (has estrogenic effects on bone & anti-estrogenic actions on effects on bone & anti-estrogenic actions on the uterus and breast)the uterus and breast)

- Vit. D + CaVit. D + Ca++++

- BiophpsphanatesBiophpsphanatesEtidronate, Alendronate…Etidronate, Alendronate…

- CalcitoninCalcitonin (intranasal) (intranasal)- Small doses of fluoride Small doses of fluoride (slow release sodium (slow release sodium

flouride)flouride)- Synthetic rPTH rPTH ((Teriparatide), recently

approved by FDA in the management of osteoporosis

Treatment of osteoporosisTreatment of osteoporosis- Denosumab:

Given SC, every 6 months.An inhibitor to Receptor activator of nuclear factor kappa-B ligand (RANKL).Recently approved for use in postmenaupausal osteoporosis, drug-induced bone loss and in bone metastasisRANKL is a protein present on osteoblasts and activates activity of osteoclasts, osteoporosis Many side effects:

Hypocalcemia, serious infections of skin, bladder, heart(endocarditis), high blood cholesterol levels, pain in jaws and back...

Postmenopausal osteoporosis RPostmenopausal osteoporosis Rxx or prophylaxis or prophylaxis- Estrogen + alendronate + CaEstrogen + alendronate + Ca++++& vit. D + & vit. D +

intranasal calcitoninintranasal calcitonin- Raloxifene + alendronate + CaRaloxifene + alendronate + Ca++++& vit. D + & vit. D +

calcitonincalcitonin- Estrogen + progesteroneEstrogen + progesterone- Raloxifene + alendronateRaloxifene + alendronate- Teriparatide (rPTH) (S.C)- Denosumab