Jake Endocrine 4

PARATHYROID GLANDS, CALCIUM AND VITAMIN D

Distribution and Functions of Calcium (7)

1. muscle contraction

2. exocytosis

3. blood clotting

4. formation of cardiac action potentials

5. enzyme activation

6. cell signaling (as in second messenger systems like IP3)

7. bone & tooth structure

Gross Anatomy of the Parathyroid Glands

Humans typically have 4 parathyroid glands, but as few as 2 and as many as 8 have been observed.

• Each gland is a flattened ellipsoid measuring about 6 mm in its longest diameter.

• The aggregate mass of the adult parathyroid glands is less than 150 mg.

• These glands adhere to the posterior surface of the thyroid gland or occasionally are embedded with the thyroid tissue.

• They are well vascularized and derive their blood supply mainly from the inferior thyroid arteries.

Histology of the Parathyroid Glands (2 Important Cells)

1. The principal or Chief cells

2. Oxyphil cells

The principal or chief cells (Parathyroid)

Are the most predominant cells in the parathyroid glands.

• They have 2 main functions:

  • a.) synthesis & secretion of PTH

  • b.) sensors of minute fluctuations of ECF Ca+2.

Oxyphil cells

The function of the second cell type, the oxyphil cells, is

unknown.

.

Some recent evidence suggests that they may be degenerated principal cells.

• Few oxyphil cells are seen before puberty, but their number increases thereafter with age.

Parathyroid Hormone (PTH)

84 amino acids (Peptide Hormone)

• ½ life in the blood of 2-3 minutes

• Metabolized by its target tissues

• Major stimulus for secretion is hypocalcemia

.

a vital chemical made by four small glands in your neck that controls calcium levels in your blood.

Physiological Effects of PTH (3 Organs)

1. Bone

2. Kidneys

3. Intestines

Physiological Effects of PTH on Bones

Stimulates osteoclast activity

• Essentially breaks down bones to take calcium and phosphate in the blood

Physiological Effects of PTH on Kidneys (2)

1. Stimulates the reabsorption of Ca+2 in distal convoluted tubules

.

1. Stimulates 1-hydroxylation of 25- hydroxycholecalciferol (i.e. -- activation of Vitamin D)

Physiological Effects of PTH on Intestines

Stimulates intestinal uptake of Ca+2 by "active" Vitamin D

Physiological Effects of PTH Diagram

Vitamin D Activation

1- hydroxylation + 25- hydroxycholecalciferol

.

(PTH Synthesizes this in the kidneys)

--

• This creates the active form of vitamin D called 1,25 dihydroxycholecalciferol

Vitamin D Deficiency (2)

1) Rickets occurs in children

2) Osteomalacia in adults

• Same condition, just progresses

Rickets and Osteomalacia

Bones are inadequately mineralized, so they become soft and weak Weight-bearing bones bend and deform

Calcitonin

Calcitonin is a protein hormone (32-amino acids)

• Synthesized and secreted by the parafollicular cells (C- Cells) of the thyroid gland.

.

• The stimulus for calcitonin secretion is hypercalcemia.

.

• Calcitonin will promptly and dramatically lower the level of ECF Ca+2 by acting on the bone.

Calcitonin Effects

There are no known metabolic

consequences of calcitonin deficiency or excess.

.

In humans, thyroidectomy does not produce a

tendency toward hypercalcemia, and thyroid

tumors that secrete massive amounts of

calcitonin do not cause hypocalcemia.

.

Based on these observations, calcitonin does not appear to be a major factor in calcium homeostasis in humans.

.

Recent evidence has shown that the

importance of calcitonin may be limited to

protection against excessive bone resorption.

Hypercalcemia Causes (5)

1) Primary hyperparathyroidism (single adenomas account for up to 89% of cases)

2) Bone malignancies

3) Prolonged immobilization

4) Excess vitamin D and calcium in the diet

5) Drug-induced (e.g., thiazides, lithium)

Mnemonic for Hypercalcemia Effects (4)

Bones

Stones

Groans

Moans

DENTAL ASPECTS OF HYPERPARATHYROIDISM

1) Gradual loosening, drifting and loss of teeth, spacing of teeth

2) “brown tumor” lesions (osteolytic, radiolucent lesions) of the bones surrounding oral cavity (e.g., mandible, maxilla) raising the risk for fracture

• malocclusion

• dental pain

• soft tissue calcification

• sialolithiasis (hardened mineral deposits, or salivary stones)

Hypocalcemia

Not retaining/making enough Calcium

.

In hypocalcemia, the nervous system becomes

progressively more excitable because of increased

permeability of neuronal membranes to sodium.

• This results in spontaneous, asynchronous & involuntary contractions of skeletal muscles (tetany)

Hypocalcemia Reasons? (4)

1) Surgical removal of parathyroids

2) Primary hypoparathyroidism

3) Vitamin D deficiency

4) Impaired ability to activate vitamin D

Hypocalcemic Tetany (3)

A typical attack of hypocalcemic tetany involves muscular

1) Chvostek’s sign (spasms in the face )

2) Trousseau’s sign (haracteristic contortions of the arms and hands)

3) Laryngeal spasm and contraction of respiratory muscles may compromise breathing.

.

• Pronounced hypocalcemia may produce more generalized muscular contractions and convulsions.

Chvostek’s sign

Trousseau’s sign

Parethesia

DENTAL ASPECTS OF HYPOPARATHYROIDISM

1) Enamel hypoplasia (underdevelopment)

2) delayed eruption or multiple unerupted teeth (in pediatric patients)

• poorly calcified dentin

• microdontia (small crowns)

• malformed roots (typically short with blunt ends)

• dental caries

• paresthesia (tingling) of the tongue or lips

Treatment for hypoparathyroidism

Treatment for hypoparathyroidism consists of

.

1) Synthetic PTH

2) Oral calcium carbonate tablets

3) Vitamin D

Bone Tissue Types

Compact Bone

Spongy Bone

Bone Composition

The open spaces in living bones are filled with red or yellow bone marrow.

.

• Trabeculae align themselves along lines of stress like little struts

Bones without Collagen

Bones without Mineral

Osteogenic Cells

Found mainly in the periosteum & endosteum

Osteoblasts

1) Derived from osteogenic cells

2) Known as bone-forming cells

3) Synthesis & secrete unmineralized osteoid and collagen

4) Pump calcium & phosphate salts into and out of bone tissue

Osteocytes

Derived from osteoblasts that

have secreted osteoid around

themselves

Osteoid becomes calcified

Referred to as mature bone

cells

Osteoclasts

Derived from monocytes

Known as bone-resorbing (dissolving) cells

• Put Phosphate & Calcium back into bone

Microanatomy of Bone

Osteons (Haversian Systems)

Functionally, osteons can be thought of as tiny,

weight-bearing pillars

Lamellae

Concentric rings of compact bone tissue that

help form the osteons

Lacunae

Bony depression in the lamellae in which bone cells are housed

Haversian (Central) Canals

Canals found in the core

of osteons in which blood

vessels and nerves pass

through

Volkmann’s (Perforating)

Canals

Canals that connect osteons together

.

• also a passageway for blood vessels and nerves to enter and leave bone

Bone Remodeling

Bone is a very dynamic and active tissue – it is NOT a brick!

Bone architecture continually changes in response to the

surrounding environment.

• “Everyday remodeling”

Three facts about Bone Remodeling

1) Remodeling process is not uniform within bones or

between bones

.

2) In healthy adults, bone deposit and bone resorption

occur at equal rates

3) For optimal bone deposit, need a diet of protein,

vitamin C, vitamin A, minerals & vitamin D

Steps in Bone Remodeling (4)

1) Resorption: Specialized cells called osteoclasts break down and remove old or damaged bone matrix.

2) Reversal: Mononuclear cells prepare the excavated surface of the bone for the next phase.

3) Formation: Cells called osteoblasts deposit new bone matrix (osteoid), which eventually hardens through mineralization.

4) Resting

Osteoporosis

Generalized skeletal disorder characterized by

compromised bone strength and deterioration of

bone quality, often leading to fragility fracture

.

Low bone mass frequently found (with DEXA

scan)

Osteoporosis Who is most affected?

.

• Post-menopausal women

• Persons > 65 years old

• Caucasians and people of Asian decent

• Persons with small body frame

.

Estimated that > 10 million persons over the age

of 50 in the US have osteoporosis

DEXA Scan (For Bone Loss)

Osteoporosis Cause

Process of bone remodeling maintains healthy bone mass

throughout life

.

• In healthy bone, bone resorption (osteoclast cells) is balanced by bone formation (osteoblast cells)

• Bone loss occurs when bone resorption outpaces bone formation, resulting in decreased bone mass and increased risk of fracture

• Fracture results from overloading of weakened bones

Osteoporosis

1) Lifestyle factors - low calcium intake, vitamin D deficiency, excess vitamin A intake, inadequate physical activity, smoking, and alcohol abuse

2) Genetic factors - parental history of hip fracture, many others

3) Medical conditions – hyperparathyroidism, Cushing syndrome, many others

4) Medications – corticosteroids in particular

DENTAL ASPECTS OF OSTEOPOROSIS

1) Loss of bone mass in the mandible can cause loosening of teeth or tooth loss

2) Dentures to become ill-fitting

3) MRONJ: Medication- related osteonecrosis of the jaw

Pharmacologic Options for Treating Osteoporosis (6)

1) Calcium and Vitamin D Supplements

2) Bisphosphonates

3) Hormone Replacement Therapy (HRT; either estrogen alone or estrogen-progestin) – NOT A COMMON OPTION ANYMORE

4) Selective Estrogen Receptor Modulators (SERMs)

5) Calcitonin

6) Denosumab

Calcium & Vitamin D Supplements Disclaimer

It is important for patients with

osteoporosis to be aware the calcium and vitamin D alone are insufficient to prevent bone loss

.

Postmenopausal women who are getting adequate calcium from dietary intake alone (approx. 1200 mg daily) generally do not need to take calcium supplements

Calcium & Vitamin D Supplement Examples (2)

Women with inadequate dietary intake should take supplemental elemental calcium

• (generally 500 to 1000 mg/day), in divided doses at mealtime,

• Such that their total calcium intake (diet plus supplements) approximates 1200 mg/day

.

The most widely available calcium supplements are:

1) Calcium Carbonate

2) Calcium Citrate

Calcium Carbonate & Calcium Citrate

Is cheapest and therefore often a good first choice

• Take these Drugs Orally

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Calcium carbonate absorption is better when taken with meals

.

Calcium citrate is well absorbed in the fasting state

Calcium carbonate Side Effects

Potential side effects of high calcium intake (>2000 mg/day) include:

• Dyspepsia (Indigestion)

• Constipation

• Calcium supplements interfere with the absorption of iron and thyroid hormone and, therefore, these medications should be taken at different times.

Vitamin D Supplements

Postmenopausal women should ingest a total of 800 international units of vitamin D daily
.

Most postmenopausal women with osteoporosis often require vitamin D supplementation, as it is difficult to achieve goals with diet alone

Bisphosphonates

1) Alendronate → oral & liquid

2) Risedronate → oral

3) Ibandronate oral and IV

4) Zoledronic acid → IV

.

Oral bisphosphonates are usually considered 1st line therapy

Bisphosphonates (Ingestation)

Must be taken in a specific way:

• Take in the AM with a full glass of water (6- 8 oz.)

• At least 30 min before other food and drink

• Remain in an upright position at least 30 minutes afterwards

Why is this the case? (What side effects does this lead to?)

• Only 5% or less of oral bisphosphonates are absorbed when taken on an empty stomach

• absorption will be further reduced with food, certain medications and liquids other than water

.

Oral bisphosphonates are known to cause reflux, esophagitis and esophageal erosion

Bisphosphonates (How do they work?) (4 Steps)

1) Bind to calcium on exposed bone surfaces →

2) Imbibed by bone-resorbing osteoclasts →

3) Osteoclasts lose their bone-resorbing capabilities →

4) Eventual osteoclast apoptosis →

.

Bisphosphonates can remain bound in the bone matrix for YEARS.

• They do NOT enter or become incorporated into the teeth.

Bisphosphonates What is there effect?

End results:

1. Increase in BMD (bone mineral density)

2. Reduction in the incidence of fractures

Bisphosphonates New FDA Classification

The FDA recently changed the product labeling for the bisphosphonate class to include a statement that the optimal duration of use has not been determined.

.

• In addition the labeling suggests that for patients at low risk for fractures, consideration can be given for drug discontinuation after 3-5 years of use.

Bisphosphonates Adverse effects

1) Transient hypocalcemia

2) Musculoskeletal pain (rare)

3) Osteonecrosis of the jaw (ONJ; rare)

4) Acute flu-like reaction (IV forms only)

Osteonecrosis of the jaw (ONJ; rare)

Risk factors for developing ONJ include:

Cancer and anti-cancer therapy

invasive dental procedures (dental extractions, dental implants)

poorly fitting dentures

glucocorticoids, smoking, diabetes, and preexisting dental disease.

.

ONJ can also arise spontaneously.

• When ONJ occurs in a patient treated with bisphosphonates for osteoporosis, bisphosphonates should be discontinued.

Bisphosphonates Contraindications

1) Patients with esophageal disorders (achalasia, esophageal varices, Barrett’s esophagus)

2) Patients with severe renal impairment

Estrogen-Progestin

In the past, hormone replacement therapy (HRT) was considered the primary therapy for the prevention of postmenopausal osteoporosis → Estrogen had the additional advantage of controlling menopausal symptoms (at low doses)

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However, data from the Women's Health Initiative (WHI) revealed that estrogen increases the risk of breast cancer, stroke, and venous thromboembolic events

.

Estrogen-progestin (or just estrogen

alone) therapy is no longer a first-line approach for the

treatment of osteoporosis in postmenopausal women

because of these increased risks

How does estrogen affect bone (7)

1. PTH receptors are found on osteoblasts.

2. PTH stimulation of osteoblasts increases osteoblast production of Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL).

3. Hematopoietic cell precursors stimulated by M-CSF give rise to osteoclasts that express the RANK receptor.

4. The RANKL/RANK receptor interaction stimulates maturation of the osteoclasts so that they can resorb bone.

5. Osteoblasts also produce a “decoy receptor” called osteoprotegerin (OPG) that binds to RANKL and prevents the RANKL/RANK interaction (thereby causing osteoclastogenesis inhibitory activity).

6. Estradiol increases production of OPG to diminish bone resorption.

7. By the way, glucocorticoids stimulate RANKL expression while inhibiting OPG synthesis by osteoblasts to enhance osteoclast proliferation & differentiation, leading to bone resorption.

How does estrogen affect bone Diagram

Selective Estrogen Receptor Modulators (SERMs)

Raloxifene

• Is a tissue selective estrogen receptor modulator (SERM) that has been approved by the FDA for the prevention and treatment of osteoporosis

.

• Not Estrogen

Selective Estrogen Receptor Modulators (SERMs) vs Bisphosphinate

Still not considered as best a choice

as a bisphosphonate due to adverse

effects (namely increase risk of blood

clots)

Calcitonin (Treating Osteoporosis) (2)

Another treatment for osteoporosis is nasal calcitonin

• This form of calcitonin is isolated from salmon.

.

Faced with the relative high Ca+2 concentration in sea water (and therefore in food), calcitonin, secreted in response to a rise in plasma Ca+2, decreases bone resorption, thus returningthe plasma Ca+2 toward normal.

Salmon calcitonin is roughly 10-50X more potent on a molar

basis in inhibiting osteoclast function than is the human

hormone

Calcitonin (Treating Osteoporosis) How it works

In osteoclasts, calcitonin raises cAMP levels which

results in a decrease in resorptive activity

Calcitonin (Treating Osteoporosis) vs bisphosphonates

Not a preferred choice for osteoporosis, as treatment with

bisphosphonates results in greater increases in spine and hip bone density compared with nasal calcitonin

.

An option for those patients who cannot take

bisphosphonates

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Adverse effects include nausea, flushing and runny nose

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There is concern is about the long-term use of calcitonin for osteoporosis and an increase in cancer rates (not any specific types or types)

Denosumab (Prolia)

Denosumab

• Is a humanized monoclonal antibody against RANKL  thereby inhibiting osteoclast formation, decreasing bone resorption, increasing BMD and reducing the risk of fracture

• Administered as a Subcutaneous injection every 6 months

Denosumab Side effects & Issues

Most common adverse effects include musculoskeletal (back and extremity) pain, hypercholesterolemia and cystitis; can also cause

• ONJ, but the risk appears lower compared to bisphosphonates

Monitor for hypocalcemia; should not be given to

patients with pre-existing hypocalcemia until it is

corrected

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Expensive: $2000 per year