Lect. 4 of 6_Parathyroid Gland Disorders & Calcium Homeostasis by Marc Imhotep Cray, M.D.

Photo: Colorized transmission electron micrograph of an endocrine cell from the anterior pituitary gland. The secretory vesicles (brown) contain hormones. From: Seeleyâ&#x20AC;&#x2122;s Anatomy & Physiology 10th ed New York, NY: McGraw-Hill 2010.

Learning Objectives cont. 3. Pharmacology of Calcium Metabolism 1. The role of key organs involved in regulation of plasma calcium concentration 2. The endocrine regulation of calcium homeostasis and mechanisms involved 3. The principles underlying the treatment of both hyper- and hypocalcemia. 4. The indications, mechanism of action, adverse effects and contraindications of the drugs used in therapy of hypo- and hypercalcemia.

Drugs That Affect Calcium Levels DRUGS THAT DECREASE CALCIUM LEVELS DRUGS THAT INCREASE CALCIUM LEVELS

Calcium citrate (many other salts) Calcium gluconate Teriparatide Vitamin D Analogues Calcitriol Cholecalciferol Dihydrotachysterol Doxercalciferol Ergocalciferol Paricalcitol

Marc Imhotep Cray, MD

Bisphosphonates Alendronate Ibandronate Pamidronate Etidronate Risedronate Tiludronate Zoledronic acid Calcitonin Calcimimetics Cinacalcet Clodronate Estrogens and raloxifene Gallium nitrate Phosphate

Parathyroid Gland Disorders & Agents Affecting Calcium Homeostasis

Marc Imhotep Cray, MD

Baron SJ and Lee CI. Lange Pathology Flash Cards. New York: McGraw-Hill, 2009

Hypoparathyroidism Definition â&#x20AC;˘ Low PTH levels, usually due to destruction of parathyroid glands (acquired) Etiology â&#x20AC;˘ Common causes: - Surgery - Infiltration and destruction of parathyroid glands (Wilson disease, hemachromatosis, and radiation) - PTH production may be suppressed in hypomagnesemia (magnesium important for PTH homeostasis) Marc Imhotep Cray, MD

Hypoparathyroidism (2) Clinical Presentation Laboratory • Decreased serum PTH • Hypocalcemia • Hyperphosphatemia • Normal 25-hydroxyvitamin D level • Decreased 1,25- dihydroxyvitamin D levels

Marc Imhotep Cray, MD

Hypoparathyroidism (3) Diagnosis • Increased urine: calcium to creatinine ratio and hypophosphaturia • ECG: prolonged Q-T interval (hypocalcemia) Treatment • Supplementation with calcium and 1,25-dihydroxyvitamin D • Caution with intravenous calcium administration

Marc Imhotep Cray, MD

Hypoparathyroidism (4) Symptoms (most due to hypocalcemia) • Seizures • Constipation • Muscle cramps • Hyperreflexia • Tetany • Abdominal pain • Lethargy • Cardiac dysrhythmia • Chvostek’s sign (facial twitching when the zygomatic arch is tapped) • Trousseau’s sign (forearm spasms induced by inflating BP cuff on upper arm) Marc Imhotep Cray, MD

Hyperparathyroidism Definition • High levels of PTH levels, usually due to excessive release Types of HPT • Primary Hyperparathyroidism • Secondary Hyperparathyroidism • Tertiary Hyperparathyroidism

Marc Imhotep Cray, MD

Primary Hyperparathyroidism • Parathyroid adenoma is the most common cause • (85% of all hyperparathyroid cases)

• Hyperplasia of the parathyroid glands • Parathyroid carcinoma (rare)

Primary Hyperparathyroidism • Feedback response to hypocalcemia stimulates parathyroid glands leading to hyperplasia and excessive PTH production • Causes of hypocalcemia: - Renal failure is most common cause - Vitamin D deficiency - Malabsorption of intestinal calcium Marc Imhotep Cray, MD

Tertiary Hyperparathyroidism • Constant stimulation of parathyroids in secondary hyperparathyroidism causes autonomous secretion of PTH by gland • End result is hypercalcemia because feedback response is functional • Correction of hypercalcemia associated with tertiary HPT requires surgical resection of most of four parathyroid glands

Marc Imhotep Cray, MD

Clinical Presentation of HPT Laboratory • Elevated serum PTH levels • Elevated 1,25-dihydroxyvitamin D levels • Hypercalcemia • Hypophosphatemia

Marc Imhotep Cray, MD

Symptoms (most due to hypercalcemia) “Stones, groans, and psychic moans”

• Kidney stones • Abdominal pain • Bone pain • Depression • Nausea & Vomiting • Weakness • Lethargy • Hypertension 13

Diagnosis & Treatment of HPT Dx • Urine: decreased calcium to creatinine ratio and hyperphosphaturia • ECG: short Q-T interval (hypercalcemia) Tx • Calcium binding agents • Treat underlying etiology

Marc Imhotep Cray, MD

Drugs That Affect Calcium Levels DRUGS THAT INCREASE CALCIUM LEVELS

Calcium citrate (many other salts) Calcium gluconate Teriparatide Vitamin D Analogues Calcitriol Cholecalciferol Dihydrotachysterol Doxercalciferol Ergocalciferol Paricalcitol

Marc Imhotep Cray, MD

DRUGS THAT DECREASE CALCIUM LEVELS

Case 44 Agents Affecting Calcium Homeostasis A 66-year-old woman presents for an annual health maintenance visit. She is generally feeling well and has no specific complaints. She takes hydrochlorothiazide for hypertension, levothyroxine sodium for hypothyroidism, and a multivitamin. She went through menopause at age 48 and never took hormone replacement therapy. She is a former cigarette smoker, having a 30 pack-year history and having quit 20 years ago. She occasionally has a glass of wine with dinner and walks three or four times a week for exercise. On examination you note that her height is 1 inch less than it was 3 years ago. Her vital signs are normal. She has a prominent kyphoscoliosis of the spine. Her examination is otherwise unremarkable. Blood work reveals normal electrolytes, renal function, blood count, calcium, and thyroidstimulating hormone (TSH) levels. You order a bone density test, which shows a significant reduction of density in the spine and hips. You diagnose her with osteoporosis and start her on alendronate sodium. _ What is the mechanism of action of parathyroid hormone (PTH) on the bone and in the kidney? _ What is the mechanism of action of alendronate sodium? Marc Imhotep Cray, MD

What are the three hormones that regulate calcium levels in the blood and tissues and their origin of secretion? 1. PTH is secreted from chief cells in parathyroid glands ď&#x201A;§ PTH is released in response to low serum calcium, and its purpose is to raise serum calcium level 2. Vitamin D is produced from diet as well as from synthesis through cholesterol with help of ultraviolet (UV) light ď&#x201A;§ Its purpose is to raise serum calcium level 3. Calcitonin comes from parafollicular cells in thyroid gland ď&#x201A;§ Calcitonin is secreted in response to high serum calcium and will lower serum calcium level

Marc Imhotep Cray, MD

Parathyroid Hormone (PTH) Biosynthesis  PTH secreted by chief cells of parathyroid gland Mode of Action  PTH binds PTH receptor → activation of guanyl nucleotide regulatory protein → activation of adenylate cyclase → increased cAMP production Regulation  Increased serum calcium and increased 1,25-(OH) 2D3 levels → decreased PTH secretion PTH secretion  Decreased serum calcium → increased PTH secretion Marc Imhotep Cray, MD

Parathyroid Hormone (PTH) cont. Function: Overall effect is to increase serum calcium and decrease serum phosphate levels Effects on bone:  Promotes osteoclastic activity  Increases rate of skeletal remodeling Effects on kidney:  Promotes calcium reabsorption in distal tubule of nephron  Increases phosphate excretion  Increases formation of 1,25-(OH) 2D3 (activated vitamin D) Effects on intestine:  Increased 1,25-(OH) 2D3 results in increased intestinal calcium and phosphate absorption Marc Imhotep Cray, MD

Calcium homeostasis: PTH & Vit D

Marc Imhotep Cray, MD

McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015

Calcium homeostasis: PTH & Vit D (2)

Marc Imhotep Cray, MD

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

Calcium Regulation by Parathyroid Hormone and Vitamin D Summary Table

Miksad RA, Meyer GK & DeLaMora PA. Last Minute Internal Medicine. New York: McGraw-Hill, 2008

Marc Imhotep Cray, MD

Vitamin D  Vitamin D3 (cholecalciferol) is absorbed by small intestine as part of diet (e.g. dairy food) or is synthesized from cholesterol in skin  VitaminD3 synthesis requires ultraviolet B (UVB) light the sun it is then converted into calcitriol Calcitriol is biologically active form of vitamin D and is a major determinant of intestinal calcium and phosphate reabsorption.  Activation  Human vitamin D is an inactive steroid called cholecalciferol (or vitamin D3) o It is a fat-soluble steroid is stored in adipose tissue

 Two reactions must take place in different organs to activate vitamin D o Activated vitamin D (1,25-dihydroxycholecalciferol) Marc Imhotep Cray, MD

Activation of Vitamin D

Actions of vitamin D on GIT, bone (PTH, parathyroid hormone) and kidney

Horton-Szar D. Crash Course: Endocrinology, 4th Ed. Elsevier, 2012 Marc Imhotep Cray, MD

Calcium-relate Diseases & Disorders Osteoporosis, Paget disease, and osteomalacia are disorders of the bone  Osteoporosis is characterized by progressive loss of bone mass and skeletal fragility  Patients with osteoporosis have an increased risk of fractures, which can cause significant morbidity  Osteoporosis occurs in older men and women but is most pronounced in postmenopausal women  Paget disease is a disorder of bone remodeling that results in disorganized bone formation and enlarged or misshapen bones  Unlike osteoporosis, Paget disease is usually limited to one or a few bones  Patients may experience bone pain, bone deformities, or fractures  Osteomalacia is softening of bones that is most often attributed to vitamin D deficiency Osteomalacia in children is referred to as rickets Marc Imhotep Cray, MD

Changes in bone morphology seen in osteoporosis

Whalen K. Lippincott Illustrated Reviews: Pharmacology 6th Ed. Wolters Kluwer, 2015 Marc Imhotep Cray, MD

Treatment of Osteoporosis  Nondrug strategies to reduce bone loss in postmenopausal women include  adequate dietary intake of calcium and vitamin D  weight-bearing exercise, and  smoking cessation  In addition, patients at risk for osteoporosis should avoid drugs that increase bone loss such as glucocorticoids [Note: Use of glucocorticoids (for example, prednisone 5 mg/day or equivalent) for 3 months or more is a significant risk factor for osteoporosis.]

Marc Imhotep Cray, MD

Drugs that can contribute to bone loss or increased fracture risk.

• • • • • • • • • • •

Aluminum antacids Anticonvulsants (e.g., phenytoin) Aromatase inhibitors Furosemide Glucocorticoids Heparin Medroxyprogesterone acetate Proton pump inhibitors SSRIs Thiazolidinediones Thyroid (excessive replacement)

Treatment of Osteoporosis cont.  Pharmacologic therapy for osteoporosis is warranted in postmenopausal women and men aged 50 years or over who have a previous osteoporotic fracture, a bone mineral density that is 2.5 standard deviations or more below that of a young adult, or a low bone mass with a high probability of future fractures Common agents used include:  Bisphosphonates: o Alendronate, Ibandronate, Risedronate, Zoledronic acid  Selective estrogen receptor modulators  Calcitonin  Denosumab  Teriparatide Marc Imhotep Cray, MD

Bisphosphonates* Mechanism of action  Bind to hydroxyapatite in bone, inhibiting osteoclast activity Uses  Postmenopausal bone loss 1. Alendronate (oral; once a week) 2. Risedronate (oral; once a week)  Osteoporosis and compression fractures 1. Alendronate (oral; once a week) 2. Risedronate (oral; once a week) 3. Ibandronate (oral; once a month) 4. Zoledronic acid (IV; once a year) Marc Imhotep Cray, MD

Uses cont.  Hypercalcemia due to malignancy 1. Clodronate 2. Etidronate 3. Tiludronate 4. Zoledronic acid  Paget’s disease 1. Clodronate 2. Etidronate 3. Tiludronate 4. Zoledronic acid *Note common ending -dronate for all bisphosphonates.

Bisphosphonates cont. Adverse effects  Reflux esophagitis (gastroesophageal reflux disease; GERD) when taken orally; avoid this by: 1. Taking these drugs on an empty stomach, with at least 8 oz. water, immediately upon awakening 2. Remaining in an upright position for at least 30 minutes after taking drug 3. Avoiding food or drink for 30 minutes after taking drug  Musculoskeletal pain  Hypocalcemia  Hypophosphatemia  Osteonecrosis (jaw) Marc Imhotep Cray, MD

Bisphosphonates cont. Pharmacokinetics Food and other medications decrease absorption of bisphosphonates, which are already poorly absorbed (less than 1%) after oral administration

Bisphosphonates are cleared from plasma by binding to bone and being cleared by kidney  not metabolized by CYP450 system Elimination half-life may be years Marc Imhotep Cray, MD

Selective estrogen receptor modulators (SERMs) Raloxifene MOA  Agonist in bone  Antagonist in breast  Antagonist in uterus Uses  Prevention and treatment of osteoporosis in postmenopausal women  Risk reduction for invasive breast cancer in postmenopausal women with osteoporosis  Risk reduction in postmenopausal women with high risk for invasive breast cancer Marc Imhotep Cray, MD

Adverse effects  Thromboembolism  Peripheral edema  Hot flashes  Headache  Depression  Vaginal bleeding

Denosumab

MOA  A monoclonal antibody that targets receptor activator of nuclear factor kappa-B ligand and inhibits osteoclast formation and function Use  Denosumab is approved for treatment of postmenopausal osteoporosis in women at high risk of fracture  It is administered via subcutaneous injection every 6 months Adverse Effects  increased risk of infections  dermatological reactions  hypocalcemia  osteonecrosis of the jaw  atypical fractures  Reserved for women at high risk of fracture and those who are intolerant of or unresponsive to other osteoporosis therapies

Marc Imhotep Cray, MD

Calcitonin Uses  Administered parenterally to treat hypercalcemia  Paget’s disease of bone  Postmenopausal osteoporosis (intranasal) Adverse effects a. Rhinitis b. Flushing c. Back pain

Marc Imhotep Cray, MD

Teriparatide (a PTH analogue) A recombinant segment of human parathyroid hormone administered subcutaneously for Tx of osteoporosis MOA Causes dissolution of bone but can more commonly cause bone formation Uses  Osteoporosis in postmenopausal women at high risk of fracture  Primary or hypogonadal osteoporosis in men at high risk of fracture Adverse effects  Hypercalcemia  Hyperuricemia  Arthralgia  Respiratory effects

Vitamin D analogues Examples  Calcitriol  Cholecalciferol  Dihydrotachysterol  Doxercalciferol  Ergocalciferol  Paricalcitol

Marc Imhotep Cray, MD

Uses  Treatment of vitamin D deficiency  Prophylaxis against vitamin D deficiency  Rickets prevention o Given with calcium to supplement diet of infants  Hypoparathyroidism (with calcium supplements)  Osteoporosis o Prevention and treatment  Chronic renal disease 1. Calcitriol 2. Paricalcitol (Oral and IV) 35

Question OP is a 65-year-old female who has been diagnosed with postmenopausal osteoporosis. She has no history of fractures and no other pertinent medical conditions. Which of the following would be most appropriate for management of her osteoporosis? A. Alendronate B. Calcitonin C. Denosumab D. Raloxifene E. Teriparatide

Marc Imhotep Cray, MD

Correct answer = A Bisphosphonates are first-line therapy for osteoporosis in postmenopausal women without contraindications. Calcitonin and raloxifene are alternatives but may be less efficacious (especially for nonvertebral fractures). Teriparatide and denosumab should be reserved for patients at high risk or those who fail other therapies.

Marc Imhotep Cray, MD

Estrogen or hormonal replacement therapy (HRT) Evidence-based medicine (EBM) states that overall health risks from HRT in postmenopausal women appear to exceed possible benefits Mechanism of action  Reduces bone resorption Uses  Postmenopausal osteoporosis (reduces bone loss)  Cannot restore bone Adverse effects  Similar to oral contraceptives but to a lesser extent because of lower estrogen content  The Women’s Health Initiative (WHI) Trial reported an increase in incidence of strokes in both estrogen-alone and the estrogen-progestin subgroups as compared with placebo groups.  Thromboembolism Marc Imhotep Cray, MD

Case 44 Answers Agents Affecting Calcium Homeostasis Summary: A 66-year-old woman with osteoporosis is prescribed alendronate. • Mechanism of action of PTH on the bone: Pulsatile administration, the normal physiologic mode, enhances bone formation. Continuous delivery, for example, as a consequence of a parathyroid tumor, results in bone resorption. • Mechanism of action of PTH in the kidney: Increases reabsorption of Ca 2+ and Mg2+ and increases production of vitamin D and the active metabolite calcitriol and decreases reabsorption of phosphate, bicarbonate, amino acids, sulfate, sodium, and chloride. • Mechanism of action of alendronate sodium: Inhibition of osteoclastic activity in bone, which reduces bone reabsorption. Marc Imhotep Cray, MD

Case 44 Answers Agents Affecting Calcium Homeostasis cont. CLINICAL CORRELATION PTH has multiple actions on bone. Chronic elevations in PTH, for example, from a tumor, stimulate the resorption of bone via its stimulation of the number and activity of osteoclasts. This is mediated by specific PTH receptors in the bone, coupled to an increase in cyclic adenosine monophosphate (cAMP). Intermittent administration of PTH stimulates bone growth. Estrogen is an indirect inhibitor of PTH activity in the bone. This effect allows premenopausal women to maintain higher levels of bone density. Following menopause, with the resultant decrease in circulating estrogen levels, there is a relative increase in osteoclastic activity and resorption of bone, with a net loss of bone mineral density.

Marc Imhotep Cray, MD

Case 44 Answers Agents Affecting Calcium Homeostasis cont. Alendronate sodium is an analog of pyrophosphate that directly binds to bone. It inhibits osteoclastic activity, reducing the resorption of bone. This retards the progression of bone density loss and may allow for increases in density, because osteoblastic activity is not affected. It is administered orally, and its most common adverse effects are gastrointestinal (GI). It may produce esophagitis, and even esophageal perforation, if the pill were to get caught in the esophagus while swallowing. For that reason, patients taking alendronate are instructed to take it on an empty stomach with a full glass of water and to remain upright for at least 30 minutes after ingesting the medication.

Marc Imhotep Cray, MD

THE END

See next slide for further study. Marc Imhotep Cray, MD

Sources and further study: eLearning Endocrine cloud folder tools and resources MedPharm Guidebook: Unit 5 Drugs Used In Disorders of Endocrine System Endocrine and Reproductive System Pharmacology eNotes Clinical Pharmacology Cases 39 to 44 (Learning Triggers) Textbooks Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilmanâ&#x20AC;&#x2122;s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011 Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012 Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009 Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014 Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014. Marc Imhotep Cray, MD