PTH and Osteoporosis-Link to Recorded Lecture and Study Guide PDF

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Parathyroid Hormone and Osteoporosis: Link to Recorded Lecture and Study Guide What are the treatments for hypercalcemia emergencies? Hypercalcemia: Hyperparathyroidism, defined by a blood calcium level of greater than 10.5 (upper limit) • Multiple causes of elevated serum calcium ◦ Cancer = various malignancies can lead to hypercalcemia ◦ Thiazide diuretics ◦ Lithium toxicity ◦ Tuberculosis • SE of elevated calcium ◦ Sometimes asymptomatic ◦ NVD ◦ Polyuria ◦ Polydipsia ◦ Shorten QT interval ◦ T-wave widens • EMERGENCY Tx: ◦ Hemodialysis (filter blood & remove excess calcium) ◦ Administer phosphate IV ◦ Administer diuretics IV What are three additional treatments for hypercalcemia? • Tx: ◦ Calcitonin ◦ Bisphosphonates ◦ Mithramycin / plicamycin What are the actions of Mithramycin? Mithramycin / plicamycin • Reduces osteoclast formation ◦ Osteoclasts involved in breakdown of bone • Increases calcium excretion • Tx: hypercalcemia

What are the treatments for hypocalcemia? Hypocalcemia • Vitamin D deficiency (enhances absorption of calcium) & hypoparathyroidism (serum calcium levels are less than 8.5 mg) • Secondary to decreased levels of parathyroid hormone • Vitamin D = pro-health molecule • SE vitamin D deficiency: ◦ Fatigue ◦ Irritability ◦ Memory loss

Parathyroid Hormone and Osteoporosis: Link to Recorded Lecture and Study Guide ◦ Delusions ◦ Hallucinations ◦ Paresthesias (pins & needles in extremities) ◦ Seizures • SE hypocalcemia: ◦ Muscle spams ◦ Cramps ◦ Prolonged QT ◦ Acute cardiac failure ◦ Hypotension ◦ Alopecia ◦ Brittle/grooved nails ◦ Eczema ◦ Psoriasis ◦ **LARYNGOSPASMS/ACUTE AIRWAY OBSTRUCTION (bronchoconstriction b/c of loss of calcium homeostasis) • Tx: ◦ Calcium gluconate ◦ Calcium chloride (CalCl2) ◦ Hypomagnesemia (Magnesium supplement) ◦ Vitamin D supplement ◦ Vitamin C supplement What is the mechanism of action of bisphosphonates? Bisphosphonates • Inhibit osteoclast activity; destroys osteoclast; decreases osteoclast progenitor development & recruitment; prevent osteocyte/osteoblast apoptosis • Tx: osteoporosis • MOA: attach to hydroxyapatite binding sites on bony surfaces, especially those undergoing active resorption • ADR: ◦ NVD ◦ Fatigue ◦ Fever ◦ Anemia ◦ Bone/joint pain ◦ Jaw pain ◦ GI-esophageal erosions Which SERM is used to treat osteoporosis? • Selective estrogen receptor modulator (SERM)  given to women for type 1 osteoporosis (post-menopausal), which replaces estrogen

Parathyroid Hormone and Osteoporosis: Link to Recorded Lecture and Study Guide ◦ In some parts of the body, it can act as an partial agonist vs. full agonist ◦ Raloxifene / evista What is the mechanism of action of Denosumab? ANTIBODIES CAN DEVELOP AGAINST OSTEOPROTEGERIN, LIMITING USE AS A THERAPEUTIC AGENT, so monoclonal antibodies developed that target the RANKL system: Denosumab / Xgeva / Prolia • Used to treat bone problems in cancer metastasized to bone • Human monoclonal antibody that can bind to RANKL • RANKL inhibitor, preventing development of osteoclasts • Mimics osteoprotegerin • MOA: binds to RANKL, prevents RANKL from binding to RANK receptor on osteoclast surface and therefore cannot promote osteoclast maturation • Reduced RANK-RANKL binding, osteoclast formation, function and survival are inhibited, bone resorption decreases & bone mass increases • SE: ◦ NVD ◦ Joint/muscle pain ◦ Low calcium levels ◦ Weakness ◦ Constipation ◦ Back pain ◦ Pain in arms & legs ◦ Anemia ◦ Skin rashes ◦ Fever ◦ Chill ◦ Night sweats ◦ Contraindicated in HYPOCALCEMIA What is the mechanism of action of Teriparatide? Forteo / teriparatide • MOA: increases bone remodeling, replaces old bone ◦ Removal of old bone = promotes formation of new bone (increases bone turnover & formation) • N-terminus (34aa) form of parathyroid hormone, which is the bio active portion of hormone (increases turnover of bone, thereby results in buildup of bone) • SE: ◦ Headache ◦ Nausea ◦ Dizziness ◦ Limb pain

Parathyroid Hormone and Osteoporosis: Link to Recorded Lecture and Study Guide ◦ Risk of osteosarcoma ◦ May increase serum calcium, urinary calcium, serum uric acid What is the mechanism of action of Romosozumab? Evenity / romosozumab • Monoclonal antibody • Targets sclerostin for treatment of osteoporosis • By targeting & eliminating sclerostin, there is increased bone formation & decreased bone resorption • Sclerostin is a protein produced by osteocytes that arrests bone formation • SE: ◦ NVD ◦ Back pain ◦ Skin rashes ◦ Low calcium levels ◦ Weakness ◦ Constipation ◦ CV (serious) Sclerostin • A small protein expressed by SOST gene in osteocytes, bone cells that respond to mechanical stress applied to skeleton & appear to play an important role in regulation of bone remodeling • Inhibits osteoblast differentiation = osteoblast cannot mature & do their job of laying down mineralized bone • Normally produced by pro-osteoclasts (precursors of osteoclasts) • Product from SOST gene • Romosozumab directly targets sclerostin so that all anti-bone forming functions are removed

Parathyroid Hormone and Osteoporosis: Link to Recorded Lecture and Study Guide Parathyroid Hormone Parathyroid hyperplasia: parathyroid becomes enlarged, and secretes excess PTH • Primary causes of hyper-parathyroidism ◦ There is something wrong with how the parathyroid gland itself is growing ◦ Hyperplasia or neoplasia ◦ Possibilities: ‣ Neoplasia • Tumor, new growth of something • Doesn’t always mean malignancy • Parathyroid adenoma nodule = benign • One parathyroid gland will be enlarged, and other 3 will be of normal size ‣ Hyperplasia • Overgrowth • Intrinsic disorder causing all 4 parathyroid glands to be enlarged • Secondary causes of hyper-parathyroidism ◦ Underlying driving force, pushing the parathyroid gland to respond & this force is HYPOCALCEMIA (serum calcium levels are too low) ◦ Hypocalcemia • Parathyroid: ◦ 4 parathyroid glands ◦ Located posterior to the thyroid ◦ Produce PTH ◦ PTH increases serum calcium levels ◦ Stops at nothing in order to increase serum calcium levels ◦ Leach calcium out of bones ◦ Thyroid have parafollicular cells which produce calcitonin ◦ Calcitonin & PTH are opposite hormones ‣ PTH increases levels of serum calcium ‣ Calcitonin decreases levels of serum calcium (helps us build thickness of bones) Hyperparathyroidism can be primary or secondary • Primary hyper-parathyroidism: ◦ Intrinsic to the parathyroid gland going on ◦ Neoplasia: nodule (adenoma) in parathyroid gland, which is secreting abnormally high levels of parathyroid hormone ◦ Hyperplasia: parathyroid gland is hyperplastic, which leads to increased parathyroid hormone (hyper-parathyroidism) • Secondary hyper-parathyroidism ◦ Occurs when serum calcium levels are low ◦ Lots of underlying causes ‣ Vitamin D deficiency • Calcium is absorbed with the help of vitamin D in small intestine

Parathyroid Hormone and Osteoporosis: Link to Recorded Lecture and Study Guide • Cannot absorb calcium without vitamin D, leading to hypocalcemia ‣ Renal failure • Altered function of the kidney • Too much excretion of calcium • Parathyroid syndrome = related to renal cell carcinoma, where cancer cells themselves produce parathyroid hormone Parathyroid hormone • Parathyroid hormone (PTH): also known as parathormone or parathyroid • PTH is a hormone secreted by parathyroid glands • Regulating serum calcium thru effects on bone (deposition/liberation), kidney (reabsorption) & intestine (reabsorption) *3 TARGETS • PT is secreted by chief cells of parathyroid glands • It is a polypeptide containing 84 amino acids and is a pro hormone (then it is processed into active form) • PTH has a molecular mass around 9500 Da. • Its action is opposed by the hormone calcitonin • PTH influences bone remodeling, which is an ongoing process in which bone tissue is alternately resorted and rebuilt over time ◦ Throughout life, bones undergo process of remodeling ◦ Osteocytes lay down new boney tissue ◦ Osteoblasts = precursors of osteocytes ◦ Osteoclasts digest the bone, and make it possible for new bone to be laid down (osteoporosis = overactive osteoclasts) • PTH is secreted due to low serum calcium levels • PTH indirectly stimulates osteoclasts activity within the bone matrix (osteon) to release more ionic calcium into blood to elevate a low serum calcium level ◦ Stimulates osteoclasts to liberate calcium from the body • Bone is the reservoir for calcium in body • Maintains calcium at appropriate levels in face of changes in metabolism, stress, nutritional variations • PTH liberates calcium Hyperparathyroidism • Increased secretion of parathyroid hormone (PTH) ◦ Loss of calcium from bones ‣ Makes bones thinner from liberating calcium from bones ◦ Hypercalcemia ‣ Too much calcium in bloodstream ‣ Can lead to many disorders • Calcium rich stones (kidney stones) • Pancreatitis • Peptic ulcer • Osteitis fibrosis cystica • Emotional disorders

Parathyroid Hormone and Osteoporosis: Link to Recorded Lecture and Study Guide

Calcitonin • Produced by parafollicular cells (C-cells) of thyroid gland • Helps to regulate levels of calcium & phosphate in blood, opposing the action of parathyroid hormone • Calcitonin reduces calcium levels in blood by 2 mechanisms: ◦ Calcitonin inhibits activity of osteoclasts. Inhibition of osteoclasts by calcitonin directly reduces released into the blood ◦ Calcitonin can also decrease resorption of calcium in kidney, leading to lower blood calcium levels PTH • Signaling mechanism, parathyroid hormones are under control of specific endocrine signals • In response to low concentration of calcium in blood, parathyroid gland will release PTH • PTH will liberate calcium from the bones • Kidney effects ◦ PTH will decrease excretion of calcium in urine ◦ Increased Vitamin D synthesis, which will enhance absorption of calcium from the intestine • Parathyroid hormone responds to altered levels of serum calcium very quickly ◦ Narrow range of what is normal for serum calcium ◦ As soon as serum calcium is too low, PTH increases ◦ The lower the serum calcium gets, the higher that PTH gets ◦ As serum calcium reaches a level above upper limit of parathyroid hormone secretion, PTH decreases Hypercalcemia • Causes of altered secretion of PTH • Normal range of calcium: 8.5-10.5 mg/dL • If serum calcium levels are low & PTH is also low, we have hypoparathyroidism ◦ Because parathyroid is not doing its job • If serum calcium levels are high, can have 2 different situations: ◦ Serum calcium levels high & high level of PTH = there is primary hyperparathyroidism ◦ Serum calcium levels high & low level of PTH = ‣ PTH levels are low because of negative feedback signaling ‣ Some type of malignancy is present • PTH has a direct effect on kidney (decreases calcium excretion in urine, & enhances renal synthesis of vitamin D) ◦ If pt has renal insufficiency (shown by renal function tests: BUN & creatinine) = can be underlying cause of abnormal calcium levels • Potassium can also be altered in pts with abnormal calcium levels

Parathyroid Hormone and Osteoporosis: Link to Recorded Lecture and Study Guide

Hypercalcemia: Hyperparathyroidism, defined by a blood calcium level of greater than 10.5 (upper limit) • Multiple causes of elevated serum calcium ◦ Cancer = various malignancies can lead to hypercalcemia ◦ Thiazide diuretics ◦ Lithium toxicity ◦ Tuberculosis • SE of elevated calcium ◦ Sometimes asymptomatic ◦ NVD ◦ Polyuria ◦ Polydipsia ◦ Shorten QT interval ◦ T-wave widens • EMERGENCY Tx: ◦ Hemodialysis (filter blood & remove excess calcium) ◦ Administer phosphate IV ◦ Administer diuretics IV • Tx: ◦ Calcitonin ◦ Bisphosphonates ◦ Mithramycin / plicamycin Mithramycin / plicamycin • Reduces osteoclast formation ◦ Osteoclasts involved in breakdown of bone • Increases calcium excretion • Tx: hypercalcemia Hypocalcemia • Vitamin D deficiency (enhances absorption of calcium) & hypoparathyroidism (serum calcium levels are less than 8.5 mg) • Secondary to decreased levels of parathyroid hormone • Vitamin D = pro-health molecule • SE vitamin D deficiency: ◦ Fatigue ◦ Irritability ◦ Memory loss ◦ Delusions ◦ Hallucinations ◦ Paresthesias (pins & needles in extremities) ◦ Seizures • SE hypocalcemia: ◦ Muscle spams ◦ Cramps

Parathyroid Hormone and Osteoporosis: Link to Recorded Lecture and Study Guide ◦ Prolonged QT ◦ Acute cardiac failure ◦ Hypotension ◦ Alopecia ◦ Brittle/grooved nails ◦ Eczema ◦ Psoriasis ◦ **LARYNGOSPASMS/ACUTE AIRWAY OBSTRUCTION (bronchoconstriction b/c of loss of calcium homeostasis) • Tx: ◦ Calcium gluconate ◦ Calcium chloride (CalCl2) ◦ Hypomagnesemia (Magnesium supplement) ◦ Vitamin D supplement ◦ Vitamin C supplement

Parathyroid Hormone and Osteoporosis: Link to Recorded Lecture and Study Guide Osteoporosis: thinning of the bones, decreased bone mineral density • Heterogenous group of diseases • Reduction in bone mass to a level below that required for normal bone support • Resorption exceeds bone formation • After 40-50 bone mass decrease (female > males) ◦ Females can get type 1 and type 2 osteoporosis ◦ Males can get type 2 osteoporosis • Osteoblast builds up bones, osteoclast breaks down bones • Causes (osteoblast & osteoclast activity imbalance) ◦ Osteoclastic activity: too much osteoclast activity ◦ Parathyroid hormone: increases osteoclast activity; hyperparathyroidism is a cause ◦ Calcium intake ◦ Adrenal cortical function: other endocrine players may affect bone homeostasis ◦ Osteoblasts activity • Most common metabolic bone disease in US • Fractures: proximal humerus, lower forearm, hip, spine, pelvis Factors that influence bone mass • Hormones (applies to women - Menopause), Nutrition, Exercise & lifestyle — affect shape & architecture, bone mass, material properties — affect falls, bone strength, postural reflexes, falls, soft tissue padding — leading to fracture • Fractures: more in females than males ◦ Hip fracture = most catastrophic = can’t walk, immobilization, increase of thrombosis, bed sores, infection Calcium Intake of females • When we get to age 9, we are behind adequate intake of calcium Osteoporosis • Vertebral column is affected, which affects posture, strength, decrease in height • Bone resorption • Vertebral (& hip & wrist) fractures • Reduction in bone mass, strength & compliance • Increased bone porosity • Reduction in total body stores of calcium & phosphate • Bone is dynamic tissue, constant remodeling occurs due to diet, exercise, diseases • Formation (osteoblast) is balanced by dissolution (osteoclasts) • Bone is also primary body store of Calcium • Decreased in mineralized bone mass ◦ Making our bones susceptible to fractures

Parathyroid Hormone and Osteoporosis: Link to Recorded Lecture and Study Guide • 2 types of primary osteoporosis ◦ TYPE 1: increased osteoclast activity (POST MENOPAUSAL WOMEN) ‣ Estrogen withdrawal ‣ Men do not get type 1 ◦ TYPE 2: decreased osteoblast activity (AGING) ‣ Both men & women can get type 2 • Secondary osteoporosis (respond to underlying problem) ◦ Endocrine disorders (like hyperparathyroidism) ◦ Hematological malignancies ◦ Malabsorption (don’t absorb enough calcium in GI tract) ◦ Alcoholism Type 1 vs Type 2 primary osteoporosis • Type 1 osteoporosis: post menopausal osteoporosis ◦ Occurs in women with estrogen deficiency ◦ Most common - fractures of distal forearm & vertebral bodies (spine) ◦ Characterized by phase of accelerated bone loss, primarily from trabecular bone ◦ Too much osteoclast activity • Type 2 osteoporosis: age-associated or senile osteoporosis ◦ Occurs in women & men ◦ Represents bone loss associated with aging ◦ Fractures occur in cortical & trabecular bone ◦ Most common - wrist, vertebral, hip fractures ◦ Too little osteoblast activity Regulation of osteoclast maturation • Relationship between osteoclast & osteoblast • RANKL: receptor activator of nuclear factor kappa B ligand • Osteoblasts are precursors for osteocyte; which increase mineral bone density • Osteoblasts & osteocytes produce a ligand (RANKL), which can bind to 2 different receptors in the bone • RANKL can bind to its receptor: RANK, which is expressed on the surface of osteoclast precursors, which stimulates osteoclast maturation; mature osteoclast breaks down bone = more bone breakdown • Another receptor of RANKL is OPG (osteoprotegerin), which is a receptor that is floating around in the bone • When RANKL binds to OPG receptor, there is less RANKL available to bind to RANK, which means that it protects bone (by trapping RANKL in outside space, preventing RANKL from binding to break, thereby preventing facilitating osteoclast maturation) = less bone breakdown • ANTIBODIES CAN DEVELOP AGAINST OSTEOPROTEGERIN, LIMITING USE AS A THERAPEUTIC AGENT Pathogenesis of Osteoporosis

Parathyroid Hormone and Osteoporosis: Link to Recorded Lecture and Study Guide • Type 1 ◦ Decreased estrogen = increased inflammatory cytokines, leads to activation of osteoclasts & bone resorption, leading to osteoporosis ◦ Bone resorption leads to liberation of calcium from bones (plasma calcium levels are increased) ◦ Kidneys respond by synthesizing less vitamin D, which leads to less calcium absorption, and decreased plasma calcium ◦ Decreased plasma calcium stimulates an increase in PTH, which means more resorption • Type 2 ◦ Less direct path to osteoporosis ◦ With aging, decreased renal alpha-hydroxylase (enzyme in kidneys that synthesized vitamin D) ◦ Kidneys respond by synthesizing less vitamin D, which leads to less calcium absorption, and decreased plasma calcium ◦ Decreased plasma calcium stimulates an increase in PTH, which means more resorption Primary osteoporosis • Type 1 osteoporosis ◦ Post menopausal osteoporosis ◦ Occurs in females ◦ Common: wrist, spine • Type 2 osteoporosis ◦ Men and women ◦ Occurs later in life (> 75 years) ◦ Common: hips, humerus, tibia Secondary osteoporosis • Due to extrinsic factors (hyper-parathyroidism) • Higher in women than men Bone is continually remodeled (balance b/t osteoblastic & osteoclastic activity) • Bone is constantly going thru a process of resorption, mediated by osteoclasts, followed by formation, mediated by osteoblasts • Osteoporosis is due to an imbalance is osteoclastic & osteoblastic activity Primary osteoporosis • 2 types • Post menopausal osteoporosis • Involutional osteoporosis • Idiopathic osteoporosis (juvenile, adult) Secondary osteoporosis • Produced by:

Parathyroid Hormone and Osteoporosis: Link to Recorded Lecture and Study Guide ◦ ◦ ◦ ◦ ◦

Neoplasm Immobilization COPD Nutritional Hyperparathyroidism

Risk factors • Gender: female ◦ Susceptible to both types of osteoporosis • Aging • Ethnic groups ◦ Caucasian or Asian races • Anorexia nervous • Chronic liver or kidney disease • High levels of cortisol (Cushing’s syndrome) • History of diabetes mellitus • History of tobacco smoking • High caffeine intake • Hyperparathyroidism • Depression (increased cortisol) • Corticosteroid use (increased cortisol) • Wheelchair bound • Radiation therapy Drugs to treat low bone density • Bisphosphonates • Selective estrogen receptor modulator (SERM) ◦ In some parts of the body, it can act as an partial agonist vs. full agonist ◦ Raloxifene / evista • Biological (monoclonal antibody) Drugs that stimulate new bone • Anabolic ◦ Teriparatide / forteo Bisphosphonates • Inhibit osteoclast activity; destroys osteoclast; decreases osteoclast progenitor development & recruitment; prevent osteocyte/osteoblast apoptosis • Tx: osteoporosis • MOA: attach to hydroxyapatite binding sites on bony surfaces, especially those undergoing active resorption • ADR: ◦ NVD ◦ Fatigue

Parathyroid Hormone and Osteoporosis: Link to Recorded Lecture and Study Guide ◦ Fever ◦ Anemia ◦ Bone/joint pain ◦ Jaw pain ◦ GI-esophageal erosions • Drugs ◦ Alendronate (Fosamax) ◦ Etidronate (didronel) ◦ Pamidronate (aredia) ◦ Risedronate (actonel) ◦ Ibandronate (boniva) ◦ Zolendronate (reclast) Forteo / teriparatide • MOA: increases bone remodeling, replaces old bone ◦ Removal of old bone = promotes formation of new bone (increases bone turnover & formation) • N-terminus (34aa) form of parathyroid hormone, which is the bio active portion of hormone (increases turnover of bone, thereby results in buildup of b...