Pales calcium lecture

Question 1

PTH is regulated by

Answer 1

ionized calcium levels. If Ca is high– thyroid releases calcitonin–> increased deposition in bones, decreased uptake in intestines and reabosorption from urine

If Ca levels low–> Parathyroid releases PTH–> increased CA release from bones, uptake in intestines and reabsorption from urine

Question 2

What Does PTH Do to Osteoblasts

Answer 2

Thought to actually INCREASE osteoblastic activity, but not too much
Net effect is still resorption

Question 3

PTH Feedback Mechanisms

Answer 3

PTH secretion is modulated by calcium sensing receptors on membranes of parathyroid cells

• High ionized Ca+ causes reduced PTH secretion
• Low Mag also decreases PTH secretion
• – High Mag can depress PTH as well
• Hypocalcemia increases secretion

PTH increases renal loss of phosphate
Decreases serum phosphate levels

Question 4

Vitamin D Axis

Answer 4

Second important regulator of Calcium
Vitamin D3 derived from diet
UV light converts cholesterol precursors to Vitamin D3
Increases calcium and phosphate absorption in gut
Suppresses parathyroid cell function

Question 5

Most common cause of hypercalcemia

Answer 5

Primary Hyperparathyroidism

Single parathyroid adenoma in over 80% of cases
Double adenoma or gland hyperplasia in 20%
Carcinoma less than 1%
– Up to 5% if patient is under 30 years

Multiple Endocrine Neoplasia (10% of cases)

• Parathyroid hyperplasia seen in MEN 1, 2A, and 2B
• Multiglandular hypothyroidism is prominent in MEN 1

Question 6

Primary Hyperparathyroidism presentation

Answer 6

Usually presents as asymptomatic hypercalcemia or with renal stones
Phosphate and bicarbonate wasting
- Non-anion gap metabolic acidosis
- Cortical bone loss leading to osteoporosis

Question 7

Tertiary Hyperparathyroidism

Answer 7

Reduced activation of Vitamin D in the setting of chronic renal disease leading to elevated PTH

Question 8

renal osteodystrophy

Answer 8

chronic renal failure –> decreased calcitriol –> decreased ca absorption–> increased PTH –> osteitis fibrosa cystica

aluminum –> osteomalacia

Question 9

Familial Benign Hypocalciuric Hypercalcemia

Answer 9

Easily mistaken for mild hyperparathyroidism
Autosomal dominant inherited disorder
- Causes loss-of-function mutation in CaSR
— Calcium Sensing Receptors on parathyroid glands (Reduced sensing of calcium = increased PTH secretion)
— Calcium Sensing Receptors on renal tubules (Reduced sensing of calcium = reduced calcium in urine)
Normal or mildly elevated PTH and magnesium
Diagnose with low urinary calcium clearance
Surgery does not help – treat medically

Question 10

Signs and Symptoms - Hypercalcemia

Answer 10

Fatigue, polyuria, weakness, anorexia, nausea, vomiting, constipation, abdominal pain, lethargy, mental status changes
Severe – coma or arrhythmias
“Stones, bones, abdominal groans, psychic moans with fatigue overtones”

Question 11

Osteitis Fibrosa Cystica

Answer 11

Excessive PTH causes

• Chronic bone resorption
• Demineralization
• Pathologic fractures
• Cystic bone lesions

Question 12

Evaluation of Hypercalcemia

Answer 12

check PTH. If High or normal- parathyroid mediated. check 24-hour urinary calcium. Ca low- benign familial hypercalcemia.
Ca high- primary hyperparathyroidism, evaluate for surgical indications

if PTH is low, non-parathyroid mediated. Cancer? granulomatous disease? thyroid, adrenal diseases? Consider checking PTHrP, vitamin D metabolites

Question 13

Management of Hypercalcemia

Answer 13

Intravenous fluids
Loop diuretic medications (such as furosemide) to help flush excess calcium from the system and keep the kidneys functioning
Intravenous bisphosphonates, a group of drugs that includes pamidronate (Aredia) and zolendronate (Zometa), to prevent bone breakdown
Calcitonin, a hormone produced by the thyroid gland, to reduce bone reabsorption and slow bone loss
Glucocorticoids (corticosteroids) to help counter the effects of too much vitamin D in the blood caused by hypercalcemia
Cinacalcet (Sensipar), a calcimimetic that activates CaSR. Primarily used to treat secondary hyperparathyroidism in renal disease or hypercalcemia with parathyroid carcinoma.
Hemodialysis or peritoneal dialysis to remove excess waste and calcium from the blood if the kidneys are damaged and there is no response to other treatments

Question 14

Acquired Hypoparathyroidism- postoperative

Answer 14

S/P thyroidectomy 
- Usually transient but can be permanent
S/P multiple parathyroidectomies
S/P removal of parathyroid adenoma
- Transient – due to suppression of remaining glands
S/P neck irradiation

Question 15

causes of Acquired Hypoparathyroidism- Parathyroid damage

Answer 15

Exposure to heavy metals
- Copper (Wilson’s Disease)
- Iron (Hemochromatosis, transfusion hemosiderosis)
Granulomas
Sporadic immunity
Tumors
Infection
Riedel’s thyroiditis

Question 16

Acquired Hypoparathyroidism- functional

Answer 16

Magnesium deficiency (malabsorbtion, alcoholism)
Prevents the secretion of PTH

Question 17

Acquired Hypoparathyroidism- PGA Type 1: Autoimmune polyendocrinopathy

Answer 17

AKA Autoimmune Polyendocrinopathy Candidiasis ectodermal dystrophy (APECED)

Presents in childhood with two of the following:
- Candidiasis
- Hypoparathyroidism
- Addison disease
May have cataracts, uveitis, alopecia, vitiligo or autoimmune thyroid disease

Question 18

Congenital Hypoparathyroidism- 3 types

Answer 18

Abnormal calcium-sensing receptors suppress the parathyroid glands

• Hypocalcemia without elevated PTH
• Autosomal dominate hypocalcemia with hypercalciuria
• Affects 1 in 70,000 infants with seizures

Barakat or HDR Syndrome

• Hypoparathyroidism, Deafness, Renal dysplasia
• Autosomal dominant mutation of GATA3
• Hypocalcemia and high frequency deafness from birth
• Later mental retardation & hypocalcemic tetany

DiGeorge’s Syndrome
- Congenital cardiac and facial anomalies
- Deletion of Chromosome 22
- Hypocalcemia with tetany
Usually in infancy, but sometimes not until adulthood

Question 19

DiGeorge’s Syndrome

Answer 19

Cardiac Abnormalities
- (tetrology of Fallot)
Abnormal fascies
Thymic aplasia
Cleft palate
Hypocalcemia
Autoimmune hypoparathyroidism

Question 20

Pseudohypoparathyroidism

Answer 20

End-organ resistance to PTH
- Several subtypes
Hypocalcemia
- Tubular resistance to PTH = hypercalciuria
Hyperphosphatemia
Increased circulating PTH
Normal PTH receptors in bone
- Boney changes of hyperparathyroidism present

Pseudopseudohypoparathyroidism
- Phenotypic abnormalities without hypocalcemia

Question 21

Albright Heredetary Osteodystrophy

Answer 21

a form of pseudohypoparathyroidism

Short stature, obese
Bradydactyly, round faces
Dermal ossifications
Mental retardation

Question 22

Vitamin D Deficiency in kids

Answer 22

Rickets
signs: soft spot on baby’s head is slow to close, bony necklace, curved bones, big, lumpy joints, bowed legs

lack of vitamin D, calcium or phosphate

Question 23

Osteomalacia

Answer 23

Soft bones’
Remodeled bone does not mineralize
pain in the bones and hips, bone fractures, and muscle weakness

Question 24

Hypo-magnesemia

Answer 24

Cofactor for PTH secretion
Required for release of stored hormone from secretory granules. 
Participates in the PTH affect on the bone and kidneys
Common in 
- chronic gastrointestinal disease
- nutritional deficiency
- Alcoholism
- cis-platinum therapy

Question 25

Clinical Findings of Hypocalcemia- acute and chronic

Answer 25

``` acute: Muscle cramps Tetany Irritability Carpopedal spasm Convulsions Perioral tingling Tingling in hands/feet ``` ``` chronic: Lethargy Personality changes Anxiety state Blurred vision (cataracts) Parkinsonism Mental retardation ```

Question 26

Signs of Hypocalcemia

Answer 26

Chvostek sign - Facial muscle contraction on tapping the facial nerve in front or ear Trousseau phenomenon - Carpal spasm after application of BP cuff due to tetany - -- Specific and sensitive for hypocalcemia Nonspecific signs - Candidiasis, brittle nails, dry skin - Cararacts, loss of eyebrows - Hyperactive DTRs - Papilledema (rare)

Question 27

Paget’s Disease of Bone

Answer 27

Osteitis Deformans Focal disorder of bone remodeling that leads to greatly accelerated rates of bone turnover. - Disruption of normal architecture - Gross deformities - --- Enlargement of skull, bowing of long bones - Etiology unknown – probably osteoclast abnormality (? viral, ? Genetic)

Question 28

Paget’s Disease Symptoms

Answer 28

``` Often asymptomatic - Only 27% have symptoms at time of diagnosis Headache Bone pain and deformity Warmth of skin over involved bone High output cardiac failure Entrapment neuropathies (hearing loss) Kyphosis Fracture with only slight trauma Affected bones develop high blood flow Increased vascularity may cause: - Warmth of skin over involved bone - High output cardiac failure - Vascular ‘steal’ from spinal cord - paralysis ```

Question 29

Radiographic Findings in Paget’s Disease

Answer 29

Osteolytic phase - Advancing, wedge-shaped resorption front at either end of long bones or circumscribed osteolytic lesions in the skull (osteoporosis circumscripta) Mixed phase - Less bone remodeling, more sclerosis - Enlarged bone, ? Bowing, fractures Osteoblastic phase - “Cotton wool” appearance with patchy increase in bone density - Bone scan shows osteoblastic uptake and can help identify the extent of the disease

Question 30

Treatment of Paget’s Disease

Answer 30

Treatment controversial if asymptomatic - Does tend to progress without treatment No cure, but can decrease the rate of osteoclastic bone resorption - Bisphosphonates – Treatment of choice - Calcitonin (SQ, IM, nasal) – shorter lived suppression - -- Can develop neutralizing antibodies - -- Not as potent as the bisphosphonates - Symptomatic therapy

Question 31

Laboratory Findings in Paget’s

Answer 31

Serum alkaline phosphatase usually elevated - Can be used to follow activity of disease - Bone-specific alk phos if near normal levels Other bone markers - Serum C-telopeptide (high) - Urinary hydroxyproline (high in active disease) - Serum calcium (usually high) - Serum 25-OH vitamin D - -- Screen for vitamin D deficiency

Question 32

Osteoporosis

Answer 32

Silent skeletal disorder characterized by compromised bone strength and increased predisposition to fracture

Question 33

Risk Factors for Osteoporosis

Answer 33

genetic: female, white, asian, FmHx of osteoporosis, small body size or weight hormonal: menopause (natural, premature, or surgical) lifestyle and nutrition; inadequate calcium intake, smoking, excessive alcohol consumption, eating disorders, excessive physical activity causing amenorrhea medications: glucocorticoids, anticonvulsants, heparin medical conditions

Question 34

Indications for Measuring BMD

Answer 34

women age > 65 postmenopausal women under 65 who have at least one risk factor for osteoporosis other than menopause postmenopausal women who present with fractures women who are considering therapy for osteoporosis and for whom bone mineral densitometry test restults would influence this decision women who have been receiving hormone replacement therapy for a prolonged period radiographic findings suggestive of osteoporosis or vertebral deformity corticosteroid therapy for more than 3 months primary hyperparathyroidism treatment for osteoporosis (to monitor therapeutic response)

Question 35

BMD Assessment

Answer 35

Dual energy X-ray absorbtiometry is the gold standard for measuring bone mass - Best correlation with fracture risk - Short scanning time - Low exposure to radiation - Can measure in all areas of skeleton Other methods: - Quantitative CT, single-photon absorbtiometry - Quantitative ultrasound

Question 36

DEXA Scan Results

Answer 36

T-Score - Standard deviation from the mean BMD of a young healthy population - Primarily used to diagnose osteoporosis - T-Score of -1 = 10% bone loss Z-Score - Standard deviation from the BMD of an age and sex matched group - Used for younger men, children, and premenopausal women

Question 37

WHO Definition of Bone Mass

Answer 37

Normal: T score > - 1 osteopenia: T score -1 to -2.5 Osteoporosis: T score less than -2.5 Established osteoporosis: T score under -2.5 and osteoporotic fracture

Question 38

Prevention of Osteoporosis

Answer 38

calcium intake Postmenopausal women with T-Score less than -1 and risk factors: Vitamin D supplementation (400-800 IU daily) Exercise Cessation of smoking Fall prevention Limitation of alcohol and caffeine ? Medications

Question 39

Exercise and physical activity | for osteoporosis

Answer 39

No consensus on how much or what type | 30 minutes of weight bearing or resistance exercise at least 4 times per week

Question 40

Bisphosphonates

Answer 40

Pyrophosphate derivatives that bind to boney surface and inhibit osteoclastic bone resorption - Poorly absorbed – must take fasting - Alendronate and risedronate --- Significant anti-fracture efficacy at spine, hip and other sites. --- Alendronate more effective in reducing fractures with severe osteoporosis than osteopenia --- Optimal duration of treatment is not known (Continued improvement after 5-7 years with no cumulative negative effects.)

Question 41

Zoledronate (Zometa)

Answer 41

Newer bisphosphonate | Single injected dose suppressed bone turnover for a full year and induced significant gains in BMD.

Question 42

Hormone Replacement Therapy

Answer 42

Women’s Health initiative - HRT increased risk of CV disease, breast cancer, stroke, DVT, and PE. SERMs – Raloxifene - Estrogen-like effect on bone but inhibits effects of estrogen on breast and uterus - Increased BMD, decreases risk of vertebral fractures, but not hip fractures - No increased risk of CV disease and decreases breast cancer risk. Increases risk for DVT/PE.

Question 43

Calcitonin

Answer 43

Nasal spray Increases BMD in spine and decreases vertebral fractures. - Does not affect incidence of hip fractures Indicated for women 5 years postmenopausal Analgesic effect on bone pain

Question 44

Teriparatide (rPTH)

Answer 44

Only anabolic agent Stimulates osteoblastic bone formation SQ injections - No more than 2 years duration Increases BMD and decreases fracture risk Indicated for patients with high fracture risk and are intolerant of other medications Avoid with Paget’s hx of radiation involving bone, or skeletal cancer – possible osteosarcoma.

Question 45

Denosumab (Prolia, Xgeva)

Answer 45

Approved by FDA in 2010 Monoclonal antibody that inhibits osteoclastic activation Binds to RANKL - Receptor Activator of Nuclear factor Kappa B Subcutaneous dosing every 6 months