Pales calcium lecture Flashcards
PTH is regulated by
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
What Does PTH Do to Osteoblasts
Thought to actually INCREASE osteoblastic activity, but not too much
Net effect is still resorption
PTH Feedback Mechanisms
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
Vitamin D Axis
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
Most common cause of hypercalcemia
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
Primary Hyperparathyroidism presentation
Usually presents as asymptomatic hypercalcemia or with renal stones
Phosphate and bicarbonate wasting
- Non-anion gap metabolic acidosis
- Cortical bone loss leading to osteoporosis
Tertiary Hyperparathyroidism
Reduced activation of Vitamin D in the setting of chronic renal disease leading to elevated PTH
renal osteodystrophy
chronic renal failure –> decreased calcitriol –> decreased ca absorption–> increased PTH –> osteitis fibrosa cystica
aluminum –> osteomalacia
Familial Benign Hypocalciuric Hypercalcemia
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
Signs and Symptoms - Hypercalcemia
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”
Osteitis Fibrosa Cystica
Excessive PTH causes
- Chronic bone resorption
- Demineralization
- Pathologic fractures
- Cystic bone lesions
Evaluation of Hypercalcemia
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
Management of Hypercalcemia
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
Acquired Hypoparathyroidism- postoperative
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
causes of Acquired Hypoparathyroidism- Parathyroid damage
Exposure to heavy metals - Copper (Wilson’s Disease) - Iron (Hemochromatosis, transfusion hemosiderosis) Granulomas Sporadic immunity Tumors Infection Riedel’s thyroiditis
Acquired Hypoparathyroidism- functional
Magnesium deficiency (malabsorbtion, alcoholism) Prevents the secretion of PTH
Acquired Hypoparathyroidism- PGA Type 1: Autoimmune polyendocrinopathy
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
Congenital Hypoparathyroidism- 3 types
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
DiGeorge’s Syndrome
Cardiac Abnormalities - (tetrology of Fallot) Abnormal fascies Thymic aplasia Cleft palate Hypocalcemia Autoimmune hypoparathyroidism
Pseudohypoparathyroidism
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
Albright Heredetary Osteodystrophy
a form of pseudohypoparathyroidism
Short stature, obese
Bradydactyly, round faces
Dermal ossifications
Mental retardation
Vitamin D Deficiency in kids
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
Osteomalacia
Soft bones’
Remodeled bone does not mineralize
pain in the bones and hips, bone fractures, and muscle weakness
Hypo-magnesemia
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
Clinical Findings of Hypocalcemia- acute and chronic
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
Signs of Hypocalcemia
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)
Paget’s Disease of Bone
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)
Paget’s Disease Symptoms
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
Radiographic Findings in Paget’s Disease
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
Treatment of Paget’s Disease
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
Laboratory Findings in Paget’s
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
Osteoporosis
Silent skeletal disorder characterized by compromised bone strength and increased predisposition to fracture
Risk Factors for Osteoporosis
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
Indications for Measuring BMD
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)
BMD Assessment
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
DEXA Scan Results
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
WHO Definition of Bone Mass
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
Prevention of Osteoporosis
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
Exercise and physical activity
for osteoporosis
No consensus on how much or what type
30 minutes of weight bearing or resistance exercise at least 4 times per week
Bisphosphonates
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.)
Zoledronate (Zometa)
Newer bisphosphonate
Single injected dose suppressed bone turnover for a full year and induced significant gains in BMD.
Hormone Replacement Therapy
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.
Calcitonin
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
Teriparatide (rPTH)
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.
Denosumab (Prolia, Xgeva)
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
