Disorders of calcium and bone metabolism

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Disorders of calcium and bone metabolism

• Olivia Baugh MD Chief Resident

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Hypercalcemia

• Parathyroid dependent
• Primary hyperparathyroidism
• Familial hypocalciuric hypercalcemia
• Thiazide-induced hypercalcemia
• Lithium
• Parathyroid independent
• Malignancy
• Vitamin D intoxication
• Granulomatous disorders (sarcoidosis, lymphoma)
• Miscellaneous

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Primary hyperparathyroidism

• Commonest cause of hypercalcemia, more common in
  females
• 80 will be caused by a single parathyroid
  adenoma
• 15 hyperplasia
• 5 multiple adenomas
• Rarely caused by parathyroid cancer
• Familial hyperparathryoidism is associated with
  MEN1 and MEN 2A, and usually see hyperplasia

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symptoms

• Usually asymptomatic
• Symptoms
• Polyuria, polydipsia
• Nephrolithiasis, nephrocalcinosis
• Fatigue, weakness, myopathy
• Depression
• Osteopenia, osteoporosis, bone pain, pathologic
  fractures

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TESTS

• Labs
• Usually mild hypercalcemia
• Normal phosphate
• Increased or inappropriately normal PTH
• Increased urinary calcium excretion
• Imaging
• Loss of cortical bone, see subperiosteal bone
  resorption (on radial borders of phalanges)
• salt and pepper appearance of skull
• Osteitis fibrosa cystica (fibrous replacement of
  resorbed bone)
• Brown tumors (collections of osteoclasts in
  poorly mineralized bone)
• Renal stones

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treatment

• Parathyroidectomy is treatment of choice
• Adenoma requires resection, localize with
  sestimibe scan
• Hyperplasia can be treated with subtotal
  parathyroidectomy, leaving 50gm of tissue intact
• Reversible, mild asymptomatic hypocalcemia is
  common in the early postop period, however if
  pts already have bone disease, correction of
  hyperparathyroidism may lead to prolonged
  hypocalcemia
• Conservative therapy used in elderly or mild
  uncomplicated disease, indications for excision
  are calcium level greater than 1 unit above
  normal range, nephrolithiasis, thinning bones, or
  pronounced hypercalciuria

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Familial hypocalciuric hypercalcemia

• Autosomal dominant
• Patients have an abnormal set point of the
  calcium-sensing receptor in the parathyroid
  glands and renal tubules
• Labs mild hypercalcemia, normal or slightly
  increased PTH, low urinary calcium, family
  history, calcium-creatinine clearance ratio of
  less than 0.01
• No intervention as complications do not develop

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Thiazide induced

• Mild hypercalcemia
• Caused by dehydration, decreased renal calcium
  clearance, possible increased PTH
• Hypercalcemia usually resolves in a few weeks
  after stopping the thiazide
• More likely to occur in patients with underlying
  hyperparathyroidism

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lithium

• Raises the threshold of inhibition of PTH
  secretion by serum calcium
• PTH inappropriately normal or increased
• Hypercalcemia resolves after lithium
  discontinuation

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Question

• You are asked to evaluate a 25-year-old woman
  with hypercalcemia, fatigue, and weakness, which
  have been ongoing for the previous 3 months.
  Laboratory data include the following serum
  calcium 10.2 mg/dL, PTH 5.2 pmol/L (1-5.2
  pmol/L), and urinary calcium excretion 40mg/24h
  (20-275mg/24 h). She is not known to be taking
  any medication, and there is no history of
  nephrolithiasis or fracture. Which of the
  following is indicated?
• A. parathyroidectomy
• B. measurement of 25-0H-vit D
• C. parathyroid imaging
• D. calculation of fractional calcium excretion
  and thiazide screen
• E. measurement of PTHrP

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Answer D

• This patient has elevated serum calcium with a
  normal PTH level (not suppressed). This is
  compatible with primary hyperparathyroidism but
  you would expect an increased urinary calcium
  excretion level. Hypercalcemic hypocalciuria is
  familial but the same clinical picture and lab
  studies can be seen with thiazide administration.
  This patient also had hypokalemia and was taking
  diuretics for weight loss. Hypocalcemia
  accompanies elevated PTH due to 25-OH-D
  deficiency but this patient has hypercalcemia.

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Parathyroid-independent hypercalcemia

• Hypercalcemia of malignancy
• Acute, severe and life-threatening
• Commonest cause in hospitalized patients
• Due to destruction of bone by mets or
  paraneoplastic disease (PRHrP)
• Hypercalcemia resolves after malignancy treatment
  in paraneoplastic disease
• Serum PTH is low

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Vitamin d intoxication

• Hypercalcemia
• Hypercalciuria
• Renal insufficiency
• Soft tissue calcification
• Hypercalcemia may persist for months after vit D
  is discontinued due to fat stores
• Can also occur in vit A intoxication

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Sarcoidosis, granulomatous dz, lymphoma

• Vitamin D-dependent granulomas and some lymphomas
  express high concentrations of 1
  alpha-hydroxylase enzyme that generates
  1,25-dihydroxyvitamin D
• 25-OH-vit D is normal level
• 1,25-(OH)2-vit D is increased
• Treat with glucocorticoids

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Miscellaneous causes

• Hyperthyroidism enhances bone turnover and may
  lead to bone loss, see hypercalciuria
• Resolves with treatment of thyrotoxicosis
• Addisonian crisis causes dehydration and
  increased albumin concentration
• Treat with glucocorticoids
• Immobilization causes increased bone turnover

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Question

• A 64-year-old woman is referred for evaluation of
  hypercalcemia detected on routine testing 2 days
  ago. She is asymptomatic, but her serum calcium
  is elevated (13.4 mg/dL). A chest radiograph
  shows mediastinal lymphadenopathy. Which test
  result does NOT support a diagnosis of
  granuloma-associated hypercalcemia?
• A. normal serum phosphate concentrations
• B. PTH 4.8 pmol/L (1-5.2 pmol/L)
• C. undetectable PTH-related peptide (PTHrP)
• D. 25-OH-D 30 ng/mL
• E . 1,25-(OH)2-D gt70pg/mL

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Answer B

• Asymptomatic hypercalcemia in an otherwise
  asymptomatic patient is most often caused by
  primary hyperparathyroidism. If the parathyroid
  glands are normal, secretion of PTH is suppressed
  by hypercalcemia. Granulomas and some lymphomas
  express 1-alpha-hydroxylase and activate vitamin
  D to produce excess 1,25-(OH)2-D, the mediator of
  hypercalcemia. 25-(OH)-D levels are typically
  normal.

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Hypercalcemia management

• Saline rehydration
• Loop diuretics
• Pamidronate (IV bisphosphonate) inhibits bone
  resorption and has a prolonged effect on calcium
  concentration
• Dialysis if pt has renal failure
• Calcitonin rarely used due to modest effect and
  rapid onset of tachyphylaxis (rapid decrease in
  response to the drug over a short period of time)

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Hypoparathyroidism

• Results from surgical damage to the parathyroid
  glands, autoimmune disease, infiltration (Wilsons
  or hemochromatosis), or congenital disease
  (DiGeorge syndrome, also see thymic aplasia),
  hypomagnesemia impairs secretion and action of
  PTH (functional hypoparathyroidism)
• Hypocalcemia symptoms include Chvostek and Tinel
  signs
• Pseudohypoparathyroidism is due to end-organ
  resistance to PTH due to a receptor defect (short
  stature, round face, short metacarpals and
  metatarsals, calcification of the basal ganglia
  and mild mental retardation)

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Making the diagnosis

• Parasthesias, carpopedal spasm, laryngeal
  stridor, convulsions, prolonged QT interval,
  cataracts, alopecia, malabsorption, mucocutaneous
  candidiasis (in DiGeorge)
• Hypocalcemia and hyperphosphatemia with normal
  renal function
• PTH is low in hypoparathyroidism and elevated in
  psuedohypoparathyroidism
• Determine level of ionized calcium and Mag
• High PTH with low calcium can also suggest vit D
  deficiency

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therapy

• IV calcium for acute, severe disease with
  continuous EKG monitoring
• Oral calcium for chronic disease with vit D
• Thiazide diuretics to decrease amount of
  calciuria
• Phosphate binders
• Goal calcium level is 8.5mg/dL and urinary
  calcium level is less than 300 mg/24 h

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osteoporosis

• Osteopenia is bone mass 1-2.5 standard deviations
  below the mean peak bone mass
• Osteoporosis is bone mass value of greater than
  2.5 standard deviations below the mean
• Causes menopause, senile osteoporosis
• Secondary hypogonadism, hyperparathyroidism,
  hyperthyroidism, hypercortisolism, malnutrition,
  malabsorption, neoplasia, bone collagen
  abnormalities
• Drugs heparin, MTX, corticosteroids, GnRH
  analogues

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Features of osteoporosis

• Bone fracture
• NORMAL calcium, phosphorus, alkaline phosphatase
• A decrease of 1 standard deviation from the mean
  peak bone density leads to double the fracture
  risk
• Diagnose with bone densitometry

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Treatment

• Estrogen replacement is the therapy of choice in
  post-menopausal women with no contraindications
  (give with progesterone if pt still has her
  uterus to prevent endometrial hyperplasia)
• Oral bisphosphonates
• Calcium and vit D supplements
• Calcitonin nasal spray

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Paget disease (osteitis deformans)

• Affects 3 of the population over 45
• Abnormal osteoclasts increase rate of bone
  resorption
• Most commonly affects the sacrum, spine, femur,
  tibia, skull, and pelvis (bone scan is sensitive
  test)
• Increased alk phos, (may be over 1000 also used
  as a marker to therapy) pain and deformity are
  used to diagnose
• Complications hydrocephalus, nerve entrapment,
  high-output cardiac failure, hypercalcemia,
  hypercalciuria

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Treatment of paget disease

• Bisphosphonates IV or oral (preffered over
  calcitonin due to tachyphylaxis over time)
• Orthopedic surgery to correct deformity or treat
  pain
• Neurosurgical intervention for nerve entrapment

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