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Endo by Minnie: AH Version > 189b/190b - Calcium, Parathyroid, Bone > Flashcards

189b/190b - Calcium, Parathyroid, Bone Flashcards

1
Q

What is the most common cause of outpatient hypercalcemia?

A

Hyperparathyroidism

The point of PTH is to increase calcium.

(Benign, solitary parathyroid adenoma = most common cause of primary hyperparathyroidism)

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2
Q

MOA: denosumab

What is it used for?

A

Human monoclonal antibody against RANKL

RANKL promotes differentiation/activity of osteoclasts.

Tx for:

  • Osteoporosis
  • Bone metastases
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3
Q

List 3 things that promote Ca2+ excretion in the kidney

A
  • Loop diuretics
  • Dietary protein
  • Glucocorticoids
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4
Q

Describe the pathogenesis of Ricketts/Osteomalacia

A

Vitamin D deficiency

Can’t absorb enough calcium, so calcium is taken from bone to maintain serum calcium levels

  • Chronic low vitamin D
  • -> Decreased Ca2+ absorption, reabsorption
  • -> Low Ca2+
  • -> PTH release
  • -> Bone resorption, Ca2+ absorption/reabsorption, PO4 excretion
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5
Q

How does long term glucocorticoid use affect the bone?

List 5 mechanisms

A

Decreased bone density -> osteoporosis

  • Increased PTH (increased calcium release, more reabsorption of bone)
  • Increased renal excretion of calcium
  • Decreased intestinal absorption of calcium
  • Decreased gonadal steroids (less estrogen)
  • Decreased protein synthesis in bone
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6
Q

What 3 deficiencies can lead to Ricketts/Osteomalacia?

A
  • Vitamin D (most common)
  • Ca2+
  • Phosphate
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7
Q

What is the MOA of raloxifene?

What tissues are effected?

A

Raloxifine = SERM (selective estrogen response modulator)

  • In the bone:
    • Acts like estrogen = anti-resorptive
  • In the mammary gland:
    • Acts against estrogen = decreased breast cancer risk

Prevent and treat osteoporosis, reduce risk of breast cancer

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8
Q

What is the major stimulus that causes osteoclast precursors to mature?

A

RANKL

  • Secreted by osteoblasts (negative feedback!)
  • Binds to RANK on osteoclasts and precursors
    • Causes precursor differentiation
    • Causes mature osteoclast activation
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9
Q

Describe the action of PTH on the bone if exposure is:

  • Continuous:
  • Intermittent:
A
  • Continuous: Bone resorption
    • Increases RANKL expression
    • Would get this in a tumor
  • Intermittent: Bone formation
    • ​Decreased osteoblast apoptosis
    • Increased osteoblast differntiation
    • Suppression of sclerostin
      • Sclerostin inhibits wnt signaling -> inhibits osteoblast maturation
      • Physiologic/normal release

Teriparatide = PTH analog that can be used as tx for osteoporosis

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10
Q

Which bones in the body are made up of trabecular bone?

A

Axial skeleton (vertebrae)

Hips

Ankles

**These locations have the highest turnover => greatest risk of osteoporosis**

Long bones are appendicular bones (corticol bone)

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11
Q

Which bone is most susceptible to fracture in…

  • Osteoporosis:
  • Hyperparathyroidism:
A
  • Osteoporosis: Trabecular bone (axial skeleton, hip, ankle)
    • This is the higher turnover bone in general; most likely place where osteoblasts will fail to keep up
  • Hyperparathyroidism: Cortical bone (long bones)
    • Usually lower turnover, but in respose to PTH osteoclasts will burrow/tunnel into the bone (?)
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12
Q

What is the major director of intestinal Ca2+ absorption?

A

Vitamin D (calcitriol)

1,25-(OH)2 Vitamin D

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13
Q

What cell secretes sclerostin?

What is the effect?

A

Osteocytes secrete sclerostin

  • Inhibits wnt signaling -> decreased osteoblast differentiation
    • Normally, wnt causes osteoblast differentiation

Inhibiting sclerostin -> inhibit the inhibition -→ increasing bone formation

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14
Q

How do you correct a serum calcium measurement?

A

Corrected calcium = total measured calcium + [(4-albumin) x 0.8]

Low albumin = low total serum calcium, but normal free (ionized) calcium (the biologically important part)

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15
Q

How does dietary protein intake affect calcium homeostasis?

A

Increased dietary protein = increased Ca2+ excretion in kidney

-> decreased serum Ca2+

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16
Q

What are the most common cells in bone?

A

Osteocytes

(Mature/old osteoblasts)

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17
Q

Which pharmacologic therapy for osteoporosis has a very, very long half life?

A

Bisphosphonates (-dronates)

alendronate, risedronate, ibandronate, zoledronic acid

Block the action of osteoclasts

Also used for hypercalcemia, Paget’s

18
Q

What is the effect of estrogen on the bone?

Describe the mechanism

A

Antiresorptive, mildly anabolic

  • Antiresoprtive:
    • Inhibits RANKL, IL-6 production
    • Increases osteoprotegerin production
    • Causes osteoclast apoptosis
  • Mild anabolic effect:
    • Suppresses sclerostin -> increased wnt signaling (ostoblast action)

Decrease in estrogen is why post-menopausal women are susceptible to osteoporosis.

19
Q

What is the distribution of Ca2+ in the bone?

  • Stable pool: ___%
  • Exchangable pool: ___%
A
  • Stable pool: 99%
    • ​Slow turnover; affected by hormones, cytokines, growth factors, drugs
  • Exchangable pool: 1%
    • ​Rapid change
    • Buffering, acid/base balance
20
Q

What causes famililal hypocalciuric hypercalcemia?

A

Autosomal dominant mutation in CaSR (Calcium Sensing Receptor)

  • High serum calcium
  • Kidney, parathyroid cannot sense high calcium
    • Resorbs Ca2+
    • Continues to secrete PTH

Usually asymptomatic

21
Q

Describe the clinical features of hypercalcemia

A

“Stones, bones, grones, psychogenic overtones”

  • Kidney stones, nephrocalcinosis
  • Arthralgia, myalgia, weakness
  • Abdominal pain, constipation
  • Neurologic impairment
  • Polyuria
    • Shortened QT

Dose dependent

22
Q

What is the MOA of cinacalcet?

What is it used for? (2)

A

Allosterically activates the calcium sensing receptor in the parathyroid gland and kidney

  • -> percieved sufficient calcium
    • -> Decreased PTH secretion

Tx for primary hyperparathyroidism, parathyroid carcinoma

23
Q

What factors promote osteoblast differentiation and activity? (3)

A
  • Wnt signaling
  • IGF-1
  • Bone morphogenic proteins
24
Q

What is the treatment for Paget’s disease?

A

Goal - normalize osteoblast/osteoclast activity

  • Bisphosphonates
  • Calcitonin
  • NSAIDs/physical therapy for pain
25
Q

Describe the disribution of serum calcium

  • Ionized:
  • Complexed with anions:
  • Protein bound
A
  • Ionized: 50% (mediates the biological response)
  • Complexed with anions: 10%
  • Protein bound: 40%
26
Q

What products are markers of osteoblastic activity? (3)

A
  • Osteocalcin
  • Alkaline phosphatase
  • Collagen peptides
27
Q

Which bone disorder is characterized by hyperdynamic bone remodeling?

Which parts of the body are affected?

A

Paget’s disease - uncoordinated osteoblast and osteoclast activity

Usually affects one bony area (not the whole skeleton)

28
Q

Clinical features of Ricketts/Osteomalacia (4)

A
  • Bowing of legs
  • Bone pain
  • Bone fragility
  • Muscle pain/weakness

Bone can’t form properly

29
Q

What is the treatment for primary hyperparathyroidism?

A
  • Asymptomatic: observe
  • Symptomatic
    • Surgery = first line, usually only in one gland
      • MEN more likely to have multiple glands involved
    • Calcimimetics (cinacalcet) = if pt cannot/does not want to have surgery
      • Activates CaSR -> percieved increase in Ca2+ -> decreaesd PTH secretion
30
Q

What two signals normally provide negative feedback to the parathyroid gland?

A

Calcium

Calcitriol (Vitamin D)

31
Q

Describe the signaling pathway activated by the parathyroid hormone receptor?

A

GPCR

Gs -> cAMP -> PKA/PKC

Functions to increase serum Ca2+

32
Q

List the symptoms of true hypocalcemia (8)

A

Increased nueromuscular excitability

  • Twitching (Chvostek’s sign)
  • Paresthesias
  • Muscle spasm (Trousseaus’s sign)
  • Laryngospasm
  • Bronchospasm
  • Prolonged QT
  • Seizure
  • Tetany
33
Q

Name a pharmacologic PTHrP analog

What is it used for?

A

Abaloparatide

Newly approved for osteoporosis - stimulates bone formation

Super cool b/c most osteoporosis therapies only work to suppress osteoclast activity

34
Q

What are the actions of FGF-23 (2)

A

Inhibits phosphate reabsorption from the kidney

Inhibits renal calcitriol synthesis (so not as much calcium can be absorbed from the intestine)

Works to decrease phosphate and calcium levels

35
Q

Which diuretic may lead to hypercalcemia?

A

Thiazides

LOop diuretics cause HYPOcalcemia

36
Q

What is the effect of PTHrP on bone?

A

Anabolic = bone formation

Abaloparatide = PTHrP analog, approved for osteoporosis

PTHrP is also secreted by solid tumors: renal carcinoma, squamous cell lung

37
Q

List 3 medications that can treat hypercalcemia

A
  • Loop diuretics (plus hydration - hydrate first)
  • IV bisphosphonates (slow action, long acting)
  • Calcitonin (inhibits osteoclast-mediated bone resorption)
38
Q

Which hormones cause phosphate excretion in the kidney? (2)

A

PTH

FGF-23

39
Q

Which vitamin D should we measure to measure to evaluate deficiency?

A

25-(OH)-vitamin D - the storage form

  • This will be sacrificed to maintain 1,25-(OH)2-vitamin D (calcitriol-the active form)
    • => Deficiency may exist even if active form is normal
40
Q

Which osteoblast product is a RANK-L decoy?

What is the effect?

A

Osteoprotegerin

Prevents RANKL-RANK interaction -> inhibits osteoclast acitvation and differentiation

If the body needs to build more bone, osteoblasts secrete osteoprotegerin > RANKL

Endo by Minnie: AH Version (19 decks)

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