189b/190b - Calcium, Parathyroid, Bone Flashcards
What is the most common cause of outpatint hypercalcemia?
Hyperparathyroidism
(Benign, solitary parathyroid adenoma = most common cause of primary hyperparathyroidism)
MOA: denosumab
What is it used for?
Human monoclonal antibody against RANKL
Tx for:
- Osteoporosis
- Bone metastases
List 3 things that promote Ca2+ excretion in the kidney
- Loop diuretics
- Dietary protein
- Glucocorticoids
Describe the apthogenesis fo Ricketts/Osteomalacia
Serum Ca2+ is preserved at the expense of bone
- Chronic low vitamin D
- -> Decreased Ca2+ absorption, reabsorption
- -> Low Ca2+
- -> PTH release
- -> Bone resorption, Ca2+ absorption/reabsorption, PO4 excretion
How does long term glucocorticoid use affect the bone?
List 5 mechanisms
Decreaed bone density -> osteoporosis
- Increased PTH (increased resorption)
- Increased renal excretion of calcium
- Decreased intestinal absorption of calcium
- Decreased gonadal steroids (less estrogen)
- Decreased protein synthesis in bone
What 3 deficiencies can lead to Ricketts/Osteomalacia?
- Vitamin D (most common)
- Ca2+
- Phosphate
What is the MOA of raloxifene?
What tissues are effected?
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 ostteoprorsis, reduce risk of bresat cancer
What is the major stimulus that causes osteoclast precursors to mature?
RANKL
- Secreted by osteoblasts (negative feedback!)
- Binds to RANK on osteoclasts and precursors
- Causes precursor differentiation
- Causes mature osteoclast activation
Describe the action of PTH on the bone if exposure is:
- Continuous:
- Intermittent:
- Continuous: Bone resorption
- Increases RANKL expression
- Intermittent: Bone formation
- Decreased osteoblast apoptosis
- Increased osteoblast differntiation
- Suppression of sclerostin
- Sclerostin inhibits wnt signaling -> inhibits ostoblast maturation
Teriparatide = PTH analog that can be used as tx for osteoporosis
Which bones in the body are made up of trabecular bone?
Axial skeleton
Hips
Ankles
**These locations have the highest turnover => greatest risk of osteoporosis**
Long bones are appendicular bones (corticol bone)
Which bone is most susceptible to fracture in…
- Osteoporosis:
- Hyperparathyroidism:
- 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 (?)
What is the major director of intestinal Ca2+ absorption?
Vitamin D (calcitriol)
What cell secretes sclerostin?
What is the effect?
Osteocytes secrete sclerostin
- Inhibits wnt signaling -> decreased osteoblast differentiation
- Normally, wnt causes osteoblast differentiation
Inhibiting sclerostin -> increasing bone formation
How do you correct a serum calcium measurement?
Corrected calcium = total measured calcium + [(4-albumin) x 0.8]
Low albumin = low total serum calcium, but normal free (ionized) calcium
How does dietary protein intake affect calcium homeostasis?
Increased dietary protein = increased Ca2+ excretion
-> decreased serum Ca2+
What are the most common cells in bone?
Osteocytes
(Mature osteoblasts)
Which pharmacologic therapy for osteoporosis has a very, very long half life?
Bisphosphonates (-dronates)
Also used for hypercalcemia, Paget’s
What is the effect of estorgen on the bone?
Describe the mechanism
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)
What is the distribution of Ca2+ in the bone?
- Stable pool: ___%
- Exchangable pool: ___%
- Stable pool: 99%
- Slow turnover; affected by hormones, cytokines, growth factors, drugs
- Exchangable pool: 1%
- Rapid change
- Buffering, acid/base balance
What is the cause of hereditary vitamin D resistant ricketts…
- Type 1?
- Type 2?
- Type 1: 1-alpha-hydroxylase deficiency
- Cannot activate vitamin D
- Treat with calcitriol (activated form)
- Type 2: Mutation in the vitamin D receptor
- Vitamin D can’t do its job :(
What causes famililal hypoclcuric hypercalcemia?
Autosomal dominant mutation in CaSR
- High serum calcium
- Kidney, parathyroid cannot senst high calcium
- Resorbs Ca2+
- Continues to secrete PTH
Usually asymptomatic
Describe the clinical features of hypercalcemia
“Stones, bones, grones, psychogenic overtones”
- Kidney stones, nephrocalcinosis
- Arthralgia, myalgia, weakness
- Abdominal pain, constipation
- Neurologic impairment
- Polyuria
- Shortened QT
Dose dependent
What is the MOA of cinacalcet?
What is it used for? (2)
Allosterically activates the calcium sensing receptor in the parathyroid gland and kidney
- -> percieved sufficient calcium
- -> Decreased PTH secretion
Tx for primary hyperparathyroidism, parathyroid carcinoma
What factors promote osteoblast differentiation and activity? (3)
- Wnt signaling
- IGF-1
- Bone morphogenic proteins
What is the treatment for Paget’s disease?
Goal - normalize osteoblast/osteoclast activity
- Bisphosphonates
- Calcitonin
- NSAIDs/physical therapy for pain
Describe the disribution of serum calcium
- Ionized:
- Complexed with anions:
- Protein bound
- Ionized: 50%
- Complexed with anions: 10%
- Protein bound: 40%
What products are markers of osteoblastic activity? (3)
- Osteocalcin
- Alkaline phosphatase
- Collagen peptides
Which bone disorder is characterized by hyperdynamic bone remodeling?
Which parts of the body are affected?
Paget’s disease - uncordinated osteoblast and osteoclast activity
Usually affects one bony area (not the whole skeleton)
Clinical features of Ricketts/Osteomalacia (4)
- Bowing of legs
- Bone pain
- Bone fragility
- Muscle pain/weakness
What is the treamtnet for primary hyperparathyroidism?
- Asymptomatic: observe
- Symptomatic
- Surgery = first line
- Calcimimetics (cinacalcet) = if pt cannot/does not want to have surgery
- Activates CaSR -> percieved increase in Ca2+ -> decreaesd PTH secretion
What two signals normally provide negative feedback to the parathyroid gland?
Calcium
Calcitriol
Describe the signaling pathway activated by the parathyroid hormone receptor?
GPCR
Gs -> cAMP -> PKA/PKC
Functions to increase serum Ca2+
List the symptoms of true hypocalcemia (8)
- Twitching (Chvostek’s sign)
- Paresthesias
- Muscle spasm (Trousseaus’s sign)
- Laryngospasm
- Bronchospasm
- Prolonged QT
- Seizure
- Tetany
Name a pharmacologic PTHrP analog
What is it used for?
Abaloparatide
Newly approved for ostoporosis - stimulates bone formation
Super cool b/c most osteoporosis therapies only work to suppress osteoclast activity
What are the actions of FGF-23 (2)
Inhibits phosphate reabsorption from the kidney
Inhibits renal calcitriol synthesis
Works to decrease phosphate and calcium levels
Which diuretic may lead to hypercalcemia?
Thiazides
What is the effect of PTHrP on bone?
Anabolic = bone formation
Abaloparatide = PTHrP analog, approved for osteoporosis
PTHrP is also secreted by solid tumors: renal carcinoma, squamous cell lung
List 4 medications that can treat hypercalcemia
- Loop diuretics (plus hydration - hydrate first)
- IV bisphosphonates (slow action, long acting)
- Calcitonin (inhibits osteoclast-mediated bone resorption)
Which hormones cause phosphate excretion in the kidney? (2)
PTH
FGF-23
Which vitamin D should we measure to measure to evaluate deficiency?
25-(OH)-vitamin D - the storage form
- This will be sacrificed to maintain 1,25-(OH)2-vitamin D (the active form)
- => Deficiency may exist even if active form is normal
Which ostoblast product is a RANK-L decoy?
What is the effect?
Osteoprotegerin
Prevents RANKL-RANK interaction -> inhibits osteoclast acitvation and differentiation
If the body needs to build more bone, osteoblasts secrete osteoprotegerin > RANKL
