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 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 (?)

189b/190b - Calcium, Parathyroid, Bone Flashcards by David Fei-Zhang

What is the most common cause of outpatint hypercalcemia?

Hyperparathyroidism

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

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MOA: denosumab

What is it used for?

Human monoclonal antibody against RANKL

Tx for:

Osteoporosis
Bone metastases

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List 3 things that promote Ca2+ excretion in the kidney

Loop diuretics
Dietary protein
Glucocorticoids

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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

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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

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What 3 deficiencies can lead to Ricketts/Osteomalacia?

Vitamin D (most common)
Ca2+
Phosphate

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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

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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

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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

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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)

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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 (?)

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What is the major director of intestinal Ca2+ absorption?

Vitamin D (calcitriol)

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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

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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

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How does dietary protein intake affect calcium homeostasis?

Increased dietary protein = increased Ca2+ excretion

-> decreased serum Ca2+

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What are the most common cells in bone?

Osteocytes

(Mature osteoblasts)

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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*