Metabolic Bone Disease - Blank

Question 1

Describe the origin and function of osteoblasts, osteoclasts, and osteocytes.

Answer 1

Osteoblasts function to build ECM (bony marix)

Osteocytes arise from osteoblasts and acts as mechanoreceptors

Osteoclasts arise from monocyte lineages and resorb bone.

Question 2

Between cortical and trabecular bone…

1. Which is more abundant (by mass)?
2. Which has higher remodeling?
3. Which are arranged into haversian canals?
4. Which is more vascular?

Answer 2

1. Cortical (80%)
2. Trabecular
3. Cortical
4. Trabecular

Question 3

How abundant is bone remodeling?

Contrast the rates of building and breakdown

Answer 3

About 10% of bone mass is remodeling at any given time.

Building is much slower (4-6mo) than resorption (2wks). Observe haversian remodeling, with a small head of osteoclasts and long trailing tail of osteoblasts.

Question 4

Describe the structure of bone at the molecular level.

What provides compressive and tensile strength?

Answer 4

Osteoid contains type I collagen (cross-linked with pyrodinoline) to provide tensile strength, and impregnated with mineral matrix (mostly hydroxyapatite, high in calcium and phosphate, but also peppered with other ions) to provide compressive strength.

Question 5

What factors contribute to bone strength?

What is the effect of bone loading? How is this process affected in older patient populations?

Answer 5

Collagen traits and mineralization, as well as size, lamellation, as well as the moment and orientation of mechanical force.

Loading causes increase in bony mass, but this is less pronounced in older patients (lost sensitivity?)

Question 6

Challenge card!

What do osteoclasts produce at the ruffled border to promote bone resorption?

How much mineral is yielded from bone resorption on a daily basis? (relative terms)

Name two stimuli of osteoclasts.

Answer 6

Osteoclasts produce HCl to promote resorption (note that mineralization needs a basic environment)

About twice as much as through GI uptake.

PTH and Calcitriol.

Question 7

What defines osteoporosis?

What is this a risk factor for??

Answer 7

A DXA T-score of < -2.5 in a post-menopausal woman or >50yo man.

Low trauma fractures (aka osteoporotic fractures!)

Question 8

Besides bone mineral density, what other factors can predict one’s risk of fracture?

What role do risk calculators play? Can you name two?

Answer 8

Age, sex, prior fractures. Steroid use.

FRAX and Garvan, consider other factors including prior fractures, falls, GC use, RA, and lifestyle factors to give a more accurate risk calculation than BMD alone.

Question 9

What is the cause underlying osteomalacia?

What are some histological signs of this disease?

Answer 9

Defect of mineralization (eg Dietary).

Smudged tetracycline dynamic histomorphometry, abundant osteoid.

Question 10

Name 3 lab values that will be elvated in osteomalacia.

Answer 10

PTH (secondary to mineral deficiency)

Alkaline Phosphatase

P1NP (n-telopeptide from type I collagen)

Question 11

Osteomalacia and many other osteopenic disorders can be treated with diet. What should be supplemented?

Answer 11

Calcium and vitamin D (Ideally get ~1000/600mg per day)

Phosphate or digestive enzymes may be indicated.

Question 12

What role does estrogen play in treating osteoporosis?

Answer 12

In theory, it could reverse many of the effects of menopause on bone density. However, due to findings from the women’s health initiative (increased neoplasms), it is only indicated in severe and refractory cases.

Question 13

What are the indications for SERMs?

Can you name two?

Answer 13

For increasing bone mineral density (or offsetting loss).

Tamoxifen in particular is also used in treating breast cancer.

Raloxifene is used for treating bone fractures.

Question 14

Describe the mechanism of action of bisphosphonates.

Can you name 4 (and their formulations?)

Answer 14

Binds mineral matrix to induce osteoclast apoptosis via blockage of farnesyl synthesis.

Alendronate and Risedronate (oral), pamidronate & zolendronic acid (more potent; IV?)

Question 15

How are bisphosphonates cleared?

Try to name 3 side effects associated with them.

Answer 15

Renal clearance.

Oral bisphosphonates can cause esophagitis. IV bisphosphonates can cause an acute phase reaction and hypocalcemia.

Any bisphosphonate can have the bizarre side effects of jaw osteonecrosis and femoral fractures.

Question 16

Describe the mechanism of action of Denosumab

What are some side effects associated with this drug?

Answer 16

Acts as a decoy receptor for RANKL, preventing binding of RANKL to its endogenous receptor on osteoclasts. Interruption of RANK-RANKL interaction prevents osteoclast differentiation and survival

Side effects include:

• ONJ (osteonecrosis of the jaw)
• Atypical femoral fractures
• increased susceptibility to skin infections
• nause, weakness, fatigue

Question 17

Is calcitonin effective as an anti-osteoporotic drug? Why?

When is it used?

Answer 17

No. It is not considered effective in metabolic bone disease and tachyphylaxis limits its use.

Usually used as a drug-of-last-resort in patients for whom other (better) drugs are not an option

Question 18

What is Teriparatide?

How is it administered?

What are its major side effects?

Answer 18

synthetically-produced PTH frament (AAs 1-34) used to increase bone mass

Generally given episodically (daily injection) to stimulate bone mass increased (remember: continuous infustion of PTH leads to bone resorption, whereas pulsed PTH leads to bone mass increase)

Side effects: transient hypercalcemia and hypercalciuria

Question 19

Approximately what percentage of dietary calcium is actually absorbed (assuming vitamin D levels are normal)?

Answer 19

20%

Question 20

What causes Vitamin D Resistant Rickets?

Answer 20

Mutations in:

• 1-hyroxylase (encoded by CYP27B1)
• vitamin D receptor (encoded by VDR)
• hormone response element binding protein

Question 21

What is the key regulator of phosphate homeostasis, acting as a phosphaturic hormone?

Answer 21

FGF23 (fibroblast growth factor 23)

Question 22

Explain the key actions of FGF23 that contribute to its regulation of phosphate homeostasis

Answer 22

• Inhibits 1-hydroxylase expression -> reduces vitamin D activation
• Increases activity of 24-hydroxylase -> increases vitamin D clearnace

Lowering phosphate ultimately reduces PTH secretion

FGF23 may also block terminal osteocyte differentiation

Question 23

What is tumor-induced osteomalacia?

What symptoms are seen?

Answer 23

(usually) benign tumor of mesenchymal origin that secretes very large amounts of FGF23, leading to decreased serum phosphate

Patients are osteomalacic (detectable bone loss and low-trauma fractures)

Question 24

Give the genetic defect behind each of the following:

• Autosomal dominant hypophosphatemic rickets (ADHR)
• X-linked hypophosphatemic rickets (XLH)
• Autosomal recessive hypophosphatemic rickets (ARHR)

Compare the pathogenesis of each

Answer 24

• ADHR: point mutations in FGF23 that prevent normal proteolytic degradation of FGF23
• XLH: mutations in PHEX
• ARHR: mutations in DMP1

All mutations play a role in regulating the degradation of FGF23 -> the net result is increased FGF23 levels, decreased phosphate, and impaired bone mineralization

Question 25

What is rickets?

Give some clinical manifestations

What is a Looser zone?

Answer 25

Abnormal bone modeling due to osteomalacia before closure of the epiphysis (osteomalacia for children).

Symptoms/presentation:

• Bowing of the bones (tibia varus) due to chronic high strain on the bones
• Looser zone (bands of translucency in the bone, often at right angles to the cortex) -> often seen as a pseudofracture of the femur

Question 26

Name several clinical presentations common to osteomalacia

Answer 26

• Bone pain and tenderness on palpation of the long bones (tibia, femur, etc)
• Low trauma fractures
• Poor fracture healing
• Low urinary Ca2+ (hypocalcemic osteomalacia)
• High urinary phosphate (hypophophatemic osteomalacia)

Question 27

Paget’s Disease of Bone:

Broadly, what is it?

How is it diagnosed?

What is more common: mono-ostotic or polyostotic lesions?

Answer 27

Foci of exuberant, unregulated bone turnover, leading to impaired biomechanical performance, increased bone vascularity, and deformity

Diagnosis: symptoms, characteristic radiographic findings, elevated bone alkaline phosphatase, positive bone scane

polyostotic (several sites of involvement)

Question 28

What clinical presentations might be found with Paget’s Disease lesions in the skull?

Weight-bearing bones?

Answer 28

Skull: headache, increased hat size, deafness (CN8 impingement)

Weight-bearing bones: stress fractures or complete fractures

Question 29

True or false: patients suffering from Paget’s Disease have an increased risk of osteosarcoma?

Answer 29

True. Approximately 1% of patients will have Pagetic lesions undergo malignant transformation. This rate of osteosarcoma is much higher than the general population.