Metabolic Diseases of Bone

Question 1

what are the 2 types of bone

Answer 1

compact/ cortical: forms the shell

cancellous/ trabecular/ spongy: forms the meshwork within

Question 2

what type of collagen is found in the organic matrix of bone? what is this component termed in bone?

Answer 2

type I collagen, makes up osteoid protein component of bone

Question 3

what is the major regulator of phosphate metabolism and where does it come from?

Answer 3

fibroblast growth factor 23 (FGF23): secreted by osteocytes

Question 4

what is the function of osteoblast-derived alkaline phosphatase?

Answer 4

hydrolyzes inhibitors of mineralization such as pyrophosphate

Question 5

what are the zones of the growth plate? (5)

Answer 5

1. zone of reserve cartilage (outermost): typical histology of hyaline cartilage
2. zone of cell proliferation: multiplying chondrocytes appearing flattened
3. zone of cell hypertrophy: chondrocyte enlargement appearing rounded
4. zone of calcification: thin layer
5. zone of bone deposition (innermost): chondrocyte death and bone deposition by osteoblasts forming trabeculae of spongy bone

Question 6

how does bone growth fail in rickets?

Answer 6

chondrocytes proliferate and hypertrophy at the growth plate, but mineralization is delayed or fails

chondrocytes do NOT undergo apoptosis as they should, and growth plate cartilage accumulates without bone formation

Question 7

what are the 2 ways in which rickets is classified?

Answer 7

classified by mineral deficiency:

1. calcipenic: low calcium due to insufficient vitamin D (dietary or malabsorption)
2. phosphopenic: low phosphate (renal phosphate wasting)

Question 8

how would the following labs be affected by calcipenic rickets?
a. calcium
b. phosphate
c. PTH

Answer 8

due to vitamin D deficiency —>

a. calcium: low
b. phosphate: low
c. PTH: HIGH

Question 9

what kind of rickets would be caused by 25-hydroxylase or 1-alpha-hydroxylase deficiency?

Answer 9

both involved in the synthesis/activation of vitamin D - deficiency would cause calcipenic rickets

labs show low calcium, low phosphate, high PTH

Question 10

what is the #1 cause of hypophosphatemic rickets?

Answer 10

Fanconi syndrome: defect of renal PCT leading to defective reabsorption

labs show LOW phosphate, normal calcium, normal PTH

Question 11

what kind of rickets do mutations in PHEX and FGF23 cause, and how do they differ in heritability?

Answer 11

X-linked PHEX (transcriptional inhibitor of FGF23) LOF mutation
and
autosomal dominant FGF23 (decreases serum phosphate) GOF mutation

both cause hypophosphatemic rickets, and BOTH disorders result in increased FGF23 levels

Question 12

what is the genetic cause of x-linked vs autosomal dominant hypophosphatemic rickets?

Answer 12

x-linked: LOF mutation in PHEX (transcriptional inhibitor of FGF23)

AD: GOF mutation in FGF23 (decreases serum phosphate)

BOTH present with increased levels of FGF23

Question 13

how does FGF23 decrease serum phosphate in the GI tract and kidneys, respectively?

Answer 13

GI: suppresses 1-alpha hydroxylase and 1,25-hydroxyvitaminD3 needed for phosphate absorption

kidney: suppresses Na+/PO4 symporter

Question 14

what is the most common cause of osteomalacia?

Answer 14

osteomalacia: in adults, decreased mineralization of newly formed osteoid at sites of bone turnover

most commonly due to vitamin D deficiency or resistance (nutritional, malabsorption, GI surgery/disease, liver disease, CKD, drugs)

Question 15

What are the clinical features of osteomalacia?

Answer 15

asymptomatic with osteopenia

Symptom onset is slow – bone pain/tenderness (worse with activity), proximal muscle wasting, waddling gait, fractures without trauma

radiological imaging shows reduced bone mineral density and pseudofractures

Question 16

how are the following labs affected in osteomalacia?
a. calcium
b. phosphate
c. calcidiol
d. PTH
e. alkaline phosphatase

Answer 16

• Low calcium and phosphate
• VERY LOW 25-hydroxyvitaminD (calcidiol)
• high PTH
• high alkaline phosphatase

Question 17

what is the pathology of osteoporosis?

Answer 17

bone resorption > bone formation

due to loss of osteoprotogerin —> increased osteoclast activity

no defect in mineralization (just an imbalance in activity)

Question 18

what kind of bone is most affected by osteoporosis?

Answer 18

trabecular/ cancellous/ spongy bone (makes up inner matrix)

fractures occur earliest at sites where trabecular bone contributes to bone strength, such as vertebral bodies

Question 19

explain why proton pump inhibitors and aromatase inhibitors, respectively, pose a risk for osteoporosis?

Answer 19

proton pump inhibitors: suppress acid production —> lowers absorption of calcium

aromatase inhibitor: decrease formation of estrogen (which promotes bone mineralization)

Question 20

what kind of drugs are alendronate and risedronate, and what are they used for?

Answer 20

bisphosphonates: target farnesyl pyrophosphate synthase (FPPS) and induce osteoclast apoptosis

used to treatment of osteoporosis

Question 21

female patients with osteoporosis should be offered therapy with which 2 drug types?

Answer 21

1. bisphosphonates: target farnesyl pyrophosphate synthase (FPPS) and induce osteoclast apoptosis
2. denosumab: mAb RANKL inhibitor, decreases osteoclast activity

Question 22

what is the clinical indication for use of denosumab?

Answer 22

denosumab: mAb RANKL inhibitor, decreases osteoclast activity

used in treatment of osteoporosis

Question 23

what kind of drug is teriparatide, and what is it used for?

Answer 23

teriParaTide: peptide hormone PTH analog, stimulates osteoblast activity

recall intermittent exposure of PTH will activate osteoblasts, while chronic exposure activates osteoclasts

used in treatment of osteoporosis

Question 24

what kind of drug is raloxifene, and what is it used for?

Answer 24

raloxifene: selective estrogen receptor activator —> increased bone mineralization

used in treatment of osteoporosis