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SFM5 > Calcium and bone pathophys > Flashcards

Calcium and bone pathophys Flashcards

1
Q

PTH ___ serum calcium by causing bone ___, kidney ___, and indirectly gut ___ via ___

A

PTH increases serum calcium

by causing
bone
- resorption (breakdown - osteoclast activation)

kidney:

  • calcium resorption
  • phosphate excretion
  • vitamin D hydroxylation (activation)

and indirectly gut
- absorption of calcium and phosphate
via activated vitamin D

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2
Q

PTH is produced by

A

chief cells of parathyroid glands

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3
Q

PTH is increased by ___ and decreased by ___

A

PTH is increased by low serum Ca++ and decreased by high serum Ca++

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4
Q

high PTH is associated with ___ serum Ca++ and ___ bone density

A

high serum Ca++

low bone density

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5
Q

calcitonin

A

decreases serum calcium
inhibits bone resorption

no clear physiologic role in humans
tumor marker for medullary thyroid cancer

synthetic calcitonin used as tx

  • fracture pain
  • hypercalcemia
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6
Q

CaSR

A

calcium sensing receptors
G protein receptors
parathyroid chief cells - PTH production and secretion
renal tubular cells - renal resorption and excretion

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7
Q

familial hypOcalciuric hypERcalcemia (FHH)

A

inactivating CaSR mutation at PTH and kidney

mild hypER-Ca from birth
very low urinary Ca
mildly elevated or nonsuppressed PTH

(note that in hyper-PTH both serum and urinary Ca are high)

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8
Q

familial hypERcalcuric hypOcalcemia

A

activating CaSR mutation at PTH and kidney

mild hypO-Ca from birth
elevated urinary Ca
mildly low PTH

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9
Q

CaSR drugs

A

cinacalcet

lowers serum Ca in nonsurgical hypER-PTH

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10
Q

vitamin D2
D3
1,25-alphahydroxy vitamin D
24,25-dihydroxy vitamin D

A

D2 - dietary - ergocalciferol
D3 - sunlight - cholecalciferol

hydroxylated @ C 25 in liver (unregulated) and then @ C 1 in kidney (tightly regulated
1,25-alphahydroxy vitamin D is active form

24,25-dihydroxy vitamin D - inactive form

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11
Q

vitamin D reglation

A

at kidney

low Ca, low PO4
high PTH
high IGF-1
low FGF-23
=> 1-alpha hydroxylation = active

high Ca, high PO4
low PTH
high FGF-23
=> 24,25 dihydroxylation - inactive form

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12
Q

FGF 23

A

bone cytokine
lowers serum PO4

lowers active vitamin D (decreases 1-alpha hydroxylation, increases 24,25 dihydroxylation)
increases urinary PO4 (excretion)

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13
Q

causes of hypER-Ca (overview)

A
  • hypER-PTH (most common)
  • malignant or granulomatous disease
  • milk-alkali syndrome
  • immobilization
  • meds

1st step in eval: order PTH

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14
Q

hypER-PTH hypER-Ca

primary hyperparathyroidism

A

sx:

  • stones - nephrocalcinosis w/ polyuria
  • bones - osteoporosis, fractures (esp spinal)
  • groans - nausea, anorexia, constipation, lethargy
  • psychiatric overtones - memory loss, confusion, coma
  • may be asymptomatic

epidemiology:

  • age >45
  • W>M 3:1

causes:

  • adenoma (most common)
  • familial parathyroid hyperplasia (multiple endocrine neoplasia/MEN 1 or 2a)
  • parathyroid carcinoma (rare)
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15
Q

secondary hyperparathyroidism

A

d/t CKD
reduced vitamin D activation in kidney –> high PTH
same sx as primary hyperPTH

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16
Q

meds associated with hypER-CA with non-suppressed PTH

A

thiazides

lithium

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17
Q

indications for surgery in hyper-PTH

A
  1. primary
  2. any of:
    - symptomatic
    - >400 mg/dl serum Ca (severe)
    - >1 mg/dl above normal in <50
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18
Q

nonsurgical hypER-PTH management

A
  • bisphosphonate for osteoporosis

- cinacalcet for hypercalcemia

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19
Q

MEN1

A

multiple endocrine neoplasia 1
menin gene

hypER-PTH (95%)
islet tumor (30-80%)
pituitary adenoma (20%)
20
Q

MEN IIa

A

RET protooncogene

medullary (C-cell) thyroid cancer (80-100%)
pheochromocytoma (40$)
hypER-PTH (25%)

21
Q

MEN IIb

A

medullary thyroid cancer (100%)
pheochromocytoma (50%)
mucosal neuromas (100%)
marfanoid phenotype (75%)

22
Q

hypER-Ca of malignancy

A

<6 mo life expectancy

sx:

  • diminished mental status
  • dehydration

causes (any of):

  • tumor PTHrP secretion e.g. squamous cell carcinoma
  • multiple bone metastases w/ bony resorption
  • excess 1 alpha hydroxylation of vitamin D

tx:

  • hydration
  • underlying disease
  • PTHrP secretion or bony resorption: bisphosphonates
  • vitamin D: vitamin D antagonists (prevent absorption of Ca at gut)
23
Q

milk alkali syndrome

A
  • excess Ca + absorbable alkali ingestion, e.g. tums

sx:

  • hypER-Ca w/ alkalosis
  • renal imapirment
  • possible nephrocalcinosis

tx:

  • stop supplement
  • hydrate
24
Q

hypercalcemia of immobilization

A
  • hypercalcuria common w/ any immobilized person
    • weight bearing –> calcium deposition in bone; immobilization –> bone resorption
  • if other predisposing factors hypERcalcemia can occur
    • adolescents (increased bone turnover)
    • thyrotoxicosis
  • Paget’s disease

tx:

  • activity where possible
  • bisphosphonate
25
Q

hypOcalcemia

A

low Ca, high PO4:

  • hypO-PTH (most common) d/t thyroid or parathyroid surgery
  • severe Mg deficiency
  • activating CaSR mutations
  • parathyroid malformation
  • resistance to PTH following bisphosphonate tx
  • kidney failure/failure of vitamin D production

low Ca, low PO4
- “hungry bone syndrome” following surgery for hyper-PTH

sx:

  • neuromuscular excitability
  • twitching
  • cramping
  • tetanus
  • paresthesias
  • seizures
  • prolonged QT interval

tx:

  • IV calcium
  • vitamin D + calcium supplements
    • divided doses in chronic hypO-PTH
  • human recombinant PTH - not available in US
26
Q

cortical vs trabecular bone

A

cortical - outer - compact - rigidity

trabecular - inner - spongy - strength and elasticity

27
Q

bone remodeling cycle and RANK

A
  • osteoclasts dig cavity
  • osteoblasts secrete matrix and calcify
  • PTH-R on osteoBLAST stimulates RANK ligand
  • vitamin D, IL-6 also stimulate RANK
  • RANK stimulates osteoclasts
    (i. e. RANK –> bone resorption, increased serum Ca)
  • osteoBLASTs make osteoprotegerin, decoy rank receptor
28
Q

osteoprotegerin

A

decoy RANK receptor
osteoblasts
bone formation
decreased serum Ca

29
Q

RANK ligand

A 
stimulates osteoclast development and activity
make by PTH-activated osteoblasts
also stimulated by vitamin D and IL-6
bone resorption
increased serum Ca
30
Q

bone formation markers

A

alkaline phosphatase
collagen type 1 pro peptides (P1NP)
osteocalcin
high when bone turnover is high - indication for anti-resorptive therapy

31
Q

bone resorption markers

A

hydroxyproline
pyridinium crosslinks
N-telopeptides
like bone formation markers, high when bone turnover is high - indication for anti-resorptive tx

32
Q

osteomalacia

A

excess unmineralized bone (osteoid)
- impaired bone mineralization

causes:

  • severe vit D deficiency
  • renal insufficiency w/ low D hydroxylation
  • chronic very low dietary calcium
  • FGF23 tumors = low PO4
  • congenital bone matrix defects (osteogenesis imperfect, hypophosphatasia)

labs:

  • elevated serum alkaline phosphatase (except hypophosphatasia)
  • low to low-normal serum Ca and PO4
  • low urine Ca
  • gold standard: bone biopsy

sx:

  • bowing of bones
  • pseudofractures

tx:

  • vit D supplementation
  • correct hypO-PO4
  • calcium supplementation
  • hypophosphatasia: enzyme replacement
  • FGF23 tumor: excision
33
Q

Paget’s disease of bone

A
  • accelerated bone turnover
  • disruption of bone architecture
  • possible gross deformity of bone

mx:

  • osteoclast activation
  • genetic

labs:

  • elevated alkaline phosphatase
  • radiology (often incidental)

sx:

  • may be asymptomatic
  • pain
  • deformity
  • fracture
  • esp spine, femur, skull, pelvis
  • OA
  • cranial nerve dysfunction
  • spinal root compression
  • facial disfigurement
  • high output cardiac failure

tx:

  • antiresorptive therapy (mostly bisphosphonates)
  • monitor alkaline phosphatase
34
Q

primary vs secondary osteoporosis

A

primary = age-related, post-menopausal

secondary = d/t endocrinopathy, vitamin D deficiency, malabsorption, toxins (e.g. alcohol), hypERcalcURia

35
Q

fracture risk factors

A 
age
hx of frx
1st degree fhx of frx
tobacco or alcohol use
low body weight (less padding)
hx of falls
inability to rise w/o arms
low Ca++ intake
vit D deficiency
malabsorption
inactivity/bed rest
early estrogen loss (athletes, anorexia, Turner's)
low T in men
low bone density
36
Q

bone density protective factors

A

optimal diet
weight bearing activity
hormonal status

vs

poor calcium intake (incl in childhood)
delayed puberty
anorexia
exercise amenorrhea
immobilization
intestinal or renal disease
37
Q

osteoporosis complications

A 
QOL
pain
height loss
kyphosis
restrictive lung disease from vertebral compression factors
depression d/t physical changes and pain
hip frx - disability, mortality
38
Q

osteoporosis dx

A
  1. clinical - low-trauma hip or spine frx

or

  1. DXA scan w/ T-score ≤ -2.5 at spine or femoral neck
39
Q

osteopenia dx

A

= progressing toward osteoporosis
treat preventatively

  1. DXA scan w/ T-score -1.0 to -2.5 at spine or femoral neck

and

2a. FRAX score >20% risk of any frx
b. or >3% risk hip frx
c. or recent hx of non-hip or spine frx

40
Q

typical 1st line tx for osteoporis

A

bisphosphonates
calcium (1000-1200 g/day) and vitamin d (>800 IU/day) supplementation

bisphosphonates contraindicated in eGFR<35

41
Q

denosumab

A

antiresorptive
mAb vs RANK

stronger than bisphosphonates
OK until stage 5 kidney disease

vertebral, nonvertebral, hip

concern for rebound fractures =
MUST take every 6 months otherwise multiple vertebral compression frx
only studied up to 10 years

42
Q

PTHrP analogues

A

teriparitide
abaloparitide

anabolic, bone formation

daily injection
18-24 months
good for sequential tx post-fall - build up bone and then switch to antiresorptive for long term
“officially” off-label for hip

OK in kidney and heart disease

nausea, leg crams, hypERcalcemia
osteosarcoma concern (rodents)
43
Q

romosozumab

A

anabolic, bone formation
mAb vs sclerostin

every 2 wk injection
studied up to 2 years
“officially” off-label for hip
OK in kidney disease

BLACK BOX
contraindication in CVA w/in last year
STRONG caution in CVA risk

44
Q

osteoporosis histology

A

reduced bone mass
small trabeculae
more sparse

45
Q

Paget’s disease histology

A

increase bone turnover

  • more osteoclasts
  • more osteoblasts

sclerosis

  • “cement lines”
  • mosaic pattern

bowing, possible gross deformity

SFM5 (14 decks)

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