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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
hypOcalcemia
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
cortical vs trabecular bone
cortical - outer - compact - rigidity trabecular - inner - spongy - strength and elasticity
27
bone remodeling cycle and RANK
- 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
osteoprotegerin
decoy RANK receptor osteoblasts bone formation decreased serum Ca
29
RANK ligand
``` stimulates osteoclast development and activity make by PTH-activated osteoblasts also stimulated by vitamin D and IL-6 bone resorption increased serum Ca ```
30
bone formation markers
alkaline phosphatase collagen type 1 pro peptides (P1NP) osteocalcin high when bone turnover is high - indication for anti-resorptive therapy
31
bone resorption markers
hydroxyproline pyridinium crosslinks N-telopeptides like bone formation markers, high when bone turnover is high - indication for anti-resorptive tx
32
osteomalacia
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
Paget's disease of bone
- 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
primary vs secondary osteoporosis
primary = age-related, post-menopausal secondary = d/t endocrinopathy, vitamin D deficiency, malabsorption, toxins (e.g. alcohol), hypERcalcURia
35
fracture risk factors
``` 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
bone density protective factors
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
osteoporosis complications
``` QOL pain height loss kyphosis restrictive lung disease from vertebral compression factors depression d/t physical changes and pain hip frx - disability, mortality ```
38
osteoporosis dx
1. clinical - low-trauma hip or spine frx or 2. DXA scan w/ T-score ≤ -2.5 at spine or femoral neck
39
osteopenia dx
= 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
typical 1st line tx for osteoporis
bisphosphonates calcium (1000-1200 g/day) and vitamin d (>800 IU/day) supplementation bisphosphonates contraindicated in eGFR<35
41
denosumab
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
PTHrP analogues
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
romosozumab
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
osteoporosis histology
reduced bone mass small trabeculae more sparse
45
Paget's disease histology
increase bone turnover - more osteoclasts - more osteoblasts sclerosis - "cement lines" - mosaic pattern bowing, possible gross deformity

SFM5 (14 decks)

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