Calcium and bone pathophys Flashcards
PTH ___ serum calcium by causing bone ___, kidney ___, and indirectly gut ___ via ___
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
PTH is produced by
chief cells of parathyroid glands
PTH is increased by ___ and decreased by ___
PTH is increased by low serum Ca++ and decreased by high serum Ca++
high PTH is associated with ___ serum Ca++ and ___ bone density
high serum Ca++
low bone density
calcitonin
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
CaSR
calcium sensing receptors
G protein receptors
parathyroid chief cells - PTH production and secretion
renal tubular cells - renal resorption and excretion
familial hypOcalciuric hypERcalcemia (FHH)
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)
familial hypERcalcuric hypOcalcemia
activating CaSR mutation at PTH and kidney
mild hypO-Ca from birth
elevated urinary Ca
mildly low PTH
CaSR drugs
cinacalcet
lowers serum Ca in nonsurgical hypER-PTH
vitamin D2
D3
1,25-alphahydroxy vitamin D
24,25-dihydroxy vitamin D
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
vitamin D reglation
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
FGF 23
bone cytokine
lowers serum PO4
lowers active vitamin D (decreases 1-alpha hydroxylation, increases 24,25 dihydroxylation)
increases urinary PO4 (excretion)
causes of hypER-Ca (overview)
- hypER-PTH (most common)
- malignant or granulomatous disease
- milk-alkali syndrome
- immobilization
- meds
1st step in eval: order PTH
hypER-PTH hypER-Ca
primary hyperparathyroidism
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)
secondary hyperparathyroidism
d/t CKD
reduced vitamin D activation in kidney –> high PTH
same sx as primary hyperPTH
meds associated with hypER-CA with non-suppressed PTH
thiazides
lithium
indications for surgery in hyper-PTH
- primary
- any of:
- symptomatic
- >400 mg/dl serum Ca (severe)
- >1 mg/dl above normal in <50
nonsurgical hypER-PTH management
- bisphosphonate for osteoporosis
- cinacalcet for hypercalcemia
MEN1
multiple endocrine neoplasia 1
menin gene
hypER-PTH (95%) islet tumor (30-80%) pituitary adenoma (20%)
MEN IIa
RET protooncogene
medullary (C-cell) thyroid cancer (80-100%)
pheochromocytoma (40$)
hypER-PTH (25%)
MEN IIb
medullary thyroid cancer (100%)
pheochromocytoma (50%)
mucosal neuromas (100%)
marfanoid phenotype (75%)
hypER-Ca of malignancy
<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)
milk alkali syndrome
- excess Ca + absorbable alkali ingestion, e.g. tums
sx:
- hypER-Ca w/ alkalosis
- renal imapirment
- possible nephrocalcinosis
tx:
- stop supplement
- hydrate
hypercalcemia of immobilization
- 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
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
cortical vs trabecular bone
cortical - outer - compact - rigidity
trabecular - inner - spongy - strength and elasticity
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
osteoprotegerin
decoy RANK receptor
osteoblasts
bone formation
decreased serum Ca
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
bone formation markers
alkaline phosphatase
collagen type 1 pro peptides (P1NP)
osteocalcin
high when bone turnover is high - indication for anti-resorptive therapy
bone resorption markers
hydroxyproline
pyridinium crosslinks
N-telopeptides
like bone formation markers, high when bone turnover is high - indication for anti-resorptive tx
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
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
primary vs secondary osteoporosis
primary = age-related, post-menopausal
secondary = d/t endocrinopathy, vitamin D deficiency, malabsorption, toxins (e.g. alcohol), hypERcalcURia
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
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
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
osteoporosis dx
- clinical - low-trauma hip or spine frx
or
- DXA scan w/ T-score ≤ -2.5 at spine or femoral neck
osteopenia dx
= progressing toward osteoporosis
treat preventatively
- 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
typical 1st line tx for osteoporis
bisphosphonates
calcium (1000-1200 g/day) and vitamin d (>800 IU/day) supplementation
bisphosphonates contraindicated in eGFR<35
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
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)
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
osteoporosis histology
reduced bone mass
small trabeculae
more sparse
Paget’s disease histology
increase bone turnover
- more osteoclasts
- more osteoblasts
sclerosis
- “cement lines”
- mosaic pattern
bowing, possible gross deformity
