Endo - Calcium Metab/bone Disease

Front 1

What are calcium's roles in the body?

Back 1

- Intracellular second messanger - regulating cell division
- Muscle contractility
- Cell motility
- Coagulation
- Enzymatic activity
- Secretion of hormones

Front 2

What is the total adult body content of Calcium?
- how much of this is in bone?
- where is the rest?

Back 2

1000 g
>99% in bone
<1% in soluble form in extracellular and intracellular fluid compartments

Front 3

In extracellular fluid, in what forms does calcium circulate?
What form is metabolically active?

Back 3

- IONIZED Ca - 50%
- Bound to ALBUMIN - 40%
- Complexed with anions (citrate, phosphate) - 10%

***Ionized Ca is metabolically active

Front 4

How do you correct the serum Ca concentration according to serum albumin?
- why is this important?

Back 4

For every 1 gm/dL rise/fall in serum albumin >4 g/dL or <4 g/dL, subtract/add 0.8 to the total calcium.

**Must always look at serum albumin when assessing for Ca concentration bc 40% Ca bound.

Front 5

What factor might affect Ca binding to albumin?

Back 5

Extreme variations in pH

Front 6

What are the 3 organs that must always be considered when assessing Ca??

What 2 hormones??

Back 6

Kidney, Bone, GI tract

PTH, 1,25-dihydroxyvitamin D (vit D)

Front 7

Which hormone is usually associated with HYPERcalcium? HYPOcalcium?

Back 7

- hyper = PTH (99%)
- hypo = vitamin D

Front 8

What is PTH's relationship with Ca secretion?
- what monitors this relationship?
- what other factor is necessary to keep this relationship in check?

Back 8

- PTH inversely related to serum Ca
- Calcium-sensing receptors on parathyroid glands (CaSR) control PTH secretion within minutes of fluctuations in Ca
- Normal serum Mg is necessary!!!

Front 9

How does PTH lead to increased serum Ca?

Back 9

Effects on Bone
- stimulates bone remodeling - activation of osteoclasts releases Ca into circ

Effects on Kidney
- increased reabsorption of Ca in distal tubules
- decreased reabsorption of PO4-
- conversion of 25-hydroxy vitamon D to ACTIVE 1,25-hydroxyvitamin D (via renal cortical enz: 1-alpha-hydroxylase) --> increased intestinal absorption of Ca

Effect on Intestines
- By increasing availability of active vitamin D, increases Ca and PO4- absorption from duodenum and small intestine

Front 10

What is the main difference between the effects of PTH and Vitamin D?

Back 10

PTH: increased Ca, decreased PO4-
Vit D: increased Ca, increased PO4-

Front 11

What is inactive vitamin D?
What enzyme converts it to active vit D and where is it located?
What is active Vitamin D?

Back 11

Inactive = 25 hydroxyvitaminD
Enz: 1-alpha-hydroxyase (in renal cortex)
Active = 1,25 dihydroxyvitaminD

Front 12

What stimulates the release of PTH?

Back 12

- low serum Ca
- high serum PO4-

Front 13

What stimulates the release of Vitamin D?

Back 13

- low serum Ca
- low serum PO4-
- high serum PTH

Front 14

How does Vitamin D enter the circulation?

Back 14

- oral ingestion
- conversion of 7-dehydrocholesterol in skin by UV light to vitamin D

Front 15

What is the metabolism of vitamin D once it's in the circulation?

Back 15

Liver: Vitamin D to 25-hydroxyvitaminD (25-hydroxylase)

Kidney (renal cortex): 25-hydroxyvitaminD to 1,25-dihydroxyvitaminD (1-alpha-hydroxylase) !!!ACTIVE!!!

Front 16

What are the roles of vitamin D?

Back 16

**Vitamin D increases intestinal absorption of Ca
- increases intestinal absorption of PO4-
- causes decrease in PTH synthesis
- increases bone resorption and formation

Front 17

What is the lab value for HYPERCALCEMIA?
- at what value are there clinical features?
- at what value are there definite sx?

Back 17

= > 10.4 mg/dL
clinical = 12
DEF sx = 14

Front 18

What are the sx of hypercalcemia?

Back 18

Neuro-muscular
- proximal muscle weakness
- hypotonia
- depressed DTRs

Neuro (CNS depression)
- lethargy
- confusion/forgetfulness
- blurred vision
- coma

Cardiac
- shortening of QT interval
- bradycardia
- arrhythmias

Renal
***Causes nephrogenic DI
- polyuria and polydipsia
- kidney stones
- hyperchloremic acidosis
- hephrocalcinosis
- reversible renal failure

GI - secondary to dehydration...
- dry mouth, thirst
- anorexia
- nausea/vomiting
- constipation

Front 19

What are the physical findings in hypercalcemia

Back 19

- often none...
- depressed mental status
- decreased/absent DTRs
- neck messes (rarely - if parathyroid adenoma)
- muscle weakness - esp quads
- evidence of other assoc'd diseases

Front 20

What are the 3 main mechanisms behind hypercalcemia?
- which is the most common?
- what is the main exception?

Back 20

1. increased resorption of bone (exceeding formation)
2. increased Ca absorption from gut
3. increased Ca reabsorption in kidneys

*Most common = accelerated bone resorption
- except: Milk-Alkali Syndrome

Front 21

Milk Alkali Syndrome
- what is?

Back 21

***Always underlying renal disease!!

TRIAD:
- hypercalcemia
- systemic alkalosis
- renal insufficiency

(causes 16% hospital admissions for hypercalcemia)

Front 22

When elevating a patient with hypercalcemia, what do you look at first?

Back 22

Look at PTH value
- elevated?
- depressed?

Front 23

What are causes of hypercalcemia with elevated PTH?
- most common?

Back 23

***Primary Hyperparathyroidism (most common)
- Familial Hypocalciuric Hypercalcemia (FHH)
- MEN I
- MEN IIA

Front 24

What are causes of hypercalcemia with depressed PTH?

Back 24

- Malignancy (mostly inpatients)
... humoral hypercalcemia of malignancy; local osteolytic hypercalcemia; lymphoproliferative disorders

Uncommon:
- vitamin D intoxication
- vitamin A intoxication
- milk-alkali syndrome
- granulomatous disorders (#1- sarcoidosis)
- immobilization
- Non-parathyroid Endocrinopathies
... hyperthyroidism; pheochromocytoma; acromegaly; adrenal insufficiency

Front 25

What are the 2 most frequent causes of hypercalcemia?
- what % of hypercalcemia do they cause?

Back 25

Primary hyperparathyroidism
+
Malignancy-related hypercalcemia

= 90% of all cases

Front 26

Granulomatous Disorders leading to hypercalcemia...
- what is the most common?
- what is the pathology?

Back 26

#1 = sarcoidosis

Path: macrophages in granulomas synth/secrete 1-alpha-hydroxylase, so increase active vitamin D levels

Front 27

Familial Hypocaliuric Hypercalcemia (FHH)
- cause?
- path?
- lab values?
- tx?

Back 27

= autosomal dominant
- rare
- calcium sensing receptors (CaSR) in parathyroid and kidney have mutation causing decreased sensation to Ca
--> increased renal absorption
--> decreased renal excretion

LABS:
- increased serum Ca
- increased PTH
- decreased urinary Ca!!!

Tx: NO surgery

Front 28

Primary Hyperparathyroidism (HPT)
- sx?
- what type of tumors do pts have?
- tx? success rate?

Back 28

= single-most common cause of hypercalcemia in outpatients!
- 70-80% pts asymptomatic - found incidentally on routine chem screenings

- 80% have single parathyroid adenoma
- 15% have 4-gland hyperlasia
- 0.5% have parathyroid carcinoma

tx: ONLY surgery -- 95% success rate

Front 29

What are the indications for surgery in hyperparathyroidism?

Back 29

- serum Ca > 1mg/dL above upper limit of normal
- signs or sx
- urine Ca > 400 mg/24 hrs
- creatinine clearance reduced below 30%
- decreased bone mineral density (T score > 2.5 SD below mean)
- age < 50 (this pop gets max benefit from surgery)
- onset of menopause

Front 30

Malignancy Associated Hypercalcemia
- physiologic mechanisms

Back 30

- Direct bony metastases - myeloma and breast cancer
- Increased PTHrP
- Cytokine productive associated with osteoclast activation - e.g., lymphotoxin, transforming-growth factors, interleukins, TNF
- Increased Vit D production (lymphomas)
- RARE ectopic PTH production

Front 31

What is PTHrP?
- function?
- associated with?
- how does it work??

Back 31

= Parathyroid Hormone-Related Polypeptide
- causes HHM (humoral hypercalcemia of malignancy)
- assoc'd with SCC, renal cell carcinoma, breast cancer

***Mimics PTH! - binds to PTH receoptors
--> increased renal reabsorption of Ca
--> increased osteoclastic bone resorption
--> DOES NOT stim 1-alpha-hydroxylase, so no increase in active vit D

Front 32

What are the lab values in Cancer/PHTrP-assocaited hypercalcemia?
- PTH?
- Vit D?
- PO4-?
- PHTrP?

Back 32

PTH = low
Vit D = low/normal
PO4- = low/normal
PHTrP = high

Front 33

What are the lab values in granulomatous-assocaited hypercalcemia?
- PTH?
- Vit D?
- PO4-?
- PHTrP?

Back 33

PTH = normal/low
Vit D = high
PO4- = high
PHTrP = low

Front 34

What is the treatment of hypercalcemia?

Back 34

1. Enhance renal Ca excretion
- GIVE FLUIDS!!
- Diuresis (lasix)

2. Inhibit bone resorption - osteoclast inhibition
- Calcitonin
- Mithramycin
- Bisphosphonates

3. Inhibit gut absorption of Ca
- Glucocorticoids
- Restrict oral Ca intoake
- Oral PO4- therapy (if low)

Front 35

Bisphosphonates
- what do they do?
- how do they work?

Back 35

- taken up by mineralized bone matrix
- inhibit osteoclast action
- serum Ca falls within 2-5 days! remains normal for up to a week
- normalizes serum Ca in 70% patients with malig-assocd hypercalcemia

Front 36

What is the definition of Hypocalcemia?

Back 36

Serum Ca < 7.6 mg/dL or symptoms

Front 37

Symtoms of Hypocalcemia?

Back 37

- parasthesias
- muscle cramps
- neuromuscular excitation (Tetany)
- bronchospasm
- laryngeal stridor
- seizures
- basal ganglia calcifications --> Parkinson's Disease

Front 38

What are signs of Hypocalcemia?

Back 38

- cataracts
- Chvostek's Sign
- Trousseau's Sign
- Hyperreflexia
- Prolonged QT Interval

Front 39

What is Chvostek's Sign?

Back 39

In a patient with hypocalcemia, when you tap on the facial nerve, see unilateral movement/contraction on that side of the face

Front 40

What is Trousseau's Sign?

Back 40

In a patient with hypocalcemia, when use BP cuff to cut off blood supply to their hands for 3 min, hands and forearm spasm (due to even more hypocalcemia)

Front 41

What are the causes of low calcium and low PTH?
- what is the most common?

Back 41

= Hypoparathyroidism
- surgical (most common)
- autoimmune
- infiltrative - e.g., sarcoidosis
- congenital aplasia of parathyroid = DiGeorge Syndrome
- severe hypomagnesemia
- Hungry Bone Syndrome
- idiopathic

Front 42

What are the causes of low calcium and high PTH?

Back 42

- vitamin D deficiency
- pseudoparathyroid hormone
- other...

Front 43

What are the causes of a Vitamin D deficiency that lead to hypocalcemia?

Back 43

- lack of sunshine
- dietary
- malabsorption (celiac sprue, bowel surgery)
- cholestatic liver disease
- advanced renal failure
- anticonvulsants - Phenytoin
- Vit D dependent Rickets (type I)
- Vit D resistance (Rickets type II)

Front 44

What is Pseudohypoparathyroidism? What does it cause?

Back 44

= PTH resistance
... causes hypocalcemia

Front 45

What causes "Hungry Bone Syndrome"?

Back 45

Parathyroidectomy!

Front 46

What is the ONLY CANCER that causes increased OSTEOBLAST activity? What does this result in?

Back 46

PROSTATE CANCER
--> hypocalcemia!!!

Front 47

Why would advanced renal failure lead to hypocalcemia?

Back 47

Renal cortex contains 1-alpha-hydroxylase
--> can't convert to active vitamin D --> can't absorb Ca from gut

Front 48

In what conditions would you find elevated alkaline phosphatase?

Back 48

Secondary hyperparathyroidism... due to increased metabolic activity of osteoclasts (and subsequently, osteoblasts)
- also in malabsorption of vit D and renal failure

Front 49

Treatment for Hypocalcemia

Back 49

REPLACE THE DEPLETED STORE!
- oral calcium
- oral vitamin D
- magnesium (needed for PTH secretion)

Front 50

What are the 2 types of bones? What are their locations and %s in the body?

Back 50

Cortical/Compact - 85% skeleton (but little surface area) = long bones, outer envelopes of bones

Cancellous/Trabecular - 15% (but 80% surface area) = inner parts of bones; most in axial skeleton

Front 51

What is bone made up of?

Back 51

Bone Matrix = 90% collagen; 10% other proteins

Bone mineral = Hydroxyapatite (Ca and PO4-)

Front 52

What is bone modeling and remodeling?

Back 52

Modeling = to maintain bone growth; renewal of bone substance and alteration in size and shape

Remodeling = to maintain bone health; replacement of old bone with new bone: resting, activation, resporption, formation phases

Front 53

When is peak bone mass mostly complete?

Then what??

Back 53

Peak bone mass complete ~age 20

Bone always remodeling......
Replace 10% skeleton every year.
As get older, resorption > formation... leads to weak bones

Front 54

What is osteoid?

Back 54

Laid down by osteoblasts --> mineralized by calcium and phosphorous

Front 55

What are the 5 main causes of skeletal abnormalities?

Back 55

1. osteoporosis
2. mineralization defects
3. defects of osteoblasts
4. defects of osteoclasts
5. Paget's disease of bone

Front 56

What is Osteoporosis? (def and value)

Back 56

= decreased and defective bone mass and bone strength --> predisposes to increased risk of fracture (fragility fractures)

= bone mineral density >/= 2.5 SD BELOW peak bone density on DXA

Front 57

What is normal peak bone density on DXA?

Back 57

30-35

Front 58

What is Osteopenia? (def and value)

Back 58

= decreased amounts of bone mineral/calcification seen on radiograh
= bone mineral density between 1.0-2.5 SD below peak bone density on DXA

Front 59

What is RICKETS?
- population?
- signs/sx?

Back 59

= disorder of mineralization of bone matrix (osteoid) in GROWING BONE
- occurs in kids
- results: bowing, frontal bossing, softening of skull (craniotabes), muscular hypotonia, weakness

Front 60

What is OSTEOMALACIA?
- pop?
- signs/sx?
- cause? leading cause in US?

Back 60

Disorder of mineralization of bone (just like rickets), but occurring in adults after closure of epiphysial plates

- presents with skeletal pain and weakness but NO bony abnormalities

- x-rays: reduced bone density, coarsened trabeculae, pseudofractures

- cause: deficiency in Vitamin D or PO4-
- leading cause in US = intestinal malabsorption of Vit D or PO4-

Front 61

What are the calciopenic disorders that cause Rickets/Osteomalacia?

Back 61

Calciopenic = decreased calcium
- dietary vitamin D deficiency
- vitamin D malabsorption
- VDDR type I
- VDDR type II
- Enhanced breakdown of vitamin D (anti-convulsants (dilantin, phenytoin), rifampin for TB)
- Chronic renal disease

Front 62

What is the main cause of Vitamin D malabsorption?

Back 62

#1 = celiac sprue
- post-gastrectomy

Front 63

What are pseudofractures?
- aka?
- pathognomonic for what disease??

Back 63

- aka: Looser's Zones/Milkman Fracture

= microfractures at points of stress/entry points of blood vessels
- appear as radiolucent lines on x-ray

**Pathognomonic for rickets/osteomalacia

Front 64

What medications cause enhanced breakdown of vitamin D?

Back 64

- anti-convusant tx = Phenytoin (Dilantin)

- TB med - Rifampin

Front 65

What are VDDR I and VDDR II?

Back 65

Vitamin D-dependent Rickets Type I
- defective 1-alpha-hydroxylase
- rare
- autosomal recessive
- presents in childhood with hypocalcemia and rickets

Vitamin D-dependent Rickets Type II
- hereditary resistance of 1,25 vitamin D due to receptor defect

Front 66

What are phosphopenic disorders that cause Rickets/Osteomalacia?

Back 66

- nutritional phosphate deficiency (rare)
- hereditary x-linked hypophosphatemia
- renal tubular disorders (fanconi synd)
- acquired tumor-induced osteomalacia
- excess antacids (Ca binds PO4-)

Front 67

What problems could lead to rickets/osteomalacia when there are NORMAL Ca and PO4- levels??

Back 67

- primary mineralization defect - hypophosphatasia, drug-induced (e.g., bispohosphonates, fluoride, aluminum)
- abnormal matrix synthesis (fibrogenesis imperfecta osseum)

Front 68

What is Osteogenesis Imperfecta?
- aka?
- what is?
- cause?
- signs/sx?
- major sx for dx??

Back 68

- "brittle bone disease"
- paradigmatic example of primary osteoblast disease
- due to mut of type 1 collagen
- osteopenia, fragile bones, hyperextensible joints, dental abnorms, adult onset hearing loss, intrauterine fractures can affect fetus...

**Dx with BLUE DISCOLORATION OF SCLERA

Front 69

Osteopetrosis
- what is?
- cause?
- description?

Back 69

= primary osteoclast disease
- due to deficiency in carbonic anhydrase --> inability to acidify compartment inside sealing zone
- skeletal fragility in spite of impairment in bone resorption
- modeling and remodeling are INEFFECTIVE

Front 70

Paget's Disease of the bone
- normal age?
- what is?
- sx?
- cause?
- dx?
- tx?

Back 70

= disorder of bone remodeling leading to abnormal bone formation
- rare before age 60
- sx: bone pain, bowing deformities of the long bones, enlargement of skull, increased bone vascularity; common bone fractures
- can affect one bone (focal) or whole skeleton (diffuse)

- cause unknown - viral infection of osteoclasts???
- most pts asymptomatic - discovered by isolated elevations in serum alkaline phosphatase
- tx: pulse therapy with bisphosphates every 3-6 months (depending on severity)

Front 71

What is Bone Strength?

Back 71

Bone Strength = Bone Density + Bone Quality

- Bone Density = g mineral/area, volume
- Bone Quality = architecture, turnover, damage accumulation, mineralization

Front 72

What are Risk factors for Osteoporosis?

Back 72

- Family history **80% genetic!
- Slender build
- Reduced muscle mass; sedentary life-style
- Hypogonadism (in males or females)
- Inadequate dietary calcium
- Alcoholism
- Smoking

Front 73

What are the Etiologies of Osteoporosis?
- #1 cause??

Back 73

- Post-menopausal = #1 cause!!!
- Senile osteoporosis
- Hypogonadism
- Glucocorticoid excess
- Immobilization
- Hyperthyroidism
- Hyperparathyroidism
- Heparin Rx
- Multiple Myeloma

Front 74

How does menopause lead to osteoporosis?

Back 74

Post-menopausal = #1 cause!!!
- lack of Estrogen leads to rapid bone loss
- vertebral crush factors predominate in TRABECULAR BONE
- GIVE ERH!

Front 75

What is Senile Osteoporosis?

Back 75

Senile Osteoporosis
- due to aging and Ca deficiency
- fractures of hip and femur mostly
- loss of TRABECULAR AND CORTICAL BONE

Front 76

Osteoporosis
- Dx?
- Tx?

Back 76

DXA Scan: bone density > 2.5 SDs from peak controls

Tx:
- calcium + vitamin D supplements
- bisphosphonates
- calcitonin
- SERMs (raloxifene)
- PTH (small spikes daily!!!)