Endo - 2-5 - Metabolic Bone Disease

Front 1

Osteopenia

Back 1

A radiological dx

Decreased Ca++ in bone - "low bone mass"

2 refinements of this are osteomalacia and osteoporosis

Clinically can mean a mild degree of osteoporosis

Front 2

Osteomalacia

Back 2

Pathologic dx
No loss of the bone matrix, but there is less mineral content.

Due to a defect in bone being mineralized--this step never happened.

Front 3

Osteoporosis

Back 3

Patholic dx.
Decreased bone matrix and bone mineral content. No mineralization defect.

Calcium density is normal, but there is just not enough calcium AND bone matrix.

Front 4

Osteoblasts respond to...

Back 4

distant and local signals

Front 5

Metabolic actions of bone

Back 5

Osteoclasts (specialized macrophages) resorb bone by digesting mineral and organic matrix.

Osteoblasts then line up at the resorption site.

They produce unmineralized organic matrix (osteoid) with mineralization (deposition of calcium and phosphate) lagging slightly behind. Then

Front 6

Bone unit consists of...

Back 6

Osteocytes, blasts and clasts.

Front 7

Cancellous bone is the same as...

Back 7

marrow bone

Front 8

Osteoporosis - finer details

Back 8

Loss of total bone VOLUME.

The cortical and medullary bone becomes thinner and medullar trabeculae are lost.

Both mineral and organic content of the matrix are equally effected - both are diminished.

Microfractures occur which makes the bone less functional.

Amt of mineralized to unmin is the same.

Front 9

Osteomalacia - finer details

Back 9

Decreased bone (osteopenia) due to a defect in bone mineralization.

Will see more osteoid (unmineralized bone matrix) because there is less mineralization.

The number of bone trabeculae are preserved.

Amt of unmin to min increases.

Front 10

Communication btwn blasts and clasts

Back 10

rank-ligand

Front 11

Menopause

Back 11

Estrogen normally induces bone Life span of osteoclasts increased in estrogen deficiency.

Estrogen normal induces bone remodeling units(? - clarify this with notes)

with estrogen deficiency, there is higher osteoclast def and less blast activity.

Front 12

Z-score

Back 12

In dexa scan, it is the SD of patient's bone density relative to age/gender matched population

If this is very low, it tells you there is a "zebra" to watch out for that it causing abnormal bone loss.

Front 13

T-score

Back 13

In dexa scan, it is the SD of pts bone density relative to a 30-year old gender-matched individual.

Front 14

Osteopenia T score -

Back 14

-1 to -2.5

Front 15

Osteoporosis T score -

Back 15

<= -2.5

Front 16

Indications for bone density determination

Back 16

Estrogen def and risk of osteopor (incl menopause)
Vertebral abnormalities on X-ray
High glucocorticoid dose
Primary hyperparathyroidism
Receiving osteoporosis tx
Pt has metabolic disease that affects the skeleton.

Front 17

Fracture rate

Back 17

Doesn't really exist - it gradually increases

Front 18

Most fractures occur to women who have T score > ...

Back 18

-2.5 (non-osteoporotic women)

This is mainly because there are tons of non-osteoporotic women.

But either way, preventative med is key.

Front 19

Factors influencing fracture rate

Back 19

Age (regardless of the bone density. A 20 year old with T score of -1 is better than 70 year old with T score of -1..) - bc old bone is worse and old folks fall more

Hx of prev fracture

T score <= -1.8

Self rated poor health

Poor mobility

Front 20

T and Z score of a patient with tons of issues (including poor Ca++ absorption

T and Z of a healthy post-meenopausal pt

Back 20

T and Z both decreased

Only T is decreased.

Front 21

Enzymes needed for mineralization

Back 21

None - a passive process.

Just needs proper Ca, PO4 and pH.

Front 22

Slide 33

Back 22

Good slide of pathogen of osteomalacia.

Basically Vit D abnormalities and renal disease are the main culprits.

Front 23

Glucocort and bone/mineral homeostasis.

Back 23

1) reduce calcium absorption from gut
2) suppress bone formation
3) Impair calcium reabsorption in kidney
4) Secondary increase in PTH
5) Suppress gonadal activity (stimulates net bone resorption)


These effects result in a negative calcium balance which increases the PTH level. Although this serves to maintain the serum ionized calcium within a relatively normal range (I.e. patients on glucocorticoid therapy are NOT hypocalcemic when compared to the population reference range), it does so at the expense of increasing net bone resorption with resultant osteopenia.

Front 24

Tx of glucocorts causing improper bone/mineral homeostasis

Back 24

Inc calcium and vit D to increase Ca++ abs from gut

Admin a drug to block bone resorption (e.g. bisphosphonate)

Replace gonadal steroids.

Front 25

Thiazide diuretics

Back 25

Cause calium retention

Front 26

Furosemide

Back 26

Cuases calcium excretion.

Front 27

Issue with conj estrogens

Back 27

Metabolites are from horse urine - has many different metabolites in the product.

Front 28

Goals of hypercalc therapy

Back 28

Increase urinary calcium excretion

Diminish intestinal abs of calcium

Inhibit accel bone resorption

Avoid hypercalcemic meds (thiazides, Vit D)

Increase salt and water intake.

Front 29

2 things that can cause hypercalcemiA

Back 29

I THINK THIS IS VERY IMPORTANT TO KNOW

Granulomatous disease (macrophages activate Vit D from 1 to 1,25) - incl sarcoidosis

Vitamin A (mimic 1,25D) - high in megavitamins and liver.

Front 30

Why hydrate pts with hypercalcemia?

Back 30

It is the initial therapy in acute cases.

Corrects the volume deficit, enhances renal calcium clearance.

After this, add a loop diuretic (increases calc excretion)
DO NOT USE THIAZIDES!!! - increases calc reabs.

Front 31

Bisphosphonates - drugs

Back 31

Zoledronate - a highly potent newer drug - v. popular. Effects last for months.

Pamidronate - effects last weeks.

Front 32

Bisphosphonates - general

Back 32

1st choice therapy.

IV admin - single dose.

They are analogs of pyrophosphate and they bind hydroxyapatite. They are endocytosed by osteoclasts and induce apoptosis.

Front 33

Simple bisphosphonates vs. aminobisphosphonates

Back 33

Simple - clodronate or etidronate
Metab incorporated into nonhydrolyzable analogs of ATP

Aminos - more potent. Inhibit farnesyl diphosphate synthase which thus inhibits synth of a lipid that is necc for signaling.

Front 34

AEs of bisphosphonates

Back 34

Acute pphase rxn - transient flu

Nephrotoxicity - precip of calcium bisphosphonate. Doesn't occur with ibandronate.

Jaw necrosis - more common with high IV doses.

Possible long-term effects of microdamage.

Front 35

Calcitonin

Back 35

C cells of thyroid secretes this in response to high calcium.

Osteoclasts have a receptor for it and it makes them stop bone resorption.

Increases urinary calcium excretion.

Used in severe cases with other therapies.

Body may create Abs against this or down regulate receptors in response.

Front 36

Glucocorticoids

Back 36

Tx of hypercalcemia
For Vit D excess or osteolytic malig.

Inc urinary calcium and less intestinal ca abs

Front 37

Dialysis

Back 37

Tx of hypercalcemia
Used in severe cases complic by renal failure.

Front 38

Plicamycin and gallium nitrate

Back 38

Tx of hypercalcemia
Toxic - rarely used

Front 39

Phosphates

Back 39

Tx of hypercalcemia

No longer used.
Causes skeletal and renal issues.

Front 40

Hypocalcemia Tx (mild)

Back 40

Measure ionized Ca (low serum albumin?)

Oral calcium carb if mild and asymp
Increase intes calc absorption - can use Vit D (calcitriol) to help (e.g. hypoparathyroidism)

IV if acute and symp

Front 41

Magnesium and calcium

Back 41

Mg allows for PTH to work properly and for it to be secreted.

So Mg+ deficiency leads to hypocalcemia

Front 42

Hypoparathyroidism and magnesium

Back 42

Hypopara causes Mg loss in urine so it is a vicious cycle.

Giving Mg will help.

Front 43

Hypocalcemia Tx (severe)

Back 43

Increases serum Ca.
Calcium gluconate is best, but you can use calcium chloride too (v irritating to beins)

Note - can cause site necrosis if needle moves (extravasation) and it potentiates digitalis toxicity.

Front 44

Hyperparathyroidism causes

Back 44

primary - adenoma, hyperplasia or carcinoma(rare) - tx with parathyroidectomy)

Secondary - chronic renal failure or malabsorption

Tertiary - progression into auton hypersecretio of PTH assicated with hypercalcemia.

Front 45

Calcimimetics

Back 45

Cinacalcet hydrochloride.

Used for secondary hyperparathyroidism and hypercalcemia in parathyroid carcinoma.

AEs - hypocalcemia, N/V

The calcium sensing receptor on PT cell thinks this is Ca++ so it decreases PTH secretion, PTH mRNA and proliferation.

This reduces serum PTH.

Front 46

Risk of dying of osteoporosis

Back 46

Same as a woman dying of breast CA

Front 47

Best way to tx osteopor

Back 47

PRevention -

High calcium and Vit D in diet.

Weight bearing exercise to increase bone mass (anabolic) and decrease falls (via stength and balance)

Fall prevention

Front 48

Which race less likely to get osteoporosis

Back 48

african americans.

Front 49

Calcium supplement options

Back 49

Calcium carbonate (Tums) - abs impaired with achlorhydria (low gastic acid in stomach)

Calcium citrate (Citracal) - more bioavailable, lower Ca++ content.

Front 50

AEs of calcium supplements

Back 50

GI effects, pts with kidney stones, less abs of other minerals and drugs, milk-alkali syndrome.

Front 51

Action of Vit D

Back 51

Effects the intestinal Ca++ transport. More GI absorption.

Front 52

Vitamin D supplements.

Back 52

Ergocalciferol (D2) and cholecalciferal (D3).

Calcitriol - 1,25(OH)2D - shorter duration of action than the two above.

Fat soluble.

MEASURE WITH SERUM 25-HYDROXYVITAMIN D

Front 53

Ther agents for osteopor

Back 53

Anti-resorptive agents (i.e. bisphosphonates, SERMS, calcitonin) - block bone resorp.

Bone forming agnets (anabolic) - i.e. PTH

Front 54

PTH

Back 54

Used in osteopor.
Short half life. Build up bone dramatically with short stimulation of high levels.

Front 55

Bisphosphonates with osteopor

Back 55

First line therapy.

Inhibits osteoclasts

Alendronate, risedronate and ibandronate are three options...

Once weekly/monthly dosing. Poor GI abs.

Main AEs are GI irritation.

Front 56

Estrogen

Back 56

PREVIOUSLY used in postmenopausal pts. Now just treats menopausal sx.

Antiresorptive, inhibits osteoclasts, reduced turnover, nuclear ER complex regulates OB gene expression.

Increases bone mineral density and less fractures as a result.

Inc risk of MI, stroke, breast CA, migraines, blood clots.

estrogen also imp for cognitive function.

Front 57

selective estrogen receptor modulator

Back 57

Raloxifene - for postmenopausal osteopor.

Agonist at bone, antag at breast and uterus.

Not v. effective for osteopor.

Oral, doesn't help with other menopause sx (unlike actual estrogen)

Less risk of breast CA, no effect on uterine lining.

Front 58

Paradox of PTH action

Back 58

Homeostatic role - Reduces bone mass (if given contin) bc it maintains blood calcium by withdrawal from bone stores (wants to bring up serum Ca++).

Ther role - Intermittent PTH tx will build bone mass.

Front 59

PTH actions with rank ligand

Back 59

PTH signals osteoclasts to do something wehre Rank-ligand is increased and OPG is decreased and this causes osteoblasts to tell osteoclasts to start chewing up bone.
(increase in PKA and Ca++ in osteoblast)

Denosumab is the antibody that inhibits this.

Front 60

Teriparatide

Back 60

Recombinant PTH. Stimulates osteoblasts.

Increases bone mineral density, causes less fractures.

Daily subcut injection.

Use in pts with high risk of fracture or suboptimal response to other tx.

Coadmin with bisphosphonates will reduce efficacy but squential therapy will lock in the gain.

Front 61

Teriparatide AEs

Back 61

Hypercalcemia, hypercalciuria, hypomagnesmia, injection site rxn

Front 62

Best and worst at increasing bone min density and fracture reduction

Back 62

Best - PTH
Worst - Ca++/Vit D or calcitonin