Block 3 Vitamin D and Osteoporosis Flashcards
When/where is PTH secreted from
- from parathyroid glands
- - in response to decreased Ca or increased PO4
What are PTH’s effects?
1) bone resorption
2) increase Vit. D synthesis
3) suppress calcitonin release
4) decrease renal Ca excretion
When/where is calcitonin secreted?
- from parafollicular C cells of thyroid
- - in response to increased Ca
What are calcitonin’s effects?
1) inhibit osteoclast-medited bone resorption
2) increase renal PO4 excretion
3) increase renal Ca excretion
What are calcitriol’s effects?
1) increase intestinal Ca absorption
2) increase bone resorption AT HIGH LEVELS
What is the structure of calcitonin?
32 aa peptide
When/where is FGF-23 released?
- from osteoclasts
- - in response to increased PO4
What are the effects of FGF-23?
1) inhibit renal PO4 reabsorption
2) inhibit vitamin D 1a-hydroxylation
What hormones are involved in Calcium homeostasis?
1) PTH
2) Calcitonin
3) Calcitriol
4) FGF-23
5) TH, GH, androgen/estrogens, glucocorticoids
What is the UL for Ca?
teens: 3g/day
adults: 2.5g/day
elderly: 2g/day
What are the RDAs for Ca?
- adult: 1 g/day
- 70+, or 50+ woman: 1.2 g/day
- teens: 1.3 g/day
What is the average teenager intake of Ca?
750 mg/day
Where is most calcium obtained?
dairy products
How is Calcium lost?
300mg/day from bone turnover, increased by loop diuretics
- half via urine
- half via feces
How is Ca absorbed?
small bowel
1) active Vit.D-dependent transport in proximal duodenum
- - Vit.D boosts 2-fold
- - max 600 mg/day
2) facilitated transport
- - majority of uptake
How does phosphate circulate?
NaH2PO4 or Na2HPO4
How is PO4 excreted?
in urine
How is phosphate absorbed?
Vit.D facilitated active transport
- 2/3 of intake absorbed
- PO4 is abundant in food
What is the formula for hydroxyapatite? How much of body’s PO4 is there?
Ca10.P6.OH2
80%
How is Paget’s diagnosed?
elevated serum alkaline phosphatase
What are the causes of hypercalcemia?
1) primary hyper-PTH
2) familial benign hypercalcemia
3) acute hypercalcemia
4) PTH- or calcitriol-tumors
5) bone resorption tumors
6) granulomatous diseases
7) hypercalcemia of malignancy
How is acute hypercalcemia treated? Chronic?
acute
– IV saline + loop diuretic
chronic
– bisphosphonates (pam or zole) + calcitonin
What are the symptoms of primary hyperparathyroidism?
1) hypercalcemia, osteoporosis, kidney stones
2) osteitis fibrosa cystica
3) fatigue, weakness, depression/confusion, seizures
4) +/- hypophosphatemia
How is hyperparathyroidism treated?
parathyroidectomy
If you have primary hyperthyroidism, you probably also have…
low vitamin D
What causes familial benign hypercalcemia and what is the result?
defunct calcium sensor
- low renal Calcium excretion
- PTH might be slightly high
How is familial benign hypercalcemia treated?
not treated; it’s benign
How do granulomatous diseases like TB and sarcoidosis cause hypercalcemia?
excess calcitriol synthesis by mononuclear cells
How is granulomatous hyperparathyroidism treated?
1) glucocorticoids (decrease ectopic calcitriol)
2) oral phosphate (to bind Ca)
How is hypercalcemia of malignancy treated?
1) decrease dietary Ca
2) increase renal excretion and inhibit bone resorption
What are the symptoms of Paget’s?
may be asymptomatic
1) bone pain (compressed nerves from vertebral outgrowth)
2) deafness (ossicles)
3) deformed bone
What causes Paget’s?
unknown
- maybe measles (paramyxovirus), since it promotes IL-6 and IL-6 stimulates osteoclasts
- maybe genetic
Patients with Paget’s are more likely to develop…
osteosarcoma
gout
What patients are most likely to get Paget’s?
English
– 2-9% of those older than 50
Paget’s is due to…
single/multiple foci of bone turnover with 3 stages
- bone resorption
- exuberant bone production
- disorganized, unstable, and deformed bone
What is calcitonin used for?
1) Paget’s
- - primarily for relief of bone pain due to fracture (analgesic properties)
- - also reduce bone loss and fracture incidence, but BPs more effective
2) hypercalcemia
How is calcitonin supplied?
salmon (Miacalcin, Fortical)
- SQ or IN (IN is approved for osteoporosis)
- tablet equally effective but not available
What are the ADRs of calcitonin?
1) 2x greater cancer risk when used 5+ years post-menopause
2) rhinitis, erythema, excoriation if 65+
3) Ab development leads to loss of efficacy
What is the MoA of Cinacalcet?
Calcium receptor agonist
– once a day
When is Cinacalcet used?
primary and secondary hyperparathyroidism
What are the effects of cinacalcet?
1) lower [PTH] 15-50%
2) lower Ca and PO4 7%
What are the ADRs of cinacalcet?
1) hypocalcemia
2) lower seizure threshold
3) CYP3A4 substrate
What causes hypoparathyroidism?
1) removal/injury of parathyroid gland
2) autoimmune
3) genetic deficiency
What are the causes of hypocalcemia?
1) hypoparathyroidism (most common)
2) renal osteodystrophy secondary to chronic renal failure
3) dietary insufficiency / malabsorption
4) pseudohypoparathyroidism
What are symptoms of hypoparathyroidism?
neuromuscular hyperexcitability
1) tetany
2) anxiety, depression, hallucinations
- - minimal bone effects!
How is primary hypoparathyroidism treated?
1) Ca
2) Vit. D
3) synthetic PTH in development
What are symptoms of pseudohypoparathyroidism?
1) low calcitriol
2) short stature
3) short metacarpals
How is pseudohypoparathyroidism treated?
Ca + Vit D or analogs
What causes pseudohypoparathyroidism and what is the result?
1) defects in intracellular PTH signaling = resistance
- - hyperphosphatemia, hypocalcemia
- - low calcitriol level
What is concurrent with dietary insufficiency/malabsorption of calcium?
low PO4 and Mg
How is renal osteodystrophy secondary to CRF treated?
1) Ca antacids
- - bind PO4
2) low phosphate foods
- - avoid soda, dairy
3) Vit D supplement
- - improve Ca
4) Cinacalcet
- - suppress PTH
What causes renal osteodystrophy in CRF?
1) can’t excrete PO4
- - high PO4 activates FGF-23
2) can’t make calcitriol
- - less Ca absorbed
- - bone resorbed, and Ca ends up in kidney
- - hypocalcemia, hyperphosphatemia
half life of D, calcitriol, and 25-hydroxyD
D (4-6h in plasma, 2 mos in body);
calcitriol (15h);
25-hydroxy (15 days)
relative affinity for VDBP among D, calcitriol, 25-hydroxy
D less than
Calcitriol less than
25-OH
How does Vitamin D enter the circulation?
enters lymph via chylomicrons
or, made from skin
– slowly transferred to VDBP
What constitutes Vitamin D deficiency? What is normal?
25-OH-D less than
20 ng/mL (normal is 40)
What is the storage form of VitD?
25-hydroxy/calcifediol
– transported via VDBP
How is calcitriol inactivated?
24-OH in liver by p450
– results in calcitroic acid
What 25OH-D level is associated with hypercalcemia? What is normal?
25OH = 750 nmol/L = 300 ng/mL
– normal is 250 nmol/L = 100 ng/mL
How does 25OH level affect calcitriol?
normally 1000x lower than calcitriol
– if excessive, can displace to cause excessive Vit. D
What constitutes hypervitaminosis D?
elevated 25OH and calcitroic acid (no change in calcitriol!)
– but, hypercalcemia symptoms due to protein displacement
How is 7-dehydrocholesterol turn into cholecalciferol?
UV light
- stratum basale, spinosum
- melanin slows formation
How much sun is required for enough Vit. D?
10-15 mins/day on face/hands/arms
What enzyme converts cholecalciferol to 25-OH?
CYP27C1, CYP2R1 in the liver
How is 25-OH converted to 1,25-OH?
CYP27B1 (kidney)
– activated by PTH
What diseases are caused by Vit. D deficiency?
1) rickets
2) osteomalacia
What is rickets and what are sxs?
deficient bone mineralization in kids
- secondary PTH increase
- bowing of long bones and spine
What is osteomalacia and what causes it??
deficient bone mineralization in adults
– secondary PTH increase
caused by nutritional deficiency or lack of sun exposure
How does osteomalacia differ from osteoporosis?
bone formation, not just mineralization, is reduced in osteoporosis
What are the clinical features of osteomalacia?
1) bone fx
2) bone pain, tenderness
3) muscle pain, weakness (esp. large proximal muscles)
4) 25-OH less than 8 ng/mL
What are risk factors for nutritional rickets/osteomalacia?
1) dark skin
2) elderly
3) obese
4) low vit. D
5) north of SF/Philly
What causes Type I Vit. D dependent rickets?
deficiency in 1a-hydroxylase
What causes Type II Vit. D dependent rickets?
Vitamin D receptor (VDR) mutations
How is type I vit. D dependent rickets treated?
calcitriol or Vit D ANALOGS (must already be activated)
How is type II vit D dependent rickets treated?
parenteral Ca and/or hi-dose calcitriol or vit D analogs
Vit. D deficiency is linked to these things:
1) all-cause and CV mortality
2) asthma and food/air allergy
3) T1DM risk
4) 3.4x more likely to die of heart failure (the more black, the worse off)
5) CV risk indicators: CRP, IL-6, cell adhesion, O2 stress
Vit. D deficiency has one good benefit:
decreased Crohns risk
Who should be tested for Vitamin D deficiency?
1) any symptoms or potential causes
2) obese
3) drugs that increase D metabolism
4) drugs that interfere with absorption
5) lots of melaning
What drugs increase D metabolism?
antiepileptics: phenytoin, phenobarb, carbamazepine
What drugs interfere with D absorption?
- cholestyramine
- orlistat
- colestipol
In what populations is D deficiency more common?
1) old men
2) worse with age, BMI, north, inactivity
- - supplements have little impact
How does D3 relate to D2?
D3 3-10x more potent with longer duration of action
– no difference clinically
RDA of Vit. D? What if deficient?
600 IU/day (800 if 70+ or overweight
– 4000 IU/day used to raise Vitamin D?
Where is Vitamin D found? How much in a cup of milk?
1) fatty fish
2) mushrooms if UV exposed
3) eggs
4) yeast
5) fortified foods
- - 100 IU/dup milk
What is osteopenia? How prevalent?
form of osteoporosis where BMD is 1-2.4 std dev away
– 50% of women over 50
What is osteoporosis? how prevalent?
form of osteoporosis where BMD is 2.5+ std dev away
– 20% of women over 50
What are the clinical findings in osteoporosis?
1) alkaline phosphatase slightly elevated
2) normal Ca, PO4, PTH
Where are fractures most common in osteoporosis?
1) wrist
2) femur/hip
3) vertebra
What are risk factors for osteoporosis?
1) 40+
2) white
3) thin and sedentary
4) premature postmenopause
5) poor diet, smoke, drink
6) f/h
7) long-term steroid use or low T
Describe bone loss in osteoporosis?
E loss accelerates loss
– increases osteoclast activity
– decreases # of osteoblasts and osteocytes (the sensors)
lost trabecular and cortical bone
Where is trabecular bone found?
spine, hip
What are the Vit. D analogs?
good to go
– paricalcitol, oxacalcitriol
need 25 OH in liver
– alfacalcidiol, doxercalciferol
When are Vit. D analogs indicated?
to suppress PTH release
to prevent renal osteodystrophy
What are symptoms of hypercalcemia from Vit. D overdosing?
fatigue, weakness, HA
nausea
soft-tissue calcification
metallic taste
How is the interindividual variation in Vit. D analog dosing managed?
monitoring
– Ca, PO4
avoid Mg antacids
– lead to hypermagnesia
What is the indication for calcipotriene topical cream? What’s the efficacy like?
mild-moderate psoriasis
- 40-50% effective
- slightly more effective than steroids
- less likely to relapse
Describe the systemic effects of calcipotriene topical?
rapid metabolism and high VDR affinity = no systemic effects
How is Calcipotriene used? What about pregnancy?
2 week onset, avoid face
– QD or BID
Cat C
What are the risks associated with HRT?
1) thromboembolism + MI
2) slight breast cancer risk
3) uterine bleeding, breast pain
4) kidney stones
How does HRT work for osteoporosis?
1) increases BMD 2-4% in 2 years
2) suppresses IL-6 to promote osteoclast apoptosis
What does IL-6 do?
activates osteoclasts
Should you recommend HRT for osteoporosis?
no;
but don’t D/C, because that leads to hip fx risk regardless of BP use
When is Raloxifene indicated?
prevention and treatment of osteoporosis
– preferred for f/h of breast cancer
What is the black box on raloxifene?
increased thromboembolism and stroke risk
What are C/I’s of raloxifene?
1) concurrent HRT
2) pregnancy
3) f/h of thromboembolism
4) men (safety/efficacy not determined)
What is the MoA of Raloxifene?
SERM
1) ER antagonist in endometrium, breast (reduced breast cancer risk)
2) ER agonist in bone
- - reduced vertebral fx w/ Ca + D
- - increases BMD 1-3% w/ 500mg Ca
- - decreases bone resorption in 3 months, lasts for 2 years
3) lowers LDL
ADRs of raloxifene.
no significant
no effect on endometrium or bleeding
Describe PK of raloxifene.
F= 2% (first pass)
protein-bound, not SHBG tho
t1/2 = 28-32h
hepatic
Describe structure of bisphosphonates.
- 2 PO4 with connecting O replaced by C
- side chain amine can enhance activity
- ring-incorporated amine is 10000x potent
What are the ring-incorporated bisphosphonates?
risedronate
zoledrenate
What is the MoA of bisphosphonates?
1) Ca chelators, incorporated into bone and osteoclasts
2) trigger osteoblast apoptosis
3) decrease hydroxyapatite solubility
4) increase BMD 8% over 2 years
5) anti-cancer effects?
6) reduce colorectal and breast cancer risk
What are the simple BPs and what’s their MoA?
Etidronate
- non-hydrolyzable ATP analogs
- pro-apoptotic
What are the amino BPs and what’s their MoA?
Alendronate, Risedronate, Zoledronate
- inhibit isoprenoid synthesis for cholesterol
- block prenylation of cell signaling
- block enzymes, esp farnesyl synthase
– SECONDARY apoptosis
What BPs are available orally?
1) Alendronate
2) Risedronate
3) Ibandronate
4) Etidronate
5) Tiludronate
What BPs are available parenterally?
1) pamidronate
2) zoledronate
What is the indication of BPs?
Paget’s & treatment/prevention of osteoporosis:
– alendronate, risedronate, ibandronate
Paget’s only
– Etidronate, Tiludronate
IV hypercalcemia of malignancy and oral-failure for osteoporosis
- pamidronate (preferred for Paget’s)
- zoledronate
What is the oral BP dosing regimen?
1x daily, weekly (some monthly)
- 30+ min before breakfast
- 6-8 oz water
- remain upright until eating
What oral BPs can be taken once monthly?
ibrandronae
risedronate
What are administration concerns with BPs?
1) Vit D
- - get to 33+ ng/mL prior
2) renal failure if too fast/too large dose in IV
- - 90+ mg
Describe IV dosing BP regimens for the available drugs.
IV infusion w/ vigorous saline hydration due to insolubility and poor F
Pamidronate
4-24 hr infusion q3 month
Zoledronate
15 min infusion q 1 year
Describe M and E for BPs.
Renal, no metabolism
What are ADRs of bisphosphonates?
1) esophagitis, ulcers, bleeding
2) osteonecrosis of the jaw
3) atypical femur fractures if 5+ yrs use
4) mild-severe bone/joint/muscle pain
When do the bone ADRs of bisphosphonates occur?
1) osteonecrosis of jaw following dental surgery
2) atypical femur fx after 5+ years
3) bone/joint/muscle pain (2 week onset, varies from day to 1 year)
What are C/I’s to BPs?
esophageal disease
How can esophagitis be avoided with BPs?
report dysphagia/heartburn
follow dosing regimen
What are the indications for Forteo?
severe osteoporosis, including glucocorticoid-induced
What is the MoA of Forteo/Terpiaratide?
active PTH segment
- bone anabolic agent increases bone mass
- INTERMITTENT administration promotes bone FORMATION
When is Terpiaratide contraindicated?
bone cancer risk (Paget’s or radiation therapy)
What are the ADRs of Terpiaratide and how are they managed?
1) osteosarcomas in rats
- - hyperPTH levels are lower in rats
2) transient orthostasis following injection
limit use to 2 years
How is Terpiaratide administered?
SQ inj in thigh/abdomen daily
What are the effects of Terpiaratide?
12% bone mass increase (lumbar, femoral neck)
- 2x effective as alendronate
- reduced fx incidence
- coadmin with E or BP is advantageous
What is the MoA of Denosumab?
OPG-mimetic, binds to RANKL of osteoblasts
– inhibits RANK-RANKL binding
What are the effects of RANK-RANKL binding?
osteoblast precursor becomes activated
OPG stands for…
osteoprotogerin
How is OPG secreted?
by osteoblasts
– increased by estrogen
What are the indications for Denosumab? MoA?
What are its effects?
OPG-mimetic mAb
- indicated for severe osteoporosis
- decreases vertebral and hip fx
What are ADRs of Denosumab?
1) hypocalcemia (20%)
2) infection susceptibility (esp, endocarditis)
3) dermatitis
4) jaw osteonecrosis
5) bone/back/muscle pain
How often is Denosumab administered?
SQ q6 months
What are C/I’s of denosumab?
hypocalcemia
What is UL of Vit. D supplementatino?
4000 IU/day (RDA is 600 IU/day)
What was odanacatib’s MoA?
cathepsin K inhibitor
– prevented proteolytic activity of ostoclasts
What was Ronacaleret’s MoA?
Anabolic calcilytic
– Ca receptor antagonists to cause PTH pulse release
Describe effectiveness of Ca supplementation?
only effective if bottom 20th percentile Ca intake
- does not reduce hip fx risk
- might slow BMD loss
- might slow post-menopausal bone loss if prophylactic admin
What are the negative effects of Ca supplementation?
- 20% risk increase of kidney stones
- - 20% risk increase of MI/stroke
What is the most readily absorbed form of Ca?
Ca citrate
What is the Ca supplementation range for post-menopausal women? Why not over 2g?
1 - 1.5 g/day
over 2g:
- hypercalcemia, kidney stones
- no further benefit
What happens when Vit D intake exceeds 4 IU /day?
increased cancer risk
hypercalcemia
What is the effective dose in osteoporosis for Ca and Vit D combined?
800 IU/d + 1 g/day
– Vit. D analogs may be 2x as effective as Vit. D
What combo treatments are effective for osteoporosis?
1) BP + PTH cyclical therapy
- more effective than either alone
2) BP + PTH concurrent
- no better than PTH alone
