Where is 90% of Ca stored?
Which hormone senses low Ca levels in the plasma and acts to increase Ca levels?
Parathyroid Hormone (PTH)
Describe the physiologic actions of PTH on bone, kidney, and GI.
Bone - stimulates resorption to liberate stored Ca
Kidney - increases tubular reabsorption of Ca
GI - increases Ca absorption
What is bone resorption?
Bone breakdown to liberate stored Ca
In the kidneys, PTH stimulates renal activation of _____, which increases intestinal absorption of Ca.
Which cells are osteoclast precursors?
Hematopoietic stem cells
Does BMD refer to the quality or quantity of bone?
BMD of -1 to -2.5
(low bone mass, this is essentially 1 step b/f osteoporosis)
Universal, gradual reduction in bone mass; skeleton is compromised resulting in fractures w/ minimal trauma
BMD of > -2.5
How can an estrogen deficiency affect bones?
Stimulates bone breakdown
What is FRAX?
Fracture Risk Assessment Tool
10 year risk predictor for hip fractures; probability of who needs to start medications
12 sets of data - e.g. age, sex, weight, height, smoking, alcohol, GC's, etc.
What FRAX score (%) indicates the person is a candidate for pharmacotherapy for osteoporosis?
What are T scores?
Compare individual results to those in a young normal adult that is matched for race and gender; most clinically relevant value
What are Z scores?
Compare individual results to those expected of an age-matched adult that is also matched for race and gender
What is considered normal bone mass?
Describe Paget's Disease.
An increase in osteoclast activity which increases the rate of bone turnover. There is a compensatory increase in osteoblast activity. Results in increased bone formation of poor quality.
(typically asymptomatic early in the disease until bone deformities result in fractures later in life (>50))
Which types of drugs may cause drug-induced osteoporosis?
Excessive glucocorticoid therapy
(GC's increase bone resorption by increasing RANKL, decreasing estrogen and testosterone levles, and decreasing Ca absorption and increasing urinary calcium excretion)
Drug induced osteoporosis can decrease BMD by ____% in 6-12 months.
All patients starting or receiving long-term systemic GC therapy should receive at least _____mg elemental Ca and _______ IU of Vitamin D daily.
800-1200 IU Vitamin D
Products like tums, Oscal, Caltrate, etc. contain what Calcium salt?
Calcium __________ is the most commonly used calcium preparation for osteoporosis. How is converted into soluble calcium salts? What effect does food have on absorption? What's a common ADR?
GI acid converts it into soluble salts
Food improves absorption
ADR = constipation
Which calcium salt can be taken w/o regard to food?
Calcium citrate (Citracal Tabs, liquid effervescent)
What's sucky about Coral Ca? (Calcium carbonate)
contains magnesium, selenium, chromium, and lead
What types of patients do we recommend Caclium citrate for? (Citracal)
patients on PPI's or H2-RA's, elderly, b/c no acid required in stomach for drug to be effective
Why do some Ca products contain Mg?
Mg aids in the GI absorption and untilization of Ca into bone (only significant if Mg deficient)
About ____ of dietary calcium is normally absorbed. How does Vitamin D affect absorption?
absorption increases with excess vitamin D
Describe the amount of Ca and Vit D required for:
1) 9-18 y/o
2) 19-49 y/o
4) Post menopausal women w/o MHT
1) 1300mg Ca, 600 IU Vitamin D
2) 1000mg, 600
3) 1200mg, 800
4) 1200-1500, 800-1000
The body cannot absorb more than _____ elemental Ca at one time.
______ in pop inhibits calcium absorption
At what point does Ca supplementation become harmful?
What's the CV risk assoc. w/ Ca supplementation?
Women who took ~1000mg of Ca daily w/o vitamin D showed a 30% in heart attacks
List 2 Di's for Ca supplementation.
1) Ca impairs absorption of antibiotics - TC's, FQ's, Bisphosphonates, etc.
2) Verapamil (Ca channel blocker) - Ca is used to decrease verapamil toxicities(?)
List 3 Vitamin D metabolites.
Cholecalciferol D3 = Delta-D
Ergocalciferol D2 = Drisdol
Calcitriol 1,25 Vit D3 = Rocaltrol (most potent agent)
Which vitamin D metabolites are derived from fish and meat sources?
Which vitamin D metabolite is plant derived?
Half-life of vitamin D is about ______
List 2 disease states where there is a Vitamin D deficiency.
Osteoporosis recommendation for Vitamin D - NMT _____
Recommended 600-800 IU/day
Vitamin D itself is synthesized in the skin or taken exogenously, but is not biologically active until _____
activated in the liver and kidney
What's the active form of vitamin D?
1,25-dihydroxy Vitamin D3
How does 1,25 Vit D3 increase Ca absorption?
Binds to intestinal Vit D receptors and increases Ca absorption in small intestine
increases proximal tubule reabsorption causing decreased kidney excretion of Ca
Increases bone mineralization by increasing osteoblast activity
List 2 first generation bisphosphonates
Etidronate - Didronel
Tiludronate - Skelid
The first generation bisphosphonates have a limited MOA (what is it?) and so they're only used for ______
Only used for Paget's disease
Cause osteoclast apoptosis
What are the 3 2nd genration bisphosphonates? How does their potency (as measured by enzyme inhibition) compare to the 1st gens?
10-100x more potent
Alendronate - Fosamax (also comes in a +D form)
Ibandronate - Boniva
Pamidronate - Aredia
What dose of Fosamax (Alendronate) is used for treatement of osteoporosis? What about for prevention of osteoporosis?
Treatment: 10mg QD or 70mg weekly
Prevention: 5mg QD or 35mg weekly
Pamidronate is used for....
What are the 2 3rd generation bisphosphonates? How potent are they compared to the 1st gen's?
10,000x more potent than 1st gens
Risedronate - Actonel (IR) or Atelvia (DR)
Zoledronic acid - Reclast
Single most efficacious bisphosphonate?
Reclast (Zoledronic acid)
Which bisphosphonate is given IV only once a year and may cause infusion site reactions?
Reclast (Zoledronic acid)
SAR - PPi normally gets incorporated into bone. What is changed in our drugs? How does this help with osteoporosis?
We replace connecting O between the P's with a Carbon which gets incorporated into bone and is less likely to get broken down
Describe the bone mineral affinity of the bisphosphonates.
Reclast > Fosamax > Boniva > Actonel/Atelvia
Describe the enzyme affinity of the bisphosphonates.
3rd > 2nd > 1st generation
(Has to do with N-substitutions. More N's in the molecule seems to correlate with increased efficacy. Reclast is the only one with 2 N's)
Which bisphosphonates should be taken first thing in the morning?
Which should be taken with 6-8 oz of water on any empty stomach?
1st gens (Etidronate, Tiludronate)
Fosamax, Boniva (2nd gens)
Risedronate (Actonel, 3rd gen)
Which should be taken with water and a meal?
Risedronate - Atelvia (DR form)
For which drugs is it advised to remain sitting or standing for 30 mintues? For 60 minutes?
30 = 1st gens (etidronate, tiludronate), fosamax, and both forms of risedronate
60 = Boniva (ibandronate)
Which drugs require the patient to avoid food for 30 minutes? 60 minutes?
30 = 1st gens (etidronate, tiludronate), IR risedronate (actonel)
60 = Boniva (ibandronate)
Doesn't matter for DR risedronate (atelvia)
Which drug should be taken right after breakfast? (only one)
Risedronate DR - Atelvia
Why do we have to separate food from the bidphosphonates?
they're negatively charged and will bind to a lot of crap which means they won't get absorbed
Why do not want patients to lie down after taking the drug?
to prevent esophageal erosion / esophageal CA
What time of day do we reccomend concurrent vitamin D and Ca be taken?
later in the day
Which bisphosponate has shown decreased mortality assocaited with osteoporosis?
Describe the MOA for bisphosphonates.
They have a strong affinity for bone and target bone undergoing active remodeling. They are incorporated into the bone matrix to strengthen the bone and make it more resistant to breakdown. They are resistant to enzymatic hydrolysis by pyrophosphatases.
How much can bisphosphonates increase BMD by?
<10% in 3 years
Why is there potentially a new recommendation for drug holidays from bisphosphonates after 5 years of use?
because the drug stays in the bone/blood up to 10 years after D/C
(long term use of bis-P's may impair normal physiological bone turnover and repair)
Do bis-P's affect osteoclast activity?
Yes, they suppress it by inhibiting farnesyl pyrophosphate synthetase (FPP) resulting in apotosis of osteoclasts
Which enzyme do bis-P's inhibit in the cholesterol pathway?
Farnesyl pyrophosphate synthetase (FPP)
List some ADR's of bisphosphonates.
Hypocalcemia, GI disturbances, osteonecrosis of the jaw (more frequent with IV administration; risk factors include tooth extractions and invasive dental procedures), increase in atypical fractures with long term use
DI's of Bis-P's.
don't take with any other meds or w/in 1/2 hr of taking a bis-P
CI for Bis-P's.
Use caution in dosing Bis-P's in patients with _____ disease.
Which drug is a PTH derivative?
Which is the only truley anabolic agent that has been shown to actually build bone and repair micro architecture?
(stimulates new bone formation by binding to PTH receptors and increasing the number and/or activity of osteoblasts)
When can Forteo be used? When should it not be used?
Used in established osteoporosis patients with high risk of fracture or who have failued other therapy; BMD < -3.5, Corticosteroid induced bone loss, etc.
Not for use in prevention of osteoporosis
Forteo decreased vertebral fractures by ____% and non-vertebral fractures by ____%
Continuous high does PTH may have what effect on bone?
Hyper-parathyroidism - may increase bone breakdown by stimulating clasts more than blasts
DI's for Forteo
Pagets disease, pregnancy, bone CA
Which human mAB acts as a RANKL inhibitor?
Denosumab - Prolira
Which patients most commonly use denosumab - prolira?
post-menopausal women with high risk of osteoporosis or history of fracture
What is RANKL?
Receptor activator of nuclear factor-kB ligand
Where are RANK receptors located?
on developing osteoclasts
(normally osteoblasts will initiate resorption by causing the formation of osteoclasts thru stimulation of RANK by RANKL secretion)
Which drug mimics the actions of osteoprotegerin (OPG)?
Denosumab - Prolira
Normal function of OPG.
inhibit maturation of osteoclasts (inhibits resorption)
Net effect of Denosumab - Prolira
increase bone mass and stregthen bone by decreasing activity of osteoclasts
Denosumab is CI'd in which patients?
those with hypocalcemia - get Ca levels to normal prior to starting therapy
Calcitonin is released from _____ cells in the thyroid.
Is Calcitonin used for treatment or prevention of osteoporosis?
treatment in post-menopausal women, it is less effective than the other agents
Describe the pharmacologic actions of Calcitonin.
decrease ca levels (opposite of PTH)
main effect is to inhibit osteoclast activity to decrease breakdown of bone
also has an analgesic effect
Can patients develop resistance to calcitonin?