Card Set Information
Pharmacology II Exam Rutgers
For Rutgers P2 students
The structural units of compact bone. Blood vessels and nerves run through the Haversian canals, which run lengthwise through the bone.
Osteoporosis is caused by a lack of...
Collagen I or Collagen XXIV
What four factors determine peak bone mass?
1. Estrogen and
androgen (when younger)
2. Physical activity
3. Dietary calcium
Obviously, the only ones we can regulate are 1-3. And all 1-3 are needed; no compensating.
Bone remodeling pace
~90% of the bone surface is normally inactive, thus only 3% of cortical bone is remodeled/year.
In contrast, 25% of trabecular bone is remodeled/year.
Derived from marrow precursor cells in response to physical/biochemical signals (i.e. CSF-1)
Clasts "crumble" = resorb = excavate into the bone
Required for osteoclast bone resorption
Binds to RANK to induce osteoclast formation
Produced by osteoblasts (two types= membrane-bound + soluble form)
Acts as a decoy receptor for RANKL
Produced by osteoblasts
Levels are based on estrogen levels
: if estrogen-deprived, OPG is suppressed (osteoclast production increases)
Steps of Bone Reformation
: osteoclast's RANK binds to osteoblast's RANKL to induce osteoclast maturation
: osteoclasts make a ring-like seal and extent villi to digest the mineral matrix (old bone).
: end of resorption (after 3 weeks).
: osteoblasts synthesize new bone matrix
: osteoblasts become resting bone lining cells on the newly formed bone surface
Mechanism of Resorption
: Osteoclast villi secrete carbonic acid, citric acid, and H+.
: Osteoclast villi secrete cathespin K, collagenases and other proteases.
This will break down the extracellular matrix and release things that were adsorbed onto the hydroxyapatite, like IGF-1 and TGF-beta
Mechanism of Formation
: Stimulated by the cytokines and growth factors that were adsorbed onto the hydroxyapatite.
Inhibition of Bone Demineralization
: The new osteoblasts secrete alkaline phosphatase, which hydrolyzes phosphate esters, including pyrophosphate.
Promotion of Crystallization
: Inhibition of demineralization + Liberation of P
= crystallization of calcium phosphate salts and mineralization of bone matrix.
Why do we remodel bone?
Our bodies use bone as a mechanism to maintain the correct plasma Ca
is needed for neurotransmitter release, muscle contraction, and blood coagulation.
Phosphate is needed for...
Life Basics! Such as:
1. Nucleotides and ribonucleotides
2. Intermediary metabolism
3. Energy metabolism (ATP)
4. Activity of signaling
5. Within bone it is complexed with calcium as hydroxyapatites, having the general formula Ca10(PO4)6(OH)2, as well as being present as Ca3(PO4)2
Components of Daily Calcium Turnover
: for every 800-1000 mg of calcium intake, the bone remodels 300 mg of it's calcium
: active vit-D dependent transport + facillitated diffusion
1,25-dihydroxyvitamin D (Calcitriol)
Facilitates absorption of phosphate and Ca
from the small intestine
Interacts with PTH to enhance calcium and phosphate mineralization from bone (thus
Decreases renal excretion of both calcium and phosphate
Active form of vitamin D, requiring two hydroxylations
Effects are mediated by Vitamin D Receptor, which translocate to the nucleus to modify gene transcription
Parathyroid Hormone: Effects and Regulation
Increases calcium reabsorption in the
and increases absorption from intestines
Inhibits phosphate reabsorption from the
, therefore increasing urinary excretion
Enhances reabsorption of Mg
and excretion of water, aas, citrate, K
, bicarbonate, Na
Increases calcitriol production
by stimulating 1a-hydroxylase activity in kidney mitochondria
Down-regulated by an increase in Ca
levels, which are noticed by the calcium sensing receptor on parathyroid cells
R (GPCR)- binds PTH and PTH-related protein
R (GPCR)- binds only PTH
3. CPTH receptor (on osteocytes)- binds truncated amino end of PTH
The GPCRs couple with G
(adenylate cyclase) and G
(phospholipase C -> DAG + IP3 -> Ca
Parathyroid Hormone: Molecular info
True form is
84 aa PTH
Stored in secretory granules until discharged into the circulation
If aas # 1 and 2 are removed, the protein can bind to receptor, but cannot activate cAMP or IP3-Ca+2 signaling pathways
If the first 6 aas have been removed (i.e., PTH converted to aas 7-84), PTH action is inhibited.
are absorbed from the small intestine
Circulates in the blood with a vitamin D binding protein (an alpha-globulin)
Increases clearance of inorganic phosphate
Makes weird vitD metabolite w/ OH at carbon24
Increased osteocyte expression causes low plasma phosphate, low plasma calcium, and defective mineralization
Hypocalcemic hormone opposing action of PTH
Most potent inhibitor of osteoclast-mediated bone resorption (by decreasing their ruffled-border surface area)
Released in response to hypercalcemia
Salmon calcitonin is used therapeutically
At high doses, there is an increased excretion of Ca
Tx: Paget's, Osteoporosis, Hypercalcinemia
Target the GI, Kidney, and Bone
Decrease levels of Ca
Decreases Ca2+ levels
: caused by hypersecretion of PTH
: mutations in CaSR
: Saline, Calcitonin, IV bisphosphonates (inhibit osteoclast bone resorption), Oral sodium phosphate
: Tx IV CaCl, Calcitriol
: Tx Calcitriol, Ca
Toxic due to too much calcium and phosphate absorption + too much demineralization
: stop taking vitD; administer glucocorticoids
Vitamin D deficiency (Rickets)
Reduced Ca2+ absorption, thus increased PTH, thus increased demineralization, thus weak bones
Because the fetus acquires >85% of its calcium stores during the third trimester, premature infants are especially susceptible to rickets
Tx: sun, calcitriol (1000-4000 units/day for a few weeks)
Often seen in bone disease accompanying chronic renal failure
Increased phosphate levels reduce serum [Ca+2], which activates PTH secretion and exacerbates the hyperphosphatemia.
: The calcium sensing receptor agonist, cinacalcet, may be used to suppress PTH secretion
Calcium sensing receptor agonist
Suppresses PTH secretion
Anti-resorptive agents (Slow bone resorption)
3. Selective estrogen response modulators (SERMS)
The most frequently used drugs for
Also used for
and anti-tumor via anti-angiogenic effects
Three year relative efficacy of therapeutic interventions of BMD of the lumbar spine
GI distress and Osteonecrosis of the jaw
: poorly absorbed
Estrogen (Hormone Replacement Therapy)
The outcome of the Women’s Health Initiative showed estrogen as part of HRT caused an increased risk of heart disease and breast cancer.
SERMs: Selective estrogen response modulators
Estrogenic agonist on bone, inactive on uterus, anti-estrogenic on breast
Reduces the risk of vertebral compression fracture
OPG mimic; RANKL sequesterer
In Phase III clinical trials
After 3 years, therapy showed a 68% decrease in vertebral fractures, 41% decrease in hip fractures, and a 20% decrease in non-vertebral fractures
: minimal side chains
: nitro R2 side chain, 10-100x potency of 1
: ring side chain, 10,000x potency of 1
Concentrate at site of active bone remodeling
Get incorporated into bone matrix
When released by osteoclast acidic environment, this class directly inhibits osteoclasts
1. First Gen gets metabolized into a nonhydrolyzable ATP analog (AppCCl2p) that accumulates within osteoclasts and induces apoptosis
2. Second & Third Gen directly inhibit multiple steps in the pathway from mevalonate to cholesterol and isoprenoid lipids (required proteins for osteoclast activity)
: increased BMD—14% increase in lumbar spine, with smaller increments for hip, femur and forearm
: shown to decrease vertebral and non-vertebral fractures (used if GI distress occurs w/ other bisphosphonates)
: Hypercalcemia and prevention of bone loss (breast cancer & multiple myeloma) IV-only
: Prevention of bone loss (prostate and breast cancer pts w/ HRT)
: Prevention and Tx of postmenopausal osteoporosis
: suppresses bone turnover and improves BMD
: reduces cortical bone loss
Reduction they cause in Ca+2 excretion constrains bone loss in patients with hypercalcuria
Anabolic agent for osteoporosis and Paget's
Mitogen for osteoblasts and it increases trabecular bone mass.
: accelerates cortical bone loss.
: Its use leads to hydroxyapatite being converted to fluoroapatite, which is denser and more brittle.
Studies of its impact on fractures have been inconsistant.
Anabolic agent for osteoporosis and Paget's
Currently the only agent that increases new bone formation.
: for 2 years in people at high risk for fracture
: increases trabecular bone at the lumbar spine and femoral neck (near hip-see diagram). It has less significant effects at cortical bone sites.
: 20 ug qd SC
: nausea, headache, leg cramps and dizziness.
Secondary hyperparathyroidism (SHPT)
Complex alteration in bone and mineral metabolism that occurs as a direct result of chronic kidney disease (CKD)
Identifying patients at risk and evaluating for SHPT is imperative because early intervention may slow or arrest the progression of both bone and cardiac disease.
Because 40% of patients with diabetes develop nephropathy, diabetic patients alone will account for 12 million people with CKD.
Sites for intervention
: Excretion of P
, Activation of Vit D
, Serum Ca
Tx: oral phosphate binders, calcitriol or its analogs, & calcimimetics
Nonabsorbable cationic ion-exchange resin that binds dietary phosphate. It also binds bile acids leading to decreased cholesterolabsorption.
Vitamin D Analogs for CKD
Tx Secondary hyperparathyroidism
: reduces PTH without producing hypercalcemia or altering serum P
: A prodrug that must be activated by hepatic C25 hydroxylation1a25-(OH)2D2 for secondary hyperpara-thyroidism