Bone Homeostasis

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Bone Homeostasis
2013-03-28 02:05:33
Pharmacology II Exam Rutgers

For Rutgers P2 students
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  1. Haversian Systems
    The structural units of compact bone.  Blood vessels and nerves run through the Haversian canals, which run lengthwise through the bone.
  2. Osteoporosis is caused by a lack of...
    Collagen I or Collagen XXIV
  3. What four factors determine peak bone mass?
    • 1. Estrogen and androgen (when younger)
    • 2. Physical activity
    • 3. Dietary calcium
    • 4. Genetics

    Obviously, the only ones we can regulate are 1-3. And all 1-3 are needed; no compensating.
  4. 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.
  5. Osteoclasts
    • Derived from marrow precursor cells in response to physical/biochemical signals (i.e. CSF-1)
    • Multinucleated
    • Clasts "crumble" = resorb = excavate into the bone
    • Expresses RANK
  6. RANK
    • Receptor for Activating NF-kB
    • Required for osteoclast bone resorption
  7. RANKL
    • RANK Ligand
    • Binds to RANK to induce osteoclast formation
    • Produced by osteoblasts (two types= membrane-bound + soluble form)
  8. Osteoprotegerin (OPG)
    • 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)
  9. Steps of Bone Reformation
    • Activation: osteoclast's RANK binds to osteoblast's RANKL to induce osteoclast maturation
    • Resorption: osteoclasts make a ring-like seal and extent villi to digest the mineral matrix (old bone).
    • Reversal: end of resorption (after 3 weeks).
    • Formation: osteoblasts synthesize new bone matrix
    • Quiescence: osteoblasts become resting bone lining cells on the newly formed bone surface
  10. Mechanism of Resorption
    • Demineralization: Osteoclast villi secrete carbonic acid, citric acid, and H+. 
    • Proteolysis: 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
  11. Mechanism of Formation
    • Osteoblast Proliferation: 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 Pi = crystallization of calcium phosphate salts and mineralization of bone matrix.
  12. Why do we remodel bone?
    • Our bodies use bone as a mechanism to maintain the correct plasma Ca2+ level.
    • Ca2+ is needed for neurotransmitter release, muscle contraction, and blood coagulation.
  13. 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
  14. Components of Daily Calcium Turnover
    • 1. Bone: for every 800-1000 mg of calcium intake, the bone remodels 300 mg of it's calcium
    • 2. Intestine: active vit-D dependent transport + facillitated diffusion
    • 3. Kidney: excretion
  15. 1,25-dihydroxyvitamin D (Calcitriol)
    • Facilitates absorption of phosphate and Ca2+ from the small intestine
    • Interacts with PTH to enhance calcium and phosphate mineralization from bone (thus bone mobilizing)
    • 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
  16. Parathyroid Hormone: Effects and Regulation
    • Increases calcium reabsorption in the distal tubule, and increases absorption from intestines
    • Inhibits phosphate reabsorption from the proximal tubule, therefore increasing urinary excretion
    • Enhances reabsorption of Mg2+ and excretion of water, aas, citrate, K+, bicarbonate, Na+, Cl- and SO42-
    • Increases calcitriol production by stimulating 1a-hydroxylase activity in kidney mitochondria (proximal tubule)
    • Down-regulated by an increase in Ca2+ levels, which are noticed by the calcium sensing receptor on parathyroid cells
  17. PTH Receptors
    • 1. PTH1R (GPCR)- binds PTH and PTH-related protein
    • 2. PTH2R (GPCR)- binds only PTH
    • 3. CPTH receptor (on osteocytes)- binds truncated amino end of PTH

    The GPCRs couple with Gs (adenylate cyclase) and Gq (phospholipase C -> DAG + IP3 -> Ca2+)
  18. 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.
  19. Vitamin D
    • Dand D3 are absorbed from the small intestine
    • Circulates in the blood with a vitamin D binding protein (an alpha-globulin)
  20. FGF-23
    • Phosphatonin
    • 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
  21. Calcitonin
    • 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 Ca2+
    • Tx: Paget's, Osteoporosis, Hypercalcinemia
  22. Glucocorticoids
    • Target the GI, Kidney, and Bone
    • Decrease levels of Ca2+ and Pi
    • Demineralize bone
  23. Thyroid hormone
    • Targets bone
    • Increases Ca2+ levels
    • Demineralizes bone
  24. Gonadal steroids
    • Targets bone
    • Decreases Ca2+ levels
    • Mineralizes bone
  25. Hypercalcemia
    • Primary: caused by hypersecretion of PTH
    • Familial: mutations in CaSR
    • Tx: Saline, Calcitonin, IV bisphosphonates (inhibit osteoclast bone resorption), Oral sodium phosphate
  26. Hypocalcemia
    • Calcium deficient: Tx IV CaCl, Calcitriol
    • Hypoparathyroidism: Tx Calcitriol, Ca2+ supplements
  27. Hypervitaminosis D
    • Toxic due to too much calcium and phosphate absorption + too much demineralization
    • Tx: stop taking vitD; administer glucocorticoids
  28. 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)
  29. Hyperphosphatemia
    • Often seen in bone disease accompanying chronic renal failure
    • Increased phosphate levels reduce serum [Ca+2], which activates PTH secretion and exacerbates the hyperphosphatemia.
    • Tx: The calcium sensing receptor agonist, cinacalcet, may be used to suppress PTH secretion
  30. Cinacalcet
    • Calcium sensing receptor agonist
    • Suppresses PTH secretion
    • Tx hyperphosphatemia
    • ADEs: hypocalcemia
  31. Anti-resorptive agents (Slow bone resorption)
    • 1. Bisphosphates
    • 2. Estrogen
    • 3. Selective estrogen response modulators (SERMS)
    • 4. Calcium
  32. Bisphosphonates: General
    • The most frequently used drugs for osteoporosis
    • Also used for Paget's disease and Hypercalcemia, and anti-tumor via anti-angiogenic effects
    • Three year relative efficacy of therapeutic interventions of BMD of the lumbar spine
    • ADEs: GI distress and Osteonecrosis of the jaw
    • ADME: poorly absorbed
  33. 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.
  34. SERMs: Selective estrogen response modulators
    • i.e. Raloxifene
    • Estrogenic agonist on bone, inactive on uterus, anti-estrogenic on breast
    • Reduces the risk of vertebral compression fracture
  35. Denosumab
    • 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
  36. Bisphosphonates: Generations
    • First Gen: minimal side chains
    • Second Gen: nitro R2 side chain, 10-100x potency of 1st
    • Third Gen: ring side chain, 10,000x potency of 1st
  37. Bisphosphonates: MoA
    • 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)
  38. Bisphosphonates: Examples
    • Alendronate: increased BMD—14% increase in lumbar spine, with smaller increments for hip, femur and forearm
    • Zoledronate: shown to decrease vertebral and non-vertebral fractures (used if GI distress occurs w/ other bisphosphonates)
    • Etidronate: Paget's
    • Pamidronate: Hypercalcemia and prevention of bone loss (breast cancer & multiple myeloma) IV-only
    • Tiludronate: Paget's
    • Zometa: Prevention of bone loss (prostate and breast cancer pts w/ HRT)
    • Ibandronate: Prevention and Tx of postmenopausal osteoporosis
  39. Calcium
    • In elderly: suppresses bone turnover and improves BMD
    • In post-menopausal: reduces cortical bone loss
  40. Thiazide diuretics
    Reduction they cause in Ca+2 excretion constrains bone loss in patients with hypercalcuria
  41. Fluoride
    • Anabolic agent for osteoporosis and Paget's
    • Mitogen for osteoblasts and it increases trabecular bone mass.
    • ADE: accelerates cortical bone loss.
    • MoA: Its use leads to hydroxyapatite being converted to fluoroapatite, which is denser and more brittle.
    • Studies of its impact on fractures have been inconsistant.
  42. Teriparatide (rPTH)
    • Anabolic agent for osteoporosis and Paget's
    • Currently the only agent that increases new bone formation.
    • Prevention: for 2 years in people at high risk for fracture
    • MoA: increases trabecular bone at the lumbar spine and femoral neck (near hip-see diagram). It has less significant effects at cortical bone sites.
    • Dose: 20 ug qd SC
    • BBW: Osteosarcoma
    • ADEs: nausea, headache, leg cramps and dizziness.
  43. 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 Pi, Activation of Vit D3, Serum Ca2+
    • Tx: oral phosphate binders, calcitriol or its analogs, & calcimimetics
  44. Sevelamer
    • Nonabsorbable cationic ion-exchange resin that binds dietary phosphate. It also binds bile acids leading to decreased cholesterolabsorption.
    • Expensive
  45. Vitamin D Analogs for CKD
    Tx Secondary hyperparathyroidism
    • Paricalcitol: reduces PTH without producing hypercalcemia or altering serum P
    • Doxercalciferol: A prodrug that must be activated by hepatic C25 hydroxylation1a25-(OH)2D2 for secondary hyperpara-thyroidism