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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 activity3. Dietary calcium
- 4. Genetics
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
- Expresses RANK
- Receptor for Activating NF-kB
- Required for osteoclast bone resorption
- RANK Ligand
- 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
- 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
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
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.
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.
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
- 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
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
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
- 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+
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.
- D2 and D3 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 Ca2+
- Tx: Paget's, Osteoporosis, Hypercalcinemia
- Target the GI, Kidney, and Bone
- Decrease levels of Ca2+ and PiDemineralize bone
- Targets bone
- Increases Ca2+ levels
- Demineralizes bone
- Targets bone
- Decreases Ca2+ levels
- Mineralizes bone
- Primary: caused by hypersecretion of PTH
- Familial: mutations in CaSR
- Tx: Saline, Calcitonin, IV bisphosphonates (inhibit osteoclast bone resorption), Oral sodium phosphate
- Calcium deficient: Tx IV CaCl, Calcitriol
- Hypoparathyroidism: Tx Calcitriol, Ca2+ supplements
- Toxic due to too much calcium and phosphate absorption + too much demineralization
- Tx: 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.
- Tx: The calcium sensing receptor agonist, cinacalcet, may be used to suppress PTH secretion
- Calcium sensing receptor agonist
- Suppresses PTH secretion
- Tx hyperphosphatemia
- ADEs: hypocalcemia
Anti-resorptive agents (Slow bone resorption)
- 1. Bisphosphates
- 2. Estrogen
- 3. Selective estrogen response modulators (SERMS)
- 4. Calcium
- The most frequently used drugs for osteoporosis
- Also used for Paget's disease and Hypercalcemia, and anti-tumor via anti-angiogenic effectsThree year relative efficacy of therapeutic interventions of BMD of the lumbar spine
- ADEs: GI distress and Osteonecrosis of the jaw
- ADME: 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
- i.e. Raloxifene
- 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
- 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
- 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)
- 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
- In elderly: suppresses bone turnover and improves BMD
- In post-menopausal: 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.
- 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.
- 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.
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
- 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
- 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