Bone and cartilage

From Iusmhistology

  • started here on 02/21/11 at 1PM.


Contents

[edit] Bone and Cartilage

  • Starting a series of three lectures: today, Wednesday (development), and Monday (metabolic regulation).
  • Chronic musculoskeletal issues are huge!

[edit] Evaluating bone health in the clinical setting

  • Most important diagnostic is bone density imaging.
    • DXA = dual energy xray a?
    • We have a huge reference population on which to base our results.
    • Disadvantages:
  • High resolution CT scanners
    • Pretty and pretty amazing
    • Becoming more common


  • Serum / urine biomarkers:
    • These are markers that can help us know how much osteoblast and osteoclast activity and bone resorption activity.
    • Go back to this list after the lecture.
    • Don't need to know all of these


  • Bone biopsy
    • Take a coring tool, core out some from the iliac crest.
    • Then take a histological slide.
    • Not used very much.
    • Used when biomarkers just don't tell you what you need to know.
    • However, histology is very important for clinical trials

[edit] Bone cells

[edit] Osteoclasts

  • Large
  • Multiple nuclei
    • More nuclei = more metabolically active
  • Much larger than any surrounding cells
  • Originate from hematopoietic lineage
    • HSC sits in a macrophage CFU in the bone marrow
    • Become monocites
    • Stay in bone marrow
    • Become osteoclast
    • Rank ligand essential for diff into preosteoclast and full osteoclast.
  • Rank ligand
    • Made by osteoblasts
    • Made by other cells of the bone marrow.
    • Attaches to rank receptor on pre-osteocblasts
  • Multiple osteoclasts fuse to form multinucleate
  • OPG
    • A decoy receptors for rank ligand
    • Can keep osteoclasts from developing by sucking up all the rank ligand
  • After maturation and getting to bone surface it starts to resorb bone
  • Sealing zone is generated to attach firmly to the bone
    • Allows the osteoclast to target where resorption will occur
    • Compartmentalizes the enzymes
    • Generates a "focal zone"
  • Ruffled boarder is generated
    • Increases the amount of surface area so enzymes can be pumped out of the cell onto the bone in high amounts.
  • Enzymes for resorption:
    • TRAP
      • Tartrate-resistant alkaline phosphatase
      • Can be assessed in blood to know how much activity of osteoclasts is occurring
    • Cathepsin K
  • Houshets lacuna
    • Well in bone where resorption has occurred.

[edit] Osteoblast

  • Located on bone surface
  • Secrete osteoid
    • Osteoid is unmineralized
  • Osteoid ges minieralized eventually.
  • Come from mesenchymal cells
    • Need runks2 and ostrix
    • Without you get no bone
  • Runks2
  • Ostrix
  • Alkaline phosphatase is key protein involved in matrix production
  • Osteoblasts become: osteocytes, bone lining cells, or it can undergo apoptosis.
  • Osteoblasts secrete osteoid until their signal to secrete goes away then it beocmes one of thse three fates.
  • Bone lining cells:
    • Flattened
    • Lay on bone surface
    • Can still become activated
    • In a nomral state, these cells line the entire bone.
    • Signal can cause them to plump back up and resume bone formation.

[edit] Osteocyte

  • Most abundant of cells of the bone
  • Third cell within bone
  • Impt for sensing signals within the bone
  • These are terminally differentiated
  • Surrounded by osteoid or mineralized matrix.
  • MOst abundant of bone cells
  • Connected to each other and to the bone surface by filopodial processes
    • These live in channels called canaliculi
    • Connected via gap junctions.
  • There is one osteocyte per lacunae.
  • Perform matrix maintenance and mechanics.
  • This is an intricate network of osteocytes
    • Trading nutrients
    • Sending information

[edit] Genetic profile differs from osteoblasts

  • Osteocyte cannot produce any more matrix
  • Has different functions than the osteoblast
  • Don't memorize the table
  • Sclerostin is a gene unique to osteocytes and not osteoblasts.
    • This shows up in late an osteocytes differentiation.
    • It inhibits bone formation
    • We are trying to develop drugs to inhibit sclerostin help grow bone.

[edit] Bone matrix

  • Made of type 1 collagen.
    • A fibrous collagen.
  • Takes on a staggered arrangement.
    • Mineral connects them end to end.
  • The fibrils are highly crosslinked
    • Promotes structural rigidity.
  • Mineral interspersed also adds rigidity.
  • Fragments of crosslinks can be used to measure bone turn over.
  • C-propeptide in the blood means there is bone formation
When does collagen get cleaved?
From wikipedia:
  1. Inside the cell
        1. Two types of peptide chains are formed during translation on ribosomes along the rough endoplasmic reticulum (RER): alpha-1 and alpha-2 chains. These peptide chains (known as preprocollagen) have registration peptides on each end and a signal peptide.
        2. Polypeptide chains are released into the lumen of the RER.
        3. Signal peptides are cleaved inside the RER and the chains are now known as pro-alpha chains.
        4. Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on ascorbic acid (Vitamin C) as a cofactor.
        5. Glycosylation of specific hydroxylysine residues occurs.
        6. Triple helical structure is formed inside the endoplasmic reticulum from each two alpha-1 chains and one alpha-2 chain.
        7. Procollagen is shipped to the golgi apparatus, where it is packaged and secreted by exocytosis.
  2. Outside the cell
        1. Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.
        2. Multiple tropocollagen molecules form collagen fibrils, via covalent cross-linking by lysyl oxidase which links hydroxylysine and lysine residues. Multiple collagen fibrils form into collagen fibers.
        3. Collagen may be attached to cell membranes via several types of protein, including fibronectin and integrin.
  • Collagen is formed in a twisted plywood formation.
    • This gives strength to the bone.
    • So its like people and they it is twisted in an orientation that will maximixe the structural integrity.


  • Non-collagenous components:
    • Know osteopontin, osteonectin, and ostecalcin
    • Osteocalcin is a biomarker that can be measured in the blood to know how much osteoblast activity (bone formation) there is.


  • Bone mineral
    • Mineral goes between adjacent collagen fibers and in the space between.
    • As it accumulates it first goes between length wise.

[edit] Tyeps of bone tissue

[edit] Woven bone

  • AKA primary bone and Immature bone
  • Not very common in the adult skeleton
  • Found only when there is a bone injury or in some pathological state
  • This is the type of bone that is formed when you need bone right now.
    • Provides rapid stabiliation
  • Not very organized
  • Osteoid spit out in all directions
  • Relatively low mechanical strength.

[edit] Lamellar bone

  • AKA secondary bone, mature bone
  • Most of the bone oin our bodies is this type
  • Highly organized
    • As mentioned above
  • Formed slowly
  • Higher mecanical strength than primary.
  • Lamellae:
    • Differing patterns of collagen organization
    • Result in high birefringence
      • The ability to refract light differently.
    • This is a product of the alternating pattern of collagen fibers.

[edit] Bone anatomy

  • Cortical or cancellous bone
    • Cortical is called compact
      • This is the outer part
      • Main fxn is structural
      • PRovide resistance to loading
    • Cancellous bone = spongy bone = trabecular
      • NOT squishy
      • Small piece of cancellous and small piece of cortical would looke the same.
  • Four different surfaces:
    • Outer surface is called the periosteal surface
    • Within are the cancellous surfaces
    • Endocortical surface is the inside of the cortical surface.
    • Within cortical bone are the haversion units.
    • KNow the four surfaces

[edit] Haversion systems

  • AKA osteons
  • An osteon is a unit of bone that the osteoclasts have dug out and then replaced within the cortical unit of the bone.
  • Within the haversion system is a space where the blood vessels and nerves flow.
  • The center part of this haversiona canal is the central canal.
    • Run along the long axis of the bone
  • Perferating canals = volkman (?) canals
    • Go perpendicular to the long axis of the bone
    • House vessels and nerves
  • OUter edge of osteon is called the cement line.

[edit] Periosteum

  • This layer is tightly adherent to the bone
  • Both cellular and fibrous layers

[edit] Endosteum

  • Endosteum is similar to periosteum but is on the inside of the bone
    • Endostium has only cells.

[edit] Structures

[edit] Lamellae

  • Concentric lamellae:
    • These are concentric.
    • Each ring from the outside of the bone in are called lamellae.
    • Associated with a central canal.
  • External circumferential lamellae
    • Wrap all the way around the bone.
  • Interstitail lamellae
    • Within the bone tissue but not associated with central canals

[edit] Cartilage

  • Cells are housed in lacunae which are surrounded by matrix.

[edit] Hyline cartilage

  • Found in joints, respiratory passages, ends of ribs, within bones
  • Made of type 2 collagen fibrils
  • Has some non-collageneous proteins proteoglycan aggregates.
  • Proteoglycan aggregates
    • Have a central core
    • Have some protein cores and then glycoaminoglycans hanging off.
  • PG attract water and can therefore act as a shock absorber.


  • Chondronectin
    • Holds cells in place on the collagen and proteoglycans


  • Condrocytes:
    • Retain mitotic activity
      • Unlike osteoclasts
    • Can form 2, 4 or even more cells within its region.
    • These units are called isogenous groups.


  • Hyline matrix:
    • It is not uniform.
    • Terirtorial matrix = capsular
      • Found just around a chondrocyte
      • Capsule is found closer
    • INterteritorial matrix
      • Found farther out.
    • The collagen fibrils are smaller in the territorial matrix
    • The types of pg are different in the territorial than interterritorial.


  • Perichondrium
    • Fibrous tissue that lines the outside of hyline cartilage in most but not all locations of hyline cartilage
    • Allows connection of muscle to cartilage
    • Supplies the cells that can differentiate into chondroblasts (which diff into chondrocytes)

[edit] Fibrocartilage

  • Found mostly in IV disks
  • Has type 1 collagen in it.
    • Forms fibers called rows or chords
  • Between chords are the chondrocytes
  • Has no perichondrium
  • Can serve as a transition between tissues like tendon and bone.


[edit] Elastic cartilage

  • Found in the ear, epiglottis, and the larynx
  • Has type 2 collagen
    • Fibrils
  • Elastic fibers also present
  • Has a pericondrium
  • Looks much like hyline but you can see fibers in it.


  • stopped here on 02/21/11 at 3PM.
  • started here on 02/23/11 at 2PM.

[edit] Concept review from Monday

  • Osteoblasts have three possible fates:
    • Get encased in osteoid and become an osteocyte
    • Apoptosis
    • Cease activity and become an inactive osteoblast
      • These are called bone lining cells; they are inactive osteoblasts.
  • Osteocytes:
    • These are osteoblasts that have become encased in the osteoid.
    • Osteocytes are unique from osteoblasts in their genetic profile.
    • Secretes slecerotsin (which osteoblasts no not) which inhibits osteoblasts.
  • Cortical versus cancellous bone:
    • If we take a small piece of bone out of the cancellous bone (like a single trabecula), it would have the same strength of a same size piece in the cortical bone.
    • If you take a large piece of cancellous bone (like a whole chunk that looks like a sponge) it would be weaker than a similar chunk of crotical bone.
  • Bone versus hyaline cartilage
    • Cells: osteoblasts, osteoclasts, osteocytes / chondroblasts, chondrocytes
    • Matrix: type 1 collagen, NCP, minerals / type 2 collagen, PG
    • Matrix production: osteoblasts / chondroblasts or chondorcytes
    • Cell-cell connections: osteoblasts, osteocytes / none
    • Vasculature: central canals, perferoating canals, marrow, and periosteum / none
    • Supporting tissue: periosteum / perichondrium

[edit] Joints

[edit] Synarthroses

  • Very little movement
  • Can be bone to bone or bone to hyline to bone or bone to fibrous to bone.

[edit] Diarthrovidal (synovial) joints

  • Have a cavity with fluid
  • Components: bone and cartilage of one long bone and a second long bone, and then the cavity space.

[edit] Articular cartilage

  • This is hyline cartilage
  • Articular cartilage has type 2 collagen with fibrils not fibers.
  • There are several zones:
    • Superficial zone: in intimate contact with the cavity; has very few condrocytes; mostly type 2 collage fibrils; resists sheer forces
    • Intermediate (transitional) zone: a transition from superficial to radial
    • Radial (deep) zone: large number of chondrocytes; large number of collagen fibrils; compresses to absorb forces; lysogenous groups; interterritorial regions, etc.
    • Calcified zone: interface between unminderalized cartilage of the radial and the subchondrial bone (first part of the zone); distinct from radial by way of tidemark
How do you tell the diff between calcified and non calcified cartilage?

[edit] Joint capsule

  • Capsule is continuous with the periosteum
  • Periostium has two layers: fibrous and cellular layer
  • As it starts to cover the capsule, though, it loses it's cellular layer.
  • Surface of the synovial membrane is not covered with epithelial cells
    • A rare occurance in the body.
  • Synovial membrane secretes fluid that makes the joint space.
    • Gets nutrients to cells
    • Acts as shock absorber


  • Synoviocytes:
  • Type A:
    • Found on surface of the synovial membrane
    • Look like epithelium but are not because they are not connected together.
    • Act like macrophages to detect and phag foreign particles.
    • Uusually 1 cell deep but can be 2 to 3 deep.
  • Type B:
    • Deeper within the matrix
    • A fibroblast like cell
    • Makes hyaluronic acid
    • Look much like fibroblasts


  • No perichondrium on ends of bones

[edit] Osteoarthritis and Rheumatoid arthritis

  • AKA OA and RA
  • OA:
    • Mechanical
    • Rubbing of bone without cartilage
  • RA:
    • INflammation occurs
    • osteoclasts "wreak havoc" on the cavity

[edit] Chondrogenesis

  • Chondrocytes produce matrix
  • Then chondrocytes divide
  • Interstitial growth verses appositional growth
    • When matrix made "within" existing cartilage, the cells will separate from one another; this is how the bone is lengthened at the epiphyseal plates.
    • When matrix is grown around a chondrocyte the cells do not move (adding new matrix onto a surface that already exists); used in lung tissue development.

[edit] Intramembraneous bone formation

  • Much like cartilage development
  • In craniofacial bones, mesenchymal cells get the signal to be osteoblasts, then aggregate to form a bone blastema.
  • Then they secrete matrix to form the primary bone tissue with osteoblasts around the outside and some osteobalsts in the middle.
  • Bone spicules are formed through intramembraneous ossification.
  • How do you tell developing bone and cartilage apart?
    • Lack of perichondrium (most cartilage has a perichondrium).
    • Uneven activity indicates probalby not cartilage
    • Matrix is less smooth in bone
  • This is bone formation from scratch.

[edit] Endochondrial bone formation

  • Here we start with a template on and in which we build bone.
    • The template is hyline cartilage.
  • The first step:
    • Cells within the template, chondrocytes hypertrophy lending the adjacent matrix to calcification
    • A bone collar forms by appositional growth (adding bone to a surface) on the surface of the hyline cartilage template
  • Once the bone collar begins to form, the connective tissue above it becomes a periosteum.
    • Regions without bone collar still have perichondrium
  • Second, the bone collar is penetrated by an osteogenic (osteopenic) bud to start vascularizing the developing bone.
  • Once penetrated and calcified cartilage in the middle is degraded, the area will be filled with bone.
    • This is called the primary ossification center
    • This region grows along the long axis of the bone.
    • This is due in part to the activity at the epiphyseal plates.
  • Third step occurs at the epiphyseal growth plates
    • One at each en dof the developing bone
    • Here is where bone lengthening happens
    • There are 5 zones.
    • Zone of rest: (shallowest from the articular surface to the middle of the bone): no activity by chondrocytes
    • Zone of proliferation: chondrocytes become align and form rows and columns of chondrocytes (stacked coins) which contributes to bone growth as they push the entire bone unit to increase in length
      • Can see rows of fairly flat chondrocytes.
    • Zone of hypertrophy: all the chondrocytes hypertrophy; causes bone lengthening
      • Has larger cells than proliferative, but still has a similar staining matrix (lightness versus darkness).
    • Zone of calcified cartilage: chondrocytes start to die off as they can't get nutrients
      • Distinct from the zone of hypertrophy because the matrix is much darker.
    • Zone of ossification: bone formation on top of the calcified cartilage template; cartilage is resorbed by osteoclasts.
      • Distinct from the zone of calcification because the matrix turns light again (but a little different coloring than the proliferative).


  • Secondary ossification centers form
    • This occurs when blood vessels benetrate distal to the epiphyseal plate
    • So this are now has the same zones, though smaller.


  • Growth plates fuse around puberty.

[edit] Fracture healing

  • Two types: primary and secondary.


  • Primary
    • occurs when you have a very stable fracture; no movement (perhaps because of a plate and screws put in by orthopod).
    • Then bone can form without fibrous tissue or cartilage formation.
    • Can get osteons to remodel through the fractured zone.
    • There is no additional tissue being formed (see secondary repair)
    • osteoclasts dig out a region of bone...


  • Secondary bone healing:
    • Useful when fracture is unstalbe; whats happening when casted
    • Bone and cartilage formation occur
    • How exactly it works depends on how stable the fracture is:
      • The more stable (the less strain) the less cartilage, the more bone.
      • The more it moves, the more you need cartilage b/c cartilage can withstand stretching and movement.
    • Just adjacent to the fracture the vasculature is disrupted.
    • There is lots of cartilage formed here because it doesn't need vascular supply.
    • Deepr in the boen you'll have bone formation
    • Four stages:
    • First: blood clot forms which facilitates the delivery of precursor cells that will help to heal the site (essential step).
    • Second: formation of a soft callous and vascularization of the area.
      • More strain means the callous will be more fibrous cartilage; low strain will have hyline cartilage; all are some combination of the two
    • Third: form a hard callous via woven bone
      • Woven bone occurs primarilly in injury because it is formed qucikly but is disorganized.
    • Fourth: remodeling; removal of woven bone, replaced with lamellar bone.


  • stopped here on 02/23/11 at 3PM.
  • started here on 02/28/11 at 2PM.


[edit] Bone remodeling

  • This is a balance of osteoblast and osteoclast activity.
  • 2/3 of bone gets resorbed each year.
  • Just as we make new roads, the road starts to break down (cracks and such) until there are large potholes.
  • YOu can fill it with asphalt but that don't last long.
  • The better way is to remove a large chunk of the road and then resurface the entire area.


  • Same thing happens with bone.
    • Over a lifetime and with mechanical loading, we generate small cracks.
    • These are called microcracks -- about 100 microns long.
    • These are the result of daily loading on the bone.
  • What does the skeleton do?
    • It doesn't use glue or asphalt, it remodels the entire surrounding area.
    • This is called bone remodeling.

[edit] Remodeling steps

  • Think of the yellow box of a single trabeculae.
  • It is covered with lining cells.
  • Some signal causes activation of asite
    • Brings osteoclasts to come to the site and start resorption.
  • Once they have eaten a bunch, we reverse.
  • Signals bring in osteoblasts to lay down new bone.
  • Once filled back in (first with osteoid, then mineralized), you have a new-looking area and defects are gone.

[edit] Cartoon

  • Note thtat this all occurs in a continuum.
  • Death of osteocytes can signal for osteoclasts as can microcracks.
  • The reversal zone is where the osteoclasts are not resorbing but the osteoblasts have yet to arrive.
  • This process is not limited to trabechular bone but also in cortical bone.
  • The osteoclasts can dig directly into a bone causing a central canal which will be filled in with osteoblast activity.

[edit] Activation

  • This is the signaling for osteoclasts to come to the bone and start resorption.
  • The two major signals are death of an osteocyte or a microcrack in the bone.
  • The dark osteocytes are stained to pick up apoptosis markers, thus marking them as likely signals for osteoclast recruitment.
  • Microdamage can signal, too:
    • This is relatively normal for daily use.
    • Provides protection against fracture by allowing small fractures and then repair; keeps large fractures from occuring.

[edit] Resorption

  • Osteoclasts show up and seal (think sealing zone).
  • What tells the osteoclasts to stop?
    • We don't actually know.
    • It may be the osteoclasts that are alive that say "hey, don't resorb me, I'm fine."

[edit] Reversal

  • Osteoclasts leave or undergoe apoptosis.
  • Osteoblasts arrive
  • First the osteoblasts must clean up
    • Clean up mess that the osteoclast leaves: collagen fragments flowing in the wind.
    • They lay down a very thin matrix called the cement line.
    • The cement line will be at the bottom of the well, then the osteoid is laid down on top of it.
  • Then the osteoblasts lay down the normal lamellar bone
    • Osteoid is laid down
    • Mineralization occurs
  • Once they reach near the normal bone surface, the last osteoblasts become lining cells.


  • Entire process takes about 6 months.
    • Typically; though can be modulated by some stuff.


  • This process occurs at higher rates in the ribs and the jaw, probably because they are mechanically loaded more often.
  • This process also explains how we get interstitial lamellae; they used to be a complete central canal with concentric lamellae until a portion of it got remodelled.

[edit] Bone modeling

  • This is uncoupled: osteoblastas and clasts don't work in concert.
  • So, osteoclasts may come in and remove bone and then thats it.
  • IMportant in growth and development.
    • Like elongating a bone: need to add at the far end and remove at the near end (if bone is growing away from you).
  • Osteoclast deficiency demonstrates well:
    • Get elongated, clubbed-shaped femur where osteoclasts haven't come in to do their part of shaping.
  • Important for periostium, too.
    • Periostium slowly gets larger over time.
    • So this is a very slow modeling that adds material.

[edit] Bone remodeling as a cause of bone mass loss

  • Cause of reduced bone mass is due to two factors of bone remodeling.
  • First, osteoblasts get lazy over aging.
    • So normally clast and blast activity is equal.
    • But eventually the clasts dig out a little more than the blasts add back in.
    • 50-60 yo in women there is an increase in clast active sites (other than the normal clast > blast activity with aging).
      • This causes increased loss because of increased number of sites, not because of a change in osteoblast to clast activity at a given site.
      • Estrogen inhibits bone resorption so when estrogen goes away, bone resorption increases.
    • Men
      • Less osteoporsis b/c no loss of estrogen.
    • This is true for both cortical and callous bone.

[edit] Diagnostics

  • DXA
    • Doesn't tell you anything about bone resoprtion and generation activity.
  • Biomarkers
    • Does provide clast and blast activity measurements.

[edit] Pharma

  • We are concerned mostly with those people who show a low density.
  • Anti-resorptives
    • Here we are trying to stop clasta ctivity
    • Disphophonates
    • Estrogen and selective estrogen receptor modulators (SERMS)
      • These adds back the osteoclast inhibiting effect of estrogen.
      • SERMS are good becasue they focus on the osteoclasts and bone effects and not many of the other systemic effects that estrogen normally has.
    • Cacitonin
      • Not used often b/c the previous two are so successful.
    • Denosumab
      • A monoclonal antibody taht targets RANK-L.
      • Recall that RANK-L is required for dev of osteoclasts
      • Acts like OPG? (what was the endogenous decoy for RANK-L)?
    • Think "rally with sally"
    • These work by binding to the bone and inhibit osteoclast activity.
    • These do not add bone per se because they don't activate osteoblasts
Do you get brittle ness from excessive caclification?
Do you those microcracks add up and make bone more likely to break?
    • Reduce fractures 50-80%
  • Anabolics
    • Parathyroid hormone
      • An anabolic agent
      • When given pharmacologically, it builds bone.
      • Even though endogenous PTH activates clasts.

[edit] Ca, VitD, and Phosphate

[edit] Ca

  • Absorbed actively or passively in the small intestine.
  • Active in jejunum
    • Modulated by VitD
    • Enterocytes increase CalvindinD in response to VitD; which allows the cytoplasm to hold more Ca and thus to absorb more.
  • Without enough calcium you have rickets (in kids) and osteomalacia (in adults).
    • Here the bone doesn't mineralize.
    • DEformities occur
Does remodeling fix shape of bone over time if pt has rickets as a child?
    • Rickets is reversible if you treat before closure of the growth plates.

[edit] Regulation

  • PTH
    • from parathyroid
    • From chief cells = principle cells =
  • Calcitonin
    • from thyroid
What cell type?


  • In response to low calcium,
    • PTH increases
      • STimulates osteoclast activity; increases Ca+
        • Main effect
      • Reduces Ca+ loss at urine
      • INcreases CA+ absorption at the gut.
    • Calcitonin decreases
      • Allows more remodelling (less inhibitor activity).

[edit] Remodelling

  • Some resorption is occurring without the specific location signaling of a microcrack.
    • This type of resorption occurs wherever it can happen fastest b/c it is in response to low serum Ca levels.

[edit] Hypercalcemia

  • This is a chronic increase in Ca++.
  • Two etiologies: primary and secondary.
  • Primary:
    • Elevated PTH
    • Perhaps because of a tumor or something
    • Here we see that the duration of PTH exposure affects whether it stimulates clasts or blasts.
    • When using PTH is used as pharam, it is pulsatile--fast rise, fast fall-- it stimulates osteoblasts.
    • The mechanism for this is unknown.
    • Excessive levels of Ca++ reabsorption at the kidney
    • Increased VitD synthesis which feeds back to increase resorption
    • Excessive resoprtion
    • Call this pth mediated
    • Treatment
      • MOdulate the parathyroid gland


  • SEcondary
    • Three examples: toxic levels of VitD (absorb way too much ca at gut), immobilization (stimulates osteoclast activity; think space or bed-ridden), or malignancy.
    • In immobilization, lots of clast activity which increases Ca levels.
    • In malignancy, many cancer cells stimulate osteoclast activity which can result in hypercalcium.
    • Tx:
      • Use antiresorptive pharma.

[edit] Hypocalcemia

  • Can come about from decreased PTH synthesis, secretion, or even PTH resistance.
  • Can also come from low Ca diet.
  • Some drugs can cause low Ca, too.
  • TX:
    • Increased Ca and VitD.

[edit] VitD

  • Calbindin is required for good CA++ absorption at the gut and VitD is a txn factor modulating txn of Calbindin.
  • Without enough sun light we may not get 7-choleterol... converted to inactive Vd3 (in circulation).
  • Then we have to convert the vd3 to the 1 OH d2 at the liver and finally to the 1,25 OH d3 at the kidney.
  • 1 alpha hydroxylase at the kidney can be deficient to lead to VitD deficiency.
  • Can also be sunlight and dietary deficient.
One last deficiency that I didn't catch.
  • Ultimatley these cause osteomalacia and rickets.

[edit] Phosphate

  • An impt mineral.
  • REgulation is athe kidney
  • ABsorbed in the duodenum
    • Can be CA dependent or independ
    • Also regulated by vitD.
  • 90% of PHosphate is filtered at the kidney and reabsorbed.
  • Osteocytes secrete FGF23 and PTH from parathyroid act on kidney to reduce Na-Phosphate co-transporter
    • Causes icnreased loss of phosphate.
  • When phosphate is low:
    • Vitd 1,25 goes up (increase resorption at the gut)
    • PTH and FGF23 go down (decrease loss at the kidney)
  • When phosphate high:
    • vitd 1,25 is low (lower resportion at the gut)
    • Increased PHT and fGF23 (increase loss at the kidney)


  • stopped here on 02/28/11 at 3:05PM.
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