what are the major mineral components in bone
calcium and phosphorus
what three forms is extracellular calcium found in?
bound calcium -bound to albumin (40%) non diffusible
ionized calcium (50%) diffusible
remaining 10 percent is complexed with other anions (nonionized) (diffusible)
chemical gradient of ca between extracellular calcium and intracellular calcium
10,000:1 (favors calcium entry into cells)
hypocalcemia
nervous system becomes more excitable as serum calcium levels drop to a reduced activation threshold level for Na channels
tetany
contractions due to low calcium levels which causes subsequent reduced activation threshold level for Na channels
hypercalcemia
nervous system becomes depressed and reflex responses are slowed
also causes decreased QT interval of the heart, lack of appetite and constipation (due to decreased contractility of the heart and muscle walls of the GI tract)
Hypocalcemia (long explanation)
When the extracellular fluid concentration of calcium ions falls below normal, the nervous system becomes progressively more excitable because this causes increased neuronal membrane permeability to sodium ions, allowing easy initiation of action potentials. At plasma calcium ion concentrations about 50 percent below normal, the peripheral nerve fibers become so excitable that they begin to discharge spontaneously, initiating trains of nerve impulses that pass to the peripheral skeletal muscles to elicit tetanic muscle contraction. Consequently, hypocalcemia causes tetany. It also occasionally causes seizures because of its action of increasing excitability in the brain.
phosphates form in the serum
H2PO4- or HPO42-
concentration and function of extracellular calcium
total in serum 2.5x10-3 M
bone mineral
blood coagulation
membrane excitability
concentration and function of extracellular phosphate
total in serum 1.00 x10-3 M
bone mineral
concentration and function of intracellular calcium
10^-7 M
signal for:
- neuron activation
- hormone secretion
- muscle contraction
concentration and function of intracellular phosphate
1-2 x 10^-3
structural role
high energy bonds
regulation of proteins by phosphorylation
normal range of calcium in the extracellular space
8.5-10.5 mg/dL or 2.1-2.6 mM
control of calcium and phosphate in the extracellular space
PTH (parathyroid)
Calcitonin
calcitrol
fibroblast growth factor (phosphate only)
what regulates PTH release
regulated by ionized serum calcium levels and low levels trigger PTH release
Four functions of PTH
trigger the initiation of bone resorption leading to release of calcium into the serum
regulates calcium retention
regulates phosphate excretion in the kidney
increases synthesis of calcitrol–> leading to an increase in calcium absorption from the GI tract
where do PTH receptors reside
osteoblast cells
what happens with unregulated release of PTH
hypercalcemia
what produces Calcitonin
C cells in the thyroid gland
what is calcitonin released in response to….
released in response to elevated levels of serum calcium (inhibits osteoclast function)
calcitonin is not necessary to maintatin normal ca levels in humans but levels of calcitonin rise in individuals with medullary thyroid cancer and other endocrine malignancies so it is a **tumor marker*
calcitonin therapeutically?
treatment of bone disorders characterized by excessive bone resorption
where is the prohormone vitamin D converted to active form vitamin D
kidney
what is the function of calcitrol?
absorption of ca from the GI tract
bone formation
promotes both ca and phosphate resorption from the kidney
lack of vitamin D levels results in….
impaired Ca absorption and poor mineralization of bone b/c vitamin D is needed for calcitrol synthesis
also leads to increased phosphate secretion
Fibroblast growth factor does what?
phosphate regulation at the levels of the kidney
FGF23 usually results in downregulation of calcitrol levels (lowering ca absorption) and lowering levels of phosphate
absence of FGF23?
results in increased levels of phosphate and calcium due to increased levels of calcitrol
regulation of FGF23
under the control of dietary phosphorus, serum phosphorus and calcitrol levels (mechanism not really known)
trabecular bone
found on inside of long bones, the vertebrae and on large flat bones
metabolically active (more so than cortical bone)
cortical bone
dense and compact
80 percent of skeleton
strength and protection
rarely subject to metabolic processes (although it can be used)
inorganic matrix of bone
hydroxyapatite
trace amounts of Magnesium, Sodium, Potassium, Fluoride, Chloride
Organic part of bone (osteoid)
Cells –> osteoblasts, osteocytes, osteoclasts
Matrix–>
Collagen type I (90%)
Bone proteoglycan
Non-collagenous proteins
- osteocalcin
- osteonectin
- bone sialoprotein
- matrix GLA protein
- fibronectin
three principle amino acids of the collagen helix
glycine, alanine, proline and an unusual amino acid 4-hydroxyproline
primary unit of collagen?
single polypeptide –> alpha chain–> arranged in a left handed helix
why is glycine necessary in the collagen structure
it is the only aa that can accommodate the procollagen molecule
PINP
formed from cleavage of type I collagen to form larger collagen support structure
is the free amino-terminal
PICP
formed from cleavage of type I collagen to form larger collagen support structure
carboxy-terminal end
what can be measured in serum as a marker of collagen formation?
non-helical portions at the amino and carboxy terminals
what gives collagen its tremendous tensile strength
aligned tropocollagen molecules
what gives collagen its strength and flexibility
cross links b/w molecules of tropocollagen
in the bone these cross links consist of pyridinoline molecules (links form between hydroxylated lysine residues)
Absorbic acid is necessary for these cross-links!!!
Absence of ascorbic acid??
SCURVY
symptoms include: small hemorrhages caused by fragile blood vessels tooth loss poor wound healing reopening of old wounds bone pain and degeneration heart failure
The products of collagen breakdown that can be measured in serum/urine (5)
hydroxyproline NTx CTx pyridinoline deoxypridinoline
periosteal apposition
increase in bone width
during childhood this is accompanied by endosteal resorption or resorption of the bone surface in contact with the marrow cavity
bone remodeling is coupled meaning what?
bone resorption is followed by bone formation
osteoblasts are derived from what?
mesenchymal stem cells
what do osteoblasts do?
lay down collagen and noncollagen proteins prior to mineralization
why is mineralization delayed for several days
allows for collagen cross-linking
what is released during bone formation
bone specific alkaline phosphatase AND osteocalcin
these can be markers used to access bone formation
osteoclasts do what?
mediate bone resorption
how? through the secretion of proteases and hydrogen ions to lower the pH
what are osteoclasts derived from
hematopoietic stem cells and differentiate to form large multinucleated cells
what are the signals for osteoclast differentiation
derived from osteoblast cells in response to PTH stimulation
where is the receptor for calcitonin?
resides on osteoclast cells and is an INHIBITORY factor
connection b/w osteoblasts and osteocytes is important in what>
sensing mechanical stress within the bone, and this stress within the bone can be transmitted to the surface and the process of bone remodeling can be triggered
what does PTH do to osteoblasts?
stimulates them to release M-CSF
what does M-CSF do?
stimulates the differentiation of hematopoietic stem cells to osteoclasts precursors
RANK L
released by osteoblasts
triggers bone resorption by osteoclasts
RANK
receptor for RANKL
located on osteoclasts
IL-6
mediates bone resorption
OPG
after two weeks of activation (of osteoclasts) OPG terminates bone resorption by acting as a soluble receptor for RANKL thus inhibiting RANKL from binding RANK
disease states that are related to hyperactive and chaotic bone deposition result in ….
weakened bone
as people age what happens to bone resorption and bone formation?
process becomes uncoupled, usually leading to net bone resorption
Steps of bone remodeling
Activation
Resorption
Reversal
Formation
Glucocorticoids
retard bone formation
1) suppress intestinal calcium absorption and induce osteoclastogenesis
2) deplete osteoblasts through supppression of differentiation factors and induction of apoptosis
Gonadal hormones
estrogens and androgens
estrogens: needed for closure of epiphyseal plates
lack of estrogen during development results in increased adult height and decreased bone density
-decrease bone resorption (cytokines and prostaglandins)
androgens: increase bone formation
estrogen deficiency
results in loss of bone mass
cytokines do what to bone?
promote bone resorption
includes: IL-6 RANKL and RANK TNF alpha and beta IL-1 alpha and beta
prostaglandins do what?
promote bone resorption
Growth factors that influence the balance between bone resorption and formation
FGF
PDGF
IGF
BMP’s
how do we measure bone mass
bone mineral densitometry
this can determine if there is a loss of bone mass but NOT the cause
T scores
compare subject to young adult normal
Z scores
compare subject to age-matched normal
DEXA scanning
common method to measure bone densitometry
can be used to diagnose osteoporosis
WHO criteria
T-score > or equal to -1 is normal
T score between -1 and -2.5 is osteopenia
T score less than or equal to -2.5 osteoporosis
Biochemical measurements of bone formation
Alkaline phosphatase
Osteocalcin
Procollagen Peptides
Biochemical measurements of bone resorption
Urinary hydroxyproline
Collagen cross links (NTX or CTX)
true or false:
bone biopsies are not typically called for in pt’s with osteoporosis
TRUE
primary osteoporosis
found in postmenopausal women and older men who do not have a definable secondary cause
secondary osteoporosis
can result from many factors
two examples include glucocorticoid excess and hypogonadism
treatment of osteoporosis?
Antiresorptive –> bisphosphonates
anabolic–> intermittent PTH injections
osteomalacia
rickets and osteomalacia are characterized by disorders in mineralization of the organic matrix through interrupted supply or transport of minerals in renal, intestinal or bone cell disorders
most often vit D deficiency
increased fracture risk
Paget’s
characterized by excessive osteoblastic activity and hyperactive bone remodeling
commonly causes no symptoms
highly elevated phosphatase levels
common bones affected in Paget’s
spine femur pelvis skull collar bone humerus
symptoms of Paget’s
fracture
arthritis
bone pain
deformity
tingling and numbness due to enlarged bones pinching nerves
limping
treatment of paget’s
bisphosphonates
what stage is paget’s typically diagnosed in?
sclerotic phase which is characterized by extremely high levels of alkaline phosphatase
stages of Paget’s
osteolytic stage–> excess osteoclast
mixed phase–> both osteoclast and osteoblast
osteosclerotic phase–> predominant osteoblastic activity and marked sclerosis
osteogenesis imperfecta
brittle bone disease
weakening of bone due to mutations in collagen leading to bone fractures and deformity
OI type I
most common
autosomal dominant
one allele of the alpha 1 procollagen gene is missing
resulting in decreased collagen production but normal collagen structure
delayed fontanelle closure bone fragility short stature blue sclerae joint laxity hearing loss osteopenia of the long bones and wormian bones of the skull
OI type II
point mutation of COL1A1
extreme bone fragility and death intrauterine or early infancy secondary to respiratory deficiency
OI type III
similar to type II but less sever
skull deformities
OI type IV
similar to type I but less severe
osteopetrosis
marble bone disease
defective osteoclastic bone resorption and disorganized bone structure resulting in weakened bone and increased fracture risk
due to genetic mutations
bisphosphonates
inhibit osteoclast activation
prolia
denosumab monoclonal antibody directed against RANKL
inhibits bone resorption