Term
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Definition
result of imbalanced bone remodeling in which bone resorption is greater than bone formation
a disease characterized by low bone mineral density and deterioration of bone tissue leading to enhanced bone fragility and increase in fracture risk
may be categorized as primary (postmenopausal, senile, or idiopathic) or secondary (consequence of other diseases or prescription drugs) |
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Term
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Definition
outer layer; compact (higher density) where turnover (remodeling) is slower
stronger, higher density bone compared to trabecular bone
bones in the appendicular skeleton generally have thicker cortical layers |
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Term
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Definition
inner (core) bone; lower density where turnover (remodeling) is faster
lower strength, lower density compared to cortical bone
bone in the axial skeleton is composed of more trabecular bone |
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Term
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Definition
abnormal control of peripheral blood vessel diameter; common in perimenopausal and postmenopausal women
core body temperature is, in part, controlled through peripheral blood vessel heat loss which is regulated by parasympathetic and sympathetic nerve input (vasodilation and vasoconstriction)
vasomotor symptoms often referred to as hot flashes
vasomotor symptoms are caused by abnormal regulation of vessel dilation associated with fluctuating hormone levels in perimenopausal and postmenopausal years |
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Term
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Definition
strong correlation with bone fracture risk
measured by radiological methods
measurements converted to number of standard deviations from mean of a healthy population
a person greater than 2.5 standard deviations below mean bone mineral density for a young healthy population is considered to have osteoporosis |
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Term
| selective estrogen receptor modulator (SERM) |
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Definition
drugs have estrogen like activity only on certain cell or tissue types
compounds that bind and act through the estrogen receptor, but act like estrogen (agonist activity) only on particular tissues or cells
the impetus for SERM development is selective desirable activity on one tissue, while avoiding undesirable activity on other tissues |
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Term
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Definition
[image]
note: epiphysis, diaphysis, trabecular bone, cortical bone
the upper picture depicts the structure of a long bone (for example, the humerus shown above); the diaphysis has a thick shell of compact cortical bone, while the epiphysis is composed predominantly of trabecular bone
the lower right panel shows the detailed structure of bone; note difference in mineralized density between cortical and trabecular bone
osteoclasts and osteoblasts are found on the inner surfaces of cortical and trabecular bone
[image]
bone remodeling is a balance between the catabolic activity of osteoclasts and the anabolic activity of osteoblasts
after osteoblasts secrete matrix and become surrounded by mineralized bone they are called osteocytes
resorption lacuna (gap) is the site under osteoclasts where hydroxyapatite has been dissolved by organic acids secreted by osteoclasts
the rate of bone remodeling in trabecular bone is faster compared to cortical bone
any condition that disrupts the process of mineralization or remodeling preferentially affects the trabecular bone
osteoporotic fractures occur commonly in vertebral bodies and the neck of the femur because of large trabecular component |
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Term
| bone remodeling at the cellular level |
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Definition
balanced bone remodeling:
[image]
bone resportion and bone formation are coupled by the interactions between osteoblasts and osteoclasts
1) RANKL EXPRESSION
factors such as parathyroid hormone (PTH), shear stress, and transforming growth factor B (TGF-B) cause osteoblast precursors to express the osteoclast differentiation factor RANK-ligand (RANKL)
2) RANKL-RANK BINDING
RANKL binds to RANK, a receptor expressed on osteoclast precursors
3) OSTEOCLAST MATURATION
the RANKL-RANK binding interaction, together with other factors (macrophage colony stimulating factor (M-CSF)), cause osteoclast precursors to differentiate into mature osteoclasts
4) BONE RESORPTION AND FACTOR RELEASE
as mature osteoclasts resorb bone, matrix-bound factors such as TGF-B, insulin-like growth factor 1 (IGF-1), other factors are released
5) OSTEOBLAST MATURATION AND BONE FORMATION
the liberated factors stim,ulate osteoblast precursors to develop into mature osteoblasts, which begin to refill the resorption cavities excavated by the osteoclasts |
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Term
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Definition
[image]
calcium balance: actions of calcitriol, PTH, and calcitonin (CT)
in a state of daily whole-body calcium balance, net dietary uptake of 200 mg per day from the GI tract equal excretion of 200 mg per day by the kidneys
thus, the amount total body calcium is not changed (balanced)
vitamin D [1,25(OH)2D3](calcitriol) enhances absorption of Ca from the GI tract
endogenous secretion (continuous) of PTH stimulates bone resortpion and stimulates tubular reabsorption of calcium in the nephron (both effects of PTH raise plasma Ca)
PTH also enhances urinary excretion of inorganic phosphate (PO4)
in contrast, exogenous once-daily injection of PTH stimulates new bone formation (accretion)
exogenous (and endogenous) calcitonin inhibits bone resorption
points of therapeutic intervention are shown in blue |
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Term
| response to low serum calcium |
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Definition
[image]
1) INCREASE SERUM PTH
decreased plasma Ca concentration is the primary stimulus for PTH secretion by the parathyroid glands
2) PTH PROMOTES BONE RESORPTION
in bone, PTH promotes increased differentiation of osteoclast precursors into mature osteoclasts; osteoclasts resorb bone and thereby liberate inorganic phosphate (PO4) and Ca into the plasma
3) PTH INCREASES RENAL TUBULAR CALCIUM REABSORPTION
in the kidney, PTH increases the tubular reabsorption of Ca and decreases the distal tubular reabsorption of PO4
4) PTH ACTIVATES 25(OH) VITAMIN D (2ND HYDROXYLATION)
PTH stimulates proximal tubule cells to hydroxylate 25(OH) vitamin D, forming 1,25(OH)2 vitamin D; 1,25(OH)2 vitamin D then stimulates intestinal absorption of Ca by increases the expression of mucosal Ca uptake and transport of proteins
5) ELEVATED SERUM CALCIUM INHIBITS PTH SECRETION
in a tightly controlled negative feedback loop, increased plasma Ca inhibits further PTH secretion by the parathyroid glands |
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Term
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Definition
[image]
peak bone mass (determined by physical activity, genetic factors, and nutrition) occurs in young adulthood
load bearing exercises increase bone mass
gene polymorphisms in RANKL, osteoprotegerin (inhibits osteoclast maturation), RANK, vitamin D receptor, and estrogen receptor are important in affecting peak bone mass and bone remodeling
sufficient vitamin D and dietary calcium are important for peak mass especially during the adolescent growth spurt
after peak bone mass is attained there is predicable bone loss due to menopause and aging
menopause and aging are two major factors in osteoporosis
bone loss due to aging is equal for men and women
however, postmenopausal women are at greater risk of fracture because of lower peak mass and loss of estrogen production
menopause is characterized by low estrogen, increased production of cytokines (IL-1, IL-6, and TNF), RANK, and RANKL which cause bone loss
osteoclast activity is increased
bone mass in women and men over life span:
[image]
1. rapid growth (spurt)
2. peak bone mass
3. decline (age and menopause)
above is a plot of bone mass as a function of age
in both men and women, bone mass increases with age until a peak is reached in young adulthood, after which bone mass gradually declines by approximately 0.7% per year (age-related)
in women, the onset of menopause precipitates a sharp decline in bone mass as the decrease in estrogen production leads to increased bone resorption
as bone mass decreases with age, the skeleton may become sufficiently fragile that minor trauma can cause fractures
the goal of anti-resorptive agents is to decrease the rate of decline of bone mass
bone anabolic agents can be used to increase bone mass and thereby correct situations in which significant loss of bone mass has already occurred
menopause is associated with decreased estradiol and increased FSH |
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Term
| pathophysiology of osteoporosis caused by low serum estrogen |
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Definition
[image]
many of these factors are activated by the decline in estrogen levels in menopausal women
production of cytokines and other regulatory molecules leads to the activation of osteoclasts
decreased estrogen allows these osteoclasts to have a longer functional lifespan
the lack of estrogen promotes apoptosis in osteoblasts and osteocytes
imbalance between osteoclast and osteoblast activity leads to the formation of deep and large resorption cavities, which makes the bone fragile and prone to fracture
lack of osteocytes impairs the mechanosensory network on which repair of microdamage in bone depends
increased microdamage also predisposes to bone fragility and eventual fracture |
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Term
| MOA and ADRs of hormone replacement therapy for osteoporosis |
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Definition
inhibitor of bone resorption
ex) estrogens
MOA: affects osteoclast and osteoblast proliferation
ADRs: breast cancer, cardiovascular
low serum estrogen is a key feature of menopause
osteoclasts and osteoblasts have estrogen receptors
estrogen promotes apoptosis in osteoclasts and inhibits apoptosis in osteoblasts and osteocytes
clinical studies show that there is an initial gain in bone density and then a plateau
estrogen can be rotated with a progestin to reduce risk of endometrial cancer
breast cancer and cardiovascular events (VTE) are minor concerns with HRT
vaginal bleeding and breast tenderness are common |
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Term
| MOA and ADRs of selective estrogen receptor modulators (SERM) |
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Definition
inhibitor of bone resorption
ex) raloxifene
MOA: selective effect (estrogen-like) on bone
ADRs: cardiovascular, hot-flashes common
raloxifene, like other SERMs, has estrogen agonist activity on some tissues and estrogen antagonist activity on other tissues
in particular, raloxifene is an agonist on bone and an antagonist on endometrium and breast
however, like estrogen, the incidence of VTE is increased
hot flashes and edema are common
[image]
this is a model of how raloxifene has selective agonist activity on bone
ESTROGEN: X and Y cofactors (coactivators) recruited -> 3 genes expressed -> 3 tissues
estrogen binds the receptor and recruits cofactors X and Y
the cofactors are needed for expression of 3 different genes which are needed for action of 3 different tissues (bone, breast, and endometrium)
SERM (raloxifene): only X cofactor (coactivator) recruited -> 1 gene expressed -> 1 tissue
since the SERM recruits only cofactor X it has action only on bone |
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Term
| MOA and ADRs of bisphosphonates |
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Definition
inhibitors of bone resorption
ex) alendronate, risedronate, ibandronate, zoledronic acid
MOA: incorporated into bone; inhibits mevalonate pathway (HMG-CoA reductase pathway); inhibits osteoclast function and causes apoptosis
ADRs: gastrointestinal irritation common
bisphosphonates are analogues of pyrophosphate (P-O-P bond has been replaced with P-C-P bond)
the bisphophonic acid motif is conserved among bisphosphonates
bisphosphonates bind calcium ions causing concentration in mineralized bone
hydroxyapatite (with incorporated bisphosphonate) is more resistant to dissolution by organic acids secreted by osteoclasts thus slowing bone resorption
bisphosphonates also block the mevalonate pathway (HMG-CoA reductase pathway) inside osteoclasts (incorporated bisphosphonate is phagocytosed)
the pathway is important for protein prenylation (addition of certain lipids onto intracellular proteins)
inhibition of prenylation ultimately causes apoptosis
nausea, abdominal pain, and dyspepsia (feeling of indigestion) are common |
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Term
| MOA and ADRs of calcitonin |
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Definition
inhibitor of bone resorption
MOA: binds receptor on osteoclasts; reduces bone resoprtion
ADRs: hypersensitivity, tachyphylaxis
calcitonin is a 32 amino acid peptide normally produced by the thyroid gland
therapeutic source purified from salmon (has longer serum t1/2 compared to human calcitonin)
it reduces the resorption actions of osteoclasts (lowers serum calcium)
the initial treatment is more effective, thereafter drug desensitization occurs (tachyphylaxis) likely due to receptor downregulation |
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Term
| MOA and ADRs of vitamin D and calcium |
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Definition
inhibitors of bone resportion
MOA: calcitriol increases dietary calcium absorption
ADRs: hypercalcemia, soft tissue calcification
preparations include cholecalciferol, egrocalciferol, calcifediol, and calcitriol
cholecalciferol, ergocalciferol, and calcifediol are converted to calcitriol (1,25-dihyroxy vitamin D) via hydroxylation in liver and kidney
gastrointestinal epithelial cell active transport is enhanced by calcitriol
patient serum should be monitored for hypercalcemia
chronically elevated serum calcium causes ectopic calcification (soft tissue calcification)
[image]
VITAMIN D ACTIVATED BY HYDROXYLATION IN LIVER AND KIDNEY
vitamin D3 (cholecalciferol)
vitamin D2 (ergocalciferol)
25-hydroxy vitamin D (calcifediol)
1,25-dihydroxy vitamin D (calcitriol)
both endogenous and exogenous vitamin D (animal and plant sources) are converted to 25-hydroxy vitamin D (calcifediol) in the liver and then to 1,25-dihydroxy vitamin D (calcitriol) in the kidney
calcitriol is the active metabolite of vitamin D
endogenous vitamin D3 is synthesized in the skin from 7-dehydrocholesterol in a reaction that is catalyzed by UV light (not shown)
exogenous vitamin D can be provided as D3 (from animal sources) or as D2 (from plant sources)
PTH increases the activity of 1a-hydroxylase in the kidney and thereby stimulates the conversion of 25-hydroxy vitamin D to calcitriol |
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Term
| MOA and ARDs of teriparatide |
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Definition
stimulator of bone formation
MOA: administration critical; selective stimulation of osteoblasts
ADRs: osteosarcoma in animal studies
continuous administration of PTH or conditions where endogenous large amount of PTH is continuously produced (hyperparathyroidism) cuases increased bone remodeling with greater bone resorption rate resulting in net bone los
by contrast, intermittent administration (once daily injection) causes net bone formation (anabolism)
PTH is 84 amino acids, but nearly all the activity on calcium metabolism is retained in the first 34 amino acids
teriparatide is amino acids 1-34
in male and female rats teriparatide is associated with elevated incidence of osteosarcoma (a common type of malignant bone cancer) |
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Term
| MOA and ADRs of denosumab |
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Definition
MOA: blocks RANKL-RANK binding; decreases osteoclast activity
adverse effects: hypocalcemia, skin infections
a monoclonal antibody against RANK ligand |
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Term
| pathophysiology of vasomotor symptoms associated with menopause |
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Definition
[image]
narrowed thermoneutral zone causes vasomotor symptoms associated with menopause
a leading hypothesis explaining the underlying problem in vasomotor symptoms (hot flashes, sweating, chills, shivering) associated with menopause concerns the upper and lower thresholds for autonomic control of core body temperature (CBT)
A:
normal thermoneutral zone - the distance (in temperature) between the upper and lower thresholds define the zone
when the CBT reaches the upper threshold peripheral vasodilation and sweating occur
when the CBT reaches the lower threshold peripheral vasoconstriction and shivering occur
B:
narrowed thermoneutral zone found in postmenopausal patients with vasomotor symptoms - in this hypothesis, a narrowed zone (decreased upper threshold and elevated lower threshold) results in vasomotor symptoms because CBT fluctuates outside of the zone |
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Term
| pharmacologic treatments of vasomotor symptoms |
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Definition
[image]
estrogens - replacement
tibolone - weak estrogen, progestin, androgen activity
venlafaxine - serotonin reuptake inhibitor
paroxetine - serotonin reuptake inhibitor
fluoxetine - serotonin reuptake inhibitor
clonidine - alpha 2 receptor agonist
gabapentin - GABAergic mimetic
the details underlying the pathophysiology of vasomotor symptoms associated with menopause are poorly understood
the initial factor is believed to be low estrogen or unstable estrogen levels
menopausal vasomotor symptoms are associated with abnormal serum NE and NE metabolite (MHPG, 3-methoxy-4-hydroxyphenylglycol) which causes a reduced span between the upper and lower thresholds set in the hypothalmus
the autonomic nervous system responds when the core body temperature reaches a threshold
shown above, a hot flash occurs when CBT reaches the upper threshold
the classical treatment is estrogen replacement therapy
others listed above are especially important when estrogen replacement is contraindicated
the therapeutic mechanisms for relief of vasomotor symptoms are uncertain
the drugs may act to replace low estrogen activity or reset thresholds (thermoregulatory zone0 in the hypothalamus |
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