Simvastatin Attenuates Bone Loss Following Simulated

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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight

• John R. Gardner M.D., Ph.D.
• Department of Emergency Medicine
• University of Illinois College of Medicine
• at Peoria

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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight

• How does this research apply to Emergency
  Medicine?
• Diseases of bone loss constitute a major health
  problem
• 30 million Americans at risk for osteoporosis,
  100 million
• worldwide
• The elderly population is expanding
• Significant morbidity and mortality associated
  with osteoporotic
• fracture
• Loss of specialist coverage
• ED overcrowding
• Disease prevention is as important as treatment!

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Effects of Spaceflight on the Musculoskeletal
System
Muscle

• Decreased Mass and Volume
• Decreased Protein Content
• Altered Contractile Protein Phenotype
• Changes in Functional Properties

Bone

• Decreased Bone Mass
• Decreased Bone Mineral Content and Density
• Altered Mechanical Strength and Stiffness

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Effects of Spaceflight on the Musculoskeletal Syst
em

• Why is this important?
• Loss of muscle mass and altered contractile
• phenotype could prevent the completion of
• manual tasks on long term spaceflights
• Loss of bone mass and strength could pose a
• serious health risk during prolonged
  spaceflight
• Significant difficulty returning to a normal
  gravity
• environment

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Effects of Spaceflight on the Skeletal System

• Decreased Bone Mass, Mineral Content, and Density
• 2. Loss of Cortical and Trabecular Bone Volume
• 3. Changes in Trabecular bone structure
• Decreased Trabecular Number
• Decreased Trabecular Thickness
• Increased Trabecular Spacing
• 4. Decreased Bone Strength and Stiffness

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Effects of Spaceflight on the Skeletal System
A
B
C
D
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Effects of Spaceflight on the Skeletal System
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Effects of Spaceflight on the Skeletal System

• Mechanism of Bone Loss?
• Large Decrease in the Synthesis of New Bone
• Smaller Decrease in Bone Resorbtion
• Net Loss of Bone
• Maturation Deficit of New Bone

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Effects of Spaceflight on the Skeletal System

• Drugs that inhibit bone resorbtion
  (bisphosphonates) have
• been shown to attenuate bone loss in
  osteoporosis, but have
• been less successful in other conditions
  (disuse, denervation
• spaceflight)
• There are currently no pharmacological agents
  capable of
• substantially increasing bone formation in
  patients that have
• already suffered significant bone loss

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Effects of Spaceflight on the Skeletal System

• Simvastatin
• Mundy et al.,(1999) described simvaststin as a
  potential bone
• anabolic agent
• Examined 30,000 compounds using an InVitro
  BMP-2
• expression assay. Simvastatin was the only
  agent found
• to enhance BMP-2 expression
• Mouse calvarial bone culture experiments
  increased new
• bone formation 2-3 fold over controls
• Subcutaneous InVivo administration increased
  calvarial new bone
• formation by 50
• Systemic administration increased mouse femur
  trabecular bone
• volume 39-94 (dose dependant)

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The Model Hindlimb Suspension

• Hindlimb Suspension Faithfully Reproduces the
  Cardinal
• Elements of Spaceflight
• Unloading of the hindlimbs without paralysis or
• loss of range of motion
• Head-down tilt (cephaloid fluid shift)
• There Are Greater Than 100 Hindlimb Suspension
  Studies,
• Many in Direct Comparison to Actual Spaceflight

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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight

• The Experiment
• 36 mice were randomly assigned to one of three
• treatment groups
• Weight-bearing control (C )
• Hindlimb-suspension vehicle only (SV)
• Hindlimb-suspension simvastatin (SS)
• Mice underwent two weeks of hindlimb-suspension
• as described by McCarthy et al., (1997)
• Hindlimb-Suspended mice received either 10
  mg/kg
• of simvastatin or saline vehicle once daily by
  oral
• gavage

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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight

• The Experiment
• Following two weeks of hindlimb-suspension the
  mice
• were uthanized by CO2 asphixiation
• The hindlimb bones were removed and cleaned of
  all soft
• tissue
• Bones were stored at -80ºc until processing
• Bone Mineral Content
• Tibia/fibula and femur bones were thawed and
  ashed
• overnight in a Muffle Furnace (400 ºc) and
  weighed
• The resulting product is entirely inflammable
  mineral

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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight
The Results Bone Mineral Content from Control
and Hindlimb-Suspended Groups Group
Femur (mg/g) Tibia (mg/g) P
Value C (n12) 1.1200.028 0.986
0.021 SV (n10) 0.983 0.064 0.907
0.023 0.049A 0.019B SS (n11) 1.049
0.038 0.971 0.032 0.144A 0.688B ________________
__________________________________________________
____________________ Reported values are given as
mean SEM (mg bone mineral/body weight). Afemur
vs control, Btibia vs control.
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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight
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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight

• Discussion
• There are no perfect countermeasures for the
  loss of bone
• mineral observed during spaceflight
• Currently available pharmacological agents are
  only
• partially effective and may be deleterious
• Exercise regimens are equally ineffective and
  impractical

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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight

• Discussion
• Although the mechanism of bone-loss during
  spaceflight
• is not fully understood, there is a decrease
  in net bone
• formation a substantial decrease in new bone
  formation
• whereas bone resorbtion is unabated
• Currently available agents (bisphosphonates)
  focus largely
• on preventing resorbtion
• When bisphophonates are used in spaceflight,
  bone mineral
• loss is diminished but the resulting bone is
  histologically
• abnormal

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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight

• Discussion
• Simvastatin appears to promote bone formation,
  rather than
• preventing resorbtion
• Enhances BMP-2 synthesis (potent stimulator of
  bone
• synthesis)
• Blocks production of isoprenoids (modify Ras and
  Ras-like
• proteins)
• Upregulates VEGF expression (which is required
  new bone
• formation)
• Induces osteoblast differentiation and
  maturation
• Simvastatin is likely a more suitable agent for
  preventing
• bone loss in spaceflight

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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight

• Discussion
• Simvastatin administration to hindlimb suspended
  mice
• significantly impacted loss of bone mineral
  following two
• weeks of hindlimb-suspension
• Compared to weight-bearing controls (C ),
  hindlimb-suspended
• mice (SV) lost 13.7 and 7.9 of bone mineral
  content in the
• femur and tibia respectively
• Simvastatin administration (SS) attenuated this
  loss (7.9 and
• 1.4 respectively)
• The loss of bone mineral content in the (SV)
  group relative to the
• (C ) group was statistically significant
• There was no significant difference between the
  (C ) group and
• simvastatin treatment group (SS)

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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight

• Discussion
• Future studies will focus on bone morphology,
  functional
• properties, and the mechanism of action of
  simvastatin on
• bones of hindlimb-suspended mice
• Magnetic resonance microscopy
• Light microscopy
• Dynamic labeling studies
• Bone strength and fracture risk

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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight

• How does this research apply to Emergency
  Medicine?
• Diseases of bone loss constitute a major health
  problem
• 30 million Americans at risk for osteoporosis,
  100 million
• worldwide
• The elderly population is expanding
• Significant morbidity and mortality associated
  with osteoporotic
• fracture
• Loss of specialist coverage
• ED overcrowding
• Disease prevention is as important as treatment!

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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight

• Meier et al., (2000)
• Asked if use of statins decreased risk of
  fracture in humans
• Population-based, nested case control study
• Patients were identified from the UK-based
  General Practice
• Research database (3 Million Patients)
• 28,340 patients prescribed lipid-lowering
  drugs, 13,271 patients
• diagnosed with hyperlipidemia but not treated,
  50,000 patients
• without the diagnosis of hyperlipidemia
• Controlled for body mass, smoking, physician
  utilization,
• estrogen use, and corticosteroid use
• Current use of statins was associated with a
  significantly reduced
• risk of fracture (OR 0.55 95 CI 0.44-0.69)

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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight

• Wang et al., (2000)
• Examined if statin use was associted with
  reduced risk of hip fracture
• Case-control study
• Patients identified through Medicaid or
  Pharmacy Assistance for the
• Aged and Disabled Program
• 6110 patients, 65 years or older
• 1222 patients underwent surgical repair of a
  hip fracture, 4888 control
• patients matched for age and sex
• Controlled for race, insurance status,
  psychoactive medications, estrogen,
• thiazide use, number of medications, DM,
  ischemic heart disease, cancer,
• Charlson comorbidity index, recent nursing
  hone stay, and physician
• utilization
• Use of statins in the prior 180 days (OR 0.50
  95 CI 0.33-0.76) and
• prior three years (OR 0.57 CI 0.40-0.82) was
  associated with a
• significant reduction in the risk of hip
  fracture
• Adjusted for extent of use in the past three
  years, current use at time of
• fracture showed a 71 decrease in fracture
  risk (OR 0.29 CI 0.10-0.81)

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Simvastatin Attenuates Bone Loss Following
Simulated Spaceflight

• Wantanabe et al., (2001)
• Examined if treatment with statins affected
  bone mineral density over
• a 12 month period
• Randomized trial
• Postmenopausal patients with hypercholesterolemi
  a who had not been
• previously treated
• 31 patients assigned to either fluvastatin
  (lipophilic) or pravastatin
• (hydrophilic) treatment groups
• No significant differences in age, years after
  menopause, body weight
• body mass index, or baseline bone mineral
  density between groups
• Lumbar bone mineral density decreased in the
  pravastatin group but
• but not in the fluvastatin group. Whole body
  bone mineral density
• was not significantly different between groups
• Lumbar bone mineral density increased in the
  fluvastatin group at 6
• and 12 months