1. Osteoporosis
Luke Lightning
Luke Lightning, PhD

2. Osteoporosis
• Affects >10 million people in the US – 8 million
women
– Another 34 million are at risk
– Number of fractures increased 55% since 1995
• > 20 drugs approved for this condition
• Low bone mass and bone deterioration
–  increase in risk of fracture Medications
– 1.5 million fractures/year
– Hip, spine, wrist
• No known cure
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3. Who is At Risk for Osteoporosis?
“Really Naked Calendar” - UK
Postmenopausal women
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4. Universal Prevention Measures
Some ways you can minimize risk of fractures:
• avoid clothing that increases risk of fall
• ingest > 1200 mg of calcium/day
• supplement diet with 700-800 IU/day of vitamin D
• exercise regularly
•wear clothing that protects against fractures
Confidential 4

5. Bone Remodeling
Dynamic process
Osteoclasts: break down bone Osteoblasts: build bone
Confidential 5

6. Confidential 6

7. Risk Factors for Osteoporosis
• Old age
– Postmenopausal women
• Lose bone 2-4 X faster Primary
• Estrogen deficiency  increased bone resorption
Osteoporosis
• Sedentary lifestyle
• Genetics
• Hormonal disorders Secondary
• Smoking and alcoholism Osteoporosis
• Diseases (e.g. celiac)
• Medications (e.g. some cancer drugs)
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8. Preclinical and Clinical Trial
Considerations
• Significant differences in bone mineral density among species
• Ovariectomized rat model for postmenopausal osteoporosis
• Phase III Clinical Trials
– Proven fracture efficacy after 3 years
– Endpoints: vertebral and non-vertebral fractures
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9. Diagnostic Test
• Bone densitometry scan
– DEXA measures calcium
•  T-score
– FRAX  risk of fracture
T-score:
Comparison
to young
adult mean
Confidential 9

10. Current Therapies and Market
Selective Estrogen
Bisphosphonates: Modulators
Fosamax (SERMs):
$10 billion market
Evista
(2010, projected)
Denosumab
Peptide Hormones: and
Forteo, Calcitonin Other Potential
Targets
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11. Sales
• Fosamax has 50% market share
– $3 billion, 16% of Merck’s total drug sales
Bisphosphonates
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12. Bisphosphonates
• Considered to be the standard of care
– Revolutionized treatment of osteoporosis (1960’s)
– Fosamax (Merck, generic), Boniva (GSK, Roche)
pharmacokinetics
phosphonate phosphonate
efficacy
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13. Bisphosphonates
• Can reduce risk of fracture by 40-50% over 3-5 years
• Very high affinity for and rapid absorption to bone tissue
• Inhibit osteoclast bone resorption
• Dosing intervals vary:
– Orally on a daily or weekly basis
– Monthly
– Once yearly IV infusion
• Compliance is 25-40% after 1 year
• Major side effect:
– Osteonecrosis of the jaw
• Cost: $400/year (Fosamax), $2,000/year (Boniva)
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14. Calcium Homeostasis
• Calcitonin vs. Parathyroid Hormone
Calcium
deposited
Into bone
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15. Salmon Calcitonin
• 32 amino acid peptide
• Open IND for oral calcitonin (Bone Medical Ltd., Australia)
– Phase III pathway identified More active than human form
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16. Teriparatide (Forteo)
• 34 amino acid analog of parathyroid hormone
• 20 µg s.c. once/day
– Thigh or abdomen
Parathyroid hormone
• Enhances bone strength and size Teriparatide
– Intermittent exposure
•  activates osteoblasts > osteoclasts
– Chronic exposure
•  enhances bone resorption
• 2nd line therapy
• Only used for 2 years
• Major side effect: bone cancer (in rats)
• Cost: $7,000/year
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17. Raloxifene (Evista)
• Selective Estrogen Receptor Modulator (SERM)
• Orally administered
• Effective in women only
• Reduced risk of vertebral fracture by 30-50%
– Higher incidence of stroke
– Teratogen
• Cost: >$1,000/year
• August 2009: Lilly dropped Arzoxifene
– Did not meet secondary endpoints
– More frequent adverse events
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18. Prolia (Denosumab)
• Biologic from Amgen supposedly better than others because:
– Targeted mechanism – RANKL inhibitor
• Inhibits formation and function of osteoclasts
– Improved dosing schedule
• s.c. once every 6 months
– Superior tolerability
– Reduced fracture risk by 68%
– Cost >$10,000/year
• August 2009 FDA panel:
– Data from 30 clinical trials
– Only 2 of 6 indications
• Safety issues
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19. Other
Potential
Targets or
Products In
Development
(2008)
>16 Targets
> 40 Products
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20. Cats purr to strengthen their bones!!
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21. Whole Body Vibration and Effects on
Bone
• Potential Benefit of vibration therapy:
– Astronauts: bone density loss and muscle atrophy are a serious
concern at zero gravity for extended periods of time
– Postmenopausal women: ~100 patient study, 6 month (2008)
• 30 Hz, 5X/week for 10 min 
• reduced back pain and increased femoral neck (3.2%) and lumbar BMD
(4.3%)
• Cat purring:
– Frequency = 25-150 Hz  improve bone density and healing
– Low energy mechanism that stimulates muscles and bones
– Potential source of self-healing
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22. New Therapy?
● Leather Vibrating Massage Chair with Cooler
Milk
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23. Osteoporosis Summary
• Very large patient population and large market
– Affects 75 million people in the US, Europe, and Japan
• Bone tissue is dynamic and undergoes constant remodeling
• Several current therapies
– Can slow the progression of the disease, but no known
cure
– Significant side effects
– At least 15 potential targets
under investigation
• Stem Cells
• Crazy cat lady may be
not so crazy!
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