Osteoporosis Luke Lightning ke Lightning, PhD
Jun 02, 2015
Osteoporosis
Luke Lightning
Luke Lightning, PhD
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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– 1.5 million fractures/year– Hip, spine, wrist
• No known cure
Medications
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Who is At Risk for Osteoporosis?“Really Naked Calendar” - UK
Postmenopausal women
Confidential 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
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Bone Remodeling
Osteoblasts: build boneOsteoclasts: break down bone
Dynamic process
Confidential 6
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Risk Factors for Osteoporosis• Old age– Postmenopausal women
• Lose bone 2-4 X faster• Estrogen deficiency increased bone resorption
• Sedentary lifestyle
• Genetics• Hormonal disorders• Smoking and alcoholism• Diseases (e.g. celiac)• Medications (e.g. some cancer drugs)
PrimaryOsteoporosis
SecondaryOsteoporosis
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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
Confidential 9
Diagnostic Test• Bone densitometry scan
– DEXA measures calcium• T-score
– FRAX risk of fracture
T-score:Comparisonto youngadult mean
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Current Therapies and Market
Bisphosphonates:Fosamax
Selective Estrogen Modulators(SERMs):Evista
Peptide Hormones:Forteo, Calcitonin
Denosumab and Other PotentialTargets
$10 billion market(2010, projected)
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Sales• Fosamax has 50% market share– $3 billion, 16% of Merck’s total drug sales
Bisphosphonates
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Bisphosphonates• Considered to be the standard of care– Revolutionized treatment of osteoporosis (1960’s)– Fosamax (Merck, generic), Boniva (GSK, Roche)
phosphonate phosphonate
pharmacokinetics
efficacy
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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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Calcium Homeostasis• Calcitonin vs. Parathyroid Hormone
Calcium depositedInto bone
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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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Teriparatide (Forteo)• 34 amino acid analog of parathyroid hormone• 20 µg s.c. once/day
– Thigh or abdomen
• Enhances bone strength and size– 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
Parathyroid hormoneTeriparatide
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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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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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Other Potential Targets or
Products In Development
(2008)
>16 Targets> 40 Products
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Cats purr to strengthen their bones!!
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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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New Therapy?● Leather Vibrating Massage Chair with Cooler
Milk
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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 benot so crazy!