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

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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

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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

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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!