2010-2011 professional associations - ucsf cme · new and emerging therapies for osteoporosis...

New and Emerging Therapies for Osteoporosis

Steven T Harris MD FACP Clinical Professor of Medicine

University of California, San Francisco

2010-2011 Professional Associations

Consultation

h Amgen

h Eli Lilly & Company

h Gilead Sciences

h Merck

h Roche

Sponsored Presentations

h Amgen

h Eli Lilly & Company

h Genentech

h Gilead Sciences

h Novartis

h Roche

h sanofi-aventis

h Warner Chilcott

Key Topics

h Brief review of bone remodeling

h Current guidelines for osteoporosis treatment

h Summary of contemporary osteoporosis treatment options—and the major safety concerns

h New and emerging therapies

Osteoclast Precursor

Osteoclast Mononuclear Cells

Osteoblast Precursors Osteoblast

LC = Lining Cells CL = Cement Line OS = Osteoid BRU = Bone Remodeling Unit

Normal Bone Remodeling Sequence

é resorption or ê formation

Net bone loss (osteoporosis)

Unbalanced Remodeling

0 20 30 40 50 60 70 80 100

Men Women

Bone Mass

Adapted from Wasnich RD, et al. Osteoporosis: Critique and Practicum. Honolulu, Banyan Press 1989;179

Change In Bone Mass With Age

Age

Postmenopausal Osteoporosis

Increased fracture risk due to low bone density and microarchitectural deterioration: “poor bone quality”

Modified from Riggs BL and Melton LJ III. Osteoporosis: Etiology, Diagnosis, and Management. New York: Raven Press; 1988

MENOPAUSE AGING OTHER RISK FACTORS

LOW PEAK BONE MASS

POOR BONE QUALITY

RESORPTION > FORMATION

LOW BONE DENSITY

FRACTURES

Bone Loss

Pathogenesis of Osteoporosis

FALLS

Assess Risk Factors and Measure BMD if Patient Has Risk Factors

T-score between -1.0 and -2.5

10-year Probability of Hip Fracture >3% or

Probability of All Major Fractures >20%

Hip or Vertebral Fractures

or T-score ≤-2.5 (Spine,

FN or Total Hip)

2008 NOF Guidelines: Treatment Initiation Post-menopausal Women And Men ≥50

http://www.nof.org

Other Fractures after Age 50 (Excluding

Fingers, Toes and Face)

Secondary Causes with High Fracture

Risk*

*such as glucocorticoid use or total immobilization

Treatment Summary

h We have the tools to identify patients at risk; in FRAX©, bone mineral density (BMD), age and previous fractures in particular are strong, independent predictors of fracture risk

h Treatments significantly decrease fracture risk:

0 “Antiresorptive” therapy produces a modest BMD increase, yet decreases fracture risk—especially in the spine—much faster and to a larger extent than predicted by the relatively small change in BMD. This implies an important improvement in bone “quality”

0 Anabolic therapy with teriparatide increases BMD more than antiresorptive treatment, but it is not yet obvious that fracture protection is greater

Objective of Intervention

The most important clinical objective is the

prevention of fractures—both vertebral and non-

vertebral fractures

Changes in surrogate markers--bone mineral density

(BMD) and biochemical markers of bone turnover--are

“necessary” but are not “sufficient”

Non-Pharmacological Options

h Taken as a whole, non-pharmacological options seem to be relatively inexpensive, and modestly effective

h Exercise in particular has other health benefits, although the same is likely to be true for diet optimization

h Optimization of the diet, exercise and fall prevention should be viewed as important adjuncts to the treatment of osteoporotic patients

FDA-Approved Therapeutic Options in the USA

Prevention Stops bone loss

Treatment Reduces vertebral fractures

Estrogen

Alendronate Risedronate Ibandronate

Zoledronic acid Raloxifene

Calcitonin

PTH (teriparatide) Denosumab

Resorption = Formation

Normal Coupling of Bone Remodeling

i Most treatment agents (bisphosphonates, SERMs, calcitonin, estrogen) act primarily on the left side of the equation—to decrease bone resorption

i A decrease in resorption is followed by a decrease in formation—and BMD improvement tends to “plateau” after several years

i Only teriparatide acts on the right side of the equation—to stimulate formation

Antiresorptive Treatment: Summary

i Antiresorptive treatment decreases fracture risk more rapidly and to a larger extent than one would predict from the relatively small changes in BMD Fracture protection can be observed in the

absence of a significant change in BMD i Fracture protection persists even when the BMD

reaches a plateau BMD stability does not mean “non-response”

i Fracture reduction is most conspicuous in older patients with prevalent vertebral fractures

+ documented in randomized, controlled trial; – effect not documented § effect documented only in a post hoc analysis of a high-risk sub-group (femoral neck T score < -3)

Anti-resorptive Agents: Clinical Trial Results

Trials of Different Agents Cannot Be Compared Directly

Agent Spine Non-spine Hip

Estrogen + + +

Raloxifene + - -

Calcitonin + - -

Denosumab + + +

Alendronate + + +

Risedronate + + +

Ibandronate + § -

Zoledronic acid + + +

Effect on fracture risk

Bisphosphonates Alendronate, Risedronate, Ibandronate and Zoledronic Acid

A number of different bisphosphonates are now available for the prevention and treatment of osteoporosis—in daily oral, intermittent oral and intermittent parenteral formulations:

h Alendronate 10 mg daily or 70 mg weekly for treatment, 5 mg daily or 35 mg weekly for prevention

h Risedronate 5 mg daily or 35 mg weekly; 150 mg monthly; 35 mg weekly after breakfast

h Ibandronate 150 mg monthly by mouth; 3 mg iv over 15-30 seconds every 3 months

h Zoledronic acid 5 mg by infusion over a minimum of 15 minutes every year

h Increased bone density in the spine by 5-8% and at the hip by 3-6% after 3 years

h Reduced incidence of vertebral fractures by 40-70%

h Alendronate, risedronate and zoledronic acid reduced non-vertebral fractures (25-40%), including hip fractures (40-60%), in women with osteoporosis

h Ibandronate: overall, no effect observed on non-vertebral or hip fractures. In a post-hoc analysis, non-vertebral fracture reduction was seen in a high-risk subgroup with a baseline femoral neck T-score less than -3.0

Bisphosphonates: Effects Alendronate, Risedronate, Ibandronate and Zoledronic Acid

h  “Class warning” regarding UGI symptoms (no increase in UGI complaints in randomized controlled trials)

h  “Class warning” regarding infrequent bone, joint and/or muscle pain

h  “Class warning” regarding jaw osteonecrosis

h  “Class warning” about atypical fractures following long-term therapy

h  Influenza-like symptoms may occur after first monthly oral dose or IV injection

Bisphosphonates: Side Effects Atypical Fractures of the Femur Patients on Bisphosphonate Therapy for Osteoporosis

Shane E, et al. J Bone Miner Res 2010;25:2267 Watts NB and Diab D. J Clin Endocrinol Metab 2010;95:1555-1655 Park-Wyllie JY, et al. JAMA 2011;305(8):783-789

h Hypothesis that “over-suppression” of bone remodeling could impair the repair of microdamage—and increase the risk of atypical fractures

h Transverse (not spiral) fractures of femoral diaphysis or in subtrochanteric region

h May begin with stress reaction or stress fracture of lateral femoral cortex (arrow)

h Often bilateral h Prodromal pain in thigh or groin in 70% h Can occur in untreated patients, but

increased incidence in patients on bisphosphonates > 5 years, often in combination with other drugs, especially steroids or estrogen

FDA Safety Update

h Be aware of the possibility of atypical fractures in patients on bisphosphonates

h Evaluate any patient who presents with new groin or thigh pain to rule out a femoral shaft fracture

h Discontinue potent antiresorptive medication in patients with atypical fractures

h Periodically reevaluate the need to continue bisphosphonate therapy, particularly in patients treated for 5 years or more

Link to MedWatch Online Voluntary Reporting Form: https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm

New and Emerging Therapies

h Denosumab h SERMs: lasofoxifene, bazedoxifene h Strontium

0 strontium ranelate 0 strontium malonate

h Anti-sclerostin antibody h Cathepsin K inhibitor – odanacatib h Cyclic analog of PTH (1-31) h Calcium receptor antagonist – “calcilytic”

RANKL Antibody/RANKL: Activation Of Osteoclasts

Activated osteoclast

CFU-M

Pre-fusion osteoclast

Multinucleated osteoclast

Bone

OB

Growth factors Hormones

Cytokines

RANK OPG RANKL

RANK = Receptor Activator of Nuclear factor Kappa B RANKL = RANK Ligand CFU-M = Colony-Forming-Unit Macrophage OPG = Osteoprotegerin Adapted from Boyle, et al. Nature 2003;423:337

OPG

Denosumab

Y

Y

Y Y

Y

Y Y

Month -2 -1 0 1 2 3 4 5 6 7 8 9

10

0 6 12 18 24

Spin

e B

MD

Cha

nge

(%)

a P < 0.001 vs placebo

Adapted in part from McClung MR, et al. N Engl J Med 2006;354:821-31

Denosumab vs Alendronate % Change Spine BMD

– Denosumab 60 mg sq every 6 mos a

-- Alendronate 70 mg weekly a

– Placebo

Denosumab Fracture Trial: FREEDOM Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months

Cummings SR, et al. Presented at 30th Annual Meeting of the ASBMR, Montreal 2008. Abstract 1286. Cummings SR, et al. N Engl J Med 2009;368:756-765

h Phase 3 RCT in postmenopausal women age 60–90 with lumbar spine or total hip T-score <-2.0 and ≥-4.0

h Randomized to denosumab 60 mg subcutaneously every 6 months vs PBO

h Endpoints

h Primary: new vertebral fractures at 36 months

h Secondary: time to first hip and nonvertebral fractures

3.1%3.1%

2.2%

1.1%

0.7%0.9%

0

0.5

1

1.5

2

2.5

3

3.5

Crud

e Inc

iden

ce (%

)

FREEDOM: Vertebral Fracture Risk Reduction

65% ↓ (P<0.0001) 78% ↓ (P<0.0001) 61% ↓ (P<0.0001)

Year 2 Year 1 Year 3

Placebo Denosumab


FREEDOM: Nonvertebral Fractures

20% P=0.011

95% CI, (5 to 33%)

6.5%

8.0%

PlaceboDenosumab

0

2

4

6

8

10

0 6 12 18 24 30 360 6 12 18 24 30 36

Study Month

Cum

ulat

ive In

ciden

ce (%

)

Total nonvertebral fractures, n = 531 Rates represent Kaplan-Meier estimates at 36 months


FREEDOM: Selected Safety Data

Event Placebo Prolia

Cancer 3.2% 3.7%

Infection 3.4% 4.1%

Cellulitis * <0.1% 0.3%

Concussion * 0.3% <0.1%

* > 0.1% and p < 0.01 Cummings SR, et al. N Engl J Med 2009;368:756-765





The Concept of a SERM Selective Estrogen Receptor Modulator

(“EAA”: Estrogen Agonist/Antagonist)

h Binds to the estrogen receptors

h Produces an estrogen agonist effect in some tissues

h Produces an estrogen antagonist effect in others

h tamoxifen

h raloxifene

h bazedoxifene

h lasofoxifene

The Concept of a SERM Selective Estrogen Receptor Modulator

(“EAA”: Estrogen Agonist/Antagonist)

Bazedoxifene: “BZA”: Investigational SERM

Pivotal fracture trial compared placebo, BZA 20 mg daily, BZA 40 mg daily and raloxifene 60 mg daily over 3 years

h Spinal BMD increase at 24 months – roughly 1.5% relative to placebo

h New vertebral fracture risk reduction: 42%, 37% and 42% with BZA 20, BZA 40 and raloxifene, respectively

h Non-vertebral fracture risk reduction of 40% with BZA in a subgroup (FN T-score ≤ -3.0 or ≥1 moderate/multiple vertebral fractures), but not in the entire study group

h Increase in hot flashes and venous thromboembolic events, relative to placebo

Silverman SL, et al. J Bone Miner Res 2008;23:1923-1934

Major outcomes at the end of 5 years: h 42% and 31% reductions in vertebral fracture with lasofoxifene 0.5

mg and 0.25 mg, respectively h 24% reduction in non-vertebral fracture with lasofoxifene 0.5 mg;

no significant effect on hip fracture alone h 85% reduction in invasive breast cancer with lasofoxifene 0.5 mg h Reductions in coronary artery disease and stroke h  Increases in venous thromboembolic disease h  Increases in leg cramps, hot flushes, uterine polyps, endometrial

hypertrophy, vaginal candidiasis and arthralgias with lasofoxifene h 38% increase in all cause mortality with lasofoxifene 0.25 mg, no

significant increase with lasofoxifene 0.5 mg Cummings SR, et al. N Engl J Med 2010;362:686-696

Lasofoxifene: Investigational SERM Postmenopausal Evaluation and Risk reduction with Lasofoxifene

The PEARL Trial





h Orally administered form of strontium h Increases BMD, due in large part to the strontium itself being

incorporated into bone h Small changes in bone turnover (increase in bone formation

and decrease in bone resorption markers) h Reduction in vertebral and non-vertebral fracture in women

with osteoporosis1,2,3 h Approved in other countries—available in Europe as a powder h Other strontium salts available (none approved in the United

States)–no clinical data

Strontium Ranelate

1 Meunier P, et al. N Engl J Med 2004;350:459-468 2 Reginster J-Y, et al. J Clin Endocrinol Metab 2005 May;90(5):2816-22 3 Cochrane Database Syst Rev 2006;18(4):CD005326





Regulation Of Bone Mass By Wnt Signaling Wnt, LRP5, Sclerostin Pathway

Krishnan V, Bryant HU, Macdougald OA. J Clin Invest 2006;116(5):1202-9

Osteoblastic gene expression!

h Sclerostin 0 From osteocytes1

0 Inhibits the anabolic Wnt signaling pathway 2

0 Deficiency results in a sclerosing bone disease (sclerosteosis) 3

0 Antibody to sclerostin restores bone mass and bone architecture in rats and monkeys 2,4

0 Clinical trials just beginning

A New Anabolic Approach: Inhibit A Regulator Of Bone Formation

1 van Bezooijen, et al. J Bone Miner Res. 2005;20 (Suppl 1):S9 2 Warmington K, et al. J Bone Miner Res. 2005;20(Suppl 1):S22 3 Gardner JC, et al. J Clin Endocrinol Metab. 2005;90(12):6392-5 4 Ominsky M, et al. J Bone Miner Res. 2006;21(Suppl 1):S44

h Rats ovariectomized at age 6 months

h Treatment for 3 months beginning at 18 months of age

Warmington K, et al. J Bone Miner Res. 2005;20(Suppl 1):S22

Anti-sclerostin Antibody Therapy

Sham Ovx PTH Anti-SCL

Bon

e Vo

lum

e (%

) 16

12

8

4

Anti-Sclerostin Antibody h Anti-sclerostin antibody – first human study

0 48 healthy postmenopausal women 0 Doses: 0.1 to 10mg/kg: single subcutaneous dose 0 Followed for 85 days

h Results 0 Dose-related increases in P1NP (similar results for BSAP

and OC, two other markers of bone formation) 0 sCTX decreased >50% for the 5 and 10mg/kg doses 0 Increases in BMD at 3 months with the 5 and 10mg/kg

doses h Spine: 3-5% h Total hip: 1.5-3%





Cathepsin K and Bone Resorption

Cathepsin K is highly expressed in the osteoclast, where it is localized in the lysosomes and released during bone resorption.

Rodan SB, Duong le T. BoneKey 2008

Cathepsin K Inhibitor – Odanacatib (MK-0822)

h Postmenopausal women with low BMD: 1-year results h N=399; received 3, 10, 25, or 50 mg once weekly vs placebo h Endpoints: changes in BMD and biochemical markers h Idiosyncratic results from 3 mg dose 0 No increase in BMD or markers higher than in placebo arm 0 Reason for these findings is unknown

Wei

ghte

d LS

Mea

n Pe

rcen

t C

hang

e fr

om B

asel

ine

Month LS BMD

0 1 3 6 12

-1.5 -1.0 -0.5

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Placebo

MK-0822 3mg MK-0822 10mg MK-0822 25mg MK-0822 50mg

Month FN BMD

0 1 3 6 12

-1.0

-0.5

0

0.5

1.0

1.5

2.0

2.5

3.0

Results





Ostabolin-C – Cyclic Analog of PTH (1-31)

h Phase II trial results – 1-year increases in BMD h N=261; postmenopausal women with BMD T-score ≤ -2 h Doses: 7.5, 15, 30 or 45 mcg/day subcutaneously h Results

0 Spinal BMD (45 mcg dose) – 11% increase 0 Total Hip BMD (45 mcg dose) – 2.4% increase 0 P1NP: >120% increase; osteocalcin: >100% increase 0 Adverse events

h Mild nausea – transient h Hypercalcemia - infrequent

h Pulmonary inhalation – Phase I





Calcium Receptor (CaR) Antagonist: “Calcilytic”

h Antagonism of the CaR in the parathyroid gland stimulates endogenous PTH secretion

h Short-term pharmacokinetic studies are modestly encouraging

Safe and effective therapies are available Antiresorptive agents

i Prevent bone loss and preserve architecture i Improve quality of bone i Reduce the risk of vertebral fractures (all agents) i Alendronate, risedronate, zoledronic acid and denosumab

proven to reduce the risk of nonvertebral and hip fractures Anabolic agent: rhPTH [1-34] (teriparatide)

i Increases bone density and size i Improves quality of bone i Reduces the risk of vertebral and nonvertebral fractures;

no hip fracture data

Patient factors determine the most appropriate drug to use

Treatment: Summary

Treatment: Summary, continued

h The risk of fracture is determined by the complex interactions among bone mineral density (BMD), bone quality and trauma

h Contemporary pharmacologic treatments will typically reduce vertebral fracture risk by 30%-70%, with smaller reductions in non-vertebral fracture risk

h No pharmacologic treatment is likely to reduce fracture risk to zero, in part because of the inability to eliminate trauma

h There are a number of promising pharmacologic agents—with most of the emphasis to be placed on the development of novel anabolic agents

1 AWP (Average Wholesale Price) varies by region and distributor * Medi-Span Drug Data. Price Rx® Prescription drug database (Accessed 30 October 2009) Red Book: Pharmacy’s Fundamental Reference. Thomson Medical Economics: Montvale, NJ. 2007.

Drugs to Treat Osteoporosis Cost per Effect on Fracture Risk

Agent year1 Vertebral Nonvert Hip

Raloxifene $976 ü -- -- Calcitonin $1517* ü -- -- Brand alendronate $1103 ü ü ü Generic alendronate $108 Risedronate $1110 ü ü ü Ibandronate (oral) $1024 ü -- -- Ibandronate (IV) $1938 Zoledronic acid $1249 ü ü ü Denosumab $1650 ü ü ü Teriparatide $9786 ü ü --

ü: antifracture efficacy proven in clinical trial --: antifracture efficacy not proven in clinical trial

2010-2011 professional associations - ucsf cme · new and emerging therapies for osteoporosis...

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