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1 Osteoporosis Treatment 2013: Limitations Osteoporosis Treatment: - - PDF document

Old and Possible New Treatments for Disclosure and Conflicts of Interest Osteoporosis: How Do We Choose? North American Menopause Society North American Menopause Society I serve on the Global Advisory Boards of the following companies: Annual


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Old and Possible New Treatments for Osteoporosis: How Do We Choose?

North American Menopause Society North American Menopause Society Annual Meeting Grapevine, Texas

Michael McClung, MD, FACP mmcclung@orost.com

p October 11, 2013

Disclosure and Conflicts of Interest

I serve on the Global Advisory Boards of the following companies: Amgen, Novartis, Lilly, Merck I receive research grants from the following companies: g g p Amgen, Merck I serve on speaker’s panel for these companies: Amgen, Novartis, Lilly, Merck, Warner-Chilcott Michael McClung, MD 2013

  • Anti-remodeling agents (inhibit bone turnover)
  • Bisphosphonates (oral and IV)
  • Estrogen agonists/antagonist (raloxifene)
  • RANK ligand inhibitor (denosumab)

Osteoporosis Treatment Options - 2013

  • Calcitonin
  • Remodeling stimulator (increases formation and resorption)
  • Parathyroid hormone (teriparatide)
  • Other (no effect on bone turnover)
  • Strontium ranelate (not available in USA)

Osteoporosis Treatment 2013: Benefits

1. 1. Effective protection from fractures Effective protection from fractures

Vertebral fracture by 60 Vertebral fracture by 60-

  • 70%

70% Multiple vertebral fractures by 75 Multiple vertebral fractures by 75-

  • 96%

96% Hip fracture by 40 Hip fracture by 40 50% 50% Hip fracture by 40 Hip fracture by 40-

  • 50%

50% Non Non-

  • vertebral fracture by 20

vertebral fracture by 20-

  • 35%

35%

2. 2. Multiple dosing options Multiple dosing options 3. 3. In general are well tolerated In general are well tolerated 4. 4. In clinical trials, have been very safe In clinical trials, have been very safe

McClung M et al. Am J Med. 2013;126:13 McClung M et al. Am J Med. 2013;126:13-

  • 20

20

Choosing Among Treatments for Osteoporosis

  • No head-to-head fracture studies in postmenopausal
  • steoporosis
  • Patient populations studied in clinical trials differ

Patient populations studied in clinical trials differ among studies

  • Very difficult to compare efficacy among drugs

McClung MR: Personal opinion-2013

Choosing Among Treatments for Osteoporosis

  • Bisphosphonates: always a first line option in absence of

contraindications (swallowing difficulties, impaired renal function) or concerns about GI absorption of oral drugs

  • Calcitonin: not an appropriate treatment; may be withdrawn

from US market

  • Raloxifene: appropriate for younger postmenopausal

women at risk for spine but not hip fracture, especially if there are concerns about breast cancer risk

  • Denosumab: first line option; not contraindicated with

impaired renal function. Theoretical concerns about use in immuno-compromised patients

  • Teriparatide: for patients at very high risk of spine fracture;

effects on hip fracture risks not known. Of special interest in patients on glucocorticoid therapy

McClung MR: Personal opinion-2013

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  • Real or perceived intolerance
  • Concerns about safety, especially the long-term safety of

bisphosphonates

Osteoporosis Treatment 2013: Limitations

  • Inconvenient or awkward dosing regimens
  • Poor adherence to therapy
  • No agent restores skeletal structure or strength to normal

levels

  • i.e., no “cure” for osteoporosis
  • Expense
M McClung. Personal opinion

CATEGORY RESORPTION FORMATION

Anti-remodeling agents

Osteoporosis Treatment: Mechanisms

  • bisphosphonates, RANKL inhibitor

Anti-resorptive agent Remodeling stimulator

p p ,

  • PTH analogues

CAT-K and Its Inhibition

  • Cathepsin K is major proteolytic enzyme secreted by
  • steoclasts. It’s action required to resorb bone.
  • Genetic deficiency - pycnodysostosis

Short stature, high bone mass with skeletal fragility

Gelb,et al.,1996; Schilling et al 2007 , , ; g

  • Inhibition in animals:
  • Decreased bone resorption
  • Increased periosteal bone formation
  • Increased cortical volumetric BMD (31% vs controls)
  • Increased cortical thickness in the radius (30%) and femur

Cusik T et al. J Bone Miner Res. 2012;27:524-37.

Odanacatib: Bone Mineral Density: 5 Years

Langdahl et al. J Bone Min Res 2012 DOI 10.1002/jbmr.1695

Discontinue therapy

Odanacatib: Bone Turnover Markers

Serum CTx (vs. baseline, %)

rom Baseline

100 150

Serum P1NP (vs. baseline, %)

60 85

Placebo/Placebo 50 mg/Placebo 50 mg/50 mg Placebo/Placebo 50 mg/Placebo 50 mg/50 mg Mean Percent Change fr

W1 1 3 6 12 18 24 25 27 30 33 36

Month

  • 100
  • 50
50
  • 40
  • 15
W1 1 3 6 12 18 24 25 27 30 33 36

Month

10 35

Eisman JA, McClung MR et al. J Bone Miner Res. 2011;26:242–51

Odanacatib: Clinical Trials

  • Phase II – 5 year follow-up
  • Modest decrease in bone resorption with little effect on bone

formation

  • Progressive increase BMD over 5 years
  • No major safety issues

No major safety issues

  • Phase III:
  • Event-driven, randomized, placebo-controlled, multi-

center, spine and hip fracture endpoint trial

  • >16,000 postmenopausal women with osteoporosis
  • DSMB recently recommended stopping Phase 3 trial

because of “robust” efficacy

  • Results and filing anticipated in 2014

http://www.huffingtonpost.com/2012/07/12/odanacatib-osteoporosis-drug-fracture- bone_n_1666631.html

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  • Another option
  • Unique mechanism of action
  • anti-resorptive with minimal effect on formation

What Will Odanacatib Offer?

  • indirect “anabolic” agent
  • Better efficacy
  • Different tolerability and safety profile
  • Possible combinations with anabolic agents
M McClung. Personal opinion
  • possibly

Bone Formation

Normalize BMD

Anti-remodeling Agents: What They Do Not Do

Restore trabecular architecture Increase bone formation

Images Courtesy of Dr. David Dempster

CATEGORY RESORPTION FORMATION

Anti-remodeling agents

Osteoporosis Treatment: Mechanisms

Anti-resorptive agent Remodeling stimulator Anabolic agent

Genetic Disorders of LRP5/Wnt Signaling Pathway

  • Loss of LRP5 function
  • Osteoporosis pseudoglioma syndrome
  • Activating mutation of LRP5
  • High bone mass
Boyden, L.M., et al. N Engl. J. Med. 2002 346:1513–21 Gong, Y., et al. Cell. 2001 107:513–23

g

  • Sclerosteosis & van Buchem’s Disease
  • Increased bone mass throughout the skeleton
  • Very low fracture risk
  • Due to absence or deficiency of sclerostin (SOST) - a

bone formation inhibitor

  • Heterozygotes have increased bone mass and no
  • ther abnormalities

Janssens and Van Hul. Hum Mol Genet. 2002;11:2385-93 Gardner JC, et al. J Clin Endocrinol Metab. 2005;90:6392-5

BMP PTH LRP5/Wnt

LRP5/Wnt Signaling Pathway

β-catenin Altered transcription of several genes Enhanced bone formation

LRP5 binding to Wnt receptor activates intracellular β-catenin cascade, resulting in increased osteoblast actviity and bone formation

BMP PTH LRP5/Wnt

Sclerostin and LRP5/Wnt Signaling Pathway

__

β-catenin Altered transcription of several genes Enhanced bone formation SOST Dkk1

Mechanical Load

__

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4 5 6 e from Baseline Lumbar spine Total Hip Placebo Anti-sclerostin Antibody 10 mg/Kg SQ 2 8% 5.6%

Anti-Sclerostin Antibody

BMD: Phase 1

  • 1

1 2 3 Percent Change Days 29 52 85 29 52 85 2.8%

Padhi D et al, J Bone Miner Res 2010;26:19-26

Phase I and II studies in humans:

  • Early, marked but transient increase in markers of

bone formation Modest persistent reduction in bone resorption

Effects of Sclerostin Inhibition

  • Modest, persistent reduction in bone resorption
  • Substantial increase in BMD
  • Phase III studies are underway
  • Other anti-sclerostin agents are under development

M McClung. Personal opinion

  • Longer duration of “anabolic window”
  • Possibility of “cure” with short-term treatment

What Might Anti-sclerostin Therapy Offer?

  • Caveat: Tissue specificity is required
  • stimulation of only bone formation
  • no off-target effects

M McClung. Personal opinion

  • We have therapies that effectively prevent bone loss and

significantly reduce fracture risk in patients with

  • steoporosis.
  • No single treatment is ideal for all patients

Every drug has its place and its limitations

Choosing Among Therapies: Summary

  • Every drug has its place and its limitations
  • In choosing a drug for our patients, we must consider
  • convenience of dosing
  • strength of evidence of fracture protection
  • tolerability
  • serious safety concerns
  • cost
  • Recent insights into regulation of bone remodeling are

leading to exciting new treatment strategies

  • In the future, we will likely use drugs in sequence or

combination

Choosing Among Therapies: Summary

  • Matching therapy to the needs of the patient is the clinical

challenge