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 Meeting Amgen, Novartis, Lilly, Merck Grapevine, Texas p I receive research grants from the following companies: g g p October 11, 2013 Amgen, Merck I serve on speaker’s panel for these companies: Michael McClung, MD, FACP Amgen, Novartis, Lilly, Merck, Warner-Chilcott mmcclung@orost.com Michael McClung, MD 2013 Osteoporosis Treatment 2013: Benefits Osteoporosis Treatment Options - 2013 Anti-remodeling agents (inhibit bone turnover) 1. 1. Effective protection from fractures Effective protection from fractures • • Bisphosphonates (oral and IV) Vertebral fracture by 60- Vertebral fracture by 60 -70% 70% • Estrogen agonists/antagonist (raloxifene) Multiple vertebral fractures by 75 Multiple vertebral fractures by 75- -96% 96% • RANK ligand inhibitor (denosumab) Hip fracture by 40 Hip fracture by 40 50% Hip fracture by 40 Hip fracture by 40- -50% 50% 50% • Calcitonin Non- Non -vertebral fracture by 20 vertebral fracture by 20- -35% 35% 2. 2. Multiple dosing options Multiple dosing options Remodeling stimulator (increases formation and resorption) • 3. 3. In general are well tolerated In general are well tolerated • Parathyroid hormone (teriparatide) 4. 4. In clinical trials, have been very safe In clinical trials, have been very safe Other (no effect on bone turnover) • • Strontium ranelate (not available in USA) 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 Choosing Among Treatments for Osteoporosis Bisphosphonates: always a first line option in absence of • contraindications (swallowing difficulties, impaired renal No head-to-head fracture studies in postmenopausal • function) or concerns about GI absorption of oral drugs osteoporosis Calcitonin: not an appropriate treatment; may be withdrawn • from US market Patient populations studied in clinical trials differ Patient populations studied in clinical trials differ • Raloxifene: appropriate for younger postmenopausal • among studies 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 Very difficult to compare efficacy among drugs • • 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 McClung MR: Personal opinion-2013 1
Osteoporosis Treatment 2013: Limitations Osteoporosis Treatment: Mechanisms CATEGORY RESORPTION FORMATION Real or perceived intolerance • Concerns about safety, especially the long-term safety of • Anti-remodeling agents bisphosphonates - bisphosphonates, RANKL inhibitor p p , Inconvenient or awkward dosing regimens • Anti-resorptive agent Poor adherence to therapy • No agent restores skeletal structure or strength to normal • Remodeling stimulator levels - PTH analogues • i.e., no “cure” for osteoporosis Expense • M McClung. Personal opinion Odanacatib: Bone Mineral Density: 5 Years CAT-K and Its Inhibition Cathepsin K is major proteolytic enzyme secreted by • osteoclasts. 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 Discontinue therapy 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. Langdahl et al. J Bone Min Res 2012 DOI 10.1002/jbmr.1695 Odanacatib: Bone Turnover Markers Odanacatib: Clinical Trials Serum CTx (vs. baseline, %) Serum P1NP (vs. baseline, %) Phase II – 5 year follow-up • • Modest decrease in bone resorption with little effect on bone rom Baseline 150 formation Placebo/Placebo Placebo/Placebo 85 • Progressive increase BMD over 5 years 50 mg/Placebo 50 mg/Placebo 100 50 mg/50 mg 50 mg/50 mg • No major safety issues No major safety issues 60 Mean Percent Change fr 50 35 Phase III: 0 • 10 • Event-driven, randomized, placebo-controlled, multi- center, spine and hip fracture endpoint trial -50 -15 • >16,000 postmenopausal women with osteoporosis -40 -100 • DSMB recently recommended stopping Phase 3 trial 0 1 6 18 25 30 36 0 1 6 18 25 30 36 because of “robust” efficacy W1 3 12 24 27 33 W1 3 12 24 27 33 Month • Results and filing anticipated in 2014 Month http://www.huffingtonpost.com/2012/07/12/odanacatib-osteoporosis-drug-fracture- Eisman JA, McClung MR et al. J Bone Miner Res . 2011;26:242–51 bone_n_1666631.html 2
Anti-remodeling Agents: What Will Odanacatib Offer? What They Do Not Do � Bone Formation Another option • Normalize Unique mechanism of action • BMD • anti-resorptive with minimal effect on formation • indirect “anabolic” agent Restore trabecular Better efficacy - possibly • architecture Different tolerability and safety profile • Possible combinations with anabolic agents • Increase bone formation M McClung. Personal opinion Images Courtesy of Dr. David Dempster Genetic Disorders of LRP5/Wnt Osteoporosis Treatment: Mechanisms Signaling Pathway Loss of LRP5 function • CATEGORY RESORPTION FORMATION • Osteoporosis pseudoglioma syndrome Gong, Y., et al. Cell. 2001 107:513–23 Activating mutation of LRP5 Anti-remodeling agents • • High bone mass g Boyden, L.M., et al. N Engl. J. Med. 2002 346:1513–21 Sclerosteosis & van Buchem’s Disease Anti-resorptive agent • • Increased bone mass throughout the skeleton • Very low fracture risk Remodeling stimulator • Due to absence or deficiency of sclerostin (SOST) - a bone formation inhibitor Anabolic agent • Heterozygotes have increased bone mass and no other abnormalities Janssens and Van Hul. Hum Mol Genet. 2002;11:2385-93 Gardner JC, et al. J Clin Endocrinol Metab. 2005;90:6392-5 LRP5/Wnt Signaling Pathway Sclerostin and LRP5/Wnt Signaling Pathway BMP PTH BMP PTH __ LRP5/Wnt LRP5/Wnt LRP5 binding to Wnt receptor activates SOST Dkk1 intracellular β -catenin cascade, __ resulting in increased osteoblast β -catenin β -catenin Mechanical actviity and bone formation Load Altered transcription of several genes Altered transcription of several genes Enhanced bone formation Enhanced bone formation 3
Anti-Sclerostin Antibody Effects of Sclerostin Inhibition BMD: Phase 1 Placebo e from Baseline 6 5.6% Anti-sclerostin Antibody Phase I and II studies in humans: 10 mg/Kg SQ 5 Early, marked but transient increase in markers of • bone formation 4 Lumbar spine Total Hip Modest, persistent reduction in bone resorption Modest persistent reduction in bone resorption 2.8% 2 8% Percent Change • 3 Substantial increase in BMD • 2 Phase III studies are underway • 1 Other anti-sclerostin agents are under development • 0 -1 29 52 85 29 52 85 Days M McClung. Personal opinion Padhi D et al, J Bone Miner Res 2010;26:19-26 What Might Anti-sclerostin Therapy Offer? Choosing Among Therapies: Summary We have therapies that effectively prevent bone loss and • Longer duration of “anabolic window” • significantly reduce fracture risk in patients with osteoporosis. Possibility of “cure” with short-term treatment • No single treatment is ideal for all patients • Every drug has its place and its limitations Every drug has its place and its limitations Caveat: Tissue specificity is required • • In choosing a drug for our patients, we must consider • • stimulation of only bone formation • convenience of dosing • no off-target effects • strength of evidence of fracture protection • tolerability • serious safety concerns • cost M McClung. Personal opinion Choosing Among Therapies: Summary 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 Matching therapy to the needs of the patient is the clinical • challenge 4
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