Silent Killer: Osteoporosis

Transcription

1 Special Dedication to the Old Females Silent Killer: Osteoporosis David Goltzman, Discoveries, Drugs and Skeletal Disorders Nature, Volume 1, October 2002, pp BII Journal Club Wang Zhengyuan 5:00-5:30pm August 22, 2003 Medical Informatics Group

2 Osteoporosis Osteoporosis: A skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. (1991) A bone disease characterized by: Low bone mass Tissue deterioration Susceptibility to fracture Typical location: Hip, spine, wrist One Salient Feature: Going on stealthily every day Ref: J A Kanis, Textbook of OTP, /13

3 Worldwide Public Threat Osteoporosis afflicts an estimated 1/3 of women aged 60 to 70, and 2/3 of women aged 80 or older; approximately 200 million women worldwide suffer from osteoporosis. Osteoporosis is second only to cardiovascular disease as a leading health care problem, according to WHO. Worldwide, number of hip fractures could rise from 1.7 million in 1990 to 6.3 million by Most dramatic increase expected to be in Asia during the next decades. Mortality after first facture: avg. 20% within one year; Loss of independence: >40% Cost in US: Cost in 2001: $17 billion/yr ($47 million each day!) Ref: Pic: 2/13

4 Worldwide Public Threat Approximately 20% of hip fracture patients >50yrs die within one year due to medical complications following their fracture. 1 in 3 women and 1 in 9 men over age 80 will have hip fracture as a result of osteoporosis. 1 in 4 women with osteoporotic hip fracture will require long-term nursing home care. Half of those will be unable to walk without assistance. While osteoporosis is often thought of as an older person's disease, it can strike at ANY age regardless of ethnicity Ref: L.K.H.Koh, et al, Hip Facture Incidence Rates in Singapore , Osteoporosis Int(2001)12: /13

5 What is going on within the bone? Pic: 4/13

6 Formation vs Absorption Osteoblast vs Osteoclast Osteoblast Osteopetrosis Formation Dominates Endocrine Signalling Promoters Promoters I I Promoters II Bone Formation Bone Remodeling Bone Resorption Inhibitors Inhibitors I I Inhibitors II Resorption Dominates Osteoclast Osteoporosis 5/13

7 6/13

8 Osteoblastogenesis Ref: Nature October 2002 Volume 1 pp /13

9 WNT-mediated Osteoblast Stimulation Ref: Nature October 2002 Volume 1 pp /13

10 Osteoclast: Multinucleated giant cells 4-20 nuclei in vivo Calcitonin receptor Vitronectin Regulation: Estrogens PTH Calcitonin Extracellular ph Extracellular [Ca + ] Bisphosphonates c-src PYK2 α β v 3 Ref: Nature October 2002 Volume 1 pp /13

11 Osteoclast-Osteoblast Interactions RANKL Inhibitor: OPG IFN-gamma IFN-beta Ref: Nature October 2002 Volume 1 pp /13

12 To Kill The Killer: Anti-Resorptive Drug Discovery Smart manipulation of the regulation of the bone remodeling process Anti-Resorptive Therapy: Estrogen; Bisphosphonates; SERMs*; Calcitonin; PTH(Forteo TM : approved by FDA in 2002) *SERMs: Selective Estrogen Receptor Modulators Ref: 11/13

13 To Kill The Killer: Anti-Sense Drug Discovery Loma Linda University, California: anti-sense RNA lowering the production of this enzyme in osteoclasts would slow its bone-destroying activity. To reduce the amount of enzyme made by cells, anti-sense RNA is used to destroy the enzyme s messenger RNA (mrna). In this method, researchers cause the osteoclasts to express an RNA complementary to the mrna sequence encoding the protein. This so-called anti-sense RNA binds to the target mrna, just like two complementary strands of DNA bind together. Double-stranded RNA is not tolerated by cells and is degraded, leaving very little if any mrna available for translation. Ref: 12/13

14 To Kill The Killer: State of the Art October 2002 Science Stavros C. Manolagas from the University of Arkansas Two different mechanisms of estrogen: reproductive/non-reproductive ANGELS: Activators of Non-Genomic Estrogen-Like Signaling Estren vs Estrogen Ref: Clifford J. Rosen, Restoring Aging Bones, Scientific American, March /13