OSTEOPOROSIS

1. OSTEOPOROSIS “Disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fractural risk.” (1)

2. Bone Remodeling • Bone remodeling is the continuous destruction and renewal of bones • Initiated by hormonal signals that activate osteoclasts • Once osteoclasts are activated they create cavities in bones by secreting protons and enzymes that dissolve bone mineral • Osteoblasts then enter the cavities created and form new bone by secreting collagen and matrix constituents that eventually mineralize into bone

3. (2)

4. Remodeling Imbalance • Bone remodeling is NOT perfect! • A small amount of bone is lost in each remodeling cycle (2)

5. Peak Bone Mass • Maximum bone tissue in the skeleton achieved from normal growth • “as early as 17 or 18 to as late as 35” (3) • Bone growth most significant during infancy and adolescence • “peak bone mass serves as the ‘bone bank’ for the remainder of adult life. Thereafter, there are inevitable ‘withdrawals’ from this ‘account’.” (4)

6. Osteoporosis

7. Primary Osteoporosis Naturally occurring osteoporosis (no medical conditions that effect bone remodeling) • Idiopathic Osteoporosis A. Juvenile – children 8-14 years old, decreased/failed osteoblast function B. Young Adults – age 20-44, increased bone resorption or inadequate peak bone mass

8. Primary Osteoporosis (cont.) II. Involutional Osteoporosis – most common form, result of age and/or hormonal factors A. Type I (Postmenopausal Osteoporosis) - result of estrogen deficiency - 10-20% postmenopausal women - Osteoclast development increased -Interleukins (IL-1 & IL-6) - Impairs calcium absorption - Includes exercise or anorexia nervosa related amenorrhea related osteoporosis - Fractures in forearm, ankle, vertebrae (crush) (5)

9. Primary Osteoporosis (cont.) B. Type II (Senile Osteoporosis) - Men & Women around age 70 - By age 90, bone mass could be ~50% less in women and ~37% less in men - Remodeling imbalance, hormonal changes, nutritional factors, inactivity - Fractures of hip, pelvis, proximal humerus and tibia, vertebrae (wedge) - Peak bone mass especially important

10. Secondary Osteoporosis “Caused by specific conditions, for example, certain diseases and surgical procedures and the use of some drugs, that might be responsible for bone loss.” (6) • Drug-related – glucocorticoids, anticonvulsants, methotrexate, lithium, oral anticoagulants = increased osteoclast activation • Endocrine Disorders – hypothyroidism, diabetes mellitus (IDD), hyperparathyroidism, hypercorticolism = increased ostoclast function • Gastrointestinal disorders – gastrectomy, inflammatory bowel disease = steroid related osteoclast activation, malabsorption syndrome = inability to absorb calcium & vitamin D

11. Secondary Osteoporosis (cont.) • Marrow disorders – leukemia, lymphomas, plasma cell dyscrasia, anemias • Connective tissue disorders – Marfan syndrome, esteogenesis imperfecta = impaired collagen biosynthesis, rheumatiod arthritis = bone deterioration around inflamed joints, inactivity • Miscellaneous – immobilization, alcohol abuse, anorexia nervosa, pregnancy/lactation, chronic neurological disease, malignancy, cadmium poisoning

12. Diagnosis • Radiology - MRI & X-Ray • Collagen cross-link identification - (+)-deoxypyridinoline (Dpd) detection in urine by amino acid analysis, HPLC, immunoasseys (very expensive)

13. Treatment • NO ‘Cure’ • Drug Therapies - Calcuim & Vitamin D - Calcitonin - Bisphosphonates – most widely used osteoclast inhibitor - Estrogen Replacement Therapy • Musculoskeletal Rehabilitation – exercise, braces, weights

14. ©The Medical Journal of Australia 2004 www.mja.com.au ISSN: 0025-729X

15. Prevention • ONLY ‘CURE’ • Peak bone mass • Nutrition • Exercise • Weight • Tobacco, alcohol, steroids • Hormonal state

16. Statistics • 2006 ~ 10 million Americans had osteoporosis, 30 million had low bone mass • “Each year in the US, osteoporosis is responsible for more than 2 million osteoporotic-related fractures at a cost of more than $17 billion.” (7)

17. Sources Used (1) R. Nuti, G. Martini, and C. Gennari, “Bone Mass Loss in Secondary Osteoporosis,” in Bone Densitometry and Osteoporosis, eds. H. K. Genant, G. Guglielmi, M. Jergas, 504 (Heidelberg: Springer, 1998). (2) Robert Marcus, “Introduction: Organizational and Functional Aspects of Skeletal Health,” in Osteoporosis, ed. Robert Marcus, 1-16 (Boston: Blackwell Scientific Publications, 1994). (3) Robert P. Heaney and Velimir Matkovic, “Inadequate Peak Bone Mass,” in Osteoporosis: Etiology, Diagnosis, and Management, Second Edition; eds. B. Lawrence Riggs, L. Joseph Melton III, 115 (Philadelphia: Lippincott-Raven Publishers, 1995). (4) Laura Bachrach, “Bone Acquisition in Childhood and Adolescence,” in Osteoporosis, ed. Robert Marcus, 69 (Boston: Blackwell Scientific Publications, 1994). (5) www.4women.gov/FAQ/Pix/osteo3.jpg (6) Sundeep Khosla, L. Joseph Melton III, “Secondary Osteoporosis,” in Osteoporosis: Etiology, Diagnosis, and Management, Second Edition; eds. B. Lawrence Riggs, L. Joseph Melton III, 183-204 (Philadelphia: Lippincott-Raven Publishers, 1995). (7) T. W. Weiss, E. S. Siris, E. Barrett-Conner, P. D. Miller, C. A. McHorney, “Osteoporosis practice patterns in 2006 among primary care physicians participating in NORA study,” Osteoporosis International 18.11 (Nov 2007): 1473 (8). Info Used: Gideon A. Rodan and Sevgi B. Rodan, “The Cells of Bone,” in Osteoporosis: Etiology, Diagnosis, and Management, Second Edition; eds. B. Lawrence Riggs, L. Joseph Melton III, 1-39 (Philadelphia: Lippincott-Raven Publishers, 1995). Robert L. Jilka, Stavros C. Manolages, “The Cellular and Biochemical Basis of Bone Remodeling,” in Osteoporosis, ed. Robert Marcus, 17-48 (Boston: Blackwell Scientific Publications, 1994). Sundeep Khosla, B. Lawrence Riggs, L. Joseph Melton III, “Clinical Spectrum” in Osteoporosis: Etiology, Diagnosis, and Management, Second Edition; eds. B. Lawrence Riggs, L. Joseph Melton III, 205-223 (Philadelphia: Lippincott-Raven Publishers, 1995). Maciej Adamczyk, Donald D. Johnson, Rajarathnam E. Reddy, “Collagen Cross-Links. Synthesis of Immunoreagents for Development of Assays fro Deoxypyrodinoline, a Marker for Diagnosis of Osteoporosis,” Bioconjugate Chem, 2000, 11, 124-130 Charles H. Chesnutt III, “Drug Therapy: Calcitonin, Bisphosphonates, and Anabolic Steroids,” in Osteoporosis: Etiology, Diagnosis, and Management, Second Edition; eds. B. Lawrence Riggs, L. Joseph Melton III, 391-402 (Philadelphia: Lippincott-Raven Publishers, 1995). R. Greig, Aymen I. Idris, Stuart H. Ralston, Rob J. van’t Hof, “Development and Characterization of Biphenylsulfonamides as Novel Inhibitors of Bone Resorption,” J. Med Chem., 2006, 49, 7487-7492. Aviva Ezra, Ammon Hoffman, Eli Breuer, Ivan S. Alferiev…, “A Peptide Prodrug Approach for Improving Bisphosphonate Oral Absorption,” J. Med. Chem.,2000, 43, 3641-3652.