Drugs for Diseases of Bone

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Drugs for Diseases of Bone Vanderbilt Center for Bone Biology Drugs for Diseases of Bone Gregory R Mundy MD

Bone Remodeling Trabecular (cancellous) Cortical (compact)

Frost’s Contribution Osteoclastic Bone resorption New Bone Formation Nature 1965:206, 489 Hattner et al

Analogy

Video courtesy of Dr. Susan Ott, University of Washington

Video courtesy of Dr. Susan Ott, University of Washington

Remodeling Sequence Same events in cancellous and cortical bone Bone remodeling packets localized Bone remodeling sequence prolonged (~3M) Resorption and formation balanced Thus, cellular events highly coordinated Eriksen, 1986

Balanced Disease State NORMAL Pr. HPT. Paget’s Disease Thyrotoxicosis

Imbalance Breast cancer, Myeloma Prostrate cancer Osteoporosis

3 generations-screening for anabolic drugs

Normal (age 20-50) Osteoporosis (age 60+)

Video courtesy of Dr. Susan Ott, University of Washington Osteoporosis Video courtesy of Dr. Susan Ott, University of Washington

Bone Disease in Cancer Bone metastasis Osteoporosis Hypercalcemia

Skeletal-related events bone pain hypercalcemia pathologic fracture nerve compression syndromes Cancer and Bone Metastasis Lytic lesions

Fractures

Accelerating fracture repair Model 3 month old healthy rats Left femoral mid-shaft fracture Outcomes – X-rays, uCT Biomechanical

Nanobeads Local – 2 Weeks Drug NP 1.5ug lovastatin/day Vehicle 6 Radiographic score Average of two observers * * * 5 * 87% 73% 75% 4 52% 3 17% 2 The animal numbers (randomized)I used for the uCT are vehicle - 42,44,43,5 Nanobeads - 27,25,23,38 These are the number which appear on the web site 1 PBS 0.2 1.0 1.5 7.5 Nanobeads (drug release ug/day) * p< 0.05 compared to either PBS or nanobead control (no Lovastatin)