1. ECTS symposium 5 Anabolic treatment of osteoporosis

2. Limitations to anabolic stimulation of bone formation Roland Baron, Professor, Harvard Medical School, Boston, Massachusetts, USA

3. T Baron R. and Kneissel M. Nature Medicine, 2013

4. Sclerosteosis and Van Buchem: Bone Specific Activation of WNT Signaling Sclerosteosis and Van Buchem syndrome Human genetics: Increased bone density, thick cortices in: --Sclerosteosis: All null mutations in Sost, the gene that encodes Sclerostin --Van Buchem: deletion with decreased Sclerostin expression -- Carriers have high bone mass and no side effects )

5. Padhi et al., JBMR 2011 Effects of a Single Dose of Romosozumab on BMD at the Spine and Hip

6. Sclerostin Antibodies Increase Bone Formation in both Trabecular and Cortical Bone via both Modeling and Remodeling in rats and monkeys

7. PTH is Anabolic but Bone Resorption Increases Bone Formation – e.g P1NP Bone Resorption – e.g CTX Leder at al., JCEM 2014

8. Teriparatide OW: Effects on Fracture Risk Fujita et al., CTI, 2014

9. Abaloparatide: PTHrP-based Mechanism of Action

10. Abaloparatide: Lumbar Spine BMD at 48 weeks

11. Clinical use of anabolic drugs Adolfo Diez-Perez Professor of Medicine, The Autonomous University of Barcelona, Catalonia

12. Effect of Teriparatide on New Vertebral Fractures Fracture Prevention Trial RR = relative risk vs. placebo ARR = absolute risk reduction % of women with >1 fracture Placebo (22 / 448) TPTD20 (5 / 444) ARR = 3.78% RR  77%* Multiple Neer, et al.N Engl J Med 2001; 344:1434-1441 *P<0.001 vs. placebo

13. Clinical Criteria for Treatment Failure (IOF Working Group on TF) Two or more incident fragility fractures One incident fracture AND: No change in bone turnover markers OR No increase in BMD No change in bone turnover markers AND no increase in BMD Diez-Perez A et al. Osteoporos Int 2012;23:2769-74

14. Is an anabolic superior to an oral AR? Efficacy in Postmenopausal Osteoporosis Body JJ et al. J Clin Endocrinol Metab 2002; 87: 4528-35 Alendronate Teriparatide (n=73) (n=73) Total n 10 3 women w Fx (13.7%) (4.1%)* Skeletal site Radius 3 0 Ankle 2 0 Ribs 1 2 Foot 1 1 Other 3 0 * P = 0.042 Bone Mineral Density Non-vertebral Fractures

15. Is an anabolic superior to an oral AR? Favors treatment Favors control 1. Murad MH et al. J Clin Endocrinol Metab. 2012;97:1871-80. 2. Freemantle N et al. Osteoporos Int 2013; 24: 209-17. Network meta-analysis of effectiveness 1 Mixed treatment analysis 2 - Comparative analysis of the pivotal randomized controlled trials

16. Saleh A et al. HSS J 2012; 8: 103-10 Patel V et al. J Musculoskelet Neuronal Interact 2013; 13: 251-4 Two out of 9 incomplete fractures healed with TPTD baseline one year on TPTD Atypical fractures

17. PTH (1-84) and Alendronate Alone or in Combination Black DM et al. N Engl J Med 2003;349:1207-15.

18. Teriparatide + Denosumab Leder BZ et al. J Clin Endocrinol Metab. 2014 Feb 11: [Epub ahead of print] While spine and hip BMD continued to increase in the second year in all groups, these year-2 increases did not differ between groups.