Assessment and Treatment of Osteoporosis Professor T.Masud

Assessment and Treatment of Osteoporosis Professor T.Masud Nottingham University Hospitals NHS Trust University of Nottingham University of Derby University of Southern Denmark

What is Osteoporosis? Osteoporosis is a skeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength Bone quality architecture damage accumulation bone turnover Bone density (gm/cm 2) NIH Consensus Development Panel on Osteoporosis. JAMA 285 (2001): 785-95

Incidence per 10,000/year Incidence of Osteoporotic Fractures Men Women 400-400 - 300 - = Hip fracture = Vertebral fracture = Forearm fracture 300-200 - 200-100 - 100-0 - 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ Age group 0-50 - 54 55-59 60-64 65-69 70-74 75-79 80-84 85+ Age group

Traditional case-finding strategy CRFs BMD T-score < -2.5 Treat

Majority of fractures are not in osteoporotic patients Fractures/1,000 person-years Number of fractures 50 40 30 20 10 Fracture rate Women with fractures 400 300 200 100 0 1.0 0.5 0.0-0.5-1.0-1.5-2.0-2.5-3.0-3.5 0 Siris. Surgeon General s Workshop on Osteoporosis and Bone Health, December 2002

Bone Remodeling Bone is in a constant cycle of remodeling Central to this process are the balanced activity of the osteoclast and the osteoblast Resorption and formation are balanced Resorption exceeds formation Mundy GR. In: Primer On The Metabolic Bone Diseases And Disorders Of Mineral Metabolism, 4th ed. Lippincott 1999.

Current Therapeutic Options Anti-resorptive Estrogens Calcitriol SERMs Calcitonin Bisphosphonates Denusomab Anabolic - stimulators of bone formation Parathyroid Hormone 1-34 Parathyroid Hormone 1-84 Calcium + Vit D Dual action? Strontium ranelate

Bisphosphonate - Alendronate Effects on hip fracture 3% Absolute risk of hip fracture 2% 1% 2.1% ARR = 1.1% P = 0.047 1.0% n = 1005 n = 1022 0% Black DM, et al. Lancet 1996; 348: 1535-1541. Control Alendronate

Persistence probability Compliance of Bisphosphonates 1.0 0.5 Ibandronate + PSP Alendronate 60 120 180 Time to failure from randomisation (days) Time-to-failure-to-persist data for the ITT population were used to estimate the probability of persistence at each time-point Int J Clin Practice 2006;60:896-905 Cooper A et al

Zoledronic Acid annual 5mg IV (Black et al N Eng J M 2007) Pivotal Fracture Trial 7736 women aged 65-89 3 years 70% vertebral #s 41% hip #s 25% non-vert #s Zoledronic acid- fractures and mortality after hip fractures (HORIZON) Mortality NEJM 2007 Lyles K et al

The RANK/RANK Ligand/OPG Concept Receptor Ligand Decoy Receptor RANK (Receptor Activator of Nuclear factor-kappab) RANK Ligand A ligand is a small molecule that binds to a site on a macromolecular surface by intermolecular forces OPG (OsteoProteGerin) provides an alternative binding site for RANK Ligand Ligand binding activates cellular signalling Ligand bound to decoy receptor can not activate cellular signalling

Absolute risk Denosumab 60mg s/c twice yearly: Effect on vertebral and non-vertebral fractures 3 year FREEDOM trial (7808 women mean age 72.3) 8.0 7.0 7.2 8.0 6.5 20% Mean F/N T score -2.2 Mean L/S T score -2.8 24% prevalent VCF 6.0 5.0 4.0 68% Placebo Denosumab 60mg 3.0 2.3 2.0 1.0 1.2 0.7 40% 0.0 New vertebral fracture New non-vert fracture Hip fracture p < 0.0001 p < 0.011 p < 0.036 Cummings SR et al. J Bone Miner Res (2008) 23:S80

Bone Strength What Is the Optimal Reduction in Bone Turnover for an Antiresorptive Drug? Insufficient turnover Accumulation of microdamage Increased brittleness due to excessive mineralization Excessive turnover Increase in stress risers (weak zones) Increase in perforations Loss of connectivity Physiological Range Bone Turnover Adapted from Weinstein RS, J Bone Miner Res 2000; 15 621.

SEQUENCE OF X-RAY CHANGES (Kwek 2008) 2008: Ernest Kwek 1 May 2005 to 31 January 2007: 17 patients with a low energy subtrochanteric femur fracture on alendronate therapy. Half had bilateral morbidity (fracture or stress reaction). Prodromal pain in 9 (53%). BMD status prior to alendronate: Osteoporosis: 10 Osteopenia: 6 Not done: 1 Prior fracture: Femoral: 4 Other: 4 None: 9 Injury 2008;39:224

% change (mean ± SE) Teriparatide in Women: Effects TPTD20 on in Lumbar Women: Effects on Spine LS BMD BMD 12 10 8 6 * * * * 4 * 2 0 0 3 6 12 18 End of 24 Months Treatment Study Placebo TPTD (LOCF) Marcus, et al. J Bone Miner Res 2003;18:18-23 *P<0.001

% of Women Effect of Teriparatide on the Risk of Nonvertebral Fragility Fractures 7 6 5 4 3 2 1 0 53% 54% 30 14 14 Placebo PTH20 PTH40 (N=544) RR 0.46 (95% CI, 0.25 to 0.86)** RR 0.47 (95% CI, 0.25 to 0.88)* (N=541) (N=552) *P = 0.02 vs. Placebo **P = 0.01 vs. Placebo No. of women who had > 1 nonvertebral fragility fracture

Teriparatide Baseline Patient 2582 Fracture Prevention Trial Follow-Up Female, age 59 Duration of therapy: 625 days (approx 21 mos) BMD Change: Lumbar Spine: +7.9% (group mean = 9.7 ± 7.4%) Total Hip: +5.6% (group mean = 2.6 ± 4.9%) Jiang Y et al. JBMR 2002

Strontium- dual action FORMATION Protelos RESORPTION Pre-OB REPLICATION Protelos - Pre-OC DIFFERENTIATION OB OB OB Protelos - OC + BONE FORMING ACTIVITY BONE RESORBING ACTIVITY Bone Marie PJ et al. Calcif Tissue Int. 2001;69:121-129.

Patients (%) Osteoporos Int. 2005;16(3):56;OC21. Strontium- Effects on Non-Vertebral Fracture Risk in Elderly Patients Over 3 years N = 1488 30 RR: - 31% 25 20 P = 0.011 Placebo Strontium 15 19.7% 10 14.2% 5 0 RR= 0.69; 95% CI [0.52; 0.92]

FRACTURE The link between osteoporosis and falls Osteoporosis Fracture Falls Bone Strengthening Therapy Identifying and Reducing falls risk