Division of Geriatrics and Nutritional Science Pharmacological and Non-Pharmacological Interventions after Hip Fracture Ellen F. Binder, MD Division of Geriatrics and Nutritional Science ebinder@wustl.edu

Disclosures of Interest Research Support: National Institute on Aging Eli Lilly, USA Consulting Regeneron Pharmaceuticals, Inc.

Percentage New Impairment at 12 Months Lower Extremity Activities of Daily Living Percentage of those Unimpaired Pre-Fracture With Impairment at 12 months Post-Fracture 10 20 30 40 50 60 70 80 90 100 Put on Pants In/Out Bed Walk 10 Feet Rise From Chair Walk 1 Block On/Off toilet Bath Climb 5 Stairs Percentage New Impairment at 12 Months Magaziner, J., Hawkes, W., Hebel, J.R., Zimmerman, S.I., Fox, K.M., Dolan, M., Felsenthal, G., Kenzora, J. Recovery from hip fracture in eight areas of function. J Gerontol A Biol Sci Med Sci, 55A, (9), 2000, M498-M507. Magaziner J, et al. J Gerontol A Biol Sci Med Sci. 2000;55A:M498-M507.

Other Functional Consequences of Hip Fracture Loss of Neuromuscular Function gait/balance More Difficulties with Instrumental Tasks Shopping/housework Increase in Cognitive Deficits 50% in hospital; 25% at 2 months Increase in Depressive Symptoms Changes in Social Function visiting with others/participating in activities Magaziner, J., Hawkes, W., Hebel, J.R., Zimmerman, S.I., Fox, K.M., Dolan, M., Felsenthal, G., Kenzora, J. Recovery from hip fracture in eight areas of function. J Gerontol A Biol Sci Med Sci, 55A, (9), 2000, M498-M507. Magaziner, J., Simonsick, E.M., Kashner, T.M., Hebel, J.R., Kenzora, J.E. Predictors of functional recovery one year following hospital discharge for hip fracture: a prospective study. J Gerontol, 45, (3), 1990, M101-M107. Magaziner J, et al. J Gerontol A Biol Sci Med Sci. 2000;55A:M498-M507. Magaziner J, et al. J Gerontol. 1990;45:M101-M107.

Recovery In Lower Extremity ADLs 10 20 30 40 50 60 70 80 2 6 12 18 24 Get In/Out of Bed Walk 10 Feet Rise From Chair Walk 1 Block Months Unpublished data from Baltimore Hip Studies Cohort 2

Dependency in Walking 10 Feet Following Hip Fracture 100 90 80 70 60 % Dependent 50 40 Magaziner, J., Hawkes, W., Hebel, J.R., Zimmerman, S.I., Fox, K.M., Dolan, M., Felsenthal, G., Kenzora, J. Recovery from hip fracture in eight areas of function. J Gerontol A Biol Sci Med Sci, 55A, (9), 2000, M498-M507. 30 Observed % Dependent 20 Predicted % Dependent 10 2 6 12 18 24 Time (Month) Magaziner J, et al. J Gerontol A Biol Sci Med Sci. 2000;55A:M498-M507.

Risk Factors for Poor Functional Recovery after Hip Fracture Older age Pre-fracture functional status Multiple co-morbidities Cognitive impairment Poor social support Depression Delayed mobility after surgery Hip pain at 2 months after surgery Decline in muscle strength (& mass?)

Falls and Injury after Hip Fracture ~50% of hip fracture patients fall within 12 mo ~30% have recurrent falls within a year ~30% sustain a fall-related injury ~12% sustain a fall-related fracture Lloyd BD et al. J Gerontol Med Sci 2009; 64A: 599-=609

Risk Factors for Falls and Injury 12 months after Hip Fracture Recurrent Falls Number of co-morbidities & medications Congestive Heart Failure* Post-fracture vitamin D levels Pre-fracture disability Handgrip strength SF-36 Quality of life* * Independent risk factor in multivariate model Lloyd BD et al. J Gerontol Med Sci 2009; 64A: 599-=609

Risk Factors for Falls and Injury 12 months after Hip Fracture Injurious Falls Number of co-morbidities & medications Post-fracture vitamin D levels Pre-fracture disability Multiple strength measures Static balance Habitual physical activity Depth perception SF-36 Quality of life Lloyd BD et al. J Gerontol Med Sci 2009; 64A: 599-=609

Risk Factors for Falls and Injury 12 months after Hip Fracture Fractures Age* Osteoarthritis Nutritional status (MNA score)* Pre-fracture disability SF-36 Quality of life Lloyd BD et al. J Gerontol Med Sci 2009; 64A: 599-=609

Challenges to Designing & Comparing Interventions for Hip Fracture Recovery Heterogeneous patient characteristics Timing and duration of interventions Intensity of interventions Location of intervention delivery Adherence to interventions Multi-component intervention design Variation in global health care systems Outcome measurement

Potential Interventions for Hip Fracture Recovery and Injury Prevention Non-Pharmacologic Interventions - Interdisciplinary team management - Post-discharge GRN case management - Nutritional interventions - Exercise training/physical therapy Pharmacologic Interventions - Anabolic steroids - Vitamin D - Antidepressants

Nutritional Interventions (RCT n=24 trials) Oral Nutritional Supplements (n=10 trials) - Trend toward decrease in acute complications - Variable effects on LOS - Variable mostly NS effects on FXN & QOL - No effects on mortality Nasogastric Feedings - No beneficial effects Limitations Small samples, no ITT analysis Lack of blinding Variable assessment of nutritional status

Pooled Outcomes From RCTs (n=11) of Extended Rehabilitation after Hip Fracture -2.00 -1.00 0.0 1.0 2.0 From Auais MA et al Phy Ther 2012; 92: 1437-1451

Pooled Outcomes from RCTs of Extended Rehabilitation after Hip Fracture -2.00 -1.00 0.0 1.0 2.0 From Auais MA et al Phy Ther 2012; 92: 1437-1451

Pooled Outcomes from RCTs of Extended Rehabilitation after Hip Fracture From Auais MA et al Phy Ther 2012; 92: 1437-1451

Effects of High-Intensity PRT and Targeted Multidisciplinary Treatment after Hip Fracture Singh NA et al. JAMDA 2012 13: 24-30 12 months of PRT + targeted geriatrician supervised multi-component TX vs. UC 81% reduction in mortality 84% reduction in NH admissions Improvements in physical impairments and depression correlated with ADL improvements Improvements in BADL, vision, walking endurance correlated with NH use

Key Characteristics of Successful Exercise/Rehab Interventions Progressive resistance exercises ≥ 12 weeks of resistance training Cognitively intact or MCI level Attention to nutrition Multi-component approach

Other Considerations Cost-effectiveness Cognitive-behavioral strategies Appropriate patient targeting Integration in existing health care programs

Why Consider Anabolic Agents to Enhance Hip Fracture Recovery?

Potential Pharmacological Agents Anabolic steroids -Growth Hormone (n=161, 6 mo tx) -Nandrolone & Testosterone Myostatin Antagonists GDF8 is a negative regulator of muscle growth. When inhibited it can induce skeletal muscle hypertrophy. Antidepressant medications

Testosterone Replacement in Female Hip Fracture patients Baseline Sample Characteristics

Testosterone Replacement in Female Hip Fracture patients Effects on Body Composition Variable Time Placebo (n=5) Testosterone (n = 9) p-value Total Fat-Free Mass by DXA (kg) Baseline 38.6 ± 2.2 38.0 ± 6.3 Final 38.5 ± 2.0 39.6 ± 7.8 change -0.01 ± 0.9 1.6 ± 1.8* 0.03 Total Fat Mass DEXA (kg) 17.2 ± 6.6 20.9 ± 8.8 18.7 ± 6.8 20.6 ± 8.6 1.5 ± 1.4 -0.3 ± 2.3 0.20 Thigh Muscle Area (cm2) FX’d side 56.2 ± 7.1 50.1 ± 10.8 63.2 ± 8.3 58.6 ± 11.2 6.9 ± 5.7 8.5 ± 6.5* 0.88

Testosterone Replacement in Female Hip Fracture patients Effects on Physical Performance Variable Time Placebo (n=5) Testosterone (n = 9) p-value Total Modified PPT Score Baseline 24.5 ± 4.1 23.0 ± 4.8 Final 29.0 ± 2.9 26.4 ± 4.8 Change 4.5 ± 4.6 3.4 ± 3.5* 0.46 Knee Extension 1-RM (lbs) 63.1 ± 16.3 61.4 ± 22.0 68.4 ± 23.4 74.2 ± 26.8 6.3 ± 9.2 12.8 ± 8.6* 0.20

Vitamin D Replacement in Hip Fracture Patients 8 ng/dl Mak JCS et al. JAGS 58: 382-383, 2010

Vitamin D Replacement After Fracture Papaioannou A et al. BMC Musculoskeletal Disorders 2011; 12: 135

Summary Optimal management strategies for hip fracture recovery require further study. A multi-disciplinary, multi-component approach may have greatest effectiveness. Extended physical rehabilitation/exercise with PRT for several months after fracture can improve physical performance, ADL performance, and QOL at 12 mo after fracture. Pharmacologic approaches have not been adequately tested, but have the potential to enhance recovery. Cost effectiveness of most interventions has not been adequately evaluated.

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