7/12/2019 Skeletal Response to Stress Fracture: A fracture Basic - PowerPoint PPT Presentation

7/12/2019 Skeletal Response to Stress Fracture: A fracture Basic Combat Training caused by repetitive loading of bone tissue. Common in endurance athletes and military personnel. Mary L. Bouxsein, PhD Department of Orthopedic Surgery, BIDMC Endocrine Division, MGH Harvard Medical School Disclosures Research Funding: Amgen, Radius Healthcare Consultant: AgNovos Healthcare, Keros Therapeutics Stress fractures: failure of bone adaptation to increased mechanical loading Outline Healthy Tibia Stress Fracture Callus • Stress fracture epidemiology – Race/ethnic differences in bone microstructure • Adaptive bone formation and the skeletal response to basic combat training Tibial images from ongoing ARIEM Reduction in Musculoskeletal Injury (ARMI) Study, USARIEM Protocol 17-18HC

7/12/2019 Contributors to stress fracture Prior Physical Sex Activity Age Physical Medications Use Fitness ( e.g. NSAIDS) • 1.3 million Soldiers 3.6 fold higher rate in • 21,549 SFx cases Nutrition Genetics W vs M • Sex, age, BMI, race/ethnicity Body Menstrual Composition History & Sleep Status Quantity & Quality Bulathsinhala et al, JBMR 2017 Menstrual dysfunction common Stress fractures in the military among female soldiers • Most have regular menses prior to • >9000 soldiers diagnosed with SFx each military training year • ~70% of recruits have irregular menses • 20% of women and 7% of men during or develop amenorrhea during first basic training year – 4x more likely to be discharged • 90% of freshman cadets report • Most costly overuse injury in the military changes in menses (ie, irregular, – >$100 million / yr shorter duration, lighter) – 62 lost days/incident Anderson et al, 1979 ; Welch et al 1989; Schneider et al 1999 Cowan et al, 2003; Wood et al, 2014; Milgrom et al, 1985

7/12/2019 Stress fracture risk varies with BMI White Black Risk of SFx compared to normal weight group (18<BMI<25) Men M F Advantageous bone strength among Black individuals attributable to denser, less porous, and thicker cortices, as well as thicker trabeculae compared to Whites. BMI<18.5 25<BMI<30 BMI≥30 Women Bulathsinhala et al, JBMR 2017 Popp et al Bone 2018, 2019 Race/ethnic variation in stress fracture risk (Hazard ratio ± 95% CI relative to Black Soldiers) M • Lowest risk in non- F Hispanic Black soldiers • Highest risk in white men and women • Health records database of 1.26 NSAID Prescriptions among Soldiers – 60% and 90% higher million US Army Soldiers (2002- risk than Blacks 2011) Stress Fx Control • Case-control study – N=24,196 stress fx Full cohort 41.3% 19.3% Does bone microarchitecture differ among young adults – N=96,584 controls by race/ethnic origin? – Matched by sex, time in military BCT Only 20.2% 4.2% • Full cohort and basic combat training (BCT) period Bulathsinhala et al, JBMR 2017 Hughes et al, JBMR 2019

7/12/2019 Mechanically-stimulated bone formation increases NSAID use associated with 2- to 5-fold increased resistance to skeletal fatigue risk of stress fracture Full Cohort Basic Training RR (95% CI) RR (95% CI) Cycles to Fatigue Failure Any NSAID 2.9 (2.8-2.9) 5.3 (4.9-5.7) Ibuprofen 2.2 (2.1-2.3) 4.5 (4.2-4.9) Naproxen 2.6 (2.5-2.7) 4.8 (4.1-5.8) Indomethacin 2.1 (2.0-2.2) 4.4 (3.9-4.9) • Possible reverse causation (e.g., took NSAID because of leg pain) – Analyzed only those who had NSAID prescription for non-musculoskeletal reasons – Lagged analysis: consider prescription time prior to stress fx (15 to 45 day) • NSAID’s inhibit prostaglandins, which are involved in skeletal response to increased mechanical loading Warden et al., JBMR , 2005 Outline • Stress fracture epidemiology – Race/ethnic differences in bone microstructure – Effect of NSAIDs use on stress fracture • Adaptive bone formation and the skeletal response to Determine whether changes in bone microarchitecture, indicative of adaptive bone formation, occur in female recruits over 8 weeks of basic combat training basic combat training

7/12/2019 Baseline characteristics Mean ± SD or n (%) Study Design Age (yrs) 21.5 ± 3.3 BMI (km/m 2 ) 23.7 ± 2.8 Ethnicity White 40 (44%) • Prospective observational study during 8 week BCT Black 37 (41%) • 100 recruits (Fort Jackson, SC) Other 14 (15%) Physical activity • Outcome assessments Low (0-2 days/wk) 31 (34%) – Surveys diet, health hx, physical activity Moderate (3-5 days/wk) 46 (50%) High (≥6 days/wk) 14 (15%) – Demographics (age, sex, ht, wt, body comp) Dietary Calcium (mg/d) 790 ± 390 – Serum (pre & post) Dietary Vit D (IU/d) 146 ± 118 – Bone microarchitecture at distal tibia (HR-pQCT pre & post) Current smoker 20 (22%) Current contraceptive use 17 (19%) Changes in tibial bone microstructure HR-pQCT (XCT2) • Non-invasive “bone biopsy” Ultradistal (4%) Diaphyseal (30%) – 61 µm voxel size # # # – 5 µSv # – 2-3 min scan time # – 4% and 30% of tibial length # # # # *p<0.05, # p<0.001 vs baseline (adjusted for ethnicity, age, BMI)

7/12/2019 Median responder 20 yr old, Non Hispanic Black Same bone pre/post BCT Bone on pre scan, not on post scan (bone resorption) Bone on post scan, not on pre scan (bone formation) Tb.BV/TV + 0.80% Tb.Th + 0.60% Right Tibia Tb.vBMD + 0.50% A L M Tb.Sp - 0.20% P Pre-Post BCT Overlay Top responder Discussion 19 yr old, White Woman Same bone pre/post BCT Bone on pre scan, not on First study to show post scan (bone resorption) Limitations skeletal changes in Bone on post scan, not on pre bone microstructure scan (bone formation) • Lack of control group in humans in response to novel • Small sample size mechanical loading Tb.BV/TV + 12.7% • No injury data Changes in 8 weeks Tb.Th + 8.6% exceed those reported • Only women for 1-2 year trials of Tb.vBMD + 9.7% osteoporosis Left Tibia therapies A Tb.Sp - 2.7% M L P

7/12/2019 Ongoing work… Acknowledgements USARIEM MGH Julie Hughes, PhD • Prospective • Questionnaires Kristin Popp, PhD Stephen Foulis • Whole body DXA observational study Signe Caska • HR-pQCT (pre+post) Katelyn Guerriere Sara Rudolph • Serum (pre+post) Katheryn Taylor, PhD • 4000 recruits • Whole blood (DNA) Elizabeth Loranger Wayne Methany, PhD • Urine • Injury outcomes recorded during BCT Funding from U.S. Department of Defense, Defense Health Program, • Metabolomics, proteomics, GWAS and Joint Program Committee (W811XWH-15-C-0024) and for 2 yrs after • Gait biomech NIH Shared Equipment Grant (S10 RR023405) • Oxidative stress • Reproductive hormones (women) • Enrolled >1400 to date Summary & Conclusions • Stress fractures are an critical concern for military • Etiology is incompletely understood – Risk varies with sex, race/ethnicity, age, weight, NSAID use • 8 weeks of BCT leads to measurable changes in bone structure – Increased trabecular bone and serum bone formation markers indicative of modeling-based new bone formation – Decreased cortical vBMD and increased serum bone resorption markers consistent with intracortical remodeling • Large prospective study designed to develop a risk tool and identify modifiable risk factors