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

7/12/2019

Skeletal Response to Basic Combat Training

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

Outline

• Stress fracture epidemiology

–Race/ethnic differences in bone microstructure

• Adaptive bone formation and the skeletal response to

basic combat training

Stress Fracture: A fracture caused by repetitive loading

• f bone tissue. Common in

endurance athletes and military personnel.

Stress fractures: failure of bone adaptation to increased mechanical loading

Healthy Tibia

Stress Fracture Callus

Tibial images from ongoing ARIEM Reduction in Musculoskeletal Injury (ARMI) Study, USARIEM Protocol 17-18HC

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Contributors to stress fracture

Sleep Quantity & Quality Nutrition Sex Age Prior Physical Activity Genetics Menstrual History & Status Medications Use (e.g. NSAIDS) Physical Fitness Body Composition

Stress fractures in the military

• >9000 soldiers diagnosed with SFx each

year

• 20% of women and 7% of men during

basic training

–4x more likely to be discharged

• Most costly overuse injury in the military

–>$100 million / yr –62 lost days/incident

Cowan et al, 2003; Wood et al, 2014; Milgrom et al, 1985

• 1.3 million Soldiers
• 21,549 SFx cases
• Sex, age, BMI, race/ethnicity

3.6 fold higher rate in W vs M

Bulathsinhala et al, JBMR 2017

Menstrual dysfunction common among female soldiers

• Most have regular menses prior to

military training

• ~70% of recruits have irregular menses
• r develop amenorrhea during first

year

• 90% of freshman cadets report

changes in menses (ie, irregular, shorter duration, lighter)

Anderson et al, 1979 ; Welch et al 1989; Schneider et al 1999

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Stress fracture risk varies with BMI

Bulathsinhala et al, JBMR 2017

BMI<18.5 BMI≥30 25<BMI<30

Risk of SFx compared to normal weight group (18<BMI<25)

M F

Race/ethnic variation in stress fracture risk

(Hazard ratio ± 95% CI relative to Black Soldiers)

• Lowest risk in non-

Hispanic Black soldiers

• Highest risk in white

men and women

– 60% and 90% higher risk than Blacks

Bulathsinhala et al, JBMR 2017 M F

Does bone microarchitecture differ among young adults by race/ethnic origin? Men Women Black White

Popp et al Bone 2018, 2019

Advantageous bone strength among Black individuals attributable to denser, less porous, and thicker cortices, as well as thicker trabeculae compared to Whites.

• Health records database of 1.26

million US Army Soldiers (2002- 2011)

• Case-control study

– N=24,196 stress fx – N=96,584 controls – Matched by sex, time in military

• Full cohort and basic combat

training (BCT) period

Stress Fx Control

Full cohort 41.3% 19.3% BCT Only 20.2% 4.2% NSAID Prescriptions among Soldiers Hughes et al, JBMR 2019

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NSAID use associated with 2- to 5-fold increased risk of stress fracture

Full Cohort RR (95% CI) Basic Training RR (95% CI) 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

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

basic combat training Mechanically-stimulated bone formation increases resistance to skeletal fatigue

Cycles to Fatigue Failure

Warden et al., JBMR, 2005

Determine whether changes in bone microarchitecture, indicative of adaptive bone formation, occur in female recruits over 8 weeks of basic combat training

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Study Design

• Prospective observational study during 8 week BCT
• 100 recruits (Fort Jackson, SC)
• Outcome assessments

–Surveys diet, health hx, physical activity –Demographics (age, sex, ht, wt, body comp) –Serum (pre & post) –Bone microarchitecture at distal tibia (HR-pQCT pre & post)

HR-pQCT (XCT2)

• Non-invasive “bone biopsy”

– 61 µm voxel size – 5 µSv – 2-3 min scan time – 4% and 30% of tibial length

Baseline characteristics Mean ± SD or n (%) Age (yrs) 21.5 ± 3.3 BMI (km/m2) 23.7 ± 2.8 Ethnicity White Black Other 40 (44%) 37 (41%) 14 (15%) Physical activity Low (0-2 days/wk) Moderate (3-5 days/wk) High (≥6 days/wk) 31 (34%) 46 (50%) 14 (15%) Dietary Calcium (mg/d) 790 ± 390 Dietary Vit D (IU/d) 146 ± 118 Current smoker 20 (22%) Current contraceptive use 17 (19%)

Changes in tibial bone microstructure

Ultradistal (4%)

# # # # # # #

*p<0.05, # p<0.001 vs baseline (adjusted for ethnicity, age, BMI)

Diaphyseal (30%)

# #

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Median responder

Tb.BV/TV + 0.80% Tb.Th + 0.60% Tb.vBMD + 0.50% Tb.Sp

• 0.20%

20 yr old, Non Hispanic Black

L M A P

Right Tibia

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)

Pre-Post BCT Overlay

Top responder

19 yr old, White Woman

M L A P

Left Tibia

Tb.BV/TV + 12.7% Tb.Th + 8.6% Tb.vBMD + 9.7% Tb.Sp

• 2.7%

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)

Discussion

Limitations

• Lack of control group
• Small sample size
• No injury data
• Only women

First study to show skeletal changes in bone microstructure in humans in response to novel mechanical loading Changes in 8 weeks exceed those reported for 1-2 year trials of

• steoporosis

therapies

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Ongoing work…

• Prospective
• bservational study
• 4000 recruits
• Injury outcomes

recorded during BCT and for 2 yrs after

• Enrolled >1400 to date
• Metabolomics, proteomics, GWAS
• Gait biomech
• Oxidative stress
• Reproductive hormones (women)
• Questionnaires
• Whole body DXA
• HR-pQCT (pre+post)
• Serum (pre+post)
• Whole blood (DNA)
• Urine

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

Acknowledgements

USARIEM Julie Hughes, PhD Stephen Foulis Katelyn Guerriere Katheryn Taylor, PhD Wayne Methany, PhD

MGH

Kristin Popp, PhD Signe Caska Sara Rudolph Elizabeth Loranger Funding from U.S. Department of Defense, Defense Health Program, and Joint Program Committee (W811XWH-15-C-0024) NIH Shared Equipment Grant (S10 RR023405)