Carolyn J. Crandall, MD, MS On behalf of the WHI Bone SIG

Carolyn J. Crandall, MD, MS On behalf of the WHI Bone SIG

Background One half of all postmenopausal women will have an osteoporosis related fracture during their lifetimes.

Background Low body weight is a risk factor for fracture. But: Little is known regarding how changes in body weight influence subsequent fracture patterns among postmenopausal women. Associations of intentional weight loss and unintentional weight loss with fracture risk may differ.

BMJ 2015, 350:h25 doi: 10.1136/bmj.h25

Objective: To determine longitudinal associations between change in body weight and subsequent fracture incidence. Crandall, et al, BMJ 2015, 350:h25

Recruited: n = 161,808 (n = 93,676 in WHI-OS + n = 68,132 in WHI-CT) Information available regarding weight change between baseline and year 3: n = 120,566 Data avail. for fracture analyses: n = 117,259 ppts re lower limb n = 117,428 ppts re for upper limb n = 119,323 pts re central body n = 120,112 ppts re hip Information missing regarding weight change between baseline and year 3: n = 41,242 Fracture before annual visit 3: n = 3,139 lower limb fractures n = 2,972 upper limb fractures n = 1,076 central body fractures n = 285 hip fractures Crandall, et al, BMJ 2015, 350:h25

Outcome measurements Time to first incident self-reported fracture Self-reported annually after visit 3 Hip fractures adjudicated Upper limbs (n = 8,531): elbow, hand (not fingers), lower arm/wrist, upper arm/humerus or shoulder Lower limbs (n = 8,529): foot (not toes), knee/patella, upper leg (not hip), lower leg/ankle Central body (n = 6,791): hip, pelvis, and spine

Primary predictors 1) Percentage change in measured body weight between baseline and annual follow-up visit 3 (+/- 90 days) as mutually exclusive categories: Weight loss (decrease 5% since baseline) Stable weight (change <5% from baseline) Weight gain (increase 5% since baseline) 2) Self-reported intentional and unintentional weight loss preceding the year 3 annual follow-up visit (yes vs. no): In the past 2 years, did you lose 5 or more pounds on purpose at any time?, similar question not on purpose

Statistical analysis Cox proportional hazards regression Base models adjusted for: age, race, height, baseline weight, smoking, alcohol intake, total energy expended per week, dietary and supplemental vitamin D and calcium intake, physical function score, general health status, oophorx/hysterx, Charlson Index score, medication use (menopausal hormone therapy, oral corticosteroid, diabetes medication), study group assignment (WHI-OS, WHI- CT), previous cancer diagnosis, previous fracture

Baseline analytic sample characteristics Variables Total Variables Total Age Calcium 1200 mg/d (diet + supp) 49715 (41) <50-59 39 010 (32) Vit. D 600 IU/d (diet + supp) 23 448 (20) 60-69 55 240 (46) Current smoker 7495 (6) 70 26 316 (22) 7 drinks alcohol/week 14 417 (12) BMI (kg/m 2 ) Daily oral corticosteroid use 120 566 <24.9 43 284 (36) Diabetes treatment 4639 (4) 25.0-29.9 42 099 (35) Poor self-rated health 646 (1) >30.0 34 963 (29) White 101 573 (84) Falls: Black 9539 (8) No falls past 12 mo 77773 (67) Hispanic 4058 (3) 1 fall past 12 mo 23 311 (21) Asian/Pac. Isl. 3375 (3) 2 falls past 12 mo 9499 (8) Other 1741 (2) 3 falls past 12 mo 4712 (4) Crandall, et al, BMJ 2015, 350:h25

Measured weight change baseline to year 3 Total N: 120,566 N (%) Mean ann. % change Mean (SD) wt. change kg Stable (<5% change) Wt. loss ( 5% loss) 79,279 (66%) 18,266 (15%) Wt. gain ( 5% gain) 23,021 (19%) (Ref) 3.6 %/yr 4.1%/yr (Ref.) 10.0 (15.0) 8.7 (13.4)

Body weight change (year 3 - baseline) & incident fractures HR Upper limb fracture (95% CI) HR Lower limb fracture (95% CI) HR Central Body fracture (95% CI) HR Hip fracture (95% CI) Base Base + falls Base Base + falls Base Base + falls Base Base + falls Stable Wt (ref) Wt loss Wt gain 1.00 1.00 1.00 1.00 1.09 (1.03, 1.16) 1.10 (1.04, 1.17) 0.98 (0.92, 1.05) 1.18 (1.12, 1.25) 1.30 (1.22, 1.39) 0.96 (0.90, 1.03) 1.65 (1.49, 1.82) 0.96 (0.86, 1.08) Crandall, et al, BMJ 2015, 350:h25

Body weight change (year 3 - baseline) & incident fractures HR Upper limb fracture (95% CI) HR Lower limb fracture (95% CI) HR Central Body fracture (95% CI) HR Hip fracture (95% CI) Base Base + falls Base Base + falls Base Base + falls Base Base + falls Stable Wt (ref) Wt loss Wt gain 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.09 (1.03, 1.16) 1.10 (1.04, 1.17) 1.08 (1.02, 1.15) 1.09 (1.04, 1.16) 0.98 (0.92, 1.05) 1.18 (1.12, 1.25) 0.98 (0.92, 1.04) 1.18 (1.11, 1.24) 1.30 (1.22, 1.39) 0.96 (0.90, 1.03) 1.30 (1.21, 1.38) 0.96 (0.90, 1.03) 1.65 (1.49, 1.82) 0.96 (0.86, 1.08) 1.64 (1.49, 1.82) 0.96 (0.86, 1.08) Crandall, et al, BMJ 2015, 350:h25

Similar findings after adjustment of base model for: Walking (met-hours/week) Dietary protein intake (g/d)

Intentional and unintentional weight loss Self-reported weight loss 5 lbs past 2 yrs Intentional Unintentional N (%) 27,530 (44%) 14,653 (24%)

Associations of self-reported intentional and unintentional weight loss with fracture incidence HR upper limb fx (95% CI) HR lower limb fx (95% CI) HR central body fx (95% CI) HR hip fx (95% CI) HR overall (95% CI) HR spine fx (95% CI) HR pelvis fx (95% CI) Unint. wt. loss Int. wt. loss No/DK 1.00 1.00 1.00 1.00 1.00 1.00 Yes 1.05 (0.99, 1.13) 1.03 (0.97, 1.09) 1.21 (1.13, 1.29) 1.33 (1.19, 1.47) 1.16 (1.06, 1.26) 1.14 (1.00, 1.31) No/DK 1.00 1.00 1.00 1.00 1.00 1.00 Yes 1.00 (0.94, 1.05) 1.11 (1.05, 1.17) 0.93 (0.88, 0.99) 0.85 (0.76, 0.95) 0.97 (0.89, 1.05) 0.94 (0.82, 1.07) Crandall, et al, BMJ 2015, 350:h25

Summary Compared with stable weight: Weight gain ( 5% of body weight over 3 years) is associated with increased upper and lower limb fractures. Weight loss ( 5% of body weight over 3 years) is associated with increased central body and upper limb fractures. (Confirmed marked hip fx increase seen in prior studies). First documentation of different locations of fracture associated with unintentional vs. intentional weight loss, with opposite patterns for hip and central body fractures.

Limitations Did not have information regarding circumstances of the fracture (e.g. specific activities that immediately preceded fractures). Participants might have experienced weight change during the fracture follow-up period.

Conclusions These findings challenge the traditional clinical paradigm of weight gain being protective against fractures. Weight loss intervention trials should consider potential effects on fracture incidence, consider preventive strategies.

Acknowledgements Jane A. Cauley, DrPH Zhao Chen, PhD Scott Going, PhD Karen Johnson, MD, MPH Jean Wactawski-Wende, PhD Nicole Wright, PhD Vedat Yildiz, MS (Photo: http://www.nps.gov/stli/planyourvisit/index.htm)