Challenging the Current Osteoporosis Guidelines Carolyn J. Crandall, MD, MS Professor of Medicine David Geffen School of Medicine at UCLA
Whom to screen Which test How to diagnose Whom to treat Benefits and risks of therapy Monitoring Treatment duration
Clinical guideline: Diagnosis Adulthood hip or vertebral fracture in the absence of major trauma or Bone mineral density (BMD) T-score -2.5 at lumbar spine or hip by dual-energy x-ray absorptiometry (DXA) (National Osteoporosis Foundation Clinician s Guide to Prevention and Treatment of Osteoporosis 2014 www.nof.org)
Clinical guideline: Treatment Postmenopausal women and men age 50 if: Hip or vertebral (clinical or asymptomatic) fracture, or BMD T-score -2.5 femoral neck, total hip, or lumbar spine, or Low bone mass (T-score between -1.0 and -2.5 at femoral neck, total hip, or spine) if: 10-yr probability of hip fracture 3% or 10-yr probability of major osteoporosis-related fracture 20% based on U.S. WHO FRAX. (National Osteoporosis Foundation Clinician s Guide to Prevention and Treatment of Osteoporosis 2014 www.nof.org)
Why care about wrist fracture? The incidence of wrist and distal forearm fracture rises rapidly after menopause. Wrist fractures occur at younger ages than do other osteoporotic fractures.
So the question is: Should wrist fractures be an indication for pharmacotherapy too? No U.S. studies have examined specific anatomical patterns of fracture following wrist fracture in postmenopausal women. First step.
Crandall et al, Journal of Bone and Mineral Research, Vol. 30, No. 11, November 2015, pp 2086 2095
Goal To determine among postmenopausal women the associations between wrist fracture and subsequent nonwrist fracture, according to anatomic site and age. Through end of WHI Extension 1. (Crandall et al, Journal of Bone and Mineral Research, Vol. 30, No. 11, November 2015, pp 2086 2095)
Analytic Sample Enrolled in the Women s Health Initiative Observational Study and Clinical Trials (n=161,808) Excluded: no follow-up (n=878) Analytic sample for fracture analysis (n=160,930) Crandall et al, JBMR 2015
Data collection Osteoporosis risk factors Baseline questionnaires Measured weight, height Incident fractures: F/u questionnaires: Has a doctor told you for the first time that you have a new broken, fractured, or crushed bone? Which bone(s)? (Annual in WHI-OS, semi-annual in WHI-CTs) (Crandall et al JBMR 2015)
Predictor Wrist fracture: first incident fracture of the radius or ulna (forearm) or carpal bones (Crandall et al, Journal of Bone and Mineral Research, Vol. 30, No. 11, November 2015, pp 2086 2095)
Outcome First occurrence of fracture of any of: Clinical spine Humerus Upper extremity non-wrist elbow, hand [except fingers], upper arm/humerus, shoulder Lower extremity non-hip Hip foot [except toes], knee/patella, upper leg, lower leg/ankle (Crandall et al, Journal of Bone and Mineral Research 2015)
Statistical analysis Cox proportional hazards: Age Race BMI Education Income Smoking Total METs/week Dietary and supplemental calcium and vit. D intake WHI-HT treatment assignment WHI DM Trial treatment assignment Falls frequency Alcohol intake Cancer history Physical function score (Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Results 8,792 wrist fractures occurred in 160,930 women during mean f/u 11.8 (3.4) years. (Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Baseline Characteristics Total N = 160,930 N (%) N (%) Age BMI (kg/m2) 24.9 56,087 (35.2) <55-59 53,234 (33.1) 25.0-29.9 55,419 (34.7) 60-69 72,243 (44.9) 30 48,013 (30.1) 70-79 35,453 (22.0) Meno. HT current 64,607 (40.2) Education Fracture Age 55+ 20,130 (14.0) HS 35,962 (22.5) Falls last 12 mo Some coll 60,610 (37.9) <2 times 135,119 (87.6) College 63,151 (39.5) 2 times 19,252 (12.5) Ethnicity Alc. 7+ drinks/wk 18,692 (11.7) White 133,032 (82.9) Current Smoker 11,048 (7.0) Black 14,469 (9.0) MET-hrs/wk mean (SD) 12.4 (13.7) Other 13,020 (8.0) Bisphos 3,155 (2.0) * Through end Ext. 1 (Crandall et al, JBMR, 2015)
(Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Table 4. Associations between Incident Wrist Fracture and Subsequent Fracture Wrist Fracture No Yes Total N Event HR (95% CI) Any non-wrist Crude 160,930 33,979 1 (ref) 1.54 (1.46-1.62) Spine Fracture Crude 160,930 5,373 1 (ref) 1.75 (1.57-1.96) Humerus Crude 160,930 4,361 1 (ref) 1.99 (1.76-2.26) (Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Table 4. Associations between Incident Wrist Fracture and Subsequent Fracture Wrist Fracture No Yes Total N Event HR (95% CI) Any non-wrist Crude 160,930 33,979 1 (ref) 1.54 (1.46-1.62) Model 3 136,017 28,790 1 (ref) 1.37 (1.29-1.46) Spine Fracture Crude 160,930 5,373 1 (ref) 1.75 (1.57-1.96) Model 3 136,017 4,544 1 (ref) 1.46 (1.29-1.65) Humerus Crude 160,930 4,361 1 (ref) 1.99 (1.76-2.26) Model 3 136,017 3,676 1 (ref) 1.67 (1.46-1.92) (Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Table 4. Associations between Incident Wrist Fracture and Subsequent Fracture Wrist Fracture No Yes Total N Event HR (95% CI) Upper extr. (non-wrist) Crude 160,930 7,312 1 (ref) 2.06 (1.87-2.27) Model 3 136,017 6,184 1 (ref) 1.80 (1.62-2.01) Lower extr. (non-hip) Crude 160,930 15,034 1 (ref) 1.41 (1.30-1.53) Model 3 136,017 12,718 1 (ref) 1.30 (1.19-1.43) Hip fracture Crude 160,930 3,836 1 (ref) 1.97 (1.73-2.24) Model 3 136,017 3,186 1 (ref) 1.48 (1.28-1.71) (Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Model 3 vs. crude model Associations between previous wrist fracture and subsequent non-wrist fracture persisted after adjustment for: other osteoporosis risk factors falls alcohol intake history of cancer physical function score (Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Figure 2a. Time to non-wrist fracture in the presence and absence of initial wrist fracture during the WHI follow-up (unadjusted cumulative incidence with vs. without prior wrist fracture) (Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Figure 2a. Time to non-wrist fracture in the presence and absence of initial wrist fracture during the WHI follow-up Guideline: treat women 50 y/o if 10- yr prob. of major osteoporosis -related fracture is 20% (unadjusted cumulative incidence with vs. without prior wrist fracture) (Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Figure 2b. Time to humerus fracture in the presence and absence of initial wrist fracture during the WHI follow-up (unadjusted cumulative incidence with vs. without prior wrist fracture)(crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Figure 2c. Time to hip fracture in the presence and absence of initial wrist fracture during the WHI follow-up (unadjusted cumulative incidence with vs. without prior wrist fracture)(crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Figure 2d. Time to spine fracture in the presence and absence of initial wrist fracture during the WHI follow-up (unadjusted cumulative incidence with vs. without prior wrist fracture)(crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Suppl. Table 4. Associations between wrist fracture and subsequent non-wrist fracture BMD cohort Wrist Fracture No Yes Total N Event HR (95% CI) BMD cohort (n = 11,350) Any non-wrist fracture Crude 11,350 2,303 1 (ref) 1.59 (1.30-1.94) Model 1 11,260 2,291 1 (ref) 1.42 (1.16-1.74) Crude + base. FN BMD 11,350 2,303 1 (ref) 1.36 (1.11-1.66) Model 1 + base. FN BMD 11,115 2,149 1 (ref) 1.30 (1.06-1.59) [1] Model 1 adjusted for age, race, and BMI (Crandall et al JBMR 2015)
Interaction tests Pre-specified interaction tests were performed No interaction by : MET-hrs/week RAND PF Score Falls in past year FRAX-predicted fracture risk But (Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Suppl. Table 2. Associations between incident wrist fracture & subseq. non-wrist fracture by age at wrist fracture Any nonwrist fx No Wrist Fracture Yes person-yrs Event HR (95% CI) P value Current age 0.02 <55 58,038 652 1 (ref) 2.49 (1.18-5.24) 55-<60 187,258 2,291 1 (ref) 1.96 (1.43-2.68) 60-<65 316,832 4,626 1 (ref) 1.64 (1.36-1.96) 65-<70 382,910 6,735 1 (ref) 1.45 (1.26-1.66) 70-<75 356,914 7,373 1 (ref) 1.35 (1.19-1.52) 75-<80 251,469 6,926 1 (ref) 1.45 (1.31-1.62) 80 or older 139,235 5,375 1 (ref) 1.24 (1.11-1.39) Adjusted for age, race, and BMI (Crandall et al, JBMR, 2015)
Sensitivity analyses 1. Excluded data from women who reported during follow-up: Osteoporosis medication Self-initiated menopausal hormone therapy Active arms of WHI Hormone Therapy and CaD trials 2. Included only medical record-confirmed fractures. Results similar to primary analyses. (Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Summary To our knowledge, this study is the first large multisite prospective US study that has focused on associations between wrist fracture and subsequent incidence of upper extremity, lower extremity, and spine fracture. Nearly 1 in 5 women with initial wrist fracture went on to experience a subsequent non-wrist fracture over 11 years of follow-up. (Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Summary Falls did not account for the increased risk of non-wrist fracture after an initial wrist fracture. Because associations persisted after adj. for BMD: Treatment guided by spine and/or hip BMD measurements alone may underestimate the increased risk of subsequent fracture risk in the setting of an initial wrist fracture. Aberrations in bone structure and/or strength may be at least partly responsible for placing women with wrist fracture at increased risk of subsequent fracture. (Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Implications Clinicians should identify postmenopausal women with wrist fractures as being at significantly elevated risk for multiple types of future fracture, including hip fracture. In fully-adjusted models, wrist fracture was associated with a 37% higher relative risk of subsequent nonwrist fracture, which was similar in magnitude to being 10 years older (35% higher). Be aware that the younger the woman is when she experiences wrist fracture, the higher the relative risk of subsequent fracture. (Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Whom to screen Which test How to diagnose Whom to treat Benefits and risks of therapy Monitoring Treatment duration
Diagnosis back in the day Physicians should consider a diagnosis of osteoporosis in individuals with a fragility fracture. Prevention and management of osteoporosis, report of a WHO Scientific Group, WHO technical report series 921, 2003
Treatment in UK now Women with a prior fragility fracture should be considered for treatment without the need for further risk assessment although BMD measurement may sometimes be appropriate, particularly in younger postmenopausal women. (Guideline for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK, National Osteoporosis Guideline Group 2013
The future Findings highlight the need for future studies that focus on developing and testing interventions specifically to prevent subsequent fractures after an initial wrist fracture. (Crandall et al, JBMR, 2015, 30 (11): 2086 2095)
Acknowledgements 2015-16 Jane A. Cauley, DrPh Meryl Leboff, MD Jeffrey R. Curtis, MD, MS, MPH Jean Wactawski-Wende, PhD Nicole C. Wright, PhD Wenjun Li, PhD Kristen Beavers, PhD Kathleen M. Hovey, MS Christopher A. Andrews, PhD