Canadian Multicentre Osteoporosis Study (CaMos)

What is CaMos? 10 year prospective population based epidemiologic study Sample frame: 40% Canadian of population Random sample: 9,423 subjects initial recruitment Recruitment: July 1995 to Sept Women and men  25 years Questionnaire, DXA, US, spine x-ray

Investigators David Goltzman: Principal Investigator Nancy Kreiger: Principal Investigator (Epidemiologist) Alan Tenenhouse:P.I.Emeritus (P.I., ) Brian Lentle: Consultant for X-ray QC Bill Leslie: Associate Investigator (PI of First Nations Study): Consultant for DXA QC

Investigators: Centre Directors C. Joyce, C. Kovacs …………………St John’s S. Kirkland, S. Kaiser ……………..…Halifax J. Brown, L. Bessette ……….………Quebec City T. Anastassiades, T. Towheed ….... Kingston R. Josse, S. Jamal ………………..… Toronto T. Murray (Emeritus) ……………….. Toronto J. Adachi, A. Papaioannou ………..Hamilton W. Olszynski, S. Davison ………….Saskatoon D. Hanley ……………………………..Calgary J. Prior ………………………………..Vancouver

Support Centres The National Coordinating Centre is located in Montreal in the McGill University Health Centre Suzette Poliquin: National Coordinator Regional Coordinating Centres are located at each of the nine sites The Imaging Centre for DXA and X-ray Analysis is in Quebec City at Centre Hospitalier Universite Laval Marc Gendreau: Chief Coordinator The Data Entry and Analysis Centre is in Montreal in the McGill University Health Centre Claudie Berger: Chief Statistician The Blood and Urine Collection and Analysis Centre is in the McGill University Health Centre in Montreal

Regional Centres and National Coordinating Centre (Montreal )

Organizational Structure BOARD: Chair Committee chairs Executive External Members (1) EXECUTIVE: Principal Investigator Chair of the the Board Chair Centre Director PI Emeritus National Coordinator COMMITTEES: Centre Directors Finance Design, Analysis & Publications Communication Quality Control Industry Forum NATIONAL COORDINATING CENTRE: National coordinator Administrative Secretary Regional Centres (9): Coordinators Interviewers Technologists Data Entry Centre: Research Assistant Data entry Clerk Data Analysis Centre: Statisticians Bone Markers & Genetics Centre: Technician Imaging Centre: Coordinator Quality Control Centre: Coordinator Ultrasound Data Centre: Coordinator

Data Acquisition Original Cohort 6539 women, mean age (SD): 63.1 (12.8) 2884 men, mean age (SD): 59.9(14.5) baselineAt baseline, a “long” questionnaire was administered and participants underwent bone mineral density, height and weight measurement and ultrasound testing. Participants aged 50 years and older also had thoracic and lumbar spine X-rays taken at baseline to assess the prevalence of fractures. Blood and urine samples were obtained at 2 centres.

Data Acquisition (cont’d) Participants received a follow up “short” questionnaire annually. Self reported fractures were confirmed by medical report or hospital discharge. Respondents had a “long” questionnaire repeated at three ( participants age ), five and ten years after the baseline assessment.

Data Acquisition (cont’d) fivetenAt the five and ten year follow-up, all participants underwent a repeat bone mineral density test, height and weight measurement, ultrasound and spine X-rays (aged  50 years  Blood and urine samples collected in 6 centres at year ten follow-up Participant retention was: 86% at 5 year >72% at year 9

Data Acquisition (cont’d) Youth cohort participants years Both males and females were recruited between August 2004 and June 2006 as a “Youth Cohort” They participated in a long questionnaire and in BMD studies Blood and urine samples collected in 5 centres

What is unique about CaMos? Random sample of Canadian population Men and women  25 years of age are included Prospective, annual follow-up, 3 (40-60 years of age), 5 and 10 year extensive follow-up Imaging (BMD, ultrasound, spine X-rays at  50 years of age) Blood and urine samples (including biochemical markers), in 6 centres Excellent cohort retention

CaMos Objectives 1.Demographics of Osteoporosis 2.Risk Factors 3.Impact of Osteoporosis

1.Demographics of Osteoporosis To estimate the prevalence of main fractures associated with osteoporosis (hip, wrist and vertebra) in Canadian women and men aged  50 years; To estimate the annual incidence of : - fractures of the hip and wrist and - fractures of the vertebrae, in women and men aged  50 years.

To estimate the distribution of bone mineral densities (BMD) as measured by Dual Energy X-Ray Absorptiometry (DXA), in women and men aged  25 years; To estimate the distribution of stiffness (SOS, BUA) as measured by Ultrasound of the Calcaneus (US), in women and men aged  25 years; To estimate the pattern of change in distributions of BMD and US measures over time, in women and men aged  25 years; Demographics of osteoporosis (cont’d)

To develop a Canadian reference standard for age- matched BMD (Z-scores) in females and males age 16 to 24 To estimate the age of peak bone mass at different skeletal sites as measured by DXA in women and men. Demographics of osteoporosis (cont’d)

2.Risk Factors To assess the relationship between socio- demographic characteristics (e.g. sex, age, race, geographic region) or exogenous exposure (e.g. hormones and medication, diet, physical activity) and occurrence of: minimum trauma clinical fractures and morphometric vertebral fractures in women and men aged  50 years

Risk Factors (cont’d) To assess the relationship between certain socio-demographic characteristics (e.g. sex, age, race, geographic region) and exogenous exposures (e.g. exogenous hormones and medication, diet, physical activity) and DXA and US measurements, in women and men aged  25 years.

3. Impact of Osteoporosis To assess the relationship between osteoporosis and/or fractures, and health status To examine the burden of illness as a result of fracture.

Selected Results 1.Demographics of Osteoporosis 2.Risk Factors 3.Impact of Osteoporosis

1. Demographic of Osteoporosis

A. BMD Changes with Age in Women BMD of the Lumbar Spine and Femoral Neck in Women 25 Years and Older Tenenhouse et al. Osteoporosis Int 2000;11:

B. BMD Changes with Age in Men BMD of the Lumbar Spine and Femoral Neck In Men 25 Years and Older Tenenhouse et al. Osteoporosis Int 2000;11:

C. Mean PBM in Women and Men CaMos* compared to NHANES** *CaMos subjects were years for the femoral neck and for the trochanter ** Looker et al, J Bone Miner Res 1997;12: Tenenhouse et al. Osteoporosis Int 2000;11: BMD (g/cm2) (SD) WomenMen SiteCaMosNHANESCaMosNHANES femoral neck (0.125)(0.120)(0.125)(0.137) trochanter (0.088)(0.099)(0.103)(0.118)

D. Prevalence of Vertebral Deformity Jackson et al. Osteoporos Int 2000;11:

E.What is the Prevalence of Undiagnosed Osteoporosis (as defined by BMD or prevalent minimal trauma fractures) ?

CaMos Care Gap Analysis Goal To examine the state of the diagnostic care gap in Canada over a 5-year period of time using CaMos data. Inclusion Criteria All men and women 50 years of age and older at baseline. Papaioannou et al. CaMos Annual Scientific Meeting 2006

CaMos Care Gap Analysis (cont’d) Fracture Categories All minimal trauma fractures (excluding: toes, fingers, skull, face), including: Vertebral (clinical) Hip Pelvis Rib Wrist Treatments categories Bisphosphonates HRT Raloxifene Calcitonin/Fluoride

Diagnostic Care Gap Difference in % Diagnosed with OP (Year 0 to 5): Women: +35% Men: +20%

Diagnostic Care Gap (cont’d) General Conclusions After 5 years in the study, only -55% -55% of women -25% -25% of men diagnosed with osteoporosis (determined by CaMos DXA) were actually diagnosed with OP. < 20%At baseline, < 20% of participants with fragility fracture were diagnosed with OP (further analyses needed to examine change over time)

Summary Osteoporosis is common in Canadians ≥ 50 years of age. Most men and women do not know that they have osteoporosis by BMD criteria or after a minimal trauma fracture.

F.What is the Prevalence of Untreated Osteoporosis (as defined by BMD or prevalent minimal trauma fractures) ?

Therapeutic Care Gap CaMos Participants, 50 years & older Baseline – Year 5 Papaioannou et al. CaMos Annual Scientific Meeting 2006

% of Participants on therapy* *HRT, Bisphosphonate, Raloxifene or Calcitonin/Fluoride Difference in % treated (baseline to year 5) : Women: +23%Men: +9%

% of Participants on therapy* *HRT, Bisphosphonate, Raloxifene,Calcitonin/Fluoride Difference in % treated (baseline to year 5) : Women: +29% Men:+29%

Bisphosphonate Use over 5-years (Women) Difference in % treated (baseline to year 5) = 26% % of Women with Minimal Trauma Fracture treated with a Bisphosphonate

Bisphosphonate Use over 5-years (Men) 9% Difference in % treated (baseline to year 5 ) = 9% Papaioannou et al. Osteoporos Int 2007 (accepted) % of Men with Minimal Trauma Fracture, treated with a Bisphosphonate

% of fractures treated in year 5 (Women) Vertebral fractures most commonly treated of all fracture types

% of fractures treated in year 5 (Men) Hip fractures most commonly treated of all fracture types

General Conclusions Women Increase in treatment for women: approximately 20-30% rise from baseline to year 5 (for all fracture types) Still room for improvement in women with a fragility fracture; Year 5: -1 in 2 women received any osteoporosis therapy -1 in 3 of women received a bisphosphonate

General Conclusions (cont’d) Men Significant care-gap remains At baseline, <1% of men with a fragility fracture were being treated This rose to only 10% at Year 5

2.Risk Factors for Osteoporosis

A. BMD as a Risk Factor for Fracture Men are fracturing at higher BMD’s than women (Tenenhouse CaMos Scientific Meeting 2002.) Mean femoral neck BMD in subjects with incident minimal trauma fracture: CaMos years 1,2,3

B.Other Risk Factors for Non-vertebral Fracture (RR; 95%CI) Forearm fracture after 50 (3.626; 1.876, 7.008) Other minimal trauma fractures (1.957; 1.082, 3.540) SF-36 physical summary score (0.965; 0.939, 0.991) Femoral neck bone density (0.036; 0.001, 0.937) Inflammatory bowel disease (2.207; 1.091, 4.465) (Papaioannou et al. Osteoporos Int (2005) 16: 568–578)

C.Other Risk Factors for Clinical Vertebral Fracture ( RR; 95%CI) SF-36 physical summary score (0.959; 0.924, 0.996) Femoral neck BMD (0.002; 0.00, 0.506) Prevalent vertebral deformity (2.337; 0.897, 6.088) Loss of height (1.075; 95% CI: 0.970, 1.193) (Papaioannou et al. Osteoporos Int (2005) 16: 568–578)

D.BMD versus Clinical Risk Factors for Fracture: Impact on Prevalence of Osteoporosis (Richards et al. J Bone Miner Res (2007) 167(2): Aims To compare the prevalence of osteoporosis requiring treatment using three different classification systems: 1.BMD T-score ≤-2.5 SD 2.Simplified Clinical Risk Factor System (similar to OC system) 3.Comprehensive Clinical Risk Factor System (similar to WHO system)

Aims (cont’d) Aims (cont’d) 1. Densitometric Method If T-score at the lowest site was ≤ -2.5 SD then the subject was considered to have osteoporosis (and to be a candidate for osteoporosis therapy).

Aims (cont’d) Age, sex, BMD (lowest T-score) 10-Year Absolute Risk of Fracture, based on age, sex and BMD was applied to each patient -if: -Fragility Fracture after age 40, or -Systemic Glucocorticoids >3 months -then: 10-Year Absolute Risk of Fracture increased by 10% 2.Simplified Risk Factor System

Aims (cont’d) Aims (cont’d) 3. Comprehensive Risk Factor System Age, sex, BMD (Femoral Neck) Current Cigarette Smoking Parental History of Fracture (without regard to site) Prevalent Fragility Fracture after 50 years Ever use of Systemic Corticosteroids Alcohol Intake Greater than 2 units/day BMD <20 kg/m 2 Rheumatoid Arthritis

Risk Factor Assumptions For both Risk Factor-Based Systems, subjects were assessed if their 10-year absolute risk was 15%, 20%, or 25% All Classification Systems were Age-Adjusted to the General Canadian Population

The Prevalence of Osteoporosis in Women ≥ 50 Years, in Women ≥ 50 Years, as Defined by Different Criteria

The Prevalence of Osteoporosis in Men ≥ 50 Years, in Men ≥ 50 Years, as Defined by Different Criteria

Prevalence By Age-Group with 20% 10-Year Fracture Risk, Age-Adjusted to the CDN Population MenWomen Age (years)

Prevalence By Age-Group with 25% 10-Year Fracture Risk, Age-Adjusted to the Canadian Population WomenMen Age (years)

Conclusions The application of risk factor-based systems results in an increased prevalence of the diagnosis of osteoporosis in older women. The prevalence of individuals with osteoporosis at high risk for fracture may increase with changes to the methods used to determine those who are at risk and with the level of risk considered high. These data have important implications for the pattern of care and costs of treating osteoporotic fractures.

E.The Effect of Selective Serotonin Reuptake Inhibitors on Fractures and Bone Mineral Density ( Richards et al. Arh Intern Med (2007) Objective Examine the effect of daily SSRI use on the risk of incident clinical fragility fracture

Results In 137 subjects using SSRI’s daily Increased risk of incident clinical vertebral fracture: HR 2.1 (95% CI ) In addition Increased odds of falling: or 2.2 (95% CI ) Lower BMD at the hip, and a trend towards lower BMD in the spine Effects of SSRI’s… (cont’d)

Conclusion Daily SSRI use in adults over 50 years associated with a 2-fold increased risk of clinical fragility fracture after adjustment for potential covariates

3. Impact of Osteoporosis

What is the Influence of Osteoporotic Fractures on Health Related Quality of Life (HRQoL) in Community Dwelling Men and Women Across Canada? Adachi et al. Osteoporos Int 2001;12:903–908 Adachi et al. Osteoporos Int 2003;14:895–904

Fractures and HRQL SF-36 Adachi et al. Osteoporos Int 2001;12:903–908

Fractures and HRQL SF-36 (cont’d) Adachi et al. Osteoporos Int 2001;12:903–908

Fractures and HRQL - HUI Adachi et al. Osteoporos Int (2003) 14: 895–904

Fractures and HRQL - HUI (cont’d) Adachi et al. Osteoporos Int (2003) 14: 895–904

Fractures and HRQL - HUI (cont’d) Adachi et al. Osteoporos Int (2003) 14: 895–904

CaMos HUI3 Scores: B aseline differences between diseases Sawka et al. Osteoporos Int 2005;16: 1836–1840

Conclusions Fractures have a negative impact on SF-36 quality of life, particularly on role-physical and physical functioning. Fractures have the most negative impact on HUI measured ambulation, pain, and mobility.

Selected Ongoing Projects To determine the geographic variation and age and sex specific cross-sectional distribution of bone mineral density in Canadian adults To determine the rates of change of BMD at several skeletal sites (lumbar spine (L14)), femoral neck, total hip, trochanter and ward’s triangle) in Canadian women and men ≥ 25 years from the CaMos cohort. 1. Demographics

Selected Ongoing Projects (cont’d) A Comparison of Prevalent Morphometric Vertebral Deformity versus Other Risk Factors as Predictors of Fracture Risk in women and men Depression as a Risk Factor for BMD and Fracture Beta-blockers, Bone Mineral Density and Fractures Physical Activity relationships with Bone Mineral Density and Fracture 2. Risk Factors

3. Impact of Osteoporosis Predictors of mortality in CaMos participants with baseline fracture Association between quality of life and incident osteoporotic fractures Selected Ongoing Projects (cont’d)

4. Interventions in Osteoporosis Effect of anti-resorptives on incident osteoporotic fractures Prevalence and correlates of complementary and alternative medicine use in osteoporosis Selected Ongoing Projects (cont’d)

Summary Large cohort -Women & men -Broad age range -Excellent retention 10 year follow-up Large database -Osteoporosis & fracture -Other medical & demographic

Summary (Cont) Imaging, repeated over 10 years -DXA -Spine x-rays -Bone ultrasound Archived “tissue” samples -Serum -Urine -DNA National & international collaborations Excellent productivity in advancing knowledge re osteoporosis