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29 th Annual Meeting

29 th Annual Meeting. COORDONNATEUR Pr Maurice Audran (Angers). of the A merican S ociety for B one and M ineral R esearch. 16-20 septembre 2007 - Honolulu, États-Unis. RÉDACTEURS Dr Véronique Breuil (Nice) – Pr Roland Chapurlat (Lyon)

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29 th Annual Meeting

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  1. 29th Annual Meeting COORDONNATEUR Pr Maurice Audran (Angers) of theAmerican Society forBoneand MineralResearch 16-20 septembre 2007 - Honolulu, États-Unis • RÉDACTEURS • Dr Véronique Breuil (Nice) – Pr Roland Chapurlat (Lyon) • Dr Pascal Guggenbuhl (Rennes) – Dr Éric Lespessailles (Orléans) • Dr Florence Trémollières (Toulouse)

  2. Table of contents • From Bone Acquisition to Fractures • Decrease in Cortical Thickness is Associated with the Pubertal Increase Forearm Fractures in Girls (1) • Decrease in Cortical Thickness is Associated with the Pubertal Increase Forearm Fractures in Girls (2) • High Protein Intake Enhances the Positive Effect of Physical Activity on BMC in Pre-pubertal Boys (1) • High Protein Intake Enhances the Positive Effect of Physical Activity on BMC in Pre-pubertal Boys (2) • Role of Mechanical Loading from Non-Muscular Sources on Human Skeletal Structure (1) • Role of Mechanical Loading from Non-Muscular Sources on Human Skeletal Structure (2) • Effects of Mechanical Loading and Estrogen are Structurally Distinct • Vertebral Fracture Lines are not Smooth, but Mixtures of Multiple Schmorl’s Nodes and Endplate Perforations • Decline in Age Adjusted Hip Fracture Incidence but Drastic Increase in Hip Fractures Among the Very Oldest (1) • Decline in Age Adjusted Hip Fracture Incidence but Drastic Increase in Hip Fractures Among the Very Oldest (2) • Increased Mortality in Patients with a Hip Fracture Effect of Pre-morbid Conditions and Post-Fracture Complications ASBMR 2007 La Lettre du Rhumatologue

  3. Table of contents • Osteoporosis - Assessment • Clinical Risk Factors for Incident Vertebral Fractures: the OPUS Study (1) • Clinical Risk Factors for Incident Vertebral Fractures: the OPUS Study (2) • Chronic Proton Pump Inhibitor Use is not Associated with an Increased Risk of Osteoporotic Fracture • Efficacy of Clodronate on Fracture Risk in Women Selected by 10-year Fracture Probability • Bone Mineral Density and Hip Fracture: Role of Bone Loss (1) • Bone Mineral Density and Hip Fracture: Role of Bone Loss (2) • Risk of Subsequent Fracture Depends on Bone Mineral Density and Fracture Type: a 17-Year Prospective Study • Fracture Risk is Better Predicted by Vertebral Morphometry Assessment than by the WHO score (1) • Fracture Risk is Better Predicted by Vertebral Morphometry Assessment than by the WHO score (2) • Computer-Based Measure of Kyphosis Predicts Fractures in the Thoracic Spine of Postmenopausal Women • Which Risk Factors Lead Clinicians to Treat Their Patients? • Which Risk Factors Lead Clinicians to Diagnose or Treat Their Patients for Osteoporosis? (1) • Which Risk Factors Lead Clinicians to Diagnose or Treat Their Patients for Osteoporosis? (2) • Association of Abdominal Aortic Calcifications (AAC) on Vertebral Fracture Assessment (VFA) Images with Increased Risk of Cardiovascular Diseases in Older Women (1) ASBMR 2007 La Lettre du Rhumatologue

  4. Table of contents • Association of Abdominal Aortic Calcifications (AAC) on Vertebral Fracture Assessment (VFA) Images with Increased Risk of Cardiovascular Diseases in Older Women (2) • Bone Mineralization and Vitamin D Inadequacy. Histomorphometric Analysis of Iliac Crest Bone Biopsies and Circulating 25-OH Vitamin D in 675 patients • Osteoporosis in Men • Endogenous Sex Hormones and Incident Fracture Risk in Older MenThe DUBBO Study (1) • Endogenous Sex Hormones and Incident Fracture Risk in Older MenThe DUBBO Study (2) • Serum DHEA is Independently of Sex Hormones Related to Incident Fractures in Elderly Men – The MrOS SWEDEN Study • Biochemical Markers of Bone Turnover and the Risk of Non-Vertebral Fractures in Older Men (1) • Biochemical Markers of Bone Turnover and the Risk of Non-Vertebral Fractures in Older Men (2) • Diabetes and Fracture Risk in Older Men The Osteoporotic Fractures in Men (MrOS) Study • Aortic Calcification Correlate with Volumetric Bone Mineral Density and Bone Microstructure in Men: a Population-Based Study • Asymmetry in Leg Power Increases Non-Spine and Hip Fracture Risk in Older Men: the Osteoporotic Fractures in Men (MrOS) Study • Arterial Oxygen Saturation During Sleep and the Risk of Fractures, Falls and Mortality in Older Men ASBMR 2007 La Lettre du Rhumatologue

  5. Table of contents • SSRI Use is Associated with Increased Risk of Fracture Among Older Men • High Cardiovascular Risk in Men with Increased Bone Resorption or Low Bone Mass • Osteoporosis Treatment – Anti-resorptive Agents • Effect of Bazedoxifene on Vertebral Fracture in Postmenopausal Women with Osteoporosis (1) • Effect of Bazedoxifene on Vertebral Fracture in Postmenopausal Women with Osteoporosis (2) • No Impact of Herbal Therapies on Bone Mineral Density in Women with Vasomotor Symptoms (1) • No Impact of Herbal Therapies on Bone Mineral Density in Women with Vasomotor Symptoms (2) • Efficacy of Continued Alendronate for Fractures in Women without Prevalent Vertebral Fracture: the FLEX Trial • Risedronate Prevents Bone Loss in Breast Cancer Survivors: a Two-Year, Randomized, Double-Blind, Placebo-Controlled Clinical Trial • SABRE (Study of Anastrozole with the Bisphosphonate Risedronate) 12-Month Analysis • Efficacy and Safety of Zoledronic Acid 5 mg in Preventing Fractures in Men and Women with Prevalent Hip Fracture: the HORIZON-Recurrent Fracture Trial (1) • Efficacy and Safety of Zoledronic Acid 5 mg in Preventing Fractures in Men and Women with Prevalent Hip Fracture: the HORIZON-Recurrent Fracture Trial (2) • Risk Factors for Serious Adverse Events (SAEs) of Atrial Fibrillation in the HORIZON-PFT Trial of Zoledronic Acid ASBMR 2007 La Lettre du Rhumatologue

  6. Table of contents • Osteonecrosis of the Jaw Under Bisphosphonate (BP) Therapy:Patient Profile and Risk Assessment Large Systematic Review in Germany (1) • Osteonecrosis of the Jaw Under Bisphosphonate (BP) Therapy:Patient Profile and Risk Assessment Large Systematic Review in Germany (2) • ASBMR Task Force on Bisphosphonate-Associated Osteonecrosis of the Jaw (ONJ) [1] • ASBMR Task Force on Bisphosphonate-Associated Osteonecrosis of the Jaw (ONJ) [2] • ASBMR Task Force on Bisphosphonate-Associated Osteonecrosis of the Jaw (ONJ) [3] • Giant Osteoclast Formation after Long-Term Oral Aminobisphosphonate Therapy for Postmenopausal Osteoporosis • Effect of Denosumab on Bone Mineral Density and Bone Turnover Markers: 48-Month Results (1) • Effect of Denosumab on Bone Mineral Density and Bone Turnover Markers: 48-Month Results (2) • Denosumab Increases Bone Mineral Density in Patients with Rheumatoid Arthritis: 12-month Results • A Randomized, Double-Blind, Placebo-Controlled Study of a Cathepsin K Inhibitor (odanacatib) in the Treatment of Postmenopausal Osteoporosis (1) • A Randomized, Double-Blind, Placebo-Controlled Study of a Cathepsin K Inhibitor (odanacatib) in the Treatment of Postmenopausal Osteoporosis (2) • A Randomized, Double-Blind, Placebo-Controlled Study of a Cathepsin K Inhibitor (odanacatib) in the Treatment of Postmenopausal Osteoporosis (3) ASBMR 2007 La Lettre du Rhumatologue

  7. Table of contents – Anabolics Agents • Prediction of 24 Month Change in BMD on PTH Followed by Alendronate: The PaTH Study • Efficacy of Adding Teriparatide versus Switching to Teriparatide in Postmenopausal Osteoporotic Women Previously treated with Raloxifene or Alendronate • BMD and Bone Markers Changes after Teriparatide Treatment: Differences According to Previous Treatment with Alendronate or Risedronate The OPTAMISE Study (1) • BMD and Bone Markers Changes after Teriparatide Treatment: Differences According to Previous Treatment with Alendronate or Risedronate The OPTAMISE Study (2) • BMD and Bone Markers Changes after Teriparatide Treatment: Differences According to Previous Treatment with Alendronate or Risedronate The OPTAMISE Study (3) • Bone Apposition in Patients on Teriparatide Treatment is Preferably Directed to Skeletal Regions of Local Structural Weakness: Assessment by High Resolution CT-Based Finite Element Analysis in Vivo (1) • Bone Apposition in Patients on Teriparatide Treatment is Preferably Directed to Skeletal Regions of Local Structural Weakness: Assessment by High Resolution CT-Based Finite Element Analysis in Vivo (2) • Bone Apposition in Patients on Teriparatide Treatment is Preferably Directed to Skeletal Regions of Local Structural Weakness: Assessment by High Resolution CT-Based Finite Element Analysis in Vivo (3) • Effects of 2 year Teriparatide Treatment on 3-D Femoral Neck Bone Distribution, Geometry and Bone Strength: Results from the Eurofors Study ASBMR 2007 La Lettre du Rhumatologue

  8. Table of contents • Comparison of the Effects of Teriparatide and Alendronate on Parameters of Total Hip Strength as Assessed by Finite Element Analysis: Results from the Forteo and Alendronate Comparison Trial • Effects of One Year Treatment with PTH (1-34) on Bone Microstructure at the Ultradistal Radius • Ostabolin-CTM Increases Lumbar Spine and Hip BMD after 1 Year of Therapy: Results of a Phase II Clinical Trial • Futures Directions • GLP-2 Significantly Increases Hip BMD in Postmenopausal Women: a 120-Day Study (1) • GLP-2 Significantly Increases Hip BMD in Postmenopausal Women: a 120-Day Study (2) • Calcium Receptor: Primary Regulator of Parathyroid Cell Functions • Calcium Receptor Antagonist SB-423557 used to Induce Bone Formation (1) • Calcium Receptor Antagonist SB-423557 used to Induce Bone Formation (2) • Anabolic Effect of Sclerostin Antibody Treatment in Ovariectomized Rat: Tissue Level Mechanism • Scl-mAb Increases Bone Mass by Stimulating Bone Formation but not Bone Resorption in Aged Male Rats • Anti-Sclerostin Antibody Increases Markers of Bone Formation in Healthy Postmenopausal Women (1) ASBMR 2007 La Lettre du Rhumatologue

  9. Table of contents • Anti-Sclerostin Antibody Increases Markers of Bone Formation in Healthy Postmenopausal Women (2) • ACE-011- A Soluble Activin Receptor Type IIA: a New Therapeutic Agent (1) • ACE-011- A Soluble Activin Receptor Type IIA: a New Therapeutic Agent (2) • Effects of Cyclic and Daily PTH in Combination with OPG (1) • Effects of Cyclic and Daily PTH in Combination with OPG (2) • Barrier Site Metabolism of Vitamin D: A Mechanism for Protection Against Inflammatory Bowel Disease (1) • Barrier Site Metabolism of Vitamin D: A Mechanism for Protection Against Inflammatory Bowel Disease (2) • Accelerated Bone Resorption due to Dietary Calcium Deficiency Promotes Tumor Growth in a Murine Model of Breast Cancer Bone Metastasis • Intermittent PTH Inhibits Development and Progression of Myeloma (1) • Intermittent PTH Inhibits Development and Progression of Myeloma (2) ASBMR 2007 La Lettre du Rhumatologue

  10. Chapter I. From Bone Acquisition to Fractures

  11. From Bone Acquisition to Fractures 1 Decrease in Cortical Thickness is Associated with the Pubertal Increase Forearm Fractures in Girls (1) • Cross-sectional study in 66 girls without a prior history of fracture • classification into 5 groups according to bone age (BA) • group I (n = 11): pre-puberty (age = 7.5 ± 0.3 yrs; BA: 6-8 yrs) • group II (n = 17): early puberty (age = 10.3 ± 0.3 yrs; BA: 9-11 yrs) • group III (n = 16): mid-puberty (age = 12.2 ± 0.2 yrs; BA: 12-14 yrs) • group IV (n = 10): late-puberty (age = 15 ± 0.3 yrs; BA: 15-17 yrs) • group V (n = 12): post-puberty (age = 18.3 ± 0.4 yrs; BA: 18-21 yrs) • outcomes : trabecular and cortical bone parameters by high-resolution 3D pQCT • Results • no significant differences in trabecular parameters (bone volume [BV]/total volume [TV]; trabecular number or trabecular thickness) throughout the course of puberty • Puberty is associated with minimal changes in trabecular microstructure ASBMR 2007 – From Kirmani S et al., Rochester, USA, abstract 1193, updated La Lettre du Rhumatologue

  12. From Bone Acquisition to Fractures 2 Decrease in Cortical Thickness is Associated with the Pubertal Increase Forearm Fractures in Girls (2) Changes in cortical thickness throughout puberty Comparison of cortical thickness with incidence of forearm fractures 300 *** Distal forearm incidenceCortical thickness 1,200 300 *** 200 1,000 250 100 800 200 % of 6-8 bone age-group Incidence rates (% 100,000) % of 6-8 bone age-group 600 150 ** ** p=0.01, ***p<0.001 versus bone age-group 6-8 50 400 100 200 50 0 0 0 6-8 9-11 12-14 15-17 18-21 6-8 9-11 12-14 15-17 18-21 Bone age • Cortical thickness significantly decreased by 50% during puberty and rose sharply by 89% at the end of puberty • The decrease in cortical thickness was due to increased endosteal expansion relative to periostal expansion of cortical bone • The transient increase in forearm fractures during growth in girls appears to be explained by temporary cortical thinning ASBMR 2007 – From Kirmani S et al., Rochester, USA, abstract 1193, updated La Lettre du Rhumatologue

  13. From Bone Acquisition to Fractures 3 High Protein Intake Enhances the Positive Effect of Physical Activity on BMC in Pre-pubertal Boys (1) • Cross-sectional study in 232 healthy pre-pubertal boys (mean age = 7.4 ± 0.4 yrs) • spontaneous protein and calcium intakes by frequency questionnaires • physical activity by self-reported questionnaire and expressed as physical activity energy expenditure (PAEE kcal/d) • BMC/areal BMD by DXA at various skeletal sites (radius, hip, L2-L4) • Results • mean daily calcium and protein intakes = 752 mg (± 263) and 47.3 g (± 11.6), respectively • by multiple regression analysis, physical activity and protein intake were significantly correlated to BMC whatever the bone site considered, whereas calcium intake was not • in boys with a high protein intake (> 2 g/kg body weight/d), increase in PAEE from 168 to 312 kcal/d was associated with higher BMC at all measured skeletal sites. In contrast, increased physical activity under high or low calcium intake was associated with increased BMC of similar magnitude La Lettre du Rhumatologue ASBMR 2007 - From Chevalley T et al., Geneva, Switzerland, abstract 1041, updated

  14. From Bone Acquisition to Fractures 4 High Protein Intake Enhances the Positive Effect of Physical Activity on BMC in Pre-pubertal Boys (2) • Influence of protein intake on the impact of increased physical activity on BMC, bone area and aBMD of the femoral neck FN BMC FN Area FN BMD p = 0.001 p = 0.002 p = 0.035 0.6 0.6 0.6 0.4 0.4 0.4 p = 0.896 p = 0.839 p = 0.980 0.2 0.2 0.2 Z-score + SEM Z-score + SEM Z-score + SEM 0 0 0 - 0.2 - 0.2 - 0.2 - 0.4 - 0.4 - 0.4 Physical activity(kcal.d-1) Median Protein intake(g.d-1) • Protein intake within a range above the usual recommended allowance enhances the positive effect of physical activity on BMC La Lettre du Rhumatologue ASBMR 2007 - From Chevalley T et al., Geneva, Switzerland, abstract 1041, updated

  15. From Bone Acquisition to Fractures 5 Role of Mechanical Loading from Non-Muscular Sources on Human Skeletal Structure (1) • Case-control study in post-menarcheal girls • 19 gymnast/ex-gymnasts (at least 5 h/week in gymnastic training for at least 2 yrs out of the past 10 yrs) compared to 14 non-gymnasts athletes • outcomes • fat free mass and BMC of non-dominant arm from total body DXA scans (Hologic, QDR 4500) • non-dominant polar strength-strain indices (SSI), fall strength (= SSI/[body weight x arm length]) and total bone cross-sectional areas (CSA) by pQCT at 4% and 33% distal radius sites • calcium intake by food frequency questionnaire • ANCOVA adjusted for gynecological age, calcium intake and arm fat free mass La Lettre du Rhumatologue ASBMR 2007 - From Dowthwaite JN et al., Syracuse, USA, abstract 1037, updated

  16. From Bone Acquisition to Fractures 70 60 50 40 % greater than non-gymnasts 30 20 10 0 4% 33% Arm 4% 33% 4% 33% -10 BMC CSA SSI Fall SSI 6 Role of Mechanical Loading from Non-Muscular Sources on Human Skeletal Structure (2) • Results : • Age, gynecological age, height, weight, BMI, total body fat free mass, % body fat, weight-bearing activity and calcium intake were similar in the 2 groups • Arm fat free mass was a strong predictor correlated to all bone outcomes Adjusted bone parameters (gymnasts percent advantage versus non-gymnasts) All bone variables were greater in gymnasts than in non-gymnasts by ANCOVA • Gymnastic activity modifies arm skeletal structure. Mechanical loading from non-muscular source is a distinct and important determinant of human skeletal structure La Lettre du Rhumatologue ASBMR 2007 - From Dowthwaite JN et al., Syracuse, USA, abstract 1037, updated

  17. From Bone Acquisition to Fractures 7 Effects of Mechanical Loading and Estrogen are Structurally Distinct E-L- E-L+ E+L- E+L+ • Loading alone (E-L+) resulted in thickening of individual trabeculae and estrogen effect (E+L-) was discernible as a denser (less spacing) trabecular meshwork Moreover, when the factors were combined (E+L+), the effects added up • There is a structural dimorphism in the skeletal actions of estrogen and loading so that the actions of these two factors are independent and additive in nature La Lettre du Rhumatologue ASBMR 2007 – From Jokihaara J et al., Tampere, Finland, abstract 1087, updated

  18. From Bone Acquisition to Fractures 8 Vertebral Fracture Lines are not Smooth, but Mixtures of Multiple Schmorl’s Nodes and Endplate Perforations Lateral view Frontal view Uneven vertebral fracture line La Lettre du Rhumatologue ASBMR 2007 - From Okamoto T et al., Oita, Japan, abstract S353, updated

  19. From Bone Acquisition to Fractures 9 Decline in Age Adjusted Hip Fracture Incidence but Drastic Increase in Hip Fractures Among the Very Oldest (1) • All hip fracture patients between 1993-2005, > 50 years, admitted to Umeå University Hospital were included, N = 2,919 (31% men) • The absolute numbers of fractures and incidence were mean value over the time periods 1993-1996 and 2001-2005 Hip fractures mean numbers/year • Global incidence of hip fractures decreases over the study period • Absolute number of fractures didn’t change BUT… • Hip fractures in women > 90 years increased by more than 50% Men Women 40 Mean numbers of fractures/yr 93-96 30 Mean numbers of fractures/yr 01-05 Number 20 10 0 90 90 60-64 70-74 75-79 85-89 60-64 70-74 75-79 85-89 50-54 55-59 65-69 80-84 50-54 55-59 65-69 80-84 Age La Lettre du Rhumatologue ASBMR 2007 - From Bergström U et al., Umeå, Sweden, abstract 1051, updated

  20. From Bone Acquisition to Fractures 10 Decline in Age Adjusted Hip Fracture Incidence but Drastic Increase in Hip Fractures Among the Very Oldest (2) Huge increase in hip fracture incidence in women > 90 years during the study period: from 2,700/100,000 to 3,900/100,000 Men Women 4,000 Incidence 1993-1996/100,000 3,000 Incidence 2001-2005/100,000 Incidence (per 100 000) 2,000 1,000 0 90 90 50-54 60-64 75-79 85-89 50-54 75-79 80-84 85-89 55-59 65-69 70-74 80-84 55-59 60-64 65-69 70-74 Age • Hip fracture events increase dramatically in nonagenarians with anesthesial and surgical challenges due to old age and comorbiditiesPatients need to be treated BEFORE the fracture whatever their age! La Lettre du Rhumatologue ASBMR 2007 - From Bergström U et al., Umeå, Sweden, abstract 1051, updated

  21. From Bone Acquisition to Fractures 11 Increased Mortality in Patients with a Hip Fracture Effect of Pre-morbid Conditions and Post-Fracture Complications • Mortality after hip fracture was divided into two categories • an excess mortality of 19% within the first year following the fracture (relative survival = 0.81 compared to controls) and • an excess mortality of 1.8% per year (relative survival 0.982) for every additional year following the fracture • The major causes of the excess mortality were due to complications related to the fracture event (70.8% within the first 30 days) and only to a smaller extent associated with pre-morbid conditions • Patients with a hip fracture have a pronounced excess mortality risk (HR = 2.26;CI 95%: 2.24-2.27) • The major cause was linked to the fracture event and not to pre-existing co-morbidity • Mortality rate was higher in men than in women ASBMR 2007 – From Vestergaard P et al., Aarhus Amtssygehus, Denmark, abstract 1049, updated La Lettre du Rhumatologue

  22. Chapter II. Osteoporosis - Assessment

  23. Osteoporosis - Assessment 12 Clinical Risk Factors for Incident Vertebral Fractures: the OPUS Study (1) • Multicenter European cohort study in 2,409 postmenopausal women 55-81 years • outcomes : • assessment of baseline risk factors using the EVOS questionnaire • spine and hip BMD by DXA • identification of 67 incident vertebral fractures (VF) by a semi-quantitative method in a central facility over a follow-up period of 6 years in 1,565 patients with available spine X-rays • multivariate analyses adjusted for significant risk factors Main baseline characteristics of the OPUS population La Lettre du Rhumatologue ASBMR 2007 - From Briot K et al., Paris, France, abstract 1077, updated

  24. Osteoporosis - Assessment 13 Clinical Risk Factors for Incident Vertebral Fractures: the OPUS Study (2) • Results • risk of incident VF (multivariate analysis; OR [95% CI]) • age (per 10 yr): 1.17 (1.1-2.1) • paternal history of hip fracture: 2.0 (1.0-3.8) • current intake of omeprazole at baseline: 1.8 (1.2-1.7) • prevalent VF: 1.5 (1.2-2.1) • spine or hip BMD (per 1 SD): 1.4 (1.1-1.7) • the 61 (5%) women who were using omeprazole at baseline had higher BMI, lower alcohol intake and higher thiazide intake, but did not differ with regard to corticosteroids use and gastric surgery as compared to non users • Few clinical risk factors are associated with an increased risk of vertebral fracture over 6 years in ambulatory postmenopausal European womenUse of omeprazole and paternal history of hip fracture were unexpected La Lettre du Rhumatologue ASBMR 2007 - From Briot K et al., Paris, France, abstract 1077, updated

  25. PPI use up to 4 years does not appear to be an important risk factor for the development of fractures A longer duration of continuous PPI exposure (5 years or more for all osteoporotic fractures, 4 years or more for hip fractures) is associated with a significantly increased risk Osteoporosis - Assessment 5.68 2.96 6 2.62 5 2.42 4 1.72 1.66 3 1.55 1.52 1.43 1.27 1.21 2 1.13 1.17 1.06 1.10 1.12 1.09 0.98 1.04 0.99 1.05 1 0 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 14 Chronic Proton Pump Inhibitor Use is not Associatedwith an Increased Risk of Osteoporotic Fracture Adjusted Odds Ratio (95% CI) for fracture with varying PPI exposure intervals Combined hip, vertebral and wrist fractures Combined hip and vertebral fractures Hip fractures only Adjusted Odds Ratio Minimum Years of Continuous PPI Exposure ASBMR 2007 - From Targownik LE et al., Winnipeg, Canada, abstract S351, updated La Lettre du Rhumatologue

  26. Osteoporosis - Assessment 15 Efficacy of Clodronate on Fracture Risk in Women Selected by 10-year Fracture Probability Without BMD With BMD 8 8 Placebo Clodronate 6 6 4 4 Fractures/100 patients-years 2 2 0 0 I II III IV V I II III IV V Quintiles of probability La Lettre du Rhumatologue ASBMR 2007 – From McCloskey E et al.,Sheffield, United Kingdom, abstract 1060, updated

  27. Osteoporosis - Assessment 16 Bone Mineral Density and Hip Fracture: Role of Bone Loss (1) • DUBBO Osteoporosis Epidemiology Study • 15-yr follow-up • 782 women and 566 men aged 60+ yrs • with at least 2 bone mass measurements by DXA preceding a hip fracture (average of 5 BMD measurements/subject) • 77 hip fractures in women and 23 in men over the follow-up period of time • Cox’s proportional hazard models with time-varying covariates  to evaluate the absolute risk of hip fracture for an individual based on age, history of prior fracture and fall, baseline BMD and the rate of bone loss • Results Hazard ratio for hip fracture risk in women La Lettre du Rhumatologue ASBMR 2007 - From Nguyen TV et al., Sydney, Australia, abstract 1079, updated

  28. Osteoporosis - Assessment 17 Bone Mineral Density and Hip Fracture: Role of Bone Loss (2) Underestimation of 5-yr and 10-yr risk of hip fracture by baseline BMD in women 5-year risk 10-year risk 0.35 0.35 0.5%/y1.0%/y1.5%/y 0.5%/y1.0%/y1.5%/y 0.30 0.30 0.25 0.25 Underestimated risk of hip fx Underestimated risk of hip fx 0.20 0.20 0.15 0.15 0.10 0.10 - 3 - 2.5 - 2 - 1.5 - 1 - 3 - 2.5 - 2 - 1.5 - 1 Baseline BMD T-scores • These data suggest that the evaluation of the absolute risk of hip fracture should take into account the time-varying effect of BMD La Lettre du Rhumatologue ASBMR 2007 - From Nguyen TV et al., Sydney, Australia, abstract 1079, updated

  29. Osteoporosis - Assessment Osteoporosis Osteopenia Normal 18 Risk of Subsequent Fracture Depends on Bone Mineral Densityand Fracture Type: a 17-Year Prospective Study BMD-standardized relative re-fracture risk according to initial fracture type in women (n = 1,391) • There was an overall increased re-fracture risk following initial fracture in women and men with osteopenia and osteoporosis. Hip and vertebral fractures were associated with the highest re-fracture risk, irrespective of BMD. Neither women nor men with normal BMD had an increased re-fracture risk following minor fractures. No. of fractures Minor 99 Major 50 Vertebral 91 Hip 55 Minor 101 Major 32 Vertebral 72 Hip 21 Minor 24 Major 8 Hip andVertebral 16 Hazard Ratio 0 1 2 3 4 5 6 7 8 9 10 ASBMR 2007 – From Bliuc D et al., Sydney, Australia, abstract 1050, updated La Lettre du Rhumatologue

  30. Osteoporosis - Assessment 19 Fracture Risk is Better Predicted by Vertebral Morphometry Assessment than by the WHO score (1) • CAMOS is a prospective, randomly-selected population-based cohort study of 9,423 non-institutionalized men and women ≥ 25 years of age • data from 4,744 subjects ≥ 50 years (3,452 women and 1,292 men) • baseline and 5 years follow-up lateral spine radiographs • aim: to assess the prediction of 5 yr risk of fragility fracture by the WHO fracture risk factors as well as by morphometric vertebral fracture (MVF) status Number of Subjects with New Fractures at 5 years a p < 0.0001 between women and menb p = 0.013 between women and menc Subjects who had either vertebral or non-vertebral fractures La Lettre du Rhumatologue ASBMR 2007 - From Chen P et al., Indianapolis, USA, abstract S371, updated

  31. Osteoporosis - Assessment Age (per year) 1.03 (1.02-1.04) Femoral Neck T-score(per unit decrease) 1.18 (1.09-1.29) Family History of Osteoporosis 1.24 (1.02-1.51) Glucocorticoid Use 1.04 (0.56-1.94) Prior Clinical Fracture 1.47 (1.21-1.78) SDI = 1 1.63 (1.30-2.04) 2.33 (1.77-3.06) SDI = 2 2.71 (2.01-3.65) SDI > 3 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 20 Fracture Risk is Better Predicted by Vertebral Morphometry Assessment than by the WHO score (2) Odds Ratio (OR) [95% Confidence Interval (CI)] SDI : Spinal Deformity Index 5-Year Risk of Fracture La Lettre du Rhumatologue ASBMR 2007 - From Chen P et al., Indianapolis, USA, abstract S371, updated

  32. Osteoporosis - Assessment 21 Computer-Based Measure of Kyphosis Predicts Fracturesin the Thoracic Spine of Postmenopausal Women • Could computer-based diagnostic tool be a useful supplement to existing approaches to fracture prediction? Degree of kyphosis (mean values and SEM) [n = 126] p = 0.002 p = 0.02 0.0035 0.003 0.0025 0.002 0.0015 0.001 0.0005 0 Kyphosisbaseline control Kyphosis baseline fracture group Kyphosis follow-up control Kyphosis follow-up fracture group • The measure of kyphosis, but not the measure of irregularity in vertebral alignment, can predict fragility fractures in the thoracic spine of postmenopausal women, independent of age, body weight and spine BMD ASBMR 2007 - From Pettersen PC et al., Ballerup, Denmark, abstract S356, updated La Lettre du Rhumatologue

  33. Osteoporosis - Assessment 22 Which Risk Factors Lead Clinicians to Treat Their Patients? • Women ≥ 50 years with BMD testing between 1998 and 2002 (Manitoba) • The women with prior glucocorticoid treatment or non-traumatic hip, spine, wrist or humerus fracture were excluded from the analysis • 3,826/8,654 (44.2%) were dispended an osteoporotic treatment in the year after DXA Osteoporosis treatment initiation according to T-score (minimum spine and hip) Predictors of osteoporosis treatment initiation in the year after BMD testing (logistic regression model) 100 80 60 Osteoporosis treatment initiation (%) 40 20 0 - 3.0 - 2.5 - 2.0 - 1.5 - 1.0 - 0.5 0.0 Minimum T-score Osteoporotic treatment decision was only linked to BMD La Lettre du Rhumatologue ASBMR 2007 - From Leslie WD et al., Winnipeg, Canada, S321, updated

  34. Osteoporosis - Assessment 23 Which Risk Factors Lead Clinicians to Diagnose or Treat Their Patients for Osteoporosis? (1) • ROCQ (Recognizing Osteoporosis and its Consequences in Quebec) is an ongoing health patient management program • The aim of this analysis was to evaluate the predictive factors for diagnosis and treatment • phase 1: patients were recruited at the outpatient clinic from 17 hospitals • 0 to 16 weeks following the fracture occurrence • 1,001 patients with fracture, of whom 818 didn’t have any treatment • questionnaire 1 • phase 2: patients whithout treatment were contacted by phone again 6-8 months later (n = 738) • questionnaire 2 • A multivariate analysis was conducted in order to determine the factors leading to a diagnosis of osteoporosis and those leading to the beginning of a treatment La Lettre du Rhumatologue ASBMR 2007 - From Bessette L et al., Quebec, Canada, S364, updated

  35. Osteoporosis - Assessment 24 Which Risk Factors Lead Clinicians to Diagnose or Treat Their Patients for Osteoporosis? (2) Diagnosis Treatment Despite the evidence in the literature that different clinical factors have to be taken into account (fragility fracture…), physicians based their diagnosis and treatment decision quasi exclusively on BMD results La Lettre du Rhumatologue ASBMR 2007 - From Bessette L et al., Quebec, Canada, S364, updated

  36. Osteoporosis - Assessment 25 Association of Abdominal Aortic Calcifications (AAC) on Vertebral Fracture Assessment (VFA) Images with Increased Risk of Cardiovascular Diseases in Older Women (1) • Case-control study in 5,596 women (75+ years) • 408 women with incident myocardial infarction (MI) or stroke (cases) • over the mean follow-up period of 4 yrs • 408 randomly selected controls • evaluation of AAC on VFA images in 90.7% of the population (191 MI, 171 stroke and 363 controls) using a validated Framingham scale • multivariable-adjusted associations between incident MI, stroke and AAC • Results • in cases compared to controls • lower HDL-cholesterol levels • higher triglycerides serum levels • no differences in other CV related covariables (although the % of complete covariates data set was significantly lower in cases than in controls) La Lettre du Rhumatologue ASBMR 2007 - From Schousboe JT et al., Minneapolis, USA, abstract 1076, updated

  37. Osteoporosis - Assessment 26 Association of Abdominal Aortic Calcifications (AAC) on Vertebral Fracture Assessment (VFA) Images with Increased Risk of Cardiovascular Diseases in Older Women (2) Association of AAC (OR [95% CI] with incident MI or stroke • A high level of AAC on VFA images is predictive of MI or stroke in elderly women VFA imaging offers the opportunity to evaluate this subclinical marker of CV disease La Lettre du Rhumatologue ASBMR 2007 - From Schousboe JT et al., Minneapolis, USA, abstract 1076, updated

  38. Osteoporosis - Assessment 27 Bone Mineralization and Vitamin D Inadequacy. Histomorphometric Analysis of Iliac Crest Bone Biopsies and Circulating 25-OH Vitamin D in 675 patients No mineralization defects above 30 µg/l 25-OHD3 (%) 20 16 OV/BV 12 8 Pathologic borderto osteomalacia 4 2.0% as defined by Priemel 2007 25-OH vit.D3(µg/l) 0 0 10 20 30 40 50 60 La Lettre du Rhumatologue ASBMR 2007 – From Priemel M et al., Hamburg, Germany, abstract 1300, updated

  39. Chapter III. Osteoporosis in Men

  40. Osteoporosis in Men 28 Endogenous Sex Hormones and Incident Fracture Risk in Older MenThe DUBBO Study (1) • Data on the relationship between serum testosterone and estradiol level and the risk of osteoporotic fractures in elderly men remain controversial • Prospective cohort: 1990-2006, community dwelling men > 60 years • Baseline: for all patients • risk factors, serum samples • measurements: serum testosterone, estradiol by mass spectrometry SHBG by immuno-assay • spine and femoral BMD (DPX, Lunar) • Incidence of low trauma fractures assessed by X-ray • 609 men, mean age 73 years, mean follow up 5.8 years (1-12 years) • 113 men with 149 incident fractures • 496 non fracture controls La Lettre du Rhumatologue ASBMR 2007 – From Meier CH et al., Basel, Switzerland, abstract 0358, updated

  41. Osteoporosis in Men 29 Endogenous Sex Hormones and Incident Fracture Risk in Older MenThe DUBBO Study (2) Sex hormones and fracture risk: unadjusted and adjusted analysis • Serum testosterone, but not estradiol, was an independent predictor of fracture risk in elderly men • Measurements of testosterone may provide incremental prognosis value for assessment of fracture risk La Lettre du Rhumatologue ASBMR 2007 – From Meier CH et al., Basel, Switzerland, abstract 0358, updated

  42. Osteoporosis in Men 30 Serum DHEA is Independently of Sex Hormones Related to Incident Fractures in Elderly Men – The MrOS SWEDEN Study Yearly incidence of fractures in relation to serum DHEAafter adjustment for free estradiol and free testosterone serum levels 0.12 0.10 0.08 Yearly incidence of all fractures 0.06 0.04 0.02 0 0.1 1 10 DHEA (ng/ml) • Elderly men with low free estradiol or low free testosterone have an increased risk of fracture • Serum DHEA levels are an independent predictor of fracture risk in elderly men Aged-adjusted model including free estradiol and free testosterone All incident fracture: DHEA (HR per SD decrease) = 1.25 (1.09-1.44) Non-vertebral osteoporotic fractures: DHEA (HR per SD decrease) = 1.32 (1.07-1.63) La Lettre du Rhumatologue ASBMR 2007 – From Ohlsson C et al., Gothenburg, Sweden, abstract 1200, updated

  43. Osteoporosis in Men 31 Biochemical Markers of Bone Turnover and the Risk of Non-Vertebral Fractures in Older Men (1) • Nested case-control study within the Osteoporotic Fractures in Men (MrOS) study • 406 men with ≥ 1 incident non-vertebral fracture (NVF) during a mean follow-up of 4.2 yrs (± 1.6) • 922 randomly selected controls among the 5,995 MrOS subjects • outcomes • fasting baseline serum for PINP, CTX and TRACP5b measurements • hip BMD measured by DXA (Hologic QDR 4500) at baseline and follow-up • multivariate models adjusted for age and clinic for fracture outcomes and bone loss • Results • compared to men without fracture, those with ≥ 1 incident NVF were older (75.4 ± 6.4 versus 73.6 ± 5.9 yrs, p < 0.05) and had lower baseline hip BMD • baseline hip BMD was lower and hip bone loss was greater among men in the highest quartile of PINP, CTX or TRACP5b La Lettre du Rhumatologue ASBMR 2007 - From Bauer DC et al., San Francisco, USA, abstract 1074, updated

  44. Osteoporosis in Men 32 Biochemical Markers of Bone Turnover and the Risk of Non-Vertebral Fractures in Older Men (2) • In multivariate analyses adjusted for age and baseline hip BMD, markers of bone turnover were neither associated with the risk of incident NVF nor with that of hip fracture Turnover and fracture risk, BMD adjusted (highest quartile versus other 3) Relative Hazard (95% CI)* *Age, clinic and hip BMD adjustedSeparate model for each marker and fracture type • Although higher levels of bone turnover were associated with greater hip bone loss, increased turnover was not independently associated with the risk of hip or NVF La Lettre du Rhumatologue ASBMR 2007 - From Bauer DC et al., San Francisco, USA, abstract 1074, updated

  45. Osteoporosis in Men 33 Diabetes and Fracture Risk in Older MenThe Osteoporotic Fractures in Men (MrOS) Study Risk of any non-spine fracture (compared with non-Diabetic Men [DM]) Adjusted for… Age, race, clinic site, total hipBMD, BMI, grip strength,walking speed, use arms forchair stand, osteoporosisdrug use, stroke, eGFR 2.2 Insulin 1.9 Oral DM med* Non-DM med 0.83 1.0 Non-DM All of the above andfall in previous year 2.0 1.0 0.82 * DM med: diabetic men medication 1.0 0.1 1.0RR (95% CI) 10.0 • Compared with non-DM, fracture risk was increased in older diabetic men on insulin therapy but not among others with diabetes, even after adjusting for more frequent falls La Lettre du Rhumatologue ASBMR 2007 – From Schwartz AV et al., San Francisco, USA, abstract 1161, updated

  46. Osteoporosis in Men 250 p < 0.001 200 Vert trabecular vBMD mg/cm3 * Age < 50 years* Age 50+ years 150 100 50 0 1 2 3 4 5 6 Log (Agatston per CT Slice) 34 Aortic Calcification Correlate with Volumetric Bone Mineral Densityand Bone Microstructure in Men: a Population-Based Study Relationship of vertebral vBMD and aortic calcifications in Rochester, Minnesota Men • vBMD is inversely correlated with aortic calcification (AC) in menThis correlation seems to disappear with age adjustment • Specific changes in bone microstructure correlate with AC in older men They could result from common mechanisms regulating bone structure and vascular calcification La Lettre du Rhumatologue ASBMR 2007 – From Chow JT et al., Rochester, USA, abstract 1160, updated

  47. Osteoporosis in Men Similar leg power Asymmetrical leg power Unable leg power 35 Asymmetry in Leg Power Increases Non-Spine and Hip Fracture Risk in Older Men: the Osteoporotic Fractures in Men (MrOS) Study Risk of hip fracture hazard ratio (95% CI) Model 1: Adjusted forage and clinical center 1.00 1.74* 3.32* Model 2: Multivariateadjustment* 1.00 1.66* 3.19* Model 3: Multivariateadjustment plus leg BMD 1.00 1.65* *p < 0.05 4.85* *Adjusted for age, clinical center and history of stroke Model 4: Multivariateadjustment plushistory of falls 1.00 1.66* 3.19* 0 10 • Asymmetry in leg power is associated with an increased risk of non-spine or hip fracture • Inability to complete leg power measure in one leg is associated with increased likelihood of falls and risk of fracture, especially hip fracture La Lettre du Rhumatologue ASBMR 2007 – From Cawthon PM et al., San Francisco, USA, abstract 1158, updated

  48. Osteoporosis in Men 36 Arterial Oxygen Saturation During Sleep and the Risk of Fractures,Falls and Mortality in Older Men Age-adjusted rates of fracture and mortality by oxygen saturation during sleep Non-spine fracture (n = 126 fx) Mortality rate (n = 140 deaths) 40 40 35 35 30 30 25 25 20 20 Mortality rate (per 1,000 py) Fracture rate (per 1,000 py) 15 15 10 10 5 5 0 0 < 1 1-3.5 3.5 < 10 10+ < 1 1-3.5 3.5 < 10 10+ % time SaO2 < 90% % time SaO2 < 90% • Greater time spent at nocturnal saturation levels below 90% increases risk of fractures, falls and mortality La Lettre du Rhumatologue ASBMR 2007 – From Cauley JA et al., Pittsburgh, USA, abstract 1157, updated

  49. Osteoporosis in Men 37 SSRI Use is Associated with Increased Risk of Fracture Among Older Men Medicationuse and fracture rate Multivariate analyses for SSRI use and fracture • Selective serotonin reuptake inhibitors (SSRI) use is associated with increased risk of fracture in elderly men SSRI users Non-users 50 31 40 30 Age-adjusted fracturesper 1,000 person years 15 20 10 0 Non-spine fracture *Included adjustment for age, hip BMD, BMI, non-traumatic fracture after age 50, falls in past 12 months, height change since age 25, SF-12 mental summary score, IADL impairment, SF-12 physical summary score 95% CI: SSRI users: 17.0-45.4Non-users: 13.1-15.9 La Lettre du Rhumatologue ASBMR 2007 – From Haney EM et al., Portland, USA, abstract 1159, updated

  50. This study shows, for the first time, that increased bone resorption is associated with an increased cardiovascular risk in elderly men Osteoporosis in Men 38 High Cardiovascular Risk in Men with Increased Bone Resorptionor Low Bone Mass Risk of major cardiovascular event in men with high BTM levels (> 1 SD above the mean)[n = 628], 8 years follow-up ASBMR 2007 - From Szulc P et al., Lyon, France, abstract S468, updated La Lettre du Rhumatologue

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