Seminar 28-11-2015 Prof. J. vd Bergh

•  Meet The Professors (16 clinical/transla5onal; 8 basic) •  8 Working Groups •  1448 Abstracts, 152 Oral abstracts (10.8%) •  115 Late-‐breaking abstracts, 5 Oral abstracts (4.3%) •  Abstracts 2013: -‐4%, 2014: -‐6%, 2015: -‐2.7%

Highlights ASBMR 2015 1

§  2015 Abstract handbook §  Highlights session R. Baron and J. Bilezikian §  ASBMR website / webcast §  Notes §  Published literature §  IOF congress highlights educational slide set (in agreement with Eli Lilly)

Bronnen


§  Diabetes and bone §  Fracture and mortality risk §  Bone strength / bone quality / imaging §  Vitamin D §  Bone and Cancer §  FGF23 - Klotho

Topics


Diabetes and bone

1067 Vertebral Fracture Risk in Diabetic Elderly Men: The MrOS Study

§  Diabetes is accompanied by increased risk of fracture §  Patients with T2DM have an increased risk of fracture with

increased BMD compared to controls §  The increase of hip fracture risk (RR:1.7) in T2DM §  Data for vertebral fractures (VF), particularly for men are

controversial and limited

INTRODUCTION

T2DM type 2 diabetes mellitus • BMD bone mineral density • VF vertebral fracture

NICOLA NAPOLI ET AL



§  Osteoporotic Fractures in Men (MrOS) Study §  5,994 men (≥65 years) §  Diabetes (ascertained by self-report, use of diabetes medication or elevated fasting

glucose) was reported in 875 men of whom 80 used insulin

§  Evaluate the prevalence and incidence of VFs in T2DM men compared to their non-DM counterparts §  Examine whether the association between lumbar spine BMD and VF is similar in T2DM and non-

DM men

SUBJECTS

§  Spine BMD by DXA and QCT §  Morphometric VFs identified on spine x-rays at baseline and on average 4.6 years later §  Prevalent VF defined as semi quantitative score (SQ) ≥2 §  Incident VF defined as an increase of ≥1 SQ from baseline

METHODS

VF vertebral fracture • T2DM type 2 diabetes mellitus • BMD bone mineral density • DXA dual x-ray absorptiometry • QCT quantitative computer tomography

NICOLA NAPOLI ET AL.



§  BMD (spine and hip) by DXA and QCT in T2DM compared with controls §  Bone strength (FEA) increased in T2DM compared with controls §  Association between decreased BMD (both QCT and DXA) and increased

risk of VF in both groups

§  Absence of increased risk of VF (both prevalent and incident) for patients with T2DM compared with controls

RESULTS

BMD bone mineral density • DXA dual x-ray absorptiometry • QCT quantitative computer tomography • T2DM type 2 diabetes mellitus • VF vertebral fracture • FEA finite element analysis • OR odds ratio • BMI body mass index • a areal • OR odds ratio • CI confidence interval

NICOLA NAPOLI ET AL

7

Model adjusted for Prevalent vertebral fractures OR (95%CI)

Incident vertebral fractures OR (95%CI)

Model 1: age, race, clinical site 0.91 (0.74-‐1.18) 1.05 (0.68-‐1.62) Model 2: Model 1, BMI 0.93 (0.70-‐1.25) 1.10 (0.71-‐1.71) Model 3: Model 2, spine aBMD 1.05 (0.78-‐1.40) 1.28 (0.81-‐2.00) Model 4:Model 2, spine aBMD 1.30 (0.89-‐1.88) 1.40 (0.78-‐2.53)

Reproduced with permission from the American Society for Bone and Mineral Research

Highlights ASBMR 2015

1067 Vertebral Fracture Risk in Diabetic Elderly Men: The MrOS Study NICOLA NAPOLI ET AL

8

§  T2DM is not associated with an increased risk of prevalent or incident VFs in elderly men

§  Lower BMD is associated with higher risk of prevalent VFs in DM as well as non-DM men

CONCLUSION


SA0275 Glucose Metabolism Status Is Not Associated With a Recent History of Falls, Recurrent Falls or Fractures – The Maastricht Study.

§  1577 participants had NGM, 468 had IGM and 908 had T2DM §  Mean duration 8.7 years, mean HbA1c 52.1 mmol/mol, 21.9%

insulin user.

§  Glucose metabolism status was not significantly associated with previous fractures and recent falls.

§  In addition, in this cohort of relatively young and well-treated participants with type 2 diabetes, diabetes severity was not associated with a previous fractures and recent falls.

CONCLUSION

ELLIS DE WAARD, ANNEMARIE KOSTER, TOM MELAI, TINEKE VAN GEEL, RONALD HENRY, MIRANDA SCHRAM, PIETER DAGNELIE, CARLA VAN DER KALLEN, SIMONE SEP, COEN STEHOUWER, NICOLAAS SCHAPER, HANS SAVELBERG, PIET GEUSENS, JOOP VAN DEN BERGH


9

FR0355 TBS and HbA1c but not BMD are Predictors of Incident Fractures in Type 1 Diabetes

§  105 individuals (52 males, 53 females) §  Age 43.6 ± 8.7 years §  Diabetes duration 21.8 ± 10.4 years §  Follow-up for 6.9 ± 0.3 years

Investigate potential risk predictors for incident fractures in middle-aged men and women with long-standing T1D

PARTICIPANTS

§  Associations of traditional risk factors for fractures (e.g. age, gender, family history of OP and smoking), BMD at LS, FN and TH, TBS and HbA1c with incident fractures

§  ROC analysis of TBS and HbA1c performed to identify potential threshold effects on incident fractures

OUTCOMES AND ANALYSIS

T1D Type 1 diabetes • OP osteoporosis • BMD bone mineral density • LS lumbar spine • FN femoral neck • TH total hip • TBS trabecular bone score • ROC receiver operating characteristic

THOMAS NEUMANN, MARTIN KEIL, GABRIELE LEHMANN, SABINE LODES, BETTINA KÄSTNER, THOMAS LEHMANN, MICHAEL KIEHNTOPF, DIDIER HANS, OLIVIER LAMY, ULRICH-ALFONS MÜLLER, GUNTER WOLF, ALEXANDER SÄMANN, JENA UNIVERSITY HOSPITAL, GERMANY

10 Highlights ASBMR 2015


§  No differences between individuals with or without fracture for age or BMD

§  FRAX® did not identify individuals with incident fractures

§  Individuals with incident fractures had higher HbA1c values and lower mean TBS scores at baseline; associations confirmed by logistic regression analysis

§  ROC curves showed that mean TBS score and HbA1c level can discriminate patients with incident fractures from those without fractures (AUC 0.72 [95% CI = 0.58-0.86; P=0.003] for combined mean TBS scores and HbA1c levels)

RESULTS

BMD bone mineral density • LS lumbar spine • FN femoral neck • TH total hip • TBS trabecular bone score • ROC receiver operating characteristic




§  The frequency of fractures in T1D is high and not predictable using either age or BMD

§  Only HbA1c and mean TBS score were independently associated with incident fractures

CONCLUSION

§  Measures of diabetes control, or of bone microarchitecture and material strength, and advanced glycation end-products (AGEs – e.g. pentosidine cross-links) may have a more important role in predicting fracture risk in women and men with T1D CLINICAL

IMPACT

T1D Type 1 diabetes • BMD bone mineral density • TBS trabecular bone score • ROC receiver operating characteristic



1139 Altered trabecular microarchitecture in youth with type 1 diabetes mellitus

§  83 girls, 10-16 years old (16 T1DM and 67 controls) §  Cross-sectional study §  Minimum 1 year of T1DM

Investigate the degree to which microarchitecture is affected in T1D

PARTICIPANTS

§  HR-pQCT of the distal radius and tibia §  micro-FE analysis to estimate bone strength DESIGN

§  DXA §  HR-pQCT §  Serum Ca, PTH, 25(OH)D, creatinine, glucose, HgbA1c §  Urine Ca, creatinine


T1D type 1 diabetes • HR-pQCT high resolution peripheric quantitative computer tomography • FE finite element • BMI body mass index • Ca calcium • P phosphate • PTH parathyroid hormone

DEBORAH MITCHELL, MARY BOUXSEIN, MADHUSMITA MISRA, MASSACHUSETTS GENERAL HOSPITAL, UNITED STATES



14

§  Matched groups for age, bone age, race, and height §  Higher weight in T1DM subjects with higher BMI Z-score (p<0.001) §  No difference for serum Ca, P, 25(OH)D, PTH §  No difference of Z-scores for aBMD at the spine and total body §  No difference in cortical porosity §  Strength is lower in tibia, but not in radius of T1DM

RESULTS

T1D type 1 diabetes • BMI body mass index • Ca calcium • P phosphate • PTH parathyroid hormone




§  Similar aBMD between T1DM and controls §  Impaired trabecular bone (vBMD and Tb Th) contributes to the fracture risk

in T1DM §  Early occurrence in the course of the disease

AUTHOR’S CONCLUSION

T1D type 1 diabetes • a areal • BMD bone mineral density • v volumetric • Tb trabecular • Th thickness



Bisphosphonates reduce fracture risk in postmenopausal women with diabetes: Results from FIT and HORIZON trials.

§  A post hoc subgroup analysis of combined individual-level data from two randomized placebo controlled trials, the Fracture Intervention Trial (FIT) of alendronate (ALN) and the Health Outcomes and Reduced Incidence with Zoledronic Acid (ZOL) Once Yearly-Pivotal Fracture Trial (HORIZON-PFT). Design

ANN SCHWARTZ, ERIC VITTINGHOFF, DOUGLAS C. BAUER, STEVEN R. CUMMINGS, ANDREW GREY, MICHAEL R. MCCLUNG, NICOLA NAPOLI, IAN R. REID, ANNE L. SCHAFER, ROBERT B. WALLACE, DENNIS M. BLACK

In postmenopausal women with DM and low bone density and/or prevalent vertebral fracture, bisphosphonates reduce fracture incidence

16

Fracture risk

FR0252 Contribution of Lumbar Spine BMD to Fracture risk in individuals with T-score discordance

§  The femoral neck BMD is best validated of all skeletal sites for fracture risk prediction

§  The lumbar spine BMD may be falsely elevated due to degenerative disc disease

§  Degenerative changes can also falsely elevate the femoral neck BMD to a lesser extent

§  Discordance between the LS and FN sites can impact diagnosis and fracture risk prediction based on bone densitometry

INTRODUCTION

BMD bone mineral density • LS lumbar spine • FN femoral neck

DUNIA ALARKAWI, DANA BLIUC, TUAN NGUYEN, JOHN EISMAN, JACQUELINE CENTER, GARVAN INSTITUTE OF MEDICAL RESEARCH, AUSTRALIA



§  2270 women and 1373 men aged 60+ years

Examine the impact of LS BMD on fracture risk, specifically in individuals with lower LS T-score than FN T-score

PARTICIPANTS

§  Prospective cohort from the Dubbo Osteoporosis Epidemiology Study of community-dwelling women and men DESIGN

§  LS and FN BMD data at first visit, followed from April 1989 to December 2014 OUTCOMES

AND ANALYSIS

LS lumbar spine • BMD bone mineral density • FN femoral neck • SD standard deviation • HR hazard ratio • CI confidence interval




§  LS T-score lower than FN T-score by ≥1 SD (discordant group) in 364 women and 60 men

§  In women with lower LS than FN T-score, each 1 SD lower LS T-score associated with a 30% increase in fracture risk (HR 1.30, 95% CI 1.19-1.41, P<0.0001)

§  In men with lower LS T-score than FN, no further increase in fracture risk §  Discordant women were at greater fx risk for all levels of FN T-score §  Increased fracture risk more apparent for lower levels of FN T-score and in

older age groups §  An osteoporotic LS T-score increased ten year absolute fracture risk for

women with either normal or osteopenic FN T-score by ~15%.

RESULTS

LS lumbar spine • FN femoral neck • SD standard deviation • HR hazard ratio • CI confidence interval • fx fracture




§  Significant contribution of lower LS BMD to fracture risk in individuals, over and above FN BMD

§  Women with lower LS T-score by ≥1 SD than FN T-scores consistently higher absolute fracture risks regardless of their FN T-scores

§  The risk increased exponentially with lower FN BMD and increasing age §  LS BMD lower than FN BMD should be incorporated into fracture risk

calculation algorithms at least for women


LS lumbar spine • BMD bone mineral density • FN femoral neck • SD standard deviation



1066 Predicting Imminent Risk for Fracture in Patients With Osteoporosis Using Commercially Insured Claims Data

§  163,186 patients with osteoporosis §  19.7% with a fracture

Identify risk factors associated with imminent first and subsequent fracture

PARTICIPANTS

§  Retrospective cohort study §  Patients aged ≥50 years with osteoporosis, a new fragility fracture or no

fracture DESIGN

§  Risk factors for imminent first fracture identified by logistic regression models that included >60 potential risk factors assessed in the 12 or 24 months prior to index date

§  Cox proportional hazards regression models used to identify risk factors for subsequent fracture for up to 12 months following the index fracture


MACHAON BONAFEDE, N SHI, R BARRON, X LI, DB CRITTENDEN, D CHANDLER, THOMSON REUTERS HEALTHCARE, USA



SSRI selective serotonin reuptake inhibitor • CNS central nervous system • CI confidence interval




SSRI selective serotonin reuptake inhibitor • CNS central nervous system • CI confidence interval



§  Vertebral fracture 1.62 §  Charlston index 3 or 4: 1.22 and 1.26 §  Antidepressant 1.21 §  Each decade after Age 50 1.17

Subsequent fracture

1145 Hip BMD by DXA Can Reliably Estimate Reduction in Hip Risk in Osteoporosis Trials: A Meta-Regression

§  14 trials with 73,000 women for hip fx §  30 trials with >75,000 women for NVFx

Examine the relationship between change in total hip BMD and fracture reductions

PARTICIPANTS

§  Study-level meta-regression §  Exclusion of trials with <5 hip fx DESIGN

§  Modelling of relationship between estimates of effect of treatment on change in BMD (active-placebo % difference at study end) and log relative risk of hip fx and NVFx using linear models weighted by study size


BMD bone mineral density • fx fracture • NVFx non-vertebral fracture

DENNIS BLACK, ERIC VITTINGHOFF, RICHARD EASTELL, MARY BOUXSEIN, CHARLES MCCULLOCH, PEGGY M. CAWTHON, STEVEN R. CUMMINGS, STEPHANIE L. HARRISON, ANNE DE PAPP, VICTOR DISHY, ANDREAS GRAUER, URSULA KLAUSE, BRUCE H. MITLAK, BRUCE SCHNEIDER, SANYA FANOUS-WHITAKER, JEFF ZACHWIEJA, CHIYUAN A. ZHANG, DOUGLAS BAUER ,UCSF DEPT OF EPI AND BIOSTAT, USA




For 2 drugs with 2% vs 6% hip BMD effect, model predicted a 10% vs. 59% reduction for hip fracture


§  Relationships strongest for change in hip BMD predicting hip fracture (r2=0.57, p<.0001)

§  Weaker relationships non-vertebral (r2=0.14, p=0.004) and vertebral (r2=0.21) fracture

§  For 2 drugs with 2% vs 6% hip BMD effect, model predicted a 10% vs. 59% reduction for hip fracture

§  For non-vertebral fracture with 2% or 6% change in BMD reductiosn were 6% vs 21%

RESULTS

BMD bone mineral density • fx fracture • NVFx non-vertebral fracture

DENNIS BLACK, ERIC VITTINGHOFF, RICHARD EASTELL, MARY BOUXSEIN, CHARLES MCCULLOCH, PEGGY M. CAWTHON, STEVEN R. CUMMINGS, STEPHANIE L. HARRISON, ANNE DE PAPP, VICTOR DISHY, ANDREAS GRAUER, URSULA KLAUSE, BRUCE H. MITLAK, BRUCE SCHNEIDER, SANYA FANOUS-WHITAKER, JEFF ZACHWIEJA, CHIYUAN A. ZHANG, DOUGLAS BAUER , UCSF DEPT OF EPI AND BIOSTAT, USA


Mortality risk

MO0284 Potential Years of Life Lost Following Low-Trauma Fractures in Canada

§  Administrative database of Canadians over age 50 years with low-trauma fractures 2007-2011

Estimate the potential years of life lost (PYLL) due to low-trauma fractures in Canada

REGISTRY

§  Low-trauma fractures categorized using ICD-10-CA codes as hip, humerus, vertebral, distal forearm, other sites and multiple sites fractures

§  Calculations of PYLLs for each age group, sex and fracture type by adjusting the provincial and sex-based standard life tables estimate of life expectancy for the increased risk of death associated with a fracture

§  Comparison with PYLL estimates due to other diseases reported by Statistics Canada in 2007

DESIGN ANALYSIS

PYLL potential years of life lost

ROBERT B. HOPKINS, JONATHAN D. (RICK) ADACHI, LOUIS BESSETTE, NATASHA BURKE, JACQUES P. BROWN, WILLIAM D LESLIE, SUZANNE MORIN, ALEXANDRA PAPAIOANNOU, LOUISA PERICLEOUS, JEAN-ERIC TARRIDE, UNIVERSITY OF MANITOBA, CANADA





30

13,809

21,812

36,312

44,462

89,247

104,971

127,560

138,808

159,117

Bronchitis/emphys/asth.[J40-J43 J45-J46]

Prostate cancer [C61]

HIV disease [B20-B24]

Pneumonia and influenza [J10-J18]

Low trauma fractures age 50+

Cerebrovascular diseases [I60-I69]

Colorectal cancer [C18-C21]

Breast cancer [C50]

All Respiratory diseases [J00-J99]



§  PYLL due to low-trauma fractures was 89,247 years (52,131 years for women, 37,116 years for men)

§  While being only 23% of fractures, hip fractures accounted for 43% of all PYLL

§  A hip fracture at ages 50 to 59 years decreases life expectancy by 4.0 years for women and 3.9 years for men, which corresponds to a loss of 15% of life expectancy

RESULTS




§  Low-trauma fractures are associated with a significant loss of life expectancy and are a significant burden of illness

§  Strategies to reduce the risk of fracture and improve post-fracture care should be implemented and optimized CONCLUSION

SA0289 Mortality risk following incident low-trauma osteoporotic fracture and subsequent fracture: 15- year prospective data from the Canadian Multicentre Osteoporosis Study (CaMOS)

§  7689 participants (5526 women and 2163 men) aged ≥50 years

Examine the contribution of individual fracture types on mortality risk over and above known risk factors for mortality

PARTICIPANTS

§  On-going population-based nation-wide cohort study of Canadians §  Patients followed for 15 years with scheduled interviews and annual postal

questionnaires §  Self-identified incident fractures from annual report §  Deaths ascertained through contact with a family member or obituary review

DESIGN

§  Relative survival analysis used to determine survival of CaMos participants OUTCOMES AND ANLYSIS

THACH TRAN, DANA BLIUC, DUNIA ALARKAWI, TUAN NGUYEN, JOHN EISMAN, LISA LANGSETMO, JERILYNN C PRIOR, ROBERT G JOSSE, STEPHANIE M KAISER, CHRISTOPHER S KOVACS, CLAUDIE BERGER, DAVID GOLTZMAN, DAVID A HANLEY, JONATHAN ADACHI, TENEKE VAN GEEL, PIET GEUSENS, JOOP VAN DEN BERGH, JACQUELINE CENTER, GARVAN INSTITUTE OF MEDICAL RESEARCH, AUSTRALIA



OP osteoporotic • Fx fracture • RR relative risk • CI confidence interval • SMR standardized mortality ratio



The most parsimonious model predicting premature 5-year mortality included age, current smoking, comorbidities and fracture type


§  Excessive mortality for the first 5 years post fracture for virtually all incident low-trauma fractures

§  Increased risk for an additional 5 years after subsequent fracture §  Need for early intervention to decrease subsequent fracture risk and

potentially mortality

CONCLUSION



Reduced Mortality and Subsequent Fracture Risk with Oral Bisphosphonate Treatment

in Secondary Fracture Prevention An Observational 8-year Follow-Up Study

LB-‐1153 12 October 2015

Tineke van Geel, Dana Bliuc, Piet Geusens, Jacqueline Center, Geert-‐Jan Dinant, Joop van den Bergh, Alastair McLellan, John Eisman

Faculty of Health, Medicine and Life Sciences

methods background results conclusion

9439 patients ≥ 50 yrs (1999-2007)

0509 (5.4)0 reviewed 1822 (19.3) frail elderly 2097 (22.2) declined

5011 (53.1) fully assessed; all prescribed CaD

No additional treatment 2477 (49.4%)

+ oral bisphosphonates 2534 (50.6%)

293(11.8) re-fx

235 (9.5) deceased

336 (13.3) re-fx

381 (15.0) deceased

P = 0.126 P < 0.001


Baseline Characteristics

CaD alone + BP Women, % 72.4 82.9 Age, years 64.4 73.4 BMD, T-score -1.5 -3.1 Initial hip fx, % 6.2 21.2

P < 0.001

Patients on BP had worse baseline characteristics




+ BP CaD alone

Subsequent fractures

HR: 1.17 (1.00-1.36)

P = 0.056

HR: 0.59 (0.48-0.73)

P < 0.001

Univariable Multivariable



+ BP CaD alone Mortality

HR: 1.64 (1.40-1.93)

P < 0.001

Univariable Multivariable

HR: 0.79 (0.64-0.96)

P = 0.021

Bone Quality / imaging

FR0025 Does Cortical Bone Loss Preceed Menopause?

§  Prospective study: 249 pre-, 32 peri- and 103 postmenopausal women aged 27-75 years at baseline

§  Prospective twin study in Melbourne, Australia §  173 women remained pre-, 49 changed from pre-to peri-, and 30 from peri- to

postmenopausal

Assess whether cortical bone loss occurs by intracortical and endocortical remodeling shortly before menopause

PARTICIPANTS

§  2 time points: baseline +3.1 yrs (average) §  Quantify distal tibia and radius cortical + trabecular bone microarchitecture. Images of

distal tibia by HR-pQCT DESIGN

§  Total, tb and cort vBMD, cort porosity of the total cortex, compact cortex, outer and inner transitional zones quantified using the StrAx1.0 software

§  Calculation of annual changes


HR-PQCT high resolution peripheral quantified computer tomography • Tb trabecular • Cort cortical • vBMD volumetric bone mineral density

ASHILD BJORNEREM, ALI GHASEM-ZADEH, ROGER ZEBAZE, XIAOFANG WANG, MINH BUI, JOHN L HOPPER, EGO SEEMAN, UIT THE ARCTIC UNIVERSITY OF NORWAY, NORWAY


FR0025 Does Cortical Bone Loss Preceed Menopause?

§  Less than 6% of cortical bone is lost before menopause, 94% is during and after menopause and arise more from the cortical than from the trabecular compartment

§  We infer that intracortical and endocortical remodeling produces modest cortical bone loss before menopause, most bone is lost after menopause and cortical exceeds trabecular bone loss


ASHILD BJORNEREM, ALI GHASEM-ZADEH, ROGER ZEBAZE, XIAOFANG WANG, MINH BUI, JOHN L HOPPER, EGO SEEMAN, UIT THE ARCTIC UNIVERSITY OF NORWAY, NORWAY


1054 Effects of Denosumab on Bone Matrix Mineralization: Results From the Phase 3 FREEDOM Trial.

§  In this analysis, 72 bone biopsy samples (42 DMAb, 30 Pbo) from a subset of the FREEDOM bone biopsy assessment (N = 115) were evaluated and analyzed

§  Degree of mineralization of bone (DMB) and the heterogeneity index (HI)

Results

DAVIDW DEMPSTER, JACQUES P BROWN, SUSAN YUE, DELPHINE FARLAY, SEBASTIEN RIZZO, JENNY SONG, ANDREA WANG, RACHEL B WAGMAN, GEORGES BOIVIN


1054 Effects of Denosumab on Bone Matrix Mineralization: Results From the Phase 3 FREEDOM Trial.

§  Treatment of women with postmenopausal osteoporosis with DMAb resulted in increased bone matrix mineralization and a lower HI compared with Pbo.

§  These data are consistent with expected results based on observations with other antiresorptives (Bala Eur J Endocrinol 2011) and with mechanism of action

Conclusions

DAVIDW DEMPSTER, JACQUES P BROWN, SUSAN YUE, DELPHINE FARLAY, SEBASTIEN RIZZO, JENNY SONG, ANDREA WANG, RACHEL B WAGMAN, GEORGES BOIVIN


§  Open-label single-centre study §  20 postmenopausal women (age 64.4±15.4 years) with osteoporosis (BMD

T score < -2.5 at spine or hip) treated with TPTD (20 µg/d) for 104 weeks

45

Apply a novel patient-specific finite element (FE) model of the disc-vertebra-disc (DVD) unit to quantify the effect of TPTD on vertebral strength

DESIGN

§  QCT scans of the lumbar spine at baseline, 26, 52 and 104 weeks §  DVD FE models of the L2 vertebrae generated using brick elements §  Vertebral strength defined using a 0.2% offset method in the load-

displacement curve §  Transverse-isotropic, elastic-perfectly plastic material properties at the

vertebra. §  Linear-elastic properties for the nucleus pulposus and annulus ground

matrix

METHODS

FE finite element • TPTD teriparatide • BMD bone mineral density • QCT quantitative computer tomography • DVD disc-vertebra-disc • L lumbar

FR0028 Effect of Teriparatide Treatment on Vertebral Strength in Postmenopausal Women with Osteoporosis Assessed Using a Patient-Specific Finite Element Model of the Disc-Vertebra-Disc Unit

CHUHEE LEE, MARGARET A PAGGIOSI, EUGENE V MCCLOSKEY, NICOLA FA PEEL, JENNIFER S WALSH, RICHARD EASTELL, LANG YANG, UNIVERSITY OF SHEFFIELD, UK



TPTD teriparatide • FE finite element • DXA dual x-ray absorptiometry • L lumbar • BMD bone mineral density • QCT quantitative computer tomography • v volumetric



47

§  Vertebral strength derived from the in vivo DVD FE model shows a larger treatment effect relative to the baseline value than densitometric variables

§  The present study confirms the major effect of TPTD on bone strength §  From a clinical point of view these findings reassure us that the patients on

TPTP see antifracture efficacy despite modest increases in BMD CONCLUSIONS

DVD disc-vertebra-disc • FE finite element • FEA finite element analysis • TPTD teriparatide • BMD bone mineral density • VF vertebral fracture




1055 Effect of Denosumab (DMAB) and Teriparatide (TPTD) Transitions on Peripheral Bone Mineral Density (BMD) and Microarchitecture: The DATA-Switch HR-pQCT Study

§  Postmenopausal osteoporotic women with L-spine/Hip T score <1.5; or L-spine/Hip T score <1.0 with RF; or history of low trauma fracture

Determine the effect of Denosumab (DMAB) and Teriparatide (TPTD) Transitions on Peripheral Volumetric Bone Mineral Density (vBMD) and Microarchitecture

PARTICIPANTS

Year 1 and 2 Year 3 and 4 TPTD 20µg daily g DMAB 60mg/6-months DMAB + TPTD g DMAB 60mg/6-months DMAB 60mg/6-months g TPTD 20µg/day

DESIGN

§  Net gain over 4 years of distal radial and tibial: •  Tot.vBMD, Tb.vBMD, Ct.vBMD, Ct.Th, trabecular microarchitecture


DMAB denosumab • TPTD teriparatide • BMD bone mineral density • Tot total • v volumetric • Ct cortical • Tb trabecular • Th thickness • HRpQCT high resolution peripheral computer tomography • RF risk factor

JOY TSAI, ALEXANDER UIHLEIN, SHERRI-ANN BURNETT-BOWIE, ROBERT NEER, PADRIG TUCK, PAUL WALLACE, MARY BOUXSEIN, BENJAMIN LEDER, MASSACHUSETTS GENERAL HOSPITAL, USA

48 Congress Highlights ASBMR 2015 Annual Meeting

Highlights ASBMR 2015 49 Lancet 2015; 386: 1147–55

Highlights ASBMR 2015 50 Lancet 2015; 386: 1147–55


Whether TPTD-induced Ct.vBMD decreases represent as yet under-mineralized new bone is unclear

1055 Effect of Denosumab (DMAB) and Teriparatide (TPTD) Transitions on Peripheral Bone Mineral Density (BMD) and Microarchitecture: The DATA-Switch HR-pQCT Study

Comments

Congress Highlights ASBMR 2015 Annual Meeting 52

§  The decline in Ct.vBMD with TPTD after DMAB may represent accumulation of undermineralised newly formed bone

§  Very small patient numbers limit applicability to clinical practice

MO0335 Biochemical Markers of Bone Turnover and the Prediction of the BMD Response to Teriparatide, Denosumab or Both in Postmenopausal Women in the DATA Study

§  94 postmenopausal osteporotic women (age 51-91 years) with no recent bisphosphonate

Report the relationship between BTMs and BMD in each of the treatment groups

PARTICIPANTS

§  Randomised for 2 years treatment with: •  TPTD (20µg SC daily) •  DMAB (60mg SC every 6 months) •  TPTD (20µg SC daily) + DMAB (60mg SC every 6 months)

DESIGN

§  BMD (DXA) of the hip, spine and 1/3 distal radius at 24 months §  Serum OC and CTX at 3, 6, 12, 18, and 24 months §  Pearson’s correlation coefficients & Fisher’s z-transformed normal

approximation

OUTCOMES & ANALYSIS

BTM bone turnover marker • BMD bone mineral density • TPTD teriparatide • DMAB denosumab • sc sub-cutaneous • OC osteoclacin • CTX collagen type 1 crosslinked C-telopeptide

JOY TSAI, PAUL WALLACE, SHERRI-ANN BURNETT-BOWIE, ALEXANDER UIHLEIN, ROBERT NEER, HANG LEE, BENJAMIN LEDER, MASSACHUSETTS GENERAL HOSPITAL HARVARD MEDICAL SCHOOL, USA


MO0335 Biochemical Markers of Bone Turnover and the Prediction of the BMD Response to Teriparatide, Denosumab or Both in Postmenopausal Women in the DATA Study

§  In women treated with either TPTD or DMAB, early changes in BTMs predict 2yr BMD gains, especially at the spine

§  In women treated with combination therapy, greater increases in radius BMD associated with less suppression of bone turnover

§  These results suggest that the superior efficacy of combination therapy at cortical sites, such as the radius, may depend on persistent bone turnover despite RANKL inhibition


TPTD teriparatide • DMAB denosumab • BTM bone turnover marker

JOY TSAI, PAUL WALLACE, SHERRI-ANN BURNETT-BOWIE, ALEXANDER UIHLEIN, ROBERT NEER, HANG LEE, BENJAMIN LEDER, MASSACHUSETTS GENERAL HOSPITAL HARVARD MEDICAL SCHOOL, USA


1056 Effect of Odanacatib on Bone Density and Estimated Bone Strength in Postmenopausal Women: a CT-Based Sub-study of the Phase 3 Long-Term Odanacatib Fracture Trial (LOFT)

§  164 women (78 ODN, 86 PBO)

Evaluate the effect of ODN on vBMD of trabecular and cortical bone by QCT and estimated whole-bone strength using FEA

PARTICIPANTS

§  Women ≥65 years •  Without a baseline radiographic VFx & TH/FN T-score of -2.5 to -4.0 •  With a prior VFx & TH/FN T-score of -1.5 to -4.0

§  ODN 50mg/week or PBO §  All given vitamin D3 (5600 IU/week) and calcium to achieve ~1200 mg/day

DESIGN

§  Key endpoints: % change from baseline in Tb vBMD at spine and Ct vBMD at LS and TH after 24 months (assessed by QCT)

§  All endpoints analysed by a Longitudinal Data Analysis model OUTCOMES

AND ANALYSIS

ODN odanacatib • PBO placebo • VFx vertebral fracture • TH total hip • FN femoral neck • v volumetric • BMD bone mineral density • Tb trabecular • Ct cortical • QCT quantitative computer tomography • FEA finite element analysis

BENTE LANGDAHL, TOBIAS DEVILLIERS, TONY KEAVENY, KLAUS ENGELKE, HARRY GENANT, SHABANA ATHER, HILDE GIEZEK, ANTONIO LOMBARDI, ALBERT LEUNG, ANNE DE PAPP, AARHUS UNIVERSITY HOSPITAL, DENMARK



RESULTS

ODN odanacatib • PBO placebo • vBMD volumetric bone mineral density • TH total hip • FEA finite element analysis • CI confidence interval • L lumbar




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§  In postmenopausal women with osteoporosis, ODN increased both trabecular and cortical vBMD in the spine and total hip

§  ODN also increased whole-bone strength at the spine and hip as assessed by finite element analysis


ODN odanacatib • vBMD volumetric bone mineral density • TH total hip • FEA finite element analysis


Congress Highlights ASBMR 2015 Annual Meeting

1143 Romosozumab Improves Strength at the Lumbar Spine and Hip in Postmenopausal Women With Low Bone Mass Compared With Teriparatide

§  Sclerostin is a glycoprotein coded by the SOST gene with significant effects on bone metabolism

§  Romosozumab is a bone-forming agent that inhibits sclerostin shown to increase areal BMD (aBMD) in postmenopausal women with low bone mass

§  It has also been shown to have integral volumetric BMD (vBMD) gains at the spine and hip using quantitative computed tomography imaging

§  This study investigates the effects of romosozumab on bone strength, as assessed by finite element analysis (FEA) of QCT scans of hip and spine

INTRODUCTION

BMD bone mineral density •a areal • v volumetric • QCT quantitative computer tomography

TONY KEAVENY, DB CRITTENDEN, MA BOLOGNESE, HK GENANT, K ENGELKE, B OLIVERI, JP BROWN, BL LANGDAHL, YC YANG, A GRAUER, C LIBANATI, UNIVERSITY OF CALIFORNIA, BERKELEY, USA



§  Postmenopausal women with lumbar spine, total hip, or femoral neck T-scores ≤–2.0 and ≥–3.5

Investigate the effects of romosozumab on bone strength by FEA

PARTICIPANTS

§  Randomised to •  Romosozumab 210mg SC monthly (n=24) •  Teriparatide 20µg daily (open label) (n=27) •  Placebo (n=31)

DESIGN

§  QCT: L1 & L2 lumbar vertebrae & proximal femur - baseline & 12months §  Bone strength by 3D FEA (VirtuOst, O.N. Diagnostics)


FEA finite element analysis • sc sub cutaneous • L lumbar • QCT quantitative computer tomography




CI confidence interval • FEA finite element analysis


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§  Romosozumab increased strength at the spine and hip over 12 months, with strength improving in the “cortical” and trabecular compartments at both sites

§  These strength improvements support romosozumab evaluation in the ongoing phase 3 clinical program


§  This study provides evidence of a bone strength benefit of romosozumab compared with placebo at the hip and lumbar spine in keeping improvemeents in BMD

§  This may result in improved clinical anti-fracture efficacy of romosozumab CLINICAL

IMPACT FROM REVIEWER’S

PERSPECTIVE

BMD bone mineral density


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1089 Effects of High Dose Vitamin D Supplementation on Bone metabolism in Pregnant Women with Hypovitaminosis D – a Randomized Controlled Trial.

§  Investigator-initiated double-blind, randomized, placebo-controlled, parallel-group trial.

§  Women, aged 20-40 years, with 25OHD < 50 nmol/L §  all planning pregnancy (N=193) §  randomized to a daily supplementation with 70 ug (2800 IU), 35 ug (1400

IU) vitamin D3 (VitD3), or placebo. §  Supplementation initiated before conception and continued until 16 weeks

post partum (PP). §  Main outcome measures

– BMD – trabecular bone score (TBS) – at time of inclusion and four months PP.

GITTE BLOCH RASMUSSEN, LEIF MOSEKILDE, TANJA SIKJAER, PETER VESTERGAARD, LENE HEICKENDORFF, NIELS ULDBJERG, BENTE LANGDAHL, LARS REJNMARK



§  90 women gave birth §  Vitamin D supplementation did not affect birth weight §  25OHD levels increased dosedependently reaching a peak level at the time

of giving birth of 118 nmol/l in the 70 ug and 98nmol/l in the 35 ug/day group, and 60 nmol/l in the placebo group

§  Four months PP, 86% were breast feeding their infants with no differences between groups.

§  BMD at most sites and TBS were significantly decreased 16 weeks after giving birth compared with the pre-pregnancy measurement (p<0.001).

§  Changes in BMD from pre-pregnancy to 16 weeks PP did not differ between groups at the lumbar spine (p=0.51), total hip (p=0.35), whole body (p=0.31), or for TBS (p=0.52).

§  At the femoral neck BMD decreased 4.8% in the women treated with 70 ug compared to placebo (p=0.03).

§  Bone turnover markers during pregnancy and breast feeding did not differ significantly between groups

Results




§  Pregnant women with vitamin D insufficiency experienced no major beneficial effects of high dose vitamin D supplementation.

§  The pregnancy associated decrease in BMD was not prevented by vitamin D supplementation.

§  Our finding of an aggravated BMD loss at the femoral neck in response to a daily supplement of 70 ug VitD3 calls for caution on use of high dose vitamin D supplementation during pregnancy. Conclusions



Bone and cancer

FR0359 Bisphosphonate Therapy, and the Bone Protection Treatment Care Gap, in Men on Androgen Deprivation Therapy for Non-Metastatic Prostate Cancer

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§  Androgen deprivation therapy (ADT) plays a major role in the management of men with non-metastatic prostate cancer

§  However, its use is associated with high rates of bone loss and an increased fracture risk

§  A striking evidence-treatment gap exists for bone protection in men commencing ADT for prostate cancer, where guidelines recommend a bone health assessment and initiation of treatment at the time of commencement of ADT

§  There are few data from real world settings determining if bisphosphonate (BP) treatment reduces fractures in men commencing ADT

INTRODUCTION

BP biphosphonate • ADT androgen deprivation therapy

LISA-ANN FRASER, WESTERN UNIVERSITY, CANADA


FR0359 Bisphosphonate Therapy, and the Bone Protection Treatment Care Gap, in Men on Androgen Deprivation Therapy for Non-Metastatic Prostate Cancer

§  Population level data from Ontario, Canada §  Nested case-control study among men >/=66 years diagnosed with PC §  Event-free controls matched to cases (ratio of 5:1) on age, history of

previous MOF, year of ADT initiation, long-term care (LTC) vs. community residence

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Study whether treatment with a BP prevents fractures in men on ADT for non-metastatic PC

PARTICIPANTS

§  ADT defined as >/=6 months of continuous use of pharmacological ADT or bilateral orchiectomy

§  Exclusion of men with history of metastasis, or prior BP use METHOD

§  Conditional logistic regression to estimate the odds ratio of MOF associated with BP use ANALYSES

BP biphosphonate • ADT androgen deprivation therapy • PC prostate cancer • MOF major osteoporotic fracture • LTC long term care

LISA-ANN FRASER, WESTERN UNIVERSITY, CANADA


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§  18,726 men on ADT for non-metastatic PC - Only 10.4% treated with BP within 3 years of ADT initiation - 1,298 men experienced a MOF

§  7,780 men with MOF -  6,490 matched controls -  1, 298 men on ADT -  mean age 78.5 (±6) years -  8.8% had a prior osteoporotic fracture -  1.1% resided in LTC

§  BP used in 101 (7.8%) of men on ADT and in 363 (5.6%) of controls §  BP not significantly associated with lower MOF incidence (adjusted

OR=1.29, 95%CI 0.99-1.69)

RESULTS

PC prostate cancer • BP bisphosphonate • ADT androgen deprivation therapy • MOF major osteoporotic fracture • OR odds ratio • CI confidence interval • LTC long term care


FR0359 Bisphosphonate Therapy, and the Bone Protection Treatment Care Gap, in Men on Androgen Deprivation Therapy for Non-Metastatic Prostate Cancer LISA-ANN FRASER, WESTERN UNIVERSITY, CANADA

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§  Over 10 years, there was no reduction in MOF with BP in men with non-metastatic PC on ADT therapy

§  A bone treatment care gap exists in these men as only 10.4% were commenced on BP within 3 years of starting ADT


§  BP have been shown to prevent bone loss, while denosumab prevents fractures, in men with non-metastatic PC on ADT therapy

§  Despite effective therapies and guidelines for their use being available, this study highlights that the majority of men with non-metastatic PC on ADT therapy are not receiving bone protection

§  Multidisciplinary team approaches combining urologists and radiation oncologists with bone health experts may overcome this bone treatment care gap

CLINICAL PERSPECTIVE

PC prostate cancer • BP bisphosphonate • MOF major osteoporotic fracture • ADT androgen deprivation therapy


FR0359 Bisphosphonate Therapy, and the Bone Protection Treatment Care Gap, in Men on Androgen Deprivation Therapy for Non-Metastatic Prostate Cancer LISA-ANN FRASER, WESTERN UNIVERSITY, CANADA

FR0323 Skeletal Health in Healthy Postmenopausal Women Treated with Exemestane for the Primary Prevention of Breast Cancer: 3-year data from the nested bone strength substudy of the MAP.3 trial (MAP3BSS)

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INTRODUCTION

AI aromatase inhibitor • BMD bone mineral density

MIRANDA BOGGILD, LIANNE TILE, GEORGE TOMLINSON, NATASHA GAKHAL, SANDHYA PRUTHI, JOHN ROBBINS, SHAIL RAWAL, SHARMILA MAJUMDAR, SUNDEEP KHOSLA, JAMES INGLE, HARRIET RICHARDSON, PAUL GOSS, ANGELA CHEUNG, UNIVERSITY OF TORONTO, CANADA

§  Up to 18% of women will sustain a fracture 5-6 years after commencing aromatase inhibitor (AI) therapy for breast cancer

§  Severe oestrogen deficiency deficiency induced by AI therapy leads to increased bone remodeling, rapid decreases in BMD, and a rapid increase in fracture risk

§  As AI therapy is now being used for the primary prevention of breast cancer in healthy postmenopausal women, it is important to balance the risks of treatment with its benefits

§  It is therefore important to assess the effects of AI therapy on bone in healthy postmenopausal women


§  362 postmenopausal women: 171 in exemestane group, 191 placebo §  79 crossed over from the placebo to the exemestane group after unblinding at 2 years

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The effect of exemestane (aromatase inhibitor) on bone strength after 3 years of treatment

PARTICIPANTS

§  MAP.3 trial: a placebo-controlled randomized trial §  Exemestane 25 mg/day for the primary prevention of breast cancer §  No OP (T-score >-2.0 at all sites) §  No bone medications §  No fragility fracture

DESIGN

§  Primary outcome: change from baseline to 3 years in total vBMD at the distal radius by HRpQCT

§  All outcomes: % change over time between groups with the Kruskal-Wallis test. OUTCOMES AND

ANALYSIS

Pbo placebo • OP osteoporosis • vBMD volumetric bone mineral density • HRpQCT high resolution peripheral quantitative computer tomography




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CI confidence interval • HRpQCT high resolution peripheral micro-computed tomography • BMD bone mineral density




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§  The decline in secondary bone outcomes continued into the third year and was significantly different compared to the placebo group

RESULTS

LS lumbar spine • CI confidence interval • v volumetric • a areal • BMD bone mineral density




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§  Three years of exemestane treatment results in progressive negative effects on bone, despite calcium and vitamin D supplementation

§  Further and larger studies with long-term follow-up, including fracture risk, are needed to allow an assessment of the risks and benefits of exemestane therapy for the primary prevention of breast cancer


AI aromatase inhibitor




FGF 23

SYMP Cross talk between kidney and bone: bench to bedside

§  Klotho – Enzyme, b-glucuronidase – Expresed in renal proximal tubules – Coreceptor and activator of FGF receptor – Adequate amount of Klotho is essential for phosphaturic action of FGF-23

§  FGF-23 – Member of the FGF family – Endocrine function – Main function: regulation of phosphate and vitamin D levels in plasma – Secreted by osteocytes – Acts on kidneys – Decreases the reabsorption and increases the excretion of phosphate – Suppresses vitamin D synthesis – Has different actions in presence/absence of Klotho

FGF23 AND KLOTHO

FGF fibroblast growth factor

ORSON MOE ET AL.


Komaba, H. & Fukagawa, M. (2012) The role of FGF23 in CKD—with or without Klotho Nat. Rev. Nephrol. doi:10.1038/nrneph.2012.116

Klotho-‐dependent and Klotho-‐independent effects of FGF23 in ESRD

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§  Worldwide epidemic §  FGF-23 levels increase from stage 1 to stage 5 §  Phosphate levels still normal in stage 4 §  FGF-23, but not Klotho, associated with death or ESRD §  FGF-23 and risk of cardiovascular events §  Cardiac disease in CKD §  RF: hypertension, dyslipidemia, diabetes, smoking, age, high Ca, high P §  Phosphate levels are highly correlated with vascular calcification §  Role of Klotho in vascular tissue remains uncertain

CHRONIC KIDNEY

DISEASE (CKD)

ESRD end stage renal disease • CKD-MBD chronic kidney disease-mineral and bone disorder • RF Risk factor • FGF fibroblast growth factor • Ca calcium • P phosphate

ORSON MOE, MICHAEL ECONS, REINHOLD ERBEN, MAKOTO KURO-O, CHRISTIAN FAUL, MYLES WOLF, KEITH HRUSKA, L DARRYL QUARLES, KENNETH WHITE, CECILIA GIACHELLI, MARK SARNAK, SHARON MOE, TAMARA ISAKOVA, STUART SPRAGUE SEIJI FUKUMOTO, JOVANA KALUDJEROVIC, LINDSAY COE, SOHEL SHAMSUZZAMAN, JACKIE FRETZ



§  ADHR: autosomal dominant hypophosphatemic ricket Mutation induced impaired cleavage of FGF-23 Incomplete penetrance Onset in reproductive years History of waxing and waning due to variations in FGF-23 levels

§  XLH: X-linked hypophosphatemia Inactive mutation of PHEX Overproduction of FGF-23

§  TC: tumoral calcinosis Mutation in GALNT3 Inadequate production of intact FGF-23

GENETIC DISEASES


ORSON MOE ET AL


Highlights ASBMR 2015 84 PHEX = phosphate regulating endopeptidase homolog, X-linked

a genetic disorder that affects about one in 20,000 people

Lower limb deformi5es (bow-‐knee) Waddling gait Short stature or declining growth rate Spontaneous tooth abscesses Bone pain Muscle pain and weakness


SA0284 Serum phosphate levels are associated with fracture risk: the Rotterdam Study

§  Positive association between P and all-type fracture risk in both sexes §  (men: 1.54(1.20-1.97); women: 1.23(1.01-1.49); sex-combined: 1.35

(1.15-1.58))

§  Similar after adjustments for levels of calcium, 25-OHD, kidney function (defined as creatinine-based estimated glomerular filtration rate) and BMD

§  or after restricting analyses with subjects with normal kidney function (men 1.81(1.28-2.55); women: 1.25(1.01-1.55)).

§  To conclude, P was negatively related to LS-BMD in men but not women, and no association with FN-BMD was found in either sex.

§  P was positively related to all-type fracture risk in both sexes. §  Our findings suggest that increased P even within normal range might be

deleterious for bone health in the normal population

Summary


NATALIA CAMPOS, NADIA KOEK, BRAM C VAN DER EERDEN, FERNANDO RIVADENEIRA, ALBERT HOFMAN, JOHANNES VAN LEEUWEN, ANDRE G UITTERLINDEN, CAROLA ZILLIKENS


The end

LB-1156 The Association of Race Ethnicity and Risk of Atypical Femur Fracture in Women Treated with Oral Bisphosphonate Drugs

§  Ethnicity: 65.3% white, 17.1% Asian, 17.6% other races §  During a median follow-up of 7.7 years §  68 women with AFF §  Rate of AFF 18.7 per 100,000 person-years overall §  8x higher in Asian compared to white women (64.2 vs 7.6 per 100,000

person-years, respectively) §  Race/ethnicity strongly associated with risk of AFF, with an age-adjusted

relative hazard of 8.5 (95% CI 4.9-14.9) comparing Asian to white women RESULTS

AFF atypical femoral fracture • BP biphosphonate • RA rheumatoid arthritis • CI confidence Interval

JOAN LO, RITA HUI, CHRISTOPHER GRIMSRUD, MALINI CHANDRA, ROMAIN NEUGEBAUER, JOEL GONZALEZ, AMER BUDAYR, GENE LAU, BRUCE ETTINGER, KAISER PERMANENTE, USA


LB-1156 The Association of Race Ethnicity and Risk of Atypical Femur Fracture in Women Treated with Oral Bisphosphonate Drugs

§  Overall incidence of AFF was 18.7/ 100,000 person-year §  Marked racial disparity in AFF risk that should be further examined,

particularly the mechanisms accounting for this difference §  Median duration of BP treatment was longer and existence of diabetes was

higher in Asian women, which may affect results §  Counseling of Asian women about osteoporosis drug continuation should

include consideration of their higher AFF risk

CONCLUSION

AFF atypical femoral fracture • BP biphosphonate

JOAN LO, RITA HUI, CHRISTOPHER GRIMSRUD, MALINI CHANDRA, ROMAIN NEUGEBAUER, JOEL GONZALEZ, AMER BUDAYR, GENE LAU, BRUCE ETTINGER, KAISER PERMANENTE, USA


1146 Relationship Between Total Hip BMD T-score and Incidence of Nonvertebral Fracture With up to 8 Years of Denosumab Treatment

§  3902 women received DMAb for 3 years during the FREEDOM trial

Investigate the relationship between total hip BMD T-score and the incidence of nonvertebral fracture through 8 years of DMAb therapy

PARTICIPANTS

§  Extension: 2343 women received DMAb for an additional 5 years, for a total of 8 years DMAb DESIGN

§  A repeated-measures model to estimate each subject’s BMD T-scores at the time of their nonvertebral fracture.

§  This analysis related time to nonvertebral fracture and total hip BMD T-score at the time of nonvertebral fracture

METHODS/ ANALYSIS

DMAb denosumab • BMD bone mineral density

SERGE FERRARI, C LIBANATI, CJF LIN, S ADAMI, JACQUES P. BROWN, F COSMAN, E CZERWIŃSKI, LH DE GREGÓRIO, J MALOUF, J-Y REGINSTER, NS DAIZADEH, A WANG, RB WAGMAN, EM LEWIECKI, GENEVA UNIVERSITY HOSPITAL AND FACULTY OF MEDICINE, SWITZERLAND



RESULTS

BMD bone mineral density


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§  An inverse rela5onship between total hip BMD T-‐score (at the 5me of fracture) and nonvertebral fracture incidence regardless of age or prior fracture



§  Higher total hip BMD T-scores during DMAb treatment associated with a lower incidence of nonvertebral fractures

§  Importance of BMD measurement in patients on osteoporosis treatment as a predictor of fracture risk

§  Supportive of the concept that a specific T-score may be used as a practical goal for therapy

CONCLUSION

§  BMD prior to initiating osteoporosis therapy is a strong predictor of fracture risk and response to therapy

§  BMD may be an important component in “treat to target” approaches to osteoporosis CLINICAL

IMPACT

BMD bone mineral density • DMAb denosumab



SA0330 Anabolism versus Antiresorption (AVA Study): A Comparison of the Mechanism of Action (MOA) of Teriparatide (TPTD) and Denosumab (DMAb) in Postmenopausal Women with Osteoporosis Using Quadruple Fluorochrome Labeled Bone Histomorphometry

§  The reported increase in endogenous intact parathyroid hormone (iPTH) levels 1-3 months after a dose of DMAb, a bone antiresorber, has led to speculation that elevation in iPTH could result in early anabolic effect

§  The accepted standard for demonstrating anabolic effects on bone is dynamic tetracycline labelled bone biopsy

§  Tetracycline labelled bone biopsies in a randomized control trial of iv zoledronic acid vs. teriparatide (SHOTZ) has recently differentiated the effects of antiresorber (ZOL) from anabolic (teriparatide)

§  Absence of anabolic effect of denosumab will redirect investigators to find another mechanism for the sustained increases in BMD seen on long-term denosumab therapy

§  Specific examination of the cortical envelope will help to elucidate the cortical bone effects of the 2 agents

INTRODUCTION

BMD bone mineral density • DMAb denosumab • iPTH intact parathyroid hormone

DAVID DEMPSTER, HUA ZHOU, ROBERT RECKER, JACQUES P. BROWN, CHRISTOPHER RECKNOR, E. MICHAEL LEWIECKI, PAUL MILLER, SUDHAKER RAO, DAVID KENDLER, JOHN KREGE, JAHANGIR ALAM, KATHLEEN TAYLOR, BORIS JANOS, VALERIE RUFF, COLUMBIA UNIVERSITY, USA

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§  35 PMO women

Evaluate the effects of DMAb vs TPTD

PARTICIPANTS

§  TPTD 20 µg/day §  DMAb 60 mg once §  Fasting BTMs and iPTH collected at 0, 1, 3, and 6 months §  Fluorochrome labeling before a trans-iliac bone biopsy at 3 months

DESIGN

§  MS/BS in the cancellous envelope §  Dynamic and static histomorphometric indices in cancellous, endocortical,

intracortical, and periosteal envelopes OUTCOMES

AND ANALYSIS

PMO postmenopausal osteoporosis • TPTD teriparatide • DMAb denosumab • BTM bone turnover marker • iPTH intact parathyroid hormone • BL baseline • MS mineralizing surface • BS bone surface


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§  In the DMAb group, intact PTH increased, peaked at month 1, remained above BL at months 3 and 6

§  Histomorphometric indices of bone formation in the cancellous envelope were higher in the TPTD than the DMAb group at month 3

§  Except for MAR, these indices increased with TPTD and decreased with DMAb treatment from BL to month 3

§  Similar findings observed in other envelopes §  TPTD increased BTMs from BL: P1NP starting at month 1 and CTX starting

at month 3 §  In the DMAb group, P1NP and CTX decreased from BL at all time points

RESULTS

DMAb denosumab • PTH parathyroid hormone • BL baseline • MAR mineral apposition rate • DMAb denosumab • P1NP procollagen type I N-terminal propeptide • CTX carboxyterminal cross-linking telopeptide of type I collagen • BTM bone turnover marker


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MAR mineral apposition rate • MS mineralizing surface • BS bone surface • BFR bone formation rate • Ac.F activation frequency • DMAb denosumab • TPTD teriparatide


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§  First study to use a quadruple fluorochrome labeling method to compare longitudinal changes between TPTD and DMAb at the tissue level

§  Opposite Mode Of Action (MOA) of the 2 drugs on bone remodeling §  Increase in intact PTH after DMAb associated with marked decreases in indices of

bone formation in all envelopes, inconsistent with DMAb causing early indirect anabolic action

§  TPTD increased histomorphometric indices and BTMs of bone formation in all envelopes, consistent with an anabolic MOA in trabecular and cortical bone


§  Histomorphometry did not demonstrate an anabolic effect of denosumab corresponding to the rise in PTH at month 3 from baseline

§  Iliac crest may not be the ideal site to assess impact of denosumab on bone modelling (Modeling in monkey femur at stressed sites of femoral neck)

§  A slow anabolic effect not seen with short term labelling protocols cannot be excluded

CLINICAL IMPACT FROM REVIEWER’S

PERSPECTIVE

TPTD teriparatide • DMAb denosumab • PTH parathyroid hormone • MOA mode of action


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SU0352 Effect of Teriparatide or Risedronate on Pertrochanteric Hip Fractures Recovery: 26-Week Results of a Randomized Clinical Trial

§  171 patients §  Prospective, randomized, multicenter, active-control trial of 78-wk duration

26-wk interim results of an ongoing, prospective, randomized, multicenter, active-control trial of 78-wk duration, comparing the effect of TPTD and RIS initiated within 2 weeks after the surgical treatment of a pertrochanteric hip fracture

PARTICIPANTS

§  Inclusion criteria: BMD T-score <-2.0SD, 25(OH)D >9.2 ng/mL, a recent pinned pertrochanteric hip fracture

§  Randomized to TPTD:20 µg/d or RIS:35 mg QW §  Ca and Vit D supplementation

DESIGN

§  Endpoints: function, hip pain, QoL, radiology outcomes, safety OUTCOMES

AND ANALYSIS

BMD bone mineral density • QoL quality of life • TPTD teriparatide • RIS risedronate

PER ASPENBERG, JORGE MALOUF, UMBERTO TARANTINO, PEDRO A. GARCÍA-HERNÁNDEZ, COSTANTINO CORRADINI, SOEREN OVERGAARD, JAN STEPAN, LARS BORRIS, ERIC LESPESSAILLES, FREDE FRIHAGEN, KYRIAKOS PAPAVASILIOU, HELMUT PETTO, JOSÉ RAMÓN CAEIRO, FERNANDO MARIN, ORTHOPAEDIC SURGERY, LINKÖPING UNIVERSITY, SWEDEN


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§  No differences in – SF-36 QoL questionnaire – Charnley’s scale hip pain – ability to walk or the use of walking aids during follow-up – radiographic fracture healing at 6 or 26 wk, mechanical failure of the implant, loss of reduction or non-union

§  Trends to improved TUG and reduced hip pain with teriparatide as compared to risedronate

§  Similar AEs between groups §  More frequent hypercalcemia and hyperuricemia in TPTD §  3 and 8 non-vertebral fractures in the TPTD and RIS group respectively

(p=0.14)

RESULTS

TPTD teriparatide • AE adverse event • RIS risedronate




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Reproduced with permission from authors




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§  Similar results with TPTD or RIS in several fracture-related outcomes §  TPTD: less hip pain and a shorter time on the TUG test §  This randomized trial reports interim exploratory outcomes §  Such analyses may suggest opportunities for the use of anabolic to more

rapidly and effectively mobilize patients subsequent to surgical repair of hip fracture

CONCLUSION

TPTD teriparatide • RIS risedronate • TUG time up and go




Seminar 28-11-2015 Prof. J. vd Bergh

Health & Medicine

Transcript of Seminar 28-11-2015 Prof. J. vd Bergh