Introduction The International Osteoporosis Foundation (IOF) has compiled this educational slide deck to discuss and present the most current and significant.

Introduction The International Osteoporosis Foundation (IOF) has compiled this educational slide deck to discuss and present the most current and significant advances in biomedical and clinical research in bone and mineral metabolism, osteoporosis, muscle and joint, metabolic bone diseases and therapeutics. This slide deck provides information on key abstracts selected from the ASBMR 2017 Annual Meeting of the American Society for Bone and Mineral Research. The content is not intended to be inclusive of all information presented at the meeting. The content is provided by IOF for educational purposes only. The material is for the sole use of the intended recipient and may not be altered or disseminated in any fashion by the recipient for further use. Congress Highlights ASBMR 2017 Annual Meeting

Disclosures IOF has prepared this slide kit and videos as a unique education experience especially aimed at clinicians who are unable to attend important meetings. These Congress Highlights are based on the abstracts presented at the ASBMR 2017 Annual Meeting of the American Society for Bone and Mineral Research. This project has been supported by an educational grant Congress Highlights ASBMR 2017 Annual Meeting

Objectives Develop educational material from key abstracts presented at the meeting. Material includes slides and videos. Disseminate most relevant scientific and clinical information from the meeting to the global community of qualified physicians & health-care professionals and available to free members on IOF website in the bone arena. Educate clinicians and scientists on current updates in the bone field. Congress Highlights ASBMR 2017 Annual Meeting

Steering Committee A steering committee was formed consisting of thought leaders who assisted in the review of key abstracts presented. During the conference, members of the committee listened to presentations and viewed posters to ensure accuracy of reported data. Post-conference, members will convey the scientific information to colleagues in their regions in various formats including: journal clubs hospital rounds through electronic media Congress Highlights ASBMR 2017 Annual Meeting

Steering Committee Members
Co-Chairs Prof. David Kendler (Canada) Prof. Bernard Cortet (France) Members Prof. Nicholas Harvey and Dr Elizabeth Curtis (UK) Dr Elaine Yu (USA) Prof. Teresita Bellido (USA) Dr Dominique Pierroz (Switzerland) Reviewed by Prof. Kenneth Saag, Prof. Teresita Bellido and Prof. Anna Teti on behalf of ASBMR. Congress Highlights ASBMR 2017 Annual Meeting

Roles and Responsibilities of Steering Committee Members
Co-Chairs Lead the project by directing panel of thought leaders Screened the list of more than 1,200 published abstracts to select a list of 41 key abstracts Provided an executive summary discussing the key highlights of the conference Reported a summary of selected symposia Conveyed their overall observations of the conference through a video Members Obtained additional information onsite by attending relevant oral presentations, poster sessions and by interacting with key researchers/presenters as needed Provided the information to be incorporated into the slide kit developed prior to the meeting Reported a summary of knowledge presented at symposia Conveyed a message related to a specific topic through a short video Congress Highlights ASBMR 2017 Annual Meeting

Navigation in Person The presenter will facilitate presentation with navigation in any order of the abstracts (click on topic in the index or the table of content slide) The respective slides will provide details on the findings and importance of the chosen abstracts Click on the “Return to TOC” tab on the slides to return to the topic menu of the particular category Click on the “Return to INDEX” tab on the TOC slide to return to the index slide View the full list of abstracts from the ASBMR 2017 Annual Meeting Access is free for ASBMR members, with a fee for non-members for a full year of access View the webcast of ASBMR 2017 Annual Meeting Highlights session Access is free for ASBMR members, with a fee for non-members Congress Highlights ASBMR 2017 Annual Meeting

Index Executive Summary Symposia Bone-Muscle Interactions D Kendler*
ASBMR/ECTS Clinical Debate – Anti-Resorptive Therapy During the Menopausal Transition Prevents Bone Fractures Later in Life B Cortet* Abstract categories Treatment of Osteoporosis Fractures and Falls Diabetes/Obesity and Bone Skeletal Rare Disorders Bone and HIV Cancer and Fractures Bone Assessment Basic Science * Attended and reviewed by Congress Highlights ASBMR 2017 Annual Meeting

Videos Review from ASBMR experts Overall highlights
Osteoporosis diagnosis strategies Basic science overview Fractures and atypical femoral fractures Overall highlights in basic science Clinical science overview Congress Highlights ASBMR 2017 Annual Meeting

Executive summary Congress Highlights ASBMR 2017 Annual Meeting

Executive summary Themes of main lectures
Back to TOC Cellular senescence: yin and yang CRISPR-Cas9: gene editing and beyond ASBMR-ECTS Clinical Debate: anti-resorptive therapy during the menopausal transition prevents bone fractures later in life The quest for osteoporosis mechanisms: how far we’ve come, how much further we need to go? Update on the American College of Physicians (ACP) new osteoporosis guidelines Sleep, energy metabolism and musculoskeletal systems Testosterone treatment in older men ASBMR 40th anniversary ASBMR-IOF Joint Session: reducing the treatment gap Bone-muscle interactions Congress Highlights ASBMR 2017 Annual Meeting

Executive summary Treatment of osteoporosis
Back to TOC Romosozumab FRAME: BMD in patients treated with Romo in the first 12M remained significantly higher than in those who initially received Pbo despite all patients receiving DMAb for 24M. FRAME Extension: continued lower risk of vertebral, clinical and non vertebral fractures after 12M of Romo followed by DMAb for 24M. Histomorphometry: Romo produced an early bone forming effect and a sustained decrease in bone resoprtion. ARCH: Romo followed by ALN significantly reduced new vertebral, clinical, nonvertebral, and hip fracture risk vs ALN alone. BMD: bone mineral density; Romo: romosozumab; ALN: alendronate; PBO: placebo; DMAb: denosumab Congress Highlights ASBMR 2017 Annual Meeting

Executive summary Treatment of osteoporosis (continued)
Back to TOC Denosumab The greater efficacy of DMAb for preventing non vertebral fractures for years 4-7 compared with the first 3 years is maintained over time (until 10 years). DATA-Switch: TPTD followed by DMAb superior BMD response compared to DMAb followed by TPTD. Abaloparatide ACTIVExtend: ABL followed by ALN resulted in persistent fracture risk reduction. DMAb: denosumab; ALN: alendronate; TPTD: teriparatide; ABL: abaloparatide Congress Highlights ASBMR 2017 Annual Meeting

Executive summary Treatment of osteoporosis (continued)
Back to TOC Teriparatide (TPTD) VERO trial: TPTD superior to RIS in reducing the fracture risk in older women with vertebral fractures. Decreased clinical vertebral and nonvertebral fractures in large observational real-world studies. Bisphosphonates FLEX and HORIZON studies: BMD effects of ZOL more potent and persistent than ALN. Prescribing and dispensing of BP declined in parallell. Intervention efforts should target both practitioners and patients. TPTD: teriparatide; RIS: risedronate; ZOL: zoledronic acid; ALN: alendronate; BMD: bone mineral density Congress Highlights ASBMR 2017 Annual Meeting

Executive summary Falls and Fractures
Back to TOC Features of bone microstructure may characterize women with atypical fractures. High imminent fracture risk in smokers and COPD patients indicate a need for urgent treatment, especially patients with a prevalent or incident VF. Automatically-derived fracture risk indices are associated with incident hip fracture independent of multiple covariates. SCOOP study: community-based screening using the FRAX tool is feasible and effective. FOCUS: CT (obtained for other reasons) analysis of BMD and bone strength can improve the identification of patients at high risk of hip fracture, including some without osteoporosis by DXA. Mortality risk 3 years after a recent clinical fracture was reduced by 20% subsequent to the introduction of FLS. COPD: chronic obstructive pulmonary disease; VF: vertebral fracture; CT: computer tomography; FLS: fracture liaison service; BMD: bone mineral density; DXA: dual X-ray absorptiometry Congress Highlights ASBMR 2017 Annual Meeting

Executive summary Diabetes, Obesity and Bone
Back to TOC T2DM patients are at 30% to 50% increased risk of hip fracture, and at 30% to 70% increased mortality after hip fracture. Large cumulative declines in BMD and microarchitecture occured after RYGB. Denosumab may be beneficial for treatment of T2DM/preDM in patients with osteoporosis, through effects on weight and HbA1c. Sarcopenia, alone or in combination with obesity, may increase the risk of all clinical fractures in older men. T2DM: type 2 diabetes mellitus; BMD: bone mineral density; RYGB: Roux-en-Y Gastric Bypass Congress Highlights ASBMR 2017 Annual Meeting

Executive summary Skeletal Rare Disorders
Back to TOC Burosumab (KRN23), an anti-FGF23, improved serum phosphorus and rickets radiologically, by severity score, and by fracture healing in children after 64 weeks of treatment. Burosumab was well tolerated, normalized serum Pi, reduced pain, improved physical functioning, and increased markers of bone turnover with consequent improved healing of fracture and pseudofracture in adults with XLH. Long-term improvements in HPP-related skeletal manifestations and growth were sustained at 48 weeks with asfotase alfa in infants and young children with HPP. HPP; hypophosphatasia; XLH: X-linked hypophosphatemia Congress Highlights ASBMR 2017 Annual Meeting

Executive summary Bone and HIV Cancer and Fractures Bone assessment
Back to TOC Bone and HIV HIV subjects are at higher risk of vertebral fractures when compared to control subjects. Cancer and Fractures Fracture risk remained increased for up to 10 years after cancer diagnosis. Bone assessment The BMD-independent effect of TBS on fracture risk can be expressed as a simple offset to the BMD T-score. 3D-DXA could potentially be used as a tool to asses the risk of hip fracture in patients with prevalent vertebral fractures. HIV: human immunodeficiency virus; TBS: trabecular bone structure Congress Highlights ASBMR 2017 Annual Meeting

Executive summary Basic science
Back to TOC 3D-DXA-based FE models of the femur provide descriptors with good to excellent sensitivity to hip fracture occurrence. Fat signals to bone and decreased adiposity enhances bone mass. An increase in the transcription factor GATA4 in osteoprogenitors of old mice contributes to cell senescence, and expression of the senescence associated secretory phenotype (SASP). Removal of senescent cells with senolytic agents like ABT263 may represent a novel therapeutic approach to involutional osteoporosis. Prevention of age-related bone loss by a reduction of senescent cells improves bone mass, microarchitecture and strength. Soluble RANKL is not required for osteoclast formation in growing mice, but contributes to osteoclast formation and bone remodeling in adult mice, but not to the pathological bone resorption caused by estrogen deficiency. Periosteum is highly enriched for the majority of stem cell markers compared to bone marrow and endosteum. Congress Highlights ASBMR 2017 Annual Meeting

Executive summary Basic science (continued)
Back to TOC A sub-population of breast cancer cells expressing high levels of Notch2 and other LT-HSC markers reside in the endosteal niche and stay dormant. Pyk2 deficiency triggers cell autonomous apoptotic effects and negates survival GC actions in osteoclasts. Short-term pharmacological inhibition of Notch signaling in skeletally mature mice inhibits bone resorption and favors bone gain. Congress Highlights ASBMR 2017 Annual Meeting

Symposium Congress Highlights ASBMR 2017 Annual Meeting

SYMP 1 ASBM-ECTS Clinical Debate: Anti-resorptive therapy during the menopausal transition prevents bone fractures later in life Back to TOC OUTLINE For the motion: Erik Eriksen (Oslo University Hospital, Norway) Against the motion: Gail Greendale (UCLA, USA) Congress Highlights ASBMR 2017 Annual Meeting

SYMP 1 ASBMRECTS Clinical Debate: Anti-resorptive therapy during the menopausal transition prevents bone fractures later in life Erik Eriksen, Oslo University Hospital, Norway Back to TOC FOR THE MOTION Rationale: bone loss occurs during the menopausal transition: increased bone resorption marked increase of markers of bone remodeling particularly during the 5 years after menopause leading to a marked decrease in bone mass 20-30% decline in BMD over the 10 years after menopause Among antiresorptive therapies, HRT is the best candidate: HRT reduces bone resorption and restores remodeling balance HRT: hormone replacement therapy Congress Highlights ASBMR 2017 Annual Meeting

SYMP 1 ASBMR-ECTS Clinical Debate: Anti-resorptive therapy during the menopausal transition prevents bone fractures later in life Erik Eriksen, Oslo University Hospital, Norway Back to TOC FOR THE MOTION HRT increases BV/TV and wall thickness. HRT decreases markers of bone remodeling. HRT increases BMD at spine and hip. HRT improves bone quality. HRT decreases the risk of fracture (particularly wrist fracture, VF and hip fracture). Some studies have shown that the use of HRT for 5-10 years leads to a fracture risk reduction 9-15 years after discontinuation. HRT: hormone replacement therapy; BV/TV: bone volume/tissue volume; BMD: bone mineral density, VF: vertebral fracture Congress Highlights ASBMR 2017 Annual Meeting

SYMP 1 ASBMR-ECTS Clinical Debate: Anti-resorptive therapy during the menopausal transition prevents bone fractures later in life Erik Eriksen, Oslo University Hospital, Norway Back to TOC FOR THE MOTION Other antiresorptive therapies (bisphosphonates, denosumab, SERMs) have shown to decrease markers of bone remodeling and to increase BMD. They also drastically decrease the risk of fracture in osteoporotic women when they are prescribed several years after the menopausal transition. These drugs can be used when HRT is contra-indicated. HRT: hormone replacement therapy; SERM: selective estrogen receptor modulator; BMD: bone mineral density Congress Highlights ASBMR 2017 Annual Meeting

SYMP 1 ASBMR-ECTS Clinical Debate: Anti-resorptive therapy during the menopausal transition prevents bone fractures later in life Erik Eriksen, Oslo University Hospital, Norway Back to TOC FOR THE MOTION Safety of HRT is still debated. The increased risk of deep vein thrombosis and pulmonary embolism is well demonstrated and perhaps the increased risk of cardiovascular diseases. The increased risk of breast cancer is not demonstrated and HRT does not increase the risk of death. CEE is not the optimal candidate and 17 β-estradiol is preferred. HRT is ideal antiresorptive therapy during the menopausal transition for preventing fractures later in life. HRT: hormone replacement therapy; CEE: conjugated equine estrogen Congress Highlights ASBMR 2017 Annual Meeting

SYMP 1 ASBMR-ECTS Clinical Debate: Anti-resorptive therapy during the menopausal transition prevents bone fractures later in life Gail greendale, UCLA, USA Back to TOC AGAINST THE MOTION No study showed that HRT prescribed during the menopausal transition prevents fracture several years later. Marked increase of bone loss during the menopausal transition : ≅ 2.5%/year ≅1% thereafter After a review of studies examining the relationship between bone loss and the risk of fracture, the association is still debated. Bone loss during the menopausal transition leads to irreversible microarchitectural deterioration; responsible several years later for an increased risk of fracture. HRT: hormone replacement therapy Congress Highlights ASBMR 2017 Annual Meeting

SYMP 1 ASBMR-ECTS Clinical Debate: Anti-resorptive therapy during the menopausal transition prevents bone fractures later in life Gail greendale, UCLA, USA Back to TOC AGAINST THE MOTION BMD changes were compared between 2 periods of approximately the same duration (3.5 years apart)*. Due to signal-to-noise problem the classification of the rate of BMD loss is unreliable. Significant losers at one site (lumbar spine, hip or ultra-distal radius) are not necessarily significant losers at all sites. Finally Dr. Greendale concluded with humor depending on the asked question: NYET for NOT YET !!! *Leslie W et al. Why does rate of bone loss not predcit fracture risk. JCEM 2015; 100: Congress Highlights ASBMR 2017 Annual Meeting

SYMP 2 Bone-Muscle Interactions: Bone as an endocrine organ communicating with muscle
Gerard karsenty, Columbia university, united states Back to TOC Osteocalcin signalling is required for fatty acid metabolism in muscle. IL-6 is a myokine influencing bone metabolism, increasing during exercise and under the control of osteocalcin. Crosstalk between bone and muscle is important for adaptation to exercise and bone remodelling. Replacement of osteocalcin restores muscle function in older mice, necessary and sufficient for reversal of sarcopenia. IL:interleukin Congress Highlights ASBMR 2017 Annual Meeting

SYMP 2 Bone-Muscle Interactions: Circadian rhythms and their importance to bone and muscle
Karyn esser, university of florida, usa Back to TOC Circadian rhythms prepare the organism for stress during an active phase and repair during the rest phase. Individual tissue circadian clocks modulate protein transcription. BMAL1 is a protein in mouse responsible for circadian rhythm; knockout disrupts circadian clock, decreased glucose tolerance, decreased muscle strength. BMAL1 knockout mice do not adapt well to time shifts (jet lag) and die. BMAL1 knockout leads to calcified tendons and loss of cartilage; also negative effects on brain, heart, spleen, and kidney. Increases in mortality. BMAL1: brain and muscle arnt-like protein-1 Congress Highlights ASBMR 2017 Annual Meeting

SYMP 2 Bone-Muscle Interactions: Sarcopenia and clinical considerations
Roger fielding, tufts university, USA Back to TOC Muscle is 50% of body mass and energy utilization can increased tenfold. Contractile performance varies 100 fold during daily activities. Muscle performance: strength; power; fatigue and endurance parameters. Targets for intervention: lifestyle (exercise, nutrition); medication (muscle growth, contractile properties, energy transduction, medications for other indications). Candidate medications: pro-anabolic (selective androgen receptor modulator, SARM), anti-catabolic (myostatin inhibitor), increased mitochondrial function. Clinical trials: SARM: failed clinical trials, myostatin antibody: some positive effects, skeletal troponin activator, Androgen (Androgel) trial: increased muscle function over one year. SARM: selective androgen receptor modulator Congress Highlights ASBMR 2017 Annual Meeting

Treatment of osteoporosis
Congress Highlights ASBMR 2017 Annual Meeting

Index Treatment of osteoporosis
Back to TOC Romosozumab FRAME Study: The Foundation Effect of Rebuilding Bone With One Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab (B Cortet)* Continued Fracture Risk Reduction After 12 Months of Romosozumab Followed by Denosumab Through 36 Months in the Phase 3 FRAME (FRActure study in postmenopausal woMen with osteoporosis) (B Cortet)* Effects of Romosozumab in Postmenopausal Women With Osteoporosis After 2 and 12 Months: Bone Histomorphometry Substudy (B Cortet)* A Randomized Alendronate-Controlled Trial of Romosozumab: Results of the Phase 3 ARCH Study (Active-contRolled fraCture study in postmenopausal women with osteoporosis at High risk) (D Kendler)* * Attended and reviewed by Congress Highlights ASBMR 2017 Annual Meeting

Index Treatment of osteoporosis (continued)
Back to TOC Denosumab Ten-year Continued Nonvertebral Fracture Reduction in Postmenopausal Osteoporosis With Denosumab Treatment (B Cortet)* Combination treatment with teriparatide and denosumab improves spine trabecular microarchicture in DATA-Switch: a randomized controlled trial (N Harvey and E Curtis)* Abaloparatide Sustained Fracture Risk Reduction with Sequential Abaloparatide/Alendronate: Results of ACTIVExtend (B Cortet)* * Attended and reviewed by Congress Highlights ASBMR 2017 Annual Meeting

Index Treatment of osteoporosis (continued)
Back to TOC Bisphosphonate Comparison of BMD Changes and Bone Turnover Levels 3 Years After Bisphosphonate Discontinuation: FLEX and HORIZON Studies (E Yu)* Trends in Bisphosphonate Orders and Pharmacy Dispenses, (D Kendler)* Teriparatide Teriparatide Compared with Risedronate and the Risk of Fractures in Subgroups of Postmenopausal Women with Severe Osteoporosis: The VERO Trial (E Yu)* Vertebral and Nonvertebral Fracture Risk in Subgroups of Patients Receiving Teriparatide in Real World Clinical Practice: Integrated Analysis of Four Prospective Observational Studies (B Cortet)* * Attended and reviewed by Congress Highlights ASBMR 2017 Annual Meeting

[1110] FRAME Study: The Foundation Effect of Rebuilding Bone With One Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab Felicia Cosman, Helen Hayes Hospital, and Columbia University, USA To characterize the BMD gains during the FRAME study and the effect of building bone with Romo on fracture risk reduction upon transition to DMAb BACKGROUND One year of Romo treatment resulted in large BMD increases at the lumbar spine and total hip versus placebo. Endpoints: - change from baseline in BMD T-score, - % of subjects with a BMD gain, - incidence of fractures in the second year Romo: Romosozumab; PBO: placebo; DMAb: Denosumab Congress Highlights ASBMR Annual Meeting

[1110] FRAME Study: The Foundation Effect of Rebuilding Bone With One Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab Back to TOC Felicia Cosman, Helen Hayes Hospital, and Columbia University, USA Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION Romo results in substantial T-score increases after one year. Transition to DMAb the 2nd year results in unprecedented BMD gains. As a result of one year of Romo before transition to DMAb, substantial reduction of fracture rates during year two, when subjects in both groups received DMAb. Romo: romosozumab; DMAB: denosumab Congress Highlights ASBMR Annual Meeting

[1071] Continued Fracture Risk Reduction After 12 Months of Romosozumab Followed by Denosumab Through 36 Months in the Phase 3 FRAME (Fracture study in postmenopausal women with osteoporosis) Extension E Michael Lewiecki, New Mexico Clinical Research & Osteoporosis Center, USA To determine the effect of treatment with Romosozumab (12 m) followed by Denosumab (24 m) on fracture risk FRAME Romo significantly reduced vertebral and clinical fracture risk vs placebo at 12 month Rapid and robust increases of BMD with Romo at the spine and hip, and these increases continued on transition to DMAb 75% NVF and 33% clinical fracture relative risk reduction at 24M in patients who initially received Romo, despite all patients receiving denosumab (DMAb) after 12M FRAME EXTENSION BMD: bone mineral density; Pbo: placebo; Romo: Romosozumab; DMAb: denosumab; PMW: post-menopausal women; OP:osteoporosis; TH: total hip; FN: femoral neck; NVF: non-vertebral fracture Congress Highlights ASBMR Annual Meeting

[1071] Continued Fracture Risk Reduction After 12 Months of Romosozumab Followed by Denosumab Through 36 Months in the Phase 3 FRAME (Fracture study in postmenopausal women with osteoporosis) Extension E Michael Lewiecki, New Mexico Clinical Research & Osteoporosis Center, USA Reproduced with permission from the American Society for Bone and Mineral Research Pbo: placebo; DMAb: denosumab; Romo: romosozumab; RRR: relative risk ratio Congress Highlights ASBMR Annual Meeting

[1071] Continued Fracture Risk Reduction After 12 Months of Romosozumab Followed by Denosumab Through 36 Months in the Phase 3 FRAME (Fracture study in postmenopausal women with osteoporosis) Extension Back to TOC E Michael Lewiecki, New Mexico Clinical Research & Osteoporosis Center, USA Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION BMD in patients treated with Romo in the first 12M remained significantly higher than in those who initially received Pbo despite all patients receiving DMAb for 24M. This strategy leads to a significant decrease of the risk of vertebral, clinical and non vertebral fractures. BMD: bone mineral density; Romo: romosozumab; DMAb: denosumab; Pbo: placebo Congress Highlights ASBMR Annual Meeting

[1072] Effects of Romosozumab in Postmenopausal Women With Osteoporosis After 2 and 12 Months: Bone Histomorphometry Substudy Pascale Chavassieux, INSERM UMR 1033, Université de Lyon, france To evaluate the effects of romosozumab after 2M and 12M on bone tissue by histomorphometry in postmenopausal women with osteoporosis from the FRAME trial BACKGROUND Romosozumab, a humanized sclerostin antibody, increases bone formation, reduces bone resorption, increases BMD, and reduces fracture risk. However, markers of bone remodeling (MBR) changes have shown that the anabolic effect is limited in time METHODS Transiliac bone biopsies at M2 and M12 14 placebo, 15 romosozumab with quadruple fluorochrome labeling (BL and before M2) 31 placebo, 39 romosozumab with double fluorochrome labeling at M12 M: month; BMD: bone mineral density; PMW: post-menopausal women; TH: total hip; FN: femoral neck; PBO: placebo; Romo: romosozumab Congress Highlights ASBMR Annual Meeting

[1072] Effects of Romosozumab in Postmenopausal Women With Osteoporosis After 2 and 12 Months: Bone Histomorphometry Substudy Pascale Chavassieux, INSERM UMR 1033, Université de Lyon, france Back to TOC Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION Romosozumab produces an early, significant bone forming effect and a sustained decrease in bone resorption. In agreement with the data from MBR, 12-month results indicate that Romosozumab strongly inhibits bone resorption. MBR: marker of bone remodeling Congress Highlights ASBMR Annual Meeting

[LB-1162] A Randomized Alendronate-Controlled Trial of Romosozumab: Results of the Phase 3 ARCH Study (Active-controlled fracture study in postmenopausal women with osteoporosis at High risk) Kenneth G Saag, University of Alabama, usa Efficacy and safety results of the ARCH study (Romo-ALN v. ALN-ALN) BACKGROUND Romo was previously shown to reduce vertebral and clinical fractures in postmenopausal women with osteoporosis Romo: Romosozumab; ALN: Alendronate Congress Highlights ASBMR Annual Meeting

[LB-1162] A Randomized Alendronate-Controlled Trial of Romosozumab: Results of the Phase 3 ARCH Study (Active-contRolled fraCture study in postmenopausal women with osteoporosis at High risk) Back to TOC Kenneth G Saag, University of Alabama, USA Romo 12m ALN Romo-ALN 24m ALN-ALN 24m Romo-ALN End of Study ALN-ALN End of Study VFx (HR) 4.0% (0.63) 6.3% 6.2% (0.52) 11.9% Clin Fx (0.72) (0.73) NVertFx (0.80 NS) 8.7% (0.81) 10.6% Hip Fx 2.9% (0.62) 3.2% BMD LS 13.7% 5.0% 14.9% 8.5% BMD TH 6.2% 2.8% 7% 3.6% Adjudicated serious CVE 2.5% 1.9% 6.5% 6.1% Cardiac ischemic event 0.8% 0.3% CONCLUSION Romo followed by ALN significantly reduced new vertebral, clinical, nonvertebral, and hip fracture risk vs ALN alone. In osteoporotic patients at high risk for fracture, a treatment regimen starting with Romo followed by ALN leads to superior fracture risk reduction. CVE: cardiovascular event; TH: total hip; LS: lumbar spine; HR: hazard ratio; Fx: fracture Congress Highlights ASBMR Annual Meeting

[1073] Ten-year Continued Nonvertebral Fracture Reduction in Postmenopausal Osteoporosis With Denosumab Treatment S Ferrari, Geneva University Hospital, switzerland To evaluate the reproducibility of the 7-year findings in the FREEDOM EXT cross-over group To assess long-term fracture rates with 10 years of DMAb treatment in the EXT long-term group DMAb: denosumab; Pbo: placebo; EXT: Extension;PMW: post-menopausal women; NVFx nonvertebral fractures; XO: cross-over Congress Highlights ASBMR Annual Meeting

[1073] Ten-year Continued Nonvertebral Fracture Reduction in Postmenopausal Osteoporosis With Denosumab Treatment S Ferrari, Geneva University Hospital, switzerland Back to TOC Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION Long-term reduction in bone remodeling with DMAb is associated with continued increases in BMD. The marked efficacy of DMAb for preventing non vertebral fractures for years 4-7 compared with the first 3 years is maintained over time (until 10 years). DMAb: denosumab Congress Highlights ASBMR Annual Meeting

[FR0305] Combination treatment with teriparatide and denosumab improves spine trabecular microarchicture in DATA-Switch: a randomized controlled trial Joy Tsai, Massachusetts General Hospital, USA To analyze the spine microarchitecture with combination TPTD and DMAb. TPTD: teriparatide; DMAB: denosumab Congress Highlights ASBMR Annual Meeting

[FR0305] Combination treatment with teriparatide and denosumab improves spine trabecular microarchicture in DATA-Switch: a randomized controlled trial Joy Tsai, Massachusetts General Hospital, USA Back to TOC RESULTS Drug % change TBS (SD) 24 months % change TBS (SD) 30 months % change TBS (SD) 48 months TPTD 2.7 (4.7)b TPTDDMAB + 5.1 (5.8)c DMAB 1.8 (5.0) DMABTPTD -1.1 (4.0)* 3.6 (4.2)c TPTD+DMAB 4.5 (6.7)a CombDMAB 6.1 (4.7)c p change from baseline a<0.05; b<0.01; c<0.001 *p<0.05 vs other groups CONCLUSION Findings support potential for combination therapy (TPTD+DMAB). TPTD followed by DMAB superior to DMAB followed by TPTD. Transient TBS lost at 6 months after switch from DMAB to TPTD suggests this sequence should be avoided in high risk patients. DMAB: denosumab; TBS: trabecular bone score; TPTD: teriparatide Congress Highlights ASBMR Annual Meeting

[1074] Sustained Fracture Risk Reduction with Sequential Abaloparatide/Alendronate: Results of ACTIVExtend Henry G Bone, Michigan Bone and Mineral Clinic, USA To determine the fracture rate in ACTIVExtend : switch from abaloparatide to alendronate ABL: abaloparatide; ALN: alendronate, PBO: placebo Congress Highlights ASBMR Annual Meeting

[1074] Sustained Fracture Risk Reduction with Sequential Abaloparatide/Alendronate: Results of ACTIVExtend Henry G Bone, Michigan Bone and Mineral Clinic, USA Back to TOC Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION ABL for 18M, followed by ALN for 24M, resulted in persistent risk reduction for vertebral, nonvertebral, clinical and major osteoporotic fractures compared to placebo followed by ALN. This study confirms that the use of an anti-resorptive therapy maintains antifracture efficacy after a treatment by an osteo-anabolic agent. ABL: abaloparatide; ALN: alendronate, PBO: placebo; M: month Congress Highlights ASBMR Annual Meeting

[1075] Comparison of BMD Changes and Bone Turnover Levels 3 Years After Bisphosphonate Discontinuation: FLEX and HORIZON Studies Tiffany Kim, University of California, USA To compare BMD changes and bone turnover in the placebo extension arms of 2 key bisphosphonate trials BACKGROUND An ASBMR task force recommended considering a drug holiday for certain women treated for ≥5 years with ALN or ≥3 years with ZOL, with reassessment 2-3 years later. Little evidence about drug holiday management and differences in bone loss. Aln: alendronate; ZOL: zoledronic acid Congress Highlights ASBMR Annual Meeting

[1075] Comparison of BMD Changes and Bone Turnover Levels 3 Years After Bisphosphonate Discontinuation: FLEX and HORIZON Studies Tiffany Kim, University of California, USA Back to TOC Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION A high proportion of women had unsuppressed bone turnover or BMD decline in the placebo extension arms. The effect of ZOL on BMD appears to be more potent and persistent than the effect of ALN. ZOL: zoledronic acid; ALN: alendronate; BMD: bone mineral density; P1NP: procollagen-1 N-terminal peptide Congress Highlights ASBMR Annual Meeting

[LB-1161] Trends in Bisphosphonate Orders and Pharmacy Dispenses, 2008-2016
Annette Adams, Kaiser Permanente Southern California, USA To estimate annual rates of new bisphosphonate orders and pharmacy dispenses in a large, integrated healthcare delivery system over a 9-year period BACKGROUND Retrospective cohort study Women and men aged ≥50 years Members of Kaiser Permanente Southern California during the years with pharmacy benefits with a full year of continuous health plan enrollment ANALYSIS Numerators for the annual rates were the numbers of 1) new orders for oral BP, and 2) new dispenses of oral BP The denominator, annual person-years (p-y), was determined from enrollment data Annual rates per 1000/p-y and percent changes were estimated BP: biphosphonate Congress Highlights ASBMR Annual Meeting

[LB-1161] Trends in Bisphosphonate Orders and Pharmacy Dispenses, 2008-2016
Annette Adams, Kaiser Permanente Southern California, USA Back to TOC Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION Orders and dispenses declining in parallel, suggesting that both care providers and patients are reducing their use of these medications. Intervention efforts aimed at increasing osteoporosis treatment should target both providers and patients. Congress Highlights ASBMR Annual Meeting

Double-blind, double-dummy 2-year trial
[1066] Teriparatide Compared with Risedronate and the Risk of Fractures in Subgroups of Postmenopausal Women with Severe Osteoporosis: The VERO Trial Piet Geusens, Maastricht University Medical Center, The netherlands To report fracture data in patients treated with TPTD compared to those with RIS in subgroup analyses Double-blind, double-dummy 2-year trial Primary endpoint: new VFx fractures Four key gated secondary fracture endpoints: new and worsening VFx, clinical fractures, NVFx, major NVFx TPTD: Teriparatide; RIS: Risedronate; NVF: non-vertebral fracture Congress Highlights ASBMR Annual Meeting

[1066] Teriparatide Compared with Risedronate and the Risk of Fractures in Subgroups of Postmenopausal Women with Severe Osteoporosis: The VERO Trial Piet Geusens, Maastricht University Medical Center, The netherlands RESULTS Table shows HR of morphometric vertebral fractures in TPTD vs. RIS treated patients: Results favor TPTD over RIS - 56% lower morph vert Fx - 52% lower clinical Fx - nonsignificant NVFx Results were similar across all studied subgroups Reproduced with permission from the American Society for Bone and Mineral Research TPTD: teriparatide; RIS: risedronate; NVFx: Non-vertebral fracture; Fx: fracture; HR: hazard ratio Congress Highlights ASBMR Annual Meeting

[1066] Teriparatide Compared with Risedronate and the Risk of Fractures in Subgroups of Postmenopausal Women with Severe Osteoporosis: The VERO Trial Piet Geusens, Maastricht University Medical Center, The netherlands Back to TOC Adapted from a figure and reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION In postmenopausal women with severe osteoporosis, the effect of TPTD vs RIS was consistent among the various predefined subgroups, with no evidence to conclude that the treatment effect was heterogeneous across the different categories of the subgroups in reducing the risk of new vertebral and clinical fractures. Antifracture benefit (v. RIS) was similar in patients treatment naïve and those switched from BP to TPTD. TPTD: teriparatide; RIS: risedronate; NVFx: Non-vertebral fracture; Fx: fracture; HR: hazard ratio Congress Highlights ASBMR Annual Meeting

[1034] Vertebral and Nonvertebral Fracture Risk in Subgroups of Patients Receiving Teriparatide in Real-World Clinical Practice: Integrated Analysis of Four Prospective Observational Studies Stuart Silverman, Cedars-Sinai/UCLA Medical Center and OMC Clinical Research Center, USA To report the rate of CVF and NVF with TPTD in subsets of patients from four integrated real-world observational studies BACKGROUND Phase 3 TPTD fracture prevention trial with significant reductions in VF (CVF and morphometric VF) and NVF Real-world evidence regarding the effects of TPTD in subgroups of patients is limited METHODS Data from DANCE (USA), EFOS and EXFOS (Europe), and JFOS (Japan) studies Prospective, observational studies Ambulatory women (n=8117) and men (n=710; no response=1) with OP Subcutaneous TPTD 20 µg/day for 18 to 24 months CVF: clinical vertebral fracture; NVF: nonvertebral fracture; TPTD: teriparatide; OP:osteoporosis Congress Highlights ASBMR Annual Meeting

[1034] Vertebral and Nonvertebral Fracture Risk in Subgroups of Patients Receiving Teriparatide in Real-World Clinical Practice: Integrated Analysis of Four Prospective Observational Studies Back to TOC Stuart Silverman, Cedars-Sinai/UCLA Medical Center and OMC Clinical Research Center, USA Comparison of the incidence of fracture between the first 6 month-period (reference) and beyond 6 months Mean age at baseline: 71 ± 10 years Similar results for patients with risk factors for osteoporosis: corticosteroids (current or former), RA, diabetes, prevalent hip fracture, prevalent VF and according to the gender. Slightly better results (CVF only) for patients < 75 years CVF NVF % reduction -62% -44% CONCLUSION Integrated post hoc results show a consistent decrease in clinical vertebral and nonvertebral fracture risk during TPTD treatment in large subgroups of real-world patients. CVF: clinical vertebral fracture; NVF: nonvertebral fracture; TPTD: teriparatide; OP:osteoporosis; RA: rheumatoid arthritis Congress Highlights ASBMR Annual Meeting

Fractures and falls Congress Highlights ASBMR 2017 Annual Meeting

Index Fractures and falls
Back to TOC Antiresorptives Compromise Bone’s Material Composition Predisposing to Atypical Femoral Fractures (N Harvey and E Curtis)* High imminent vertebral fracture risk in smokers and COPD patients with a prevalent or incident vertebral fracture (N Harvey and E Curtis)* Fracture Risk Indices from DXA-Based Finite Element Analysis Stratify Incident Fracture Risk Independently from FRAX: The Manitoba BMD (B Cortet)* Women Identified at High Risk of Hip Fracture based on FRAX are Responsive to Appropriate Osteoporosis Management: Results from the SCOOP Study of Population Screening (B Cortet)* Characterization of > 100 Patients with Atypical Femur Fractures: The Quebec Atypical Femur Fracture (N Harvey and E Curtis)* The Fracture, Osteoporosis, and CT Utilization Study (FOCUS) — Utilizing Pre-existing CT to Assess Risk of Hip Fracture in a Large Real-world Clinical Setting (D Kendler)* Mortality after a recent clinical fracture before and after the introduction of a Fracture Liaison Service (D Kendler)* Characterization of long- and short-range compositional and mechanical bone tissue heterogeneity in patients with atypical femoral fractures (N Harvey and E Curtis)* * Attended and reviewed by Congress Highlights ASBMR 2017 Annual Meeting

[1013] Antiresorptives Compromise Bone’s Material Composition Predisposing to Atypical Femoral Fractures Cherie chiang, Department of Medicine, Austin Health, AUSTRALIA To determine whether women treated with antiresorptives with AFFs could be identified by HRpQCT BACKGROUND Antiresorptive therapies slow bone remodeling on endocortical, trabecular and intracortical surfaces. The less renewed bone becomes more fully mineralized predisposing to brittleness and micro-damage. METHODS HR-pQCT of the forearm, StrAxX1.0 medical device software, performed in 49 women with AFFs treated with antiresorptive therapy, 60 women on antiresorptive therapy who were AFF free, and 342 pre- and 55 postmenopausal healthy women. ANALYSES Cortical porosity and matrix mineral density (MMD) were measured and deviation from the young normal mean was quantified using a Material Fragility Score (MFS). AFF: atypical femoral fracture; HR-pQCT: high resolution peripheral computer tomography Congress Highlights ASBMR Annual Meeting

[1013] Antiresorptives Compromise Bone’s Material Composition Predisposing to Atypical Femoral Fractures Cherie chiang, Department of Medicine, Austin Health, AUSTRALIA Back to TOC Back to TOC RESULTS Amongst treated women, difference cortical porosity AFF vs no AFF -0.88SD MMD greater in women with AFF vs women without AFF In women with AFF, MMD was 0.27 SD (p=0.04) higher than in premenopausal women, and was also higher than the other postmenopausal groups Difference MFS AFF vs postmenopausal women SD (p<0.0001) Area under curve 0.74, CI , p<0.001 for AFF vs non-AFF treated controls CONCLUSION Quantification of bone microstructure identifies women with atypical fractures and may help to reassure those at low risk. AFF: atypical femoral fracture; MMD: matrix mineral density; MFS: material fragility score; SD: standard deviation Congress Highlights ASBMR Annual Meeting

PATIENTS CHARACTERISTICS
[1056] High imminent vertebral fracture risk in smokers and COPD patients with a prevalent or incident vertebral fracture Mayke J. van Dort, Maastricht University Medical Center, NETHERLANDS To determine the incidence of new or worsening VFs in COPD patients and smoker controls PATIENTS Patients with COPD known to have a high risk of VFs – incidence unknown ECLIPSE Study COPD subjects (with GOLD stage 2,3 or 4) and smoker controls METHODS Chest CT scans at BL, after 1 and 3 years of follow-up – evaluating the thoracic and first lumbar vertebrae VF assessment on CT scans – SpineAnalyzer software, Genant grading PATIENTS CHARACTERISTICS 1248 subjects – 1008 with COPD, 258 (20.7%) with >=1 VFs at baseline Mean age: 61 years M: 764 COPD: chronic obstructive pulmonary disease; CT: computer tomography; VF: vertebral fracture Congress Highlights ASBMR Annual Meeting

[1056] High imminent vertebral fracture risk in smokers and COPD patients with a prevalent or incident vertebral fracture Mayke J. van Dort, Maastricht University Medical Center, NETHERLANDS Back to TOC Prevalence and incidence of VFs similar between smokers and COPD, after adjustment for age and sex Adjusted HR 1 yr new/ worsening 5.5 >1 vs 0 baseline VF Adjusted HR 3 yr new/ worsening 3.8 >1 vs 0 baseline VF Risk of incident VF during three years increased with number and severity of baseline VFs In subjects who had a new or worsening VF during the first year, risk of subsequent fracture was 56.3% during the next two years Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION >50% smokers and COPD subjects with a prevalent or incident VF sustain a subsequent VF during the next three years. High imminent fracture risk in these patients indicates a need for immediate treatment of smokers and COPD patients with a prevalent or incident VF. COPD: chronic obstructive pulmonary disease; CT: computer tomography; VF: vertebral fracture; HR: hazard ratio Congress Highlights ASBMR Annual Meeting

[1081] Fracture Risk Indices from DXA-Based Finite Element Analysis Stratify Incident Fracture Risk Independently from FRAX: The Manitoba BMD Registry William Leslie, University of Manitoba, CANADA To examine associations between fracture risk indices and incident fractures using DXA-Based Finite Element Analysis BACKGROUND FEA is a computational method to predict the behavior of materials (mechanical resistance). A software tool automatically performs FEA on DXA hip scans to generate site-specific FRIs that reflect the likelihood of hip fracture from a sideways fall. STUDY Manitoba BMD Registry Women and men age 50 years and older, mean age 65 years 13,978 DXA scans ANALYSIS Comparison of c-statistics for FRIs vs femoral neck BMD alone and FRAX probability computed with BM. Cox regression to estimate HRs and 95% CIs for hip, MOF and non-hip MOF adjusted for relevant covariates including age, sex, femoral neck BMD, FRAX probability, FRAX risk factors and hip axis length (HAL). FRI: fracture risk indice; FEA: finite element analysis; MOF: major osteoporotic fracture; FN: femoral neck; HAL: hip axis length Congress Highlights ASBMR Annual Meeting

[1081] Fracture Risk Indices from DXA-Based Finite Element Analysis Stratify Incident Fracture Risk Independently from FRAX: The Manitoba BMD Registry William Leslie, University of Manitoba, CANADA Back to TOC Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION Automatically-derived FN, intertrochanteric and subtrochanteric FRIs are associated with incident hip fracture independent of multiple covariates, including FN BMD, FRAX probability, risk factors, and HAL. However the relationship between FEA and bone strength was not studied on DXA images. FN: femoral neck; FRI: fracture risk indice; FEA: finite element analysis; MOF: major osteoporotic fracture; FN: femoral neck; HAL: hip axis length; HR: hazard ratio Congress Highlights ASBMR Annual Meeting

[1086] Women Identified at High Risk of Hip Fracture based on FRAX are Responsive to Appropriate Osteoporosis Management: Results from the SCOOP Study of Population Screening Eugene McCloskey, Centre for Metabolic Bone Diseases, University of Sheffield, UK To examine the impact of the screening intervention on hip fracture risk according to baseline FRAX hip fracture probability BACKGROUND The recently completed primary-care based SCOOP screening study targeted treatment to those at highest hip fracture risk using FRAX. Fx: fracture; BMD bone mineral density Congress Highlights ASBMR Annual Meeting

[1086] Women Identified at High Risk of Hip Fracture based on FRAX are Responsive to Appropriate Osteoporosis Management: Results from the SCOOP Study of Population Screening Back to TOC Eugene McCloskey, Centre for Metabolic Bone Diseases, University of Sheffield, UK Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION Women identified to be at high fracture risk based on FRAX hip fracture probability are responsive to appropriate osteoporosis management. The more patients have a high risk of fracture and the more benefit the screening strategy is. Community-based screening using the FRAX tool is feasible and effective. HR: hazard ratio; CI: confidence interval Congress Highlights ASBMR Annual Meeting

[1015] Characterization of > 100 Patients with Atypical Femur Fractures: The Quebec Atypical Femur Fracture Registry Suzanne Morin, McGill University, canada To characterise the pathophysiology of AFF BACKGROUND AFFs are a rare subset of atraumatic subtrochanteric and diaphyseal fractures associated with prolonged use of antiresorptive agents. METHODS Data from the Quebec Atypical femur Fracture Registry (men and women aged 45 and older), clinical and radiographic data collected 2D-3D X-Ray EOS scans for femur geometry in a subset (n=37) Descriptive statistics presented, compared with reference populations 1. Men and women with femoral fractures in Quebec, 2. Geometric parameters, data from Chaibi 2011 and Than 2012 AFF: atypical femur fracture Congress Highlights ASBMR Annual Meeting

[1015] Characterization of > 100 Patients with Atypical Femur Fractures: The Quebec Atypical Femur Fracture Registry Suzanne Morin, McGill University, canada Back to TOC 102 participants with AFF, majority Caucasian Mean age 69.5 [9.3] years at the time of AFF Mean cumulative duration of bisphosphonates 10.4 [4.5] years 154 fractures, 71% with prodromal pain, 52 bilateral 68% fractures at the diaphysis Use of PPI, hormone therapy and raloxifene higher than the Quebec population Altered femoral neck shaft angle, varus deformity at knee, femur bowing and hip knee shaft angle noted in with AFF patients compared to reference population Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION Significant differences are apparent in AFF subjects compared to reference populations and variance amongst orthopedic and medical practices may impact functional recovery in these patients. AFF: atypical femoral fracture; PPI: proton-pump inhibitor Congress Highlights ASBMR Annual Meeting

[1155] The Fracture, Osteoporosis, and CT Utilization Study (FOCUS) — Utilizing Pre-existing CT to Assess Risk of Hip Fracture in a Large Real-world Clinical Setting Annette Adams, Kaiser Permanente Southern California, USA Investigation of the validity of preexisting CT imaging data in a large real-world clinical setting, using a case-cohort analysis BACKGROUND Analysis of pre-existing clinical CT hip scans to measure both DXA-equivalent BMD and finite element analysis-derived bone strength-called here “biomechanical CT analysis” (BCT) Improve the acuity of identifying patients at high risk of hip fracture PARTICIPANTS 111,694 patients aged > 65 years, Kaiser, California - Abdominal or pelvic CT - No hip fracture - DXA within three years Hip fracture cases: 1340 women, 619 men ; similar number matched non-fracture controls CT: computer tomography; BCT: biomechanical CT; BMD: bone mineral densitometry; DXA: dual X-ray absorptiometry Congress Highlights ASBMR Annual Meeting

[1155] The Fracture, Osteoporosis, and CT Utilization Study (FOCUS) — Utilizing Pre-existing CT to Assess Risk of Hip Fracture in a Large Real-world Clinical Setting Annette Adams, Kaiser Permanente Southern California, USA Back to TOC Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION Biomechanical CT analysis of BMD and bone strength from routine clinical hip and pelvis CT scans can improve the identification of patients at high risk of hip fracture, including some without osteoporosis by DXA. BCT: biomechanical computer tomography; DXA: dual X-ray absorptiometry; BMD: bone mineral densitometry; HR: hazard ratio; CI: confidence interval Congress Highlights ASBMR Annual Meeting

[LB-1160] Mortality after a recent clinical fracture before and after the introduction of a Fracture Liaison Service Caroline E Wyers, Maastricht UMC+, VieCuri Medical Center, the netherlands To evaluate the risk of mortality within 3 years after a clinical fx in patients visiting the emergency department before and after the introduction of FLS BACKGROUND Few studies present mortality as an outcome associated with FLS implementation METHODS Historical cohort study from the Netherlands Patients aged years with fx Pre-FLS: usual fx treatment procedures Post-FLS: fx treatment + OP evaluation at FLS ANALYSIS Fx categorized by location: hip, major (pelvis, proximal humerus or tibia, vertebral, multiple rib, distal femur), minor (all other) Data on mortality obtained by the national obituary database Cox regression models adjusted for age, sex and fx location for the risk of mortality ED: emergency department; FLS: Fracture Liaison Services; fx: fracture; OP: osteoporosis Congress Highlights ASBMR Annual Meeting

[LB-1160] Mortality after a recent clinical fracture before and after the introduction of a Fracture Liaison Service Caroline E Wyers, Maastricht UMC+, VieCuri Medical Center, the netherlands Back to TOC Pre-FLS Post-FLS p Patients 2653 6415 72% women 69% women Mortality 16% 14.6% 0.015 CONCLUSION Mortality risk 3 years after a recent clinical fracture was reduced by 20% after the introduction of FLS. Cost, recurrent fracture and now mortality benefits. When will this idea catch on? FLS: Fracture Liaison Service Congress Highlights ASBMR Annual Meeting

[1028] Characterization of long- and short-range compositional and mechanical bone tissue heterogeneity in patients with atypical femoral fractures Ashley Lloyd, Cornell University, USA To examine bone tissue from women with differing histories of long-term BP treatment and AFFs to differentiate the competing effects of bone tissue heterogeneity on whole-bone fracture resistance BACKGROUND Heterogeneity of bone tissue properties is an important indicator of altered bone quality. Increased nanomechanical heterogeneity is an intrinsic toughening mechanism, but can also act as a stress riser. SAMPLES Biopsies of proximal femur obtained during fracture repair/total hip arthroplasty PMW with and without history of long-term BP treatment, and with or without history of typical and atypical femoral fracture (+BP Atyp n=12; +BP Typ n=10; -BP Typ n=11; +BP Nonfx n=5; -BP Nonfx n=12) METHODS Fourier transform infrared imaging (FTIRI) and Raman imaging used to assess bone composition. Nanoindentation to assess nanomechanics Spatial maps used to measure long and short range heterogeneity through the full width at half maximum (FWHM) of the distribution, and the initial slope of the variogram. BP: bisphosphonate; AFF: atypical femoral fracture; FTIRI: Fourier transform infrared imaging; PMW: post-menopausal women; Atyp: atypical; Typ: typical Congress Highlights ASBMR Annual Meeting

[1028] Characterization of long- and short-range compositional and mechanical bone tissue heterogeneity in patients with atypical femoral fractures Ashley Lloyd, Cornell University, USA Back to TOC Cortical bone from AFF patients narrower distributions of hardness vs BP naïve non- fracture patients (-31%, p=0.02), and on Raman imaging had narrower distributions of crystallinity (-34%, p=0.03) On FTIRI, cortical bone from patients with AFF had a wider distribution of collagen maturity compared with patients with typical femoral fractures (+112%, p=0.01), but less short range heterogeneity of crystallinity (+122% vs +BP typ, p=0.03) and collagen maturity Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION At small length-scales tissue from patients with AFFs had decreased heterogeneity. At larger length-scales the heterogeneity increased. This is consistent with the hypothesis that whilst microscale heterogeneity toughens bone, larger scale acts as a stress riser. BP: bisphosphonate; AFF: atypical femoral fracture; FTIRI: Fourier transform infrared imaging Congress Highlights ASBMR Annual Meeting

Diabetes/Obesity and Bone

Index Diabetes/Obesity and Bone
Back to TOC Predictors of Incident Fractures in Obese Subjects With Type 2 Diabetes (E Yu)* Longitudinal 5-year changes in bone density and microarchitecture after Roux-En-Y Gastric Bypass (E Yu)* The association between type 2 diabetes mellitus, hip fracture, and post-hip-fracture mortality: a multi-state cohort analysis (N Harvey and E Curtis)* Denosumab Improves Glycemic Control of Type 2 Diabetic or Prediabetic Patients with Osteoporosis (N Harvey and E Curtis)* The Risk of Fracture among men with Sarcopenia, Obesity, their combination Sarcopenic Obesity, and men with neither condition: the MrOS Study (E Yu)* * Attended and reviewed by Congress Highlights ASBMR 2017 Annual Meeting

[1127] Predictors of Incident Fractures in Obese Subjects With Type 2 Diabetes Mellitus
Anna Nilsson, Gothenburg University, sweden To study predictors of incident fractures in obese subjects with T2DM BACKGROUND T2DM is associated with increased risk of fractures, especially hip fractures, despite normal bone density and often also high BMI PARTICIPANTS 225,031 adult subjects with a clinical diagnosis of T2DM and BMI ≥ 30 kg/m2 Mean age: 63±12 (SD) years, BMI 34.0±4.1 kg/m2, height 169.9±9.9 cm, and weight 98±16 kg METHODS A link between Swedish National Diabetes Register (NDR) and the Swedish National Patient Register (NPR) Incidence of fractures and comorbidity retrieved from NPR, mean follow-up time 6.5 years T2DM: Type 2 diabetes mellitus; BMI: body mass index Congress Highlights ASBMR Annual Meeting

[1127] Predictors of Incident Fractures in Obese Subjects With Type 2 Diabetes Mellitus
Anna Nilsson, Gothenburg University, sweden Back to TOC 15,314 fractures - 7,674 MOF - 3,651 hip fx Duration of T2DM: 5+7 years HbA1c levels: mmol/mol Microalbuminuria and multiple complications, retinopathy, also increased risk of hip/MOF Also DM2 medications (particularly insulin) increased risk fractures Fracture Risk Any fx HR MOF fx Hip fx T2DM 1.012 1.013 1.018 HbA1c 1.004 1.003 CONCLUSION High HbA1c and long duration of T2DM contributed to the risk of incident fractures and a combination of the two resulted in a 45 % increased risk of hip fracture in obese subjects with T2DM. T2DM: type 2 diabetes mellitus; fx:fracture; MOF: major osteoporosis fracture; HR: hazard ratio Congress Highlights ASBMR Annual Meeting

[1125] Longitudinal 5-year changes in bone density and microarchitecture after Roux-En-Y Gastric Bypass Elaine Yu, Massachusetts General Hospital To evaluate longitudinal changes in BMD and bone microarchitecture in the 5 years after RYGB BACKGROUND RYGB leads to substantial postoperative bone loss, but it is unknown whether accelerated bone loss is sustained beyond 2 years. STUDY Prospective 5-year longitudinal study 21 adults (17F, 4M; mean age 51 ± 14 years) Severe obesity (BMI 45 ± 7 kg/m2) ANALYSIS DXA lumbar spine, total hip, and 1/3 radius QCT at L1-L2 HR-pQCT to assess bone microarchitecture of the distal radius and tibia RYGB: Roux-en-Y Gastric Bypass; DXA: dual X-ray absorptiometry; BMI: body mass index; QCT: quantitative computer tomography; L: lumbar; HR-pQCT: high resolution peripheral quantitative computer tomography Congress Highlights ASBMR Annual Meeting

[1125] Longitudinal 5-year changes in bone density and microarchitecture after Roux-En-Y Gastric Bypass Elaine Yu, Massachusetts General Hospital Back to TOC Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION Large cumulative declines in BMD and microarchitecture occur after RYGB with continued worsening between years 2 and 5 at multiple skeletal sites. The persistent deterioration raises concerns about the long-term skeletal consequences of RYGB. RYGB: Roux-en-Y Gastric Bypass; DXA: dual X-ray absorptiometry; QCT: quantitative computer tomography; HR-pQCT: high resolution peripheral quantitative computer tomography; v: volumetric; a:areal Congress Highlights ASBMR Annual Meeting

[FR0241] The association between type 2 diabetes mellitus, hip fracture, and post-hip-fracture mortality: a multi-state cohort analysis Cristian tebe, Bellvitge Biomedical Research Institute (IDIBELL), Spain To estimate the association between T2DM and the transitions to hip fracture, fracture-free death, and post-hip-fracture mortality BACKGROUND Recent studies have suggested an increased hip fracture risk in patients suffering from T2DM, whilst failing to model the effect of T2DM status on subsequent post-fracture mortality. PARTICIPANTS Subjects aged 65 to 80 years with a recorded diagnosis of T2DM (n=44,796) and T2DM-free controls (n=81,221) matched (up to 2:1) Primary care electronic medical records (SIDIAP, Spain, containing >5.5m records) Subjects were followed to study outcome (hip fracture or death) date ANALYSIS Multi-state Cox regression models Multivariable models adjusted for age at T2DM diagnosis and at hip fracture Analyses stratified by gender T2DM: type 2 diabetes mellitus; HR: Hazard Ratio Congress Highlights ASBMR Annual Meeting

[FR0241] The association between type 2 diabetes mellitus, hip fracture, and post-hip-fracture mortality: a multi-state cohort analysis Cristian tebe, Bellvitge Biomedical Research Institute (IDIBELL), Spain Back to TOC Men Women Adjusted HRs: fracture-free death; men 1.40 [ ]; women 1.86 [ ] HRs for hip fracture: men 1.30 [ ]; women 1.50 [ ] HRs for post-hip fracture mortality estimated at Men 1.30 [ ]; Women 1.69 [ ] Death Fracture Probability Probability Index Years since index Years since index Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION T2DM patients are at a 30% (men) to 50% (women) increased risk of hip fracture, and at a 30% (men) to 70% (women) risk of dying after suffering such a hip fracture. T2DM: type 2 diabetes mellitus; HR: Hazard Ratio Congress Highlights ASBMR Annual Meeting

[FR0290] Denosumab Improves Glycemic Control of Type 2 Diabetic or Prediabetic Patients with Osteoporosis Chee Kian Chew, Mayo Clinic, USA To determine if DMab could improve glycemic control in T2DM or preDM patients with osteoporosis BACKGROUND DMab has been shown to stimulate human β-cell proliferation through inhibition of the RANKL pathway in mice. DESIGN Retrospective case-control study Subjects aged 45 to 100 years with T2DM/ preDM and osteoporosis 3 groups : Dmab (n=115) BP : oral or iv (n=115) Cat/Vit D (n=115) ANALYSES Primary endpoints: change in HbA1c at 6 and 12 months Secondary endpoints: changes in FPG and BW at 6 and 12 months DMab: Denosumab; T2DM: type 2 diabetes; preDM: prediabetic; BL: baseline; BP: bisphosphonate; FPG: fasting plasma glucose; BW: body weight Congress Highlights ASBMR Annual Meeting

[FR0290] Denosumab Improves Glycemic Control of Type 2 Diabetic or Prediabetic Patients with Osteoporosis Back to TOC Chee Kian Chew, Mayo Clinic, USA Change in HbA1c and weight from 0-12 months RESULTS Intervention △HbA1c (%) △Weight (kg) Calcium/vitamin D 0.1 -0.3 Bisphosphonate 0.3 0.8 Denosumab -2.5 P between group 0.003 0.0003 CONCLUSION Denosumab may be beneficial for treatment of T2DM/preDM in patients with osteoporosis, through effects on weight and HbA1c T2DM: type 2 diabetes mellitus; preDM: prediabetic; BL: baseline; BP: bisphosphonate; FPG: fasting plasma glucose; BW: body weight Congress Highlights ASBMR Annual Meeting

[1156] The Risk of Fracture among men with Sarcopenia, Obesity, their combination Sarcopenic Obesity, and men with neither condition: the MrOS Study Rebekah Harris, University of Pittsburgh, USA To examine fracture risk among men with sarcopenia alone, obesity alone, sarcopenic obesity, and men with neither condition BACKGROUND The co-existence of sarcopenia and obesity may conceptually increase fracture risk through increased risk of falls and negative influences on BMD PARTICIPANTS MrOs Study; community-dwelling older men N=5,994, mean age: yr. METHODS Sarcopenia defined based on the European Working Group (cut points for physical performance measures) DXA for ALM and TBF Low lean mass defined using the residuals approach of Newman Obesity defined using a cut-point of 30% body fat. BMD; bone mineral density; ALM: appendicular lean mass; TBF: total body fat Congress Highlights ASBMR Annual Meeting

[1156] The Risk of Fracture among men with Sarcopenia, Obesity, their combination Sarcopenic Obesity, and men with neither condition: the MrOS Study Rebekah Harris, University of Pittsburgh, USA Back to TOC Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION Sarcopenia, alone or in combination with obesity, may increase the risk for all clinical fractures in older men. MOF: major osteoporosis fracture; HR: hazard ratio; CI: confidence interval Congress Highlights ASBMR Annual Meeting

Skeletal Rare Disorders

Index Skeletal Rare Disorders
Back to TOC Burosumab (KRN23), a Fully Human Anti-FGF23 Monoclonal Antibody for X-linked Hypophosphatemia (XLH): Final 64-Week Results of a Randomized, Open-label Phase 2 Study of 52 Children (D Kendler)* Phase 3 Randomized, 24 Week, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults with X-Linked Hypophosphatemia (XLH) (D Kendler)* Improvements in Skeletal Manifestations and Growth With Up to 6 Years of Treatment With Asfotase Alfa in Infants and Children Aged ≤5 Years With Hypophosphatasia (D Kendler)* * Attended and reviewed by Congress Highlights ASBMR 2017 Annual Meeting

[1154] Burosumab (KRN23), a Fully Human Anti-FGF23 Monoclonal Antibody for X-linked Hypophosphatemia (XLH): Final 64-Week Results of a Randomized, Open-label Phase 2 Study of 52 Children Michael Whyte, Shriners Hospital for Children, USA Final 64 wks of randomized, open-label phase 2, study investigating burosumab in children with XLH BACKGROUND In children with XLH, FGF23-mediated hypophosphatemia impairs skeletal mineralization and causes rickets Burosumab binds to, and inhibits, circulating FGF23 STUDY Phase 2 study 52 children with XLH; age 5-12 yr Burousumab Q2W or Q4W by sc injection, maximum dose 2mg/kg ANALYSIS Radiographs of wrists and knees by: the Thacher Rickets Severity Score (RSS) and the Radiographic Global Impression of Change XLH: X-linked Hypophosphatemia; FGF23: fibroblast growth factor 23 Congress Highlights ASBMR Annual Meeting

[1154] Burosumab (KRN23), a Fully Human Anti-FGF23 Monoclonal Antibody for X-linked Hypophosphatemia (XLH): Final 64-Week Results of a Randomized, Open-label Phase 2 Study of 52 Children Back to TOC Michael Whyte, Shriners Hospital for Children, USA Adapted and reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION Burosumab, a novel treatment that inhibits the biological activity of FGF23, improved serum phosphorus, improving rickets radiologically, by severity score, and by fracture healing. Treatment was generally safe and well tolerated. RSS: Rickets Severity Score ; XLH: X-linked Hypophosphatemia; FGF23: fibroblast growth factor 23 Congress Highlights ASBMR Annual Meeting

[LB-1159] A Phase 3 Randomized, 24 Week, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults with X-Linked Hypophosphatemia (XLH) Karl Insogna, Yale University School of Medicine, USA To report data from the first 24 wks of an ongoing, Phase 3, double-blind, multicenter study investigating the efficacy and safety of burosumab in adults with XLH BACKGROUND In adults with XLH, hypophosphatemia is caused by elevated circulating FGF23 levels, leading to osteomalacia, musculoskeletal pain, stiffness, pseudofractures, osteoarthritis, enthesopathy and muscle dysfunction PARTICIPANTS 134 patients serum Pi <2.5 mg/dL and skeletal pain (validated pain score ≥4) Randomized to burosumab 1mg/kg or placebo (PBO) sc q4 wks for 24 wks ANALYSIS Primary endpoint: mean serum Pi levels above the lower limit of normal Secondary endpoint: WOMAC pain score FGF23: fibroblast growth factor 23; PBO: placebo; XLH: X-Linked Hypophosphatemia; Pi: phosphate Congress Highlights ASBMR Annual Meeting

[LB-1159] A Phase 3 Randomized, 24 Week, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults with X-Linked Hypophosphatemia (XLH) Back to TOC Karl Insogna, Yale University School of Medicine, USA PBO Buro p Serum phosphate through week 24: absolute change from baseline (mg/dL) 0.16 1.21 .006 WOMAC stiffness 0.25 -7.27 .012 WOMAC physical function 8.2 -3.11 .04 Worst pain -0.32 -0.79 .09 P1NP -1.0 .003 Fracture/pseudo-fracture OR v. PBO 7.7 .0001 Updated and reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION Burosumab, antiFGF23, was well tolerated, normalized serum Pi, reduced pain, improved physical functioning, and increased markers of bone remodeling with consequent improved healing of fracture and pseudofracture in adults with XLH. FGF23: fibroblast growth factor 23; XLH: X-linked hypophosphatemia; Pi: phosphate; P1NP: procollagen type I N-propeptide Congress Highlights ASBMR Annual Meeting

[LB-MO0751] Improvements in Skeletal Manifestations and Growth With Up to 6 Years of Treatment With Asfotase Alfa in Infants and Children Aged ≤5 Years With Hypophosphatasia Anna Petryk, Alexion Pharmaceuticals, Inc., USA To report data on HPP-related skeletal manifestations and growth with asfotase alfa in patients aged ≤5 y with potentially life-threatening HPP due to onset at age <6 mo BACKGROUND HPP is a rare, inherited, systemic, metabolic disease caused by tissue-nonspecific alkaline phosphatase (TNSALP) deficiency HPP characteristics in infants and young children: impaired skeletal mineralization, craniosynostosis, respiratory failure, seizures, HPP rickets, and failure to thrive CLINICAL STUDY Asfotase alfa 6 mg/kg/wk Phase 2, single-arm, multinational, open-label study (NCT ) 69 patients aged ≤5 y with potentially life-threatening HPP due to onset at age <6 mo ANALYSES Primary outcome: radiographic Global Impression of Change (RGI-C) score at Wk 24 and 48 of treatment Secondary measures: Rickets Severity Scale (RSS) score, growth, and safety TNSALP: tissue-nonspecific alkaline phosphatase; RGI-C: radiographic global impression of change; RSS: rickets severity scale; HPP: hypophosphatasia Congress Highlights ASBMR Annual Meeting

Significant improvement from baseline
[LB-MO0751] Improvements in Skeletal Manifestations and Growth With Up to 6 Years of Treatment With Asfotase Alfa in Infants and Children Aged ≤5 Years With Hypophosphatasia Back to TOC Anna Petryk, Alexion Pharmaceuticals, Inc., USA Significant improvement from baseline WK 24 WK 48 Radiographic Global Impression of Change 2.0 Rickets Severity Scale -1.5 -2.5 Length Z-score 0.3 0.5 Weight Z-score 1.0 CONCLUSION Long-term improvements in HPP-related skeletal manifestations and growth were sustained at 48 weeks with asfotase alfa in infants and young children with HPP. HPP: hypophosphatasia Congress Highlights ASBMR Annual Meeting

Bone and HIV Congress Highlights ASBMR 2017 Annual Meeting

Index Bone and HIV Back to TOC HIV and Vertebral Fractures: a Systematic Review and Metanalysis (E Yu)* * Attended and reviewed by Congress Highlights ASBMR 2017 Annual Meeting

[1128] HIV and Vertebral Fractures: a Systematic Review and Metanalysis
Melissa Premaor, Federal University of Santa Maria, Brazil To assess the frequency of spine fractures in HIV-positive men and women aged over 18 years BACKGROUND Vertebral fractures as HIV-related comorbidities have been reported more frequently and at an early age in these subjects. METHODS Systematic review of randomized controlled trials (RCTs), cohort studies, cross-sectional studies, and case-control studies 26 studies included HIV: human immunodeficiency virus Congress Highlights ASBMR Annual Meeting

[1128] HIV and Vertebral Fractures: a Systematic Review and Metanalysis
Melissa Premaor, Federal University of Santa Maria, brazil Back to TOC Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION HIV-positive subjects are at higher risk of vertebral fractures when compared with HIV-negative subjects. Vertebral imaging should be considered in HIV-positive individuals, especially in those with risk factors for fracture, such as low BMD, height loss, kyphosis or glucocorticoid therapy. HIV: human immunodeficiency virus; BMD: bone mineral density Congress Highlights ASBMR Annual Meeting

Cancer and Fractures Congress Highlights ASBMR 2017 Annual Meeting

Index Cancer and Fractures
Back to TOC Fracture Risk Among 122,205 Cancer Patients: A Population-Based Cohort Study from Manitoba (D Kendler)* * Attended and reviewed by Congress Highlights ASBMR 2017 Annual Meeting

[1055] Fracture Risk Among 122,205 Cancer Patients: A Population-Based Cohort Study from Manitoba, Canada William Leslie, University of Manitoba, canada To estimate fracture risk for different cancers and determine predictors of fracture risk among cancer patients BACKGROUND Prior studies have assessed osteoporosis-related fracture risk among patients with breast or prostate cancer Data are limited on occurrence of fractures and their risk factors for other cancers METHODS Identification of cancer cases and matched controls, covariates and fracture events through population-based administrative data from Manitoba Canada Case definitions for clinical vertebral, forearm, and humerus fractures (“major fractures” [MF]) Fracture incidence rates and incidence rate ratios (IRRs) Competing risk time-to-event analysis (competing event=death) MF: major fracture Congress Highlights ASBMR Annual Meeting

[1055] Fracture Risk Among 122,205 Cancer Patients: A Population-Based Cohort Study from Manitoba, Canada William Leslie, University of Manitoba, canada Back to TOC Relative risk of fracture: cancer patients versus controls and relationship to timing of cancer diagnosis. Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION Fracture risk remains increased for up to 10 years after cancer diagnosis compared to noncancer controls, similar for most cancer diagnoses. Fracture risk factors in cancer patients are similar to traditional risk factors. Congress Highlights ASBMR Annual Meeting

Bone assessment Congress Highlights ASBMR 2017 Annual Meeting

Index Bone assessment Back to TOC "Risk-Equivalent" T-score Adjustment Using Lumbar Spine Trabecular Bone Score (TBS): The Manitoba BMD Registry (N Harvey and E Curtis)* Analyzing the cortical and trabecular bone of the femur of patients with vertebral fractures by 3D-DXA (E Yu)* * Attended and reviewed by Congress Highlights ASBMR 2017 Annual Meeting

[FR0218] "Risk-Equivalent" T-score Adjustment Using Lumbar Spine Trabecular Bone Score (TBS): The Manitoba BMD Registry William Leslie, University of Manitoba, CANADA To examine an alternative approach for using TBS in clinical practice based upon a "risk-equivalent" offset adjustment to the BMD T-score BACKGROUND Lumbar spine TBS can be used to modify the output from FRAX to enhance fracture prediction. However it is unclear how TBS might be integrated when using T score alone. METHODS Manitoba BMD Registry 45,185 women age 40 years and older with body mass index kg/m2 Baseline DXA, lumbar spine TBS and FRAX-based probabilities Incident non-traumatic MOF (n=3925) Age- and BMI-adjusted Cox proportional hazards models TBS added to the model to estimate the BMD-independent effect on TBS on MOF risk Generates a T-score offset to account for TBS value TBS: trabecular bone score; MOF: major osteoporotic fracture; BMD: bone mineral density Congress Highlights ASBMR Annual Meeting

[FR0218] "Risk-Equivalent" T-score Adjustment Using Lumbar Spine Trabecular Bone Score (TBS): The Manitoba BMD Registry William Leslie, University of Manitoba, CANADA Back to TOC R2=0.98 (using risk equivalent T score input) FRAX MOF Probability % (using TBS adjustment) Chart shows relationship between FRAX score including TBS adjustment and FRAX score using T-score offset accounting for TBS Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION The BMD-independent effect of TBS on fracture risk can be estimated as a simple offset to the BMD T-score. This could be used to incorporate TBS into risk assessment algorithms based on T score. TBS: trabecular bone score; MOF: major osteoporotic fracture; BMD: bone mineral density Congress Highlights ASBMR Annual Meeting

[FR0209] Analyzing the cortical and trabecular bone of the femur of patients with vertebral fractures by 3D-DXA AM GALICH, Hospital Italiano de Buenos Aires, Argentina To analyze the cortical and trabecular bone of the femur of patients with prevalent vertebral fractures PARTICIPANTS 162 postmenopausal women 133 controls 29 subjects with prevalent vertebral fractures Mean age: years METHODS Assessment of VF by questionnaire DXA 3D analysis of the femoral cortical and trabecular bone with the 3D-DXA software enCORE VF: vertebral fracture; DXA: dual X-ray absorptiometry Congress Highlights ASBMR Annual Meeting

[FR0209] Analyzing the cortical and trabecular bone of the femur of patients with vertebral fractures by 3D-DXA AM GALICH, Hospital Italiano de Buenos Aires, Argentina Back to TOC Fracture Controls (C) p Body mass index (kg/m2) 0.025 TH aBMD change -4.3% 0.080 FN aBMD change 0.081 TH cort vBMD change -2.1% 0.027 FN cort vBMD change -2.4% 0.026 TH cort thickness change -3.5% 0.089 FN cort thickness change -4.2% 0.042 TH trab vBMD change -7.9% 0.059 FN trab vBMD change -7.4% 0.043 Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION 3D-DXA could potentially be used as a tool to assess the risk of fragility fracture at the hip in patients with prevalent vertebral fractures. TH: total hip; FN: femoral neck; vBMD: volumetric bone mineral density Congress Highlights ASBMR Annual Meeting

Basic science Congress Highlights ASBMR 2017 Annual Meeting

Index Basic science Back to TOC Finite Element Analysis of 3D-DXA Femur Reconstructions to Predict Hip Fracture (D Pierroz)* Fat Talks to Bone (D Pierroz)* The Senolytic ABT263 Eliminates Senescent Osteoprogenitors in Old Mice (D Pierroz)* Causal Role of Senescent Cells in Mediating Age-Related Bone Loss (D Pierroz)* The soluble form of RANKL contributes to cancellous bone remodeling in adult mice but is dispensable for ovariectomy-induced bone loss (D Pierroz)* Identification of osteoprogenitor cells in the mouse periosteum (D Pierroz)* Notch2 pathway and breast cancer cellular dormancy. A role for osteoblasts (D Pierroz)* Life-long genetic Pyk2 deletion or short-term pharmacologic inhibition of Pyk2 prevents the increase in resorption by glucocorticoids and preserves bone mass and strength by promoting osteoclast apoptosis (T Bellido)* Bone-Targeted Pharmacological Inhibition of Notch Signaling Decreases Resorption and Induces Bone Gain in Skeletally Mature Mice (T Bellido)* Parathyroid Hormone (PTH) increased rod-shaped trabeculae and maintained modulus of cancellous bone before fatigue failure (D Pierroz)* * Attended and reviewed by Congress Highlights ASBMR 2017 Annual Meeting

[FR0208] Finite Element Analysis of 3D-DXA Femur Reconstructions to Predict Hip Fracture
Luis Del Rio, CETIR Grupo Medic, spain To validate 3D-DXA based FE models to predict femoral strength in loading charge simulations BACKGROUND 3D-DXA provides assessment of the hip geometry and spatial distribution of the trabecular and cortical BMD from a standard 2D DXA acquisition PARTICIPANTS 111 subjects (> 75 years) 62 with a recent hip fracture: 26 trochanteric and 36 femoral neck due to a fall 49 without a hip fracture METHODS 3D-DXA measurements (Galgo Medical) from 2D-DXA acquisition using QCT database FE models automatically generated by morphing a generic mesh to the patient-specific bone shape Fall simulation using a static approach 3-ways multivariate analysis FE: finite element; BMD: bone mineral density; DXA: dual X-ray absorptiometry; QCT: quantitative computer tomography Congress Highlights ASBMR Annual Meeting

[FR0208] Finite Element Analysis of 3D-DXA Femur Reconstructions to Predict Hip Fracture
Luis Del Rio, CETIR Grupo Medic, spain Back to TOC RESULTS Major principal stress (MPS), variable extracted from the FE analysis, is the parameter with the greater sensitivity –specificity better than vBMD or aBMD Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION 3D-DXA-based FE models of the femur provide descriptors with good to excellent sensitivity to hip fracture occurrence. FE: finite element; v: volumetric; a: areal; BMD: bone mineral density; DXA: dual X-ray absorptiometry Congress Highlights ASBMR Annual Meeting

[1005] Fat Talks to Bone To clarify the influence of fat on bone
Wei Zou, Washington University School of Medicine, USA To clarify the influence of fat on bone BACKGROUND BACKGROUND Studies of the effect of fat-produced molecules (leptin and adiponectin) indicate these selected adipokines impact bone METHODS DTAflox/flox mice x Adiponectin Cre mice mice completely lacking visceral, subcutaneous and brown fat Transplantation ANALYSES Phenotype Metabolism Bone Reproductive axis FF: fat free; DTA: Diphtheria toxin A Congress Highlights ASBMR Annual Meeting

[1005] Fat Talks to Bone DTAflox/flox mice X Adiponectin Cre mice
Wei Zou, Washington University School of Medicine, USA Back to TOC DTAflox/flox mice X Adiponectin Cre mice no visible body fat and virtually undetectable circulating adipocyte specific adipokines insulin resistant and fatty liver disease hypogonadal state enhanced trabecular bone volume ( %) in both long bone and vertebrate significant increase in cortical thickness increased bone mass in FF mice osteoblastic bone formation enhanced osteoclasts but compromised resorptive capacity skeletal phenotype completely rescued by transplantation of adipocyte precursors (MEFs) or various fat depots (visceral, subcutaneous and brown adipose tissue) CONCLUSION Fat signals to bone and decreased adiposity may greatly enhance bone mass, challenging the concept that obesity improves skeletal health. First direct evidence that fat regulates bone homeostasis. FF: fat free Congress Highlights ASBMR Annual Meeting

[1027] The Senolytic ABT263 Eliminates Senescent Osteoprogenitors in Old Mice
Ha-Neui Kim, University of Arkansas for Medical Sciences, USA To determine the role of GATA4 or the effects of ABT263 in senescent osteoprogenitors BACKGROUND Osteoprogenitors decline with age in mice and exhibit several markers of cellular senescence including cell cycle arrest and expression of the SASP Markers of senescence: activation of p53, increased levels of the cell cycle inhibitor p21, the transcription factor GATA4 and stimulation of NF-kB METHODS Plasmid expressing GATA4 into a retroviral vector Infection of newborn calvaria cells or bone marrow-derived primary stromal cells obtained from 3-month-old C57BL/6J mice ABT mg/kg BW (or vehicle) by daily i.p. for 5 days in 24-month-old female mice ANALYSES Osteoblastogenesis : proliferation (BrdU) Signaling pathway of SASP: IL-1a, RANKL, MMP13 SASP: senescence associated secretory phenotype Congress Highlights ASBMR Annual Meeting

Ha-Neui Kim, University of Arkansas for Medical, USA Overexpression of GATA4 increased the expression of p21 and decreased proliferation, and abrogated osteoblastogenesis GATA4 caused an 80-fold increase in IL-1α and other elements of the SASP including RANKL and MMP13 Cells from mice treated with ABT263 had decreased transcript levels of TNF-α, IL-1α, and RANKL compared to cells from mice treated with vehicle ABT263 improved the osteoblastogenic capacity of the cultures, as determined by alizarin red staining SASP: senescence associated secretory phenotype Congress Highlights ASBMR Annual Meeting

Ha-Neui Kim, University of Arkansas for Medical, USA Back to TOC Reproduced from Aging Cell 2017; 16: under the terms of the Creative Commons Attribution License (CC BY). CONCLUSION An increase in GATA4 in osteoprogenitors of old mice contributes to cell senescence, and expression of the SASP. Removal of such senescent cells with senolytic agents like ABT263 may represent a novel therapeutic approach to involutional osteoporosis. SASP: senescence associated secretory phenotype Congress Highlights ASBMR Annual Meeting

[1042] Causal Role of Senescent Cells in Mediating Age-Related Bone Loss
Joshua Farr, Mayo Clinic, USA To investigate a causal role for senescent cells in aged-related bone loss BACKGROUND Accumulation of DNA damage and other cellular stressors cause proliferating as well as terminally differentiated, non-dividing cells to undergo senescence, characterized by increased expression of the cell cycle inhibitor, p16Ink4aalong with profound morphological changes METHODS 3 strategies to reduce senescent cells Mice expressing the INK-ATTAC “suicide” transgene via drug (AP20187)-inducible caspase-8 driven by the senescence-associated p16Ink4a promoter Administration of “senolytic” compounds (dasatinib + quercetin) Inhibition of the SASP production using a JAK inhibitor (JAKi) ANALYSES Bone strength Congress Highlights ASBMR Annual Meeting

[1042] Causal Role of Senescent Cells in Mediating Age-Related Bone Loss
Joshua Farr, Mayo Clinic, USA Back to TOC In old mice (20-22 month-old), treated for 2-4 months with each of the 3 interventions, improvement of bone mass, microarchitecture and strength Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION The efficacy of this approach to prevent age-related bone loss reveals a novel treatment strategy for osteoporosis via targeting a fundamental aging mechanism. Congress Highlights ASBMR Annual Meeting

[1043] The soluble form of RANKL contributes to cancellous bone remodeling in adult mice but is dispensable for ovariectomy-induced bone loss Jinhu Xiong, University of Arkansas for Medical Sciences, USA To determine the relative importance of membrane-bound versus soluble RANKL BACKGROUND RANKL is produced as an integral membrane protein but can be cleaved to produce a soluble form. Cell culture studies suggest that the membrane-bound form is required for Oc formation. METHODS Homozygous mice producing only the membrane-bound form: RANKLsr Ovariectomy ANALYSES Bone mass and architecture by DXA and microCT RANKL by Elisa or Luminex assay Histology sRANKL: soluble form of RANKL; Oc: osteoclast; CT: computer tomography; DXA: dual X-ray absorptiometry Congress Highlights ASBMR Annual Meeting

[1043] The soluble form of RANKL contributes to cancellous bone remodeling in adult mice but is dispensable for ovariectomy-induced bone loss Back to TOC Jinhu Xiong, University of Arkansas for Medical Sciences, USA RANKLsr mice: Normal tooth eruption Bone mass and microarchitecture 5 weeks : WT = KO 3 months: higher trabecular bone volume in WT compared to KO at the femur and spine lower Oc N in cancellous bone OVX: similar bone loss in WT and RANKLsr mice CONCLUSION sRANKL is not required for Oc formation in growing mice but contributes to Oc formation and bone remodeling in adult mice but not to the pathological bone resorption caused by estrogen deficiency. Oc: osteoclast; OVX: ovariectomy: RANLKsr: membrane bound form of RANKL; sRANKL: soluble form of RANKL Congress Highlights ASBMR Annual Meeting

[1062] Identification of osteoprogenitor cells in the mouse periosteum
Ivo Kalajzic, UConn Health, USA To identify osteoprogenitor cells in the mouse periosteum BACKGROUND The periosteum is a major source of cells involved in fracture healing. METHODS aSMA as a marker of osteoprogenitor Mice aSMA CreERT2 combined with Ai9tdTomato reporter (SMA9mice) crossed with Col2.3GFP mice Fracture of the tibia in SMA9/2.3GFP mice Treatment with tamoxifen 6 or 2 weeks prior fracture, or on the day of fracture ANALYSES Flow cytometry Lineage tracing Congress Highlights ASBMR Annual Meeting

[1062] Identification of osteoprogenitor cells in the mouse periosteum
Ivo Kalajzic, UConn Health, USA Back to TOC 60% of callus osteoblasts are αSMA-labeled when tamoxifen is given the day of fracture This decreases to 40% or 20% when labeled 2 or 6 weeks prior to fracture, compared to <2% without tamoxifen αSMA labeled fewer chondrocytes initially (30%), but showed a similar trend of reduced labeling after longer tracing periods αSMA+ periosteal cells isolated from intact bones formed more CFU-F than total CD45- cells, but few CFU-ALP Following transplantation in a calvarial defect, αSMA+ cells expanded but did not form bone In contrast, αSMA+ cells isolated after injury showed enhanced CFU-F and CFU-ALP formation The majority of osteoprogenitors involved in fracture healing express αSMA A subset of these cells remain capable of contributing to osteoblast after 6 weeks αSMA+ cells do not show osteoprogenitor characteristics when isolated from intact periosteum, but show improved in vitro growth and differentiation following injury CONCLUSION Periosteum is highly enriched for the majority of stem cell markers compared to bone marrow and endosteum. Ob: osteoblast Congress Highlights ASBMR Annual Meeting

[1134] Notch2 pathway and breast cancer cellular dormancy
[1134] Notch2 pathway and breast cancer cellular dormancy. A role for osteoblasts. Mattia Capulli, University of L'Aquila, ITALY To investigate whether dormant breast cancer cells mimic long-term hematopoietic stem cells and exploit their medullary niche BACKGROUND One fifth of breast cancer patients experience recurrences after >5 years of disease-free survival. In bone, BrCa cells (BrCaCs) may stop proliferating and enter a state of cellular dormancy. METHODS Mouse model of bone BrCaCs dormancy: human osteotropic BrCaCs, MDA-MB-231 (MDA), injected in the tibia of athymic mice Injection of DBZ (g-secretase inhibitor) ANALYSES Confocal imaging In vitro assays: time-course, ALP activity, mineralisation assay, gene expression BrCA: breast cancer; BrCaC: BrCa cell; DBZ: dibenzazepine Congress Highlights ASBMR Annual Meeting

[1134] Notch2 pathway and breast cancer cellular dormancy. A role for osteoblasts. Mattia Capulli, University of L'Aquila, ITALY Injection of MDA into the tibia: - cytokeratin+ MDA reach endosteal surface and stay cell cycle arrested - non-proliferating (Ki67-) MDS bound to spindle-shaped N-cadherin+ osteoblasts (SNO), associated with LT-HSC (long-term hematopoietic stem cell) niche In vivo competition assay - engraftment of HSC declines with the increase of injected MDA In vitro - cultured SNO: less ALP, reduced osteoblast marker expression, impaired mineralization - sorted Notch 2+ MDA overexpresses LT-HSC stemness Sca-1, CxCR4, cKit - DBZ, g-secretase inhibitor, induces MDA proliferation on SNO In vivo - Notch2+/cytokeratin+ MDA bound to SNO were Ki67- - injection of DBZ in the mouse model of BrCaC –dormancy increased the mean distance of MDA from the endosteal surface SNO: spindle-shaped N-cadherin+ osteoblast; LT-HSC: long-term hematopoietic stem cell; DBZ: dibenzazepine Congress Highlights ASBMR Annual Meeting

[1134] Notch2 pathway and breast cancer cellular dormancy. A role for osteoblasts. Mattia Capulli, University of L'Aquila, ITALY Back to TOC CONCLUSION A sub-population of breast cancer cells expressing high levels of Notch2 and other LT-HSC markers reside in the endosteal niche and stay dormant. This study opened a new direction for understanding the molecular mechanisms governing the dormancy of breast cancer cells. LT-HSC: long-term hematopoietic stem cell Congress Highlights ASBMR Annual Meeting

[1029] Life-long genetic Pyk2 deletion or short-term pharmacologic inhibition of Pyk2 prevents the increase in resorption by glucocorticoids and preserves bone mass and strength by promoting osteoclast apoptosis Amy Y. Sato, Indiana University School of Medicine, USA To examine the mechanism by which Pyk2 genetic deletion overrides GC-induced resorption and whether pharmacological inhibition of Pyk2 also blocks GC effects BACKGROUND Pyk2 is a kinase of the osteoclast podosomes required for osteoclast function. Mice lacking Pyk2 are protected from resorption and bone loss induced by glucocorticoids by unknown mechanisms METHODS 4 mo, WT or Pyk2 KO mice; treated with GC for 4 wks; and 4 mo, WT mice treated with PF, a Pyk2 kinase inhibitor; GC for 2 wks; GC= Slow release pellets of 2.1 mg/kg/d prednisolone or placebo PF= PF (10mg/kg, 5x/wk) or vehicle, starting 3d before implanted pellets ANALYSES Histomorphometric analysis: osteoblast number, osteoclast number, apoptosis of osteoblasts, osteocytes and osteoclasts Bone turnover markers Ex vivo and in vitro osteoclast formation assays and apoptosis of osteoclasts Pyk2: proline-rich tyrosine kinase 2; GC: glucocorticoid Congress Highlights ASBMR Annual Meeting

[1029] Life-long genetic Pyk2 deletion or short-term pharmacologic inhibition of Pyk2 prevents the increase in resorption by glucocorticoids and preserves bone mass and strength by promoting osteoclast apoptosis Amy Y. Sato, Indiana University School of Medicine, USA, In vivo GC increased OcN and circulating TRAP5b in both WT and KO mice; and increased OcS and circulating CTX in WT but not in KO mice Oc in GC-treated WT mice were fully attached to bone whereas in KO mice were only partially attached, and instead found in the bone marrow CTX/TRAP5b ratio was reduced in KO mice 0.6-fold vs WT Oc on bone or in the BM in KO mice exhibited 5- or 62-fold increase in apoptosis, respectively, vs WT PF prevented GC-induced increase in OcS and CTX, but not in TRAP5b PF also increased marrow Oc and BM apoptotic Oc in both placebo and GC-treated mice KO mice were protected from GC-induced decreased vertebral BV/TV, TbTh, and mechanical properties (ultimate force and toughness) PF also prevented GC-induced reductions in distal femur TbTh, and midshaft BA/TA and CtTh GC: glucocorticoid; Oc: osteoclast; S: surface; N: number; CTX: C-terminal telopeptide; BM: bone marrow; BV/TV: bone volume/tissue volume; TbTh: trabecular thickness; BA/TA: bone area/tissue area; CtTh: cortical thickness; TRAP5b: tartrate-resistant acid phosphatase isoform 5b; GC: glucocorticoid Congress Highlights ASBMR Annual Meeting

[1029] Life-long genetic Pyk2 deletion or short-term pharmacologic inhibition of Pyk2 prevents the increase in resorption by glucocorticoids and preserves bone mass and strength by promoting osteoclast apoptosis Back to TOC Amy Y. Sato, Indiana University School of Medicine, USA, In vitro Oc generated in vitro from KO-derived marrow precursors exhibited 11-fold increased apoptosis vs WT GC partially reduced osteoclast apoptosis induced by alendronate in WT but not in KO cultures CONCLUSION Pyk2 deficiency triggers cell autonomous apoptotic effects and negates survival GC actions in osteoclasts. Life-long genetic Pyk2 deletion or short-term pharmacologic inhibition of Pyk2 promotes osteoclast apoptosis and detachment from bone surfaces, thus prevailing over the increase in osteoclasts and protecting from bone loss and fragility induced by GC. Oc: osteoclast ; GC: glucocorticoid; Pyk2: proline-rich tyrosine kinase 2 Congress Highlights ASBMR Annual Meeting

[1030] Bone-Targeted Pharmacological Inhibition of Notch Signaling Decreases Resorption and Induces Bone Gain in Skeletally Mature Mice Jesus Delgado-Calle, Indiana University School of Medicine, USA To dissect the effect of global inhibition of Notch signaling in the mature skeleton BACKGROUND Notch signaling plays a critical role in cell-to-cell communication among bone cells under physiological conditions and favors growth and survival of cancer cells in bone. Genetic manipulations of this pathway result in different bone phenotypes METHODS Synthesis of a Notch inhibitor by linking the g-secretase inhibitor GSI-XII to an inactive bone-targeting molecule (BT) BT-GSI-II was designed to direct the conjugate to bone where the linker is cleaved near osteoclasts, thus releasing GSI Administration of BT-GSI (5µg/g, 3xwk) or vehicle (DMSO) to 4-month old female mice for 2 weeks Measurements : BTMs, BMD, gene expression GSI-XII: g-secretase inhibitor; BT: bone-targeting molecule; BTM: bone turnover marker Congress Highlights ASBMR Annual Meeting

[1030] Bone-Targeted Pharmacological Inhibition of Notch Signaling Decreases Resorption and Induces Bone Gain in Skeletally Mature Mice Jesus Delgado-Calle, Indiana University School of Medicine, USA In vitro Control GSI decreased Notch target gene expression (Hes1) but BT-GSI had no effect. When GSI and BT-GSI were preincubated at low pH, equal inhibition of Notch target gene expression was observed. Ex vivo GSI and BT-GSI (non-preincubated) decreased Hes1/5 expression in whole bone organ cultures In vivo, 4 month-old mice BT-GSI for 2 weeks: decrease of Hes7 expression in bone, but not in brain or gut, compared to vehicle (DMSO). BT-GSI-treated mice: higher total (3%), femoral (4%), and spinal (7%) BMD compared to control mice, decreased serum CTX by 40% and upregulated Opg mRNA expression in bone. In contrast, serum P1NP, the expression of osteoblast markers, Wnt target genes, or Sost remained unchanged by BT-GSI. GSI-XII: g-secretase inhibitor; BT: bone-targeting molecule; BTM: bone turnover marker; CTX: C-terminal telopeptide; P1NP: procollagen type I N-propeptide; Opg: osteoprotegerin Congress Highlights ASBMR Annual Meeting

[1030] Bone-Targeted Pharmacological Inhibition of Notch Signaling Decreases Resorption and Induces Bone Gain in Skeletally Mature Mice Back to TOC Jesus Delgado-Calle, Indiana University School of Medicine, USA CONCLUSION Short-term pharmacological inhibition of Notch signaling in skeletally mature mice inhibits bone resorption and favors bone gain. Because BT-GSI shows bone specific Notch inhibition and lack of gut toxicity, it should circumvent the deleterious side effects that limit the use of this class of inhibitors in patients. Thus, BT-GSI is a promising approach to treat skeletal diseases characterized by bone loss, including those caused by cancer in bone. GSI-XII: g-secretase inhibitor; BT: bone-targeting molecule Congress Highlights ASBMR Annual Meeting

[FR0012] Parathyroid Hormone (PTH) increased rod-shaped trabeculae and maintained modulus of cancellous bone before fatigue failure Julia T. Chen, Cornell University, USA To test if PTH would increase compressive strength and preserve mechanical properties during cyclic fatigue loading through architectural and compositional changes. METHODS MicroCT scanning Compression test Cyclic loading Nanoindentation Raman spectroscopy Congress Highlights ASBMR Annual Meeting

Microarchitecture parameters at the distal femur
[FR0012] Parathyroid Hormone (PTH) increased rod-shaped trabeculae and maintained modulus of cancellous bone before fatigue failure Julia T. Chen, Cornell University, USA Back to TOC Microarchitecture parameters at the distal femur Veh PTH p BV/TV 0.25 0.22 ns Tb N 1.05 1.39 <0.05 Tb Sp 6.20 4.29 Tb Th 198.3 199 Reproduced with permission from the American Society for Bone and Mineral Research CONCLUSION PTH alters microarchitecture and material properties to preserve mechanical properties following cyclic loading. PTH: parathyroid hormone; BV/TV: bone volume/tissue volume; Tb: trabecular; N: number; Sp: separation; Th: thickness Congress Highlights ASBMR Annual Meeting

Disclosure IOF has prepared this slide kit and videos as a unique education experience especially aimed at clinicians who are unable to attend important meetings. IOF in collaboration with ASBMR, has produced these Highlights, based on the abstracts presented at the ASBMR 2017 Annual Meeting of the American Society for Bone and Mineral Research This project has been supported by an educational grant from Congress Highlights ASBMR 2017 Annual Meeting

Introduction The International Osteoporosis Foundation (IOF) has compiled this educational slide deck to discuss and present the most current and significant.

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Introduction The International Osteoporosis Foundation (IOF) has compiled this educational slide deck to discuss and present the most current and significant.

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Presentation on theme: "Introduction The International Osteoporosis Foundation (IOF) has compiled this educational slide deck to discuss and present the most current and significant."— Presentation transcript:

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