Osteoporos Int (2014) 25 (Suppl 6):S659–S726 DOI 10.1007/s00198-014-2893-0

Osteoporosis Conference 2014

# International Osteoporosis Foundation and National Osteoporosis Foundation 2014

Invited Plenary Lecture Abstracts IS1 TREATMENT FAILURE IN OSTEOPOROSIS A Adolfo Diez-Perez, University of Barcelona, Spain Pivotal trials for the treatment of osteoporosis have been carried out in a highly controlled setting. However, in real-life external validity of these results and poor adherence may be a problem. Still, even under ideal controlled conditions, some patients in the pivotal trials suffered fractures in the treatment arm. Bone mineral density is a common tool for evaluating a treatment response although the associated risk modification is not well captured, requires prolonged follow-up and must be greater than the least significant change. Biochemical markers of bone turnover reflect decreases in fracture risk. Nevertheless, the routine use of these markers still faces limitations. Fractures are the pathological event of the disease and the strongest predictor for future fractures. However no drug reduces the excess risk of fracture to zero. A single fracture can be a chance event, but the occurrence of a second fragility fracture is highly unlikely. The International Osteoporosis Foundation has proposed a definition of treatment failure: 1. Two or more incident fragility fractures; 2. One incident fracture and no significant reduction in βCTX or PINP or a significant decrease in BMD and; 3. Both no significant decrease in βCTX or PINP and a significant decrease in BMD. Several risk factors are associated with the problem. A case– control study identified two falls in the previous year and 25 OH D5 million

people predictors of fractures while on treatment were older age, previous fracture, underweight, inflammatory arthritis, use of proton pump inhibitors and vitamin D deficiency. In conclusion, patients on treatment still suffer fractures and a rate of 2–3 % per year. However not every incident fracture while on treatment indicates a failure of the drug. When a second incident fracture occurs or when, in addition to one fracture, surrogate markers (BMD and/or bone turnover markers) also show a negative evolution, the likelihood for that particular individual of being a non-responder is high. Several clinical variables can predict this failure in spite of being receiving an active drug with good compliance. IS2 BISPHOSPHONATES AND ATYPICAL FRACTURE B Abrahamsen, University of Southern Denmark, Denmark Anti-resorptives are the most widely used osteoporosis drugs as they have a good safety record, relatively low cost and very good short term clinical efficacy data. However, the evidence in intervention studies for anti-fracture benefits beyond 5 years remains limited, especially for non-vertebral fractures. Bisphosphonates are stored in the skeleton for months to years, depending on the binding properties of the bisphosphonate and the rate of replacement of old bone with new bone. Atypical femur fractures are rare even in long term bisphosphonate users but almost non-existent in patients who have not used some form of anti-resorptives. While preliminary studies have not at this stage confirmed a role for material properties of bone as measured by microindentation as determinants of atypical femur fractures, increased homogeneity of bisphosphonate treated bone could affect biomechanical competence. There is also a strong influence both of ethnicity and femur geometry. While the upper boundary of potential harm can be calculated from register based studies without x-rays by assuming a worst case scenario of all fractures at these sites being atypical, x-rays are of course needed to produce a realistic rather than an inflated risk estimate. Regrettably, good


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long term data sources for bisphosphonate exposure are rare as most registers were established relatively recently and studies that underestimate the duration of bisphosphonate use in fracture cases will yield inflated odds ratios even if the rates of atypical femur fractures are accurately captured. Tools to predict the likely benefit and harm, measured on the same scale, in an individual patient are highly needed to better inform clinical decision-making.

2 clinical trial has reported aBMD gains at spine and hip that were greater with romosozumab compared to placebo, but also to teriparatide. It also showed that antagonizing sclerostin results in a transient stimulation of bone formation but progressive inhibition of bone resorption. Other new medical entities that are promising for the treatment of osteoporosis include abaloparatide, a PTH related protein (PTHrP) analog with improved bone formation/ resorption ratio.

IS3 DIETARY VITAMIN D INTAKE AND BONE HEALTH A Prentice, MRC Human Nutrition Research, Cambridge, UK

IS5 OSTEOPOROSIS: IS IT TIME TO TREAT-TO-TARGET M Lewiecki, University of New Mexico, Albuquerque, New Mexico

There are many controversies that surround current recommendations for dietary vitamin D and bone health. This is a topic that is being actively reviewed by the UK Scientific Advisory Committee on Nutrition (SACN) and its Working Group on Vitamin D. In my presentation I will describe the basic biology of vitamin D, the similarities and differences in the different forms of vitamin D, and the contribution of sunlight, foods and dietary fortification to vitamin D supply in the UK and worldwide. I will introduce the concepts of why vitamin D is essential for bone and other health outcomes and the possibility of adverse effects of a high vitamin D intake, discuss ways in which we can assess vitamin D status using biochemical indicators, and describe our current understanding of the vitamin D status in the UK and other populations. I shall provide a perspective on the current controversies surrounding each of these areas and provide details of the ongoing review and timetable of the SACN Vitamin D Working Group. IS4 TREATMENTS ON THE HORIZON S Ferrari, Geneva University Hospital, Switzerland New osteoporosis therapies are being developed that target specific biological pathways, such as inhibitors of the cysteine protease and collagenolytic enzyme cathepsin K on one side, and sclerostin neutralizing antibodies on another side. Odanacatib, a selective cathepsin K inhibitor, decreases bone resorption while osteoclast number increases and bone formation is maintained, perhaps even increased on some cortical surfaces, as seen in preclinical models (rabbits and monkeys). In a Phase 2 clinical trial, post-menopausal women receiving odanacatib presented a sustained reduction of bone resorption markers, while P1NP returned to normal within 2 years. In turn aBMD increased continuously at both spine and hip for up to 5 years. A recently completed Phase III clinical trial has demonstrated the broad antifracture efficacy of odanacatib in postmenopausal women with osteoporosis, although certain safety concerns have been raised. Blosozumab and romosozumab are sclerostin neutralizing antibodies that exert potent anabolic effects on both trabecular and cortical compartments. A phase

Treat-to-target (also called treat-to-goal) is a disease management strategy intended to improve clinical outcomes by setting a biomarker level that represents treatment success. Physicians are accustomed to treatment targets for diseases such as hypertension and diabetes mellitus. Achievement of the treatment target is expected to result in a decrease of end organ damage that is better than not reaching the target. The current paradigm with osteoporosis management is to monitor for response to therapy, which presumably represents a reduction in fracture risk. However, a patient may have an excellent response to therapy with a reduction in fracture risk, yet still have a level of risk that is unacceptably high. This has led to consideration of establishing an osteoporosis treatment target(s) representing an acceptable level of fracture risk. This might help physicians to select an agent for initiating treatment that is most likely to reach this target and to change treatment when the current treatment is unlikely to reach the target. In order to explore the development of treat-to-target for osteoporosis, a joint task force of the American Society for Bone and Mineral Research and the National Osteoporosis Foundation was established in 2013. Task force members from many countries were selected for their expertise in the clinical care of osteoporosis and knowledge of the medical evidence. The goals of the task force were to consider the best available medical evidence to determine whether it is feasible to establish treatment targets for osteoporosis; if so, to identify appropriate targets and if not, to recommend a future pathway to developing treatment targets, if desired. The ideal osteoporosis treatment target is one that is supported by robust evidence, simple, intuitive, achievable with therapy, associated with reduction in fracture risk to an acceptable level, applicable for men and women worldwide, and compatible with current guidelines. Candidates for treatment targets include bone mineral density expressed as a T-score, bone turnover markers and fracture probability. While each of these has strengths and weaknesses, a T-score target may provide the greatest clinical utility. More data are needed to fully support the implementation of an osteoporosis treatment target.

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IS6 SHOULD WE BE POPULATION SCREENING FOR OSTEOPOROSIS? D Reid, University of Aberdeen, Aberdeen, UK Over 20 years ago it was the policy of the National Osteoporosis Society to lobby for a system of population screening for osteoporosis, based on assessment of Bone Mineral Density. That policy set in motion a series of studies based in Aberdeen examining the potential cost-effectiveness of population screening. While the charity quickly dropped the policy as a priority 20 years + later it may be worthwhile considering again whether there may be merits of screening the whole female population to determine those at risk. In consideration of this option it may be worthwhile learning lessons from history. The Aberdeen Prospective Osteoporosis Study (APOSS) started recruitment between 1990 and 1994 during which initially 3,645 women aged 45–54 attended for assessment following random selection from the Community Health Index (CHI), the population health register in Scotland. Women who attended completed a risk factor questionnaire and underwent a bone density scan of the spine and proximal femur. For those whose BMD fell within the lowest quartile they were advised, via their GP, to consider use of HRT when they reached the menopause or if they had undergone a hysterectomy. The aim of the research programme was to determine the practicality and cost-effectiveness of the programme. Randomised studies determined the most cost-effective method of inviting subjects for screening with the most successful methods having an attendance rate of over 70 %. Further studies determined that those who did not attend had a lower risk of having low bone density. Follow-up of the women screened showed that 1 year after screening 48 % of post-menopausal women and 59 % of those who were advised to consider using HRT were taking HRT. A comparison with women selected at baseline for screening or unscreened controls demonstrated 2years later that HRT use was significantly increased in screened women especially this who BMD was in the lowest quartile. A further RCT examining the benefit of disclosing the results of the BMD scan directly to women, as well as through their general practitioners (GPs), demonstrated an improved knowledge of their bone density results without adverse psychological sequelae in those receiving the results directly. The programme of studies was completed by the first RCT of osteoporosis screening carried out in 4,800 women aged 45– 54 years. In the screened group there was an increased use of HRT by 7.9 %, 15 % in other osteoporosis treatments and a 25.9 % reduction in fracture risk compared with controls. Thus population screening for osteoporosis significantly increases treatment use and reduces fracture incidence1. The studies have demonstrated that population screening is both feasible and effective. The cost effectiveness however is dependent on the cost and safety of the intervention used and


the age at which the female population are offered screening— the longer the period between screening and the maximum incidence of fractures the poorer the cost-effectiveness. The results of the SCOOP pragmatic RCT with 5-year follow-up which recruited 11,580 women aged 70 to 85 years, will determine the cost-effectiveness of a screening programme in older women to reduce fractures2. If successful the lessons learned from the APOSS trial could enable an effective and safe population screening programme to be introduced. References 1. Barr RJ, Stewart A, Torgerson DJ, Reid DM. Population screening for osteoporosis risk: a randomised control trial of medication use and fracture risk. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2010; 21(4): 561–8. 2. Shepstone L, Fordham R, Lenaghan E, et al. A pragmatic randomised controlled trial of the effectiveness and costeffectiveness of screening older women for the prevention of fractures: rationale, design and methods for the SCOOP study. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2012; 23(10): 2507–15.

Oral Communication Abstracts O1 LIFE COURSE DIETARY PATTERNS AND BONE DENSITY IN MALES AND FEMALES FROM THE MRC 1946 BIRTH COHORT KAWard1, A Prentice1, D Kuh2, GL Ambrosini1, JE Adams3 1 MRC, Human Nutrition Research, Cambridge, UK, 2MRC, Lifelong Health and Ageing, London, UK, 3Central Manchester University Hospitals—NHS Foundation Trust, Manchester, UK Introduction: Multiple dietary factors contribute to bone health. Using life course dietary data, we examined relationships between dietary patterns (DP) and bone health. We hypothesised that a DP rich in calcium, potassium and protein would be positively associated with bone density (SA-BMC and vBMD) in the MRC-National Survey for Health and Development 1946 Birth Cohort. Materials and Methods: Five-day diet diaries were collected at ages 36, 46, 53 and 60–64 years. DXA (size-adjusted BMC (SA-BMC)) and pQCT (total, trabecular vBMD) measurements were obtained at age 60–64 years. Reduced rank regression identified the DP best associated with calcium, potassium and protein intake. DP z-score’s were calculated for each individual, at each timepoint. To describe changes in DP


z-score over time, DP z-score trajectories were modelled for each participant completing >1 diary (n=1,418). Generalised linear regression models were used to examine cross-sectional and longitudinal associations of DP’s with SA-BMC/vBMD, adjusting for height, weight, bone area (DXA only), social class, region, physical activity, smoking, supplement use and time since menopause. Results are presented as % difference (mean [95 % CI]) in SA-BMC/vBMD. Discussion: One thousand four hundred thirty-six individuals (758 women) aged 60.3–64.8 years, were eligible for inclusion. Mean [SD], range DP Z-score was: women 2.2 [1.5], −2.2, 11.5, men 1.7 [1.6], −4.4, 11.6. A consistent, high calcium, potassium and protein DP was observed over time, and was characterised by high intakes of low fat milk and yoghurt, fruit and vegetables, and low intakes of added sugars, white bread and animal fats. In women, positive crosssectional associations were observed between the DP and SA-BMC and vBMD at all sites. In women: a 0.1 unit higher slope in DP z-score trajectory was associated with higher SABMC (spine 7 % [1.5, 12.6]; hip 6.8 % [2.4, 1.1]) and vBMD (radius total 9 % [0.6, 17.5]; trabecular 10.7 % [0.2, 21.1]). No statistically significant associations were found in men. Conclusion: An improving nutrient-dense diet during adulthood was associated with greater BMD at fracture-prone sites in women. These life course data have provide important insight into how diet may contribute to bone health. Funding: National Osteoporosis Society Project grant and MRC Program numbers U105960371, U1200632239 O2 PERSISTENCE TO OSTEOPOROSIS DRUGS FOLLOWING AN INCIDENT OSTEOPOROTIC FRACTURE: THE PREFRAC STUDY C Klop1, PMJ Welsing2,3, PJM Elders4, JA Overbeek5, P Souverein1, HGM Leufkens1, JWJ Bijlsma2, F de Vries1,6,7 1 Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Netherlands, 2Department of Rheumatology & Clinical Immunology, University Medical Center, Utrecht, Netherlands, 3Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, Netherlands, 4Department of General Practice and Elderly Care, VU University Medical Center, Amsterdam, Netherlands, 5PHARMO Institute for Drug Outcomes Research, Utrecht, Netherlands, 6MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK, 7Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center, Maastricht, Netherlands Introduction: No studies have been conducted that determine long-term persistence to osteoporosis drugs prescribed specifically for the secondary prevention of fractures. Persistence to these drugs is important in this patient group because of the high risk of subsequent fracture.

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Material and Methods: A population-based cohort study was conducted using data from the Dutch PHARMO Database Network (January 2002 to December 2011). We identified all patients≥50 years who initiated osteoporosis therapy (bisphosphonates, strontiumranelate, raloxifene, denosumab) within 1 year following their first fracture (hip, spine, forearm, upper arm). Kaplan–Meier life-table analysis was used to calculate the cumulative incidence probability (%) for persistence to osteoporosis drugs. Discontinuation of osteoporosis drugs was defined as a treatment gap of >90 days. Timedependent Cox regression was used to estimate fully adjusted hazard ratios (aHRs) with 95 % confidence intervals (95 % CIs) for determinants of discontinuation of osteoporosis drugs. Covariates included age, sex, comorbidities including the type of fracture, and drug use 6 months prior. Discussion: A total of 976 patients initiated osteoporosis drugs within 1 year after their first fracture. Within 1 year following initiation 74 % (95 % C I: 67–76 %) persisted with treatment, which had dropped to 39 % (95 % C I: 35–44 %) after 5 years. Determinants for discontinuation of osteoporosis therapy included age≥80 years (aHR 1.9; 95 % C I: 1.4–2.5) (reference: patients aged 60–69 years) and recent use of proton pump inhibitors [PPIs] or H2-receptor antagonists without use of non-steroidal anti-inflammatory drugs [NSAIDs] (aHR 1.5; 95 % C I: 1.2–1.9). Concomitant use of PPIs or H2-receptor antagonists and NSAIDs did not elevate the risk of discontinuation with osteoporosis drugs (aHR 0.9; 95 % CI: 0.7–1.3). Conclusions: This study shows a major treatment failure for the secondary prevention of osteoporotic fractures; more than half of all patients had discontinued treatment within the recommended treatment duration of 5 years. This was even worse in the elderly and discontinuation may be related to the occurrence of gastro-intestinal side-effects.

O3 LONGITUDINAL CHANGES IN LEAN, BUT NOT FAT MASS, ARE ASSOCIATED WITH BONE SIZE AND VOLUMETRIC BONE MINERAL DENSITY IN CHILDHOOD: FINDINGS FROM THE SOUTHAMPTON WOMEN’S SURVEY RJ Moon1, 2, ZA Cole1, SC Crozier1, A Aihie Sayer1, JH Davies2, SM Robinson1, HM Inskip1, KM Godfrey1,3, C Cooper1,3,4, NC Harvey1,3 1 MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK, 2Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton, UK, 3NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Trust, Southampton, UK, 4NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Nuffield Orthopedic Centre, Oxford, UK

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Background: Studies in childhood suggest that both body composition and early postnatal growth are associated with bone mineral density (BMD). However there is scant evidence relating longitudinal changes in fat (FM) and lean mass (LM) to early childhood bone development. We therefore investigated these relationships in a population-based mother-offspring cohort, the Southampton Women’s Survey. Materials and Methods: Total FM and LM were assessed at birth and 6–7 years (7y) by Dual-Energy X-ray Absorptiometry (DXA). At 7y, total cross-sectional area (CSA) and trabecular volumetric BMD at the 4 % site (metaphysis) of the tibia was assessed using peripheral quantitative computed tomography [pQCT (Stratec XCT-2000)]. Total CSA, cortical CSA, cortical vBMD and strength-strain index (SSI) were measured at the 38 % site (diaphysis). FM, LM and bone parameters were adjusted for age and sex and standardised to create within-cohort z-scores. Change in LM (ΔLM) or FM (ΔFM) was represented by change in z-score from birth to 7y, and these were then mutually adjusted. Linear regression was used to explore the associations between ΔLM or ΔFM and standardised pQCT outcomes. The β-coefficient represents SD change in outcome per unit SD change in predictor. Discussion: DXA at birth, in addition to both DXA and pQCT scans at 7y were available for 200 children (48.5 % male). There were no statistically significant associations between ΔFM and tibial geometry or vBMD. In contrast ΔLM was positively associated with tibial total CSA at both the 4 % (β= 0.30 SD/SD, p

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