Bone Biomedical Research Unit NEWSLETTER December 2009

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1 Move into the Centre for Biomedical Research In October this year, we moved into our new site, the Centre for Biomedical Research (CBR) at the NGH. The ground and 1st floors of the old Clinical Sciences Centre have been completely refurbished and now bear little resemblance to the original. The ground floor of the CBR houses both the Bone and the Cardiovascular Biomedical Research Units. The two units share a seminar room and kitchen but have their own dedicated research offices. A large biorepository is also housed on the ground floor and will be used for the storage of biological fluids and tissue obtained in our research studies. Clinical Research Facility reception area in the Centre for Biomedical Research Projects Two new research studies have been initiated in recent months. One is the Metal Ions study led by Mark Wilkinson. Whole body bone mineral density will be compared in patients who have undergone metal on metal hip resurfacing (MOMHR) or conventional total hip arthroplasty (THA). Four patients have been enrolled into this study to date. Ground floor of the CBR housing the Bone and the Cardiovascular Biomedical Research Units The Clinical Research Facility occupies the first floor of the CBR. All of our diagnostic research devices have been moved to the CRF and are fully operational. Patients and volunteers enrolled in our studies and clinical trials now attend the CRF (where our clinical trials team is based) for their study visits. Conventional THA MOMHR The second is the High Bone Mass multicentre study, which is being led locally by Eugene McCloskey. The training manual for acquisition and analysis of bone density scans was prepared by Margaret Paggiosi and the Bone BRU is the lead training centre. This aim of this research is to identify genetic 1

2 polymorphisms in individuals and the extended families of these individuals who have higher than average bone mineral density. Bone Biomedical Research Unit NIHR and BRU Developments We have two pieces of good news to report; firstly Richard Eastell (Bone BRU Director) was awarded Senior NIHR investigator status earlier this year. Secondly, the NIHR awarded a total of 1.4 million to fill the shortfall in funding needed to pay for the transformation of the Clinical Sciences Building into the CBR. Plans are now underway to apply for NIHR Biomedical Research Centre (BRC) status when the current funding period ends (2012). The 1st step towards this goal has been the formation of a BRC Strategy Board chaired by Professor Weetman. Richard Eastell recently attended a meeting of the NIHR family entitled Realising the Vision: the NIHR Family Conference at the NEC, Birmingham. Reassuringly, the NIHR confirmed at this meeting that they will have 1 billion of research funding to allocate in The Panel will meet monthly throughout 2010 to review our research protocols, participant information sheets and lay summaries. People New appointments Jemima Clarke Patient Panel Members of the Bone BRU s Patient Panel met for a joint Christmas event with the Cardiovascular BRU Patient Panel on the 2 nd of December at the MEC, NGH. Professor Eastell gave a presentation to Panel members outlining the various roles of people involved in research at the BRU. This was followed by a quiz with a Christmas theme. The buffet lunch provided an opportunity for our Panel members to meet members of staff. At their last meeting, on the 10 th of November, the Panel formalised their Terms of Reference which included a renaming of the Panel which will now be called the Lay Advisory Panel for Bone Research. The members also defined their role as being to give a lay perspective on and influence the research that is being carried out in the Bone Biomedical Research Unit. Jemima took up her post of Research Coordinator in the Bone BRU in August this year, having previously worked for CellTran Ltd, a company specialising in regenerative wound healing. Her duties there involved growing autologous human tissue in a MHRAaccredited Class 100 laboratory for nationwide treatment of burns and chronic 2

3 wounds or ulcers. The company worked to ISO9001:2000 standards and therefore Jemima gained valuable experience of Quality Management Systems. In her role she worked in accordance with Good Manufacturing Practice ensuring that her work (and that of colleagues) complied with the Human Tissue Act and participated in several MHRA and HTA inspections. Jemima s role within the Bone BRU is to work alongside Stacy Young (Research Coordinator) and Kath Knight (Bone BRU Manager) to maintain compliance to GCP in all our studies. She will be responsible for projects in the post- governance set-up phase and for both active and archived studies. These activities will include the monitoring and auditing of clinical trials, submission of ethics amendments as necessary and maintenance of study site files. Kathryn Watson Kathryn has been appointed to the post of BRU Secretary to the CBR, a joint full-time post between the Bone and Cardiovascular BRUs. and later at the Medical School, where she gained invaluable knowledge of the Sheffield NHS Foundation Trust and it s collaboration with the University. She welcomes her current appointment to the BRU as an opportunity to perform a role at the heart of a new and evolving venture in patient-based research. New students Five students have recently joined the Bone BRU. Karan Shah is a PhD student under the joint supervision of Mark Wilkinson and Allie Gartland. He will be examining the mechanism of action for the effects of metal ions on bone cell function. Annabel Burton (supervised by Lang Yang) and Elena Del Vescovo, Jenny Prentice (supervised by Mark Wilkinson) and Ian Baxter (supervised by Nicky Peel) are BMedSci students. Annabel is working on finite element analysis of the hip in elderly men (the MrOS study); Elena is studying genetic polymorphisms in the Toll signalling pathway in relation to osteolysis around total hip prostheses; Jenny is investigating the potential adverse health effects of the circulating metal ions with metal-on-metal hip replacements. Ian is studying the response of NTX to osteoporosis therapies in the clinical setting. Meeting Reports ASBMR Members of the Bone BRU were authors or co-authors on a total of 17 abstracts submitted to the ASBMR meeting in Denver, Colorado in September this year. Three of these were presented orally, 11 were posters and 3 were plenary posters. Kathryn worked as a medical secretary at the King Edward VII Orthopaedic and Weston Park Hospitals and Secretary to the Treasurer of the Sheffield Area Health Authority before coming to the University of Sheffield in Kathryn was secretary to Professor Weetman and his research team, based first at the NGH Upcoming Meetings IOF Florence, Italy 5-10 May 2010: abstract deadline 4 February ECTS Glasgow, UK June 2010: abstract deadline 18 January

4 Recent publications A randomised, double-blinded, placebo-controlled, trial to determine the individual response in bone turnover markers to lasofoxifene therapy. Rogers A, Glover SJ, Eastell R. Bone 2009 Dec;45(6): Showed that bone turnover markers are useful for monitoring response to lasofoxifene therapy Rapid and robust response of biochemical markers of bone formation to teriparatide therapy. Glover SJ, Eastell R, McCloskey EV, Rogers A, et al. Bone 2009 Dec;45(6): Bone formation markers in women with low bone density increased rapidly in response to teriparatide treatment. Update on monthly oral bisphosphonate therapy for the treatment of osteoporosis: focus on ibandronate 150 mg and risedronate 150 mg. Epstein S, Jeglitsch M, McCloskey E. Curr Med Res Opin 2009 Dec;25(12): Conclusions: risedronate is more effective given daily, ibandronate is more effective given monthly and is also effective when given intermittently. The effect of cessation of raloxifene treatment on bone turnover in postmenopausal women. Naylor KE, Clowes JA, Finigan J, Paggiosi MA, Peel NF, Eastell R. Bone 2009 Nov 6 [Epub ahead of print]. Reported the reduction in bone turnover is lost 6 months after cessation of raloxifene treatment. The effect of a fortified milk drink on vitamin D status and bone turnover in post-menopausal women from South East Asia. Kruger MC, Schollum LM, Kuhn- Sherlock B, Hestiantoro A, Wijanto P, Li-Yu J, Agdeppa I, Todd JM, Eastell R. Bone 2009 Nov 4 [Epub ahead of print]. Daily consumption of milk fortified with calcium, vitamin D, magnesium and zinc reduced vitamin D insufficiency by up to 50%. A study of the effects of the aromatase inhibitors anastrozole and letrozole on bone metabolism in postmenopausal women with estrogen receptorpositive breast cancer. McCaig FM, Renshaw L, Williams L, Young O, Murray J, Macaskill EJ, McHugh M, Hannon R, Dixon JM. Breast Cancer Res Treat 2009 Nov 26 [Epub ahead of print]. Given after tamoxifen therapy, aromatase inhibitors induced greater increases in bone turnover than in tamoxifennaive patients. The use of a point of care device for monitoring the bone resorption biomarker urinary N-telopeptide in cancer patients with bone metastases. Lester JE, Brown JE, Hannon RA, Ellis SP, Horsman JM, Purohit OP, Coleman RE. Bone 2009 Nov 18 [Epub ahead of print]. Measurement of urinary NTX using the point of care device is useful in monitoring patients with metastases. Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial. Saag KG, Zanchetta JR, Devogelaer JP, Adler RA, Eastell R, See K, Krege JH, Krohn K, Warner MR. Arthritis Rheum 2009 Nov;60(11): Teriparatide was associated with greater increases in bone density and fewer new vertebral fractures compared to alendronate. BMD, clinical risk factors and their combination for hip fracture prevention. Johansson H, Kanis JA, Oden A, Johnell O, McCloskey E. Osteoporos Int 2009 Oct;20(10): FRAX in combination with bone density assessment increased the performance of fracture risk assessment. Effect of once-yearly zoledronic acid on the spine and hip as measured by quantitative computed tomography: results of the HORIZON Pivotal Fracture Trial. Eastell R, Lang T, Boonen S, et al. Osteoporos Int Oct 3. Once-yearly zoledronate was associated with increased bone density compared to placebo. Effects of the Src Kinase Inhibitor Saracatinib (AZD0530) on Bone Turnover in Healthy Men: A Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Phase I Trial. Hannon RA, Clack G, Rimmer M, Swaisland A, Lockton JA, Finkelman RD, Eastell R. J Bone Miner Res Sep 23. Inhibition of Src reduced osteoclastic bone resorption; saracatinib could be useful to treat diseases linked to increased bone resorption. Effects of yearly zoledronic acid 5 mg on bone turnover markers and relation of PINP with fracture reduction in postmenopausal women with osteoporosis. Delmas PD, Munoz F, Black DM, Cosman F, Boonen S, Watts NB, Kendler D, Eriksen EF, Mesenbrink PG, Eastell R. J Bone Miner Res 2009 Sep;24(9): Bone turnover reduced to within the premenopausal range and remained significant after the third infusion. Effect of once-yearly zoledronic acid five milligrams on fracture risk and change in femoral neck bone mineral density. Eastell R, Black DM, Boonen S, et al; HORIZON Pivotal Fracture Trial. J Clin Endocrinol Metab 2009 Sep;94(9): Zoledronate was more effective in preventing vertebral fracture in younger or overweight/ obese women and women with normal renal function. From relative risk to absolute fracture risk calculation: the FRAX algorithm. McCloskey EV, Johansson H, Oden A, Kanis JA. Curr Osteoporos Rep 2009 Sep;7(3): Describes the development of the FRAX Algorithm. 4

5 The effects of a FRAX((R)) revision for the USA. Kanis JA, Johansson H, Oden A, Dawson-Hughes B, Melton LJ 3rd, McCloskey EV [Epub 2009 Aug 25]. The revised FRAX model for the USA did not alter fracture probability rankings but gave lower probability estimates than the earlier version. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. N Engl J Med 2009 Aug 20;361(8): Erratum in: N Engl J Med Nov 5;361(19):1914. Twice-yearly denosumab for 36 months reduced the risk of vertebral, non-vertebral, and hip fractures. Association between vitamin D receptor gene polymorphisms, falls, balance and muscle power: results from two independent studies (APOSS and OPUS). Barr R, Macdonald H, Stewart A, McGuigan F, Rogers A, Eastell R, Felsenberg D, Glüer C, Roux C, Reid DM. Osteoporos Int Jul 24 [Epub ahead of print]. Reports an association between the Bsm1 polymorphism and risk of falling. A Randomised Controlled Dose-Ranging Study of Risedronate in Children with Moderate and Severe Osteogenesis Imperfecta. Bishop N, Harrison R, Ahmed F, Shaw N, Eastell R, et al. Bone Miner Res Jul 6 [Epub ahead of print]. Increasing doses of risedronate produced greater increases in bone mass and fewer bowing deformities. The fracture rate was reduced irrespective of dose. The cost-effectiveness of risedronate in the UK for the management of osteoporosis using the FRAX(R). Borgström F, Ström O, Coelho J, Johansson H, Oden A, McCloskey EV, Kanis JA. Osteoporos Int 2009 Jun 30 [Epub ahead of print]. Risedronate was cost-effective for treatment of women with osteoporosis at age 65+ or with established osteoporosis at age 50+. Prevalence of Osteonecrosis of the Jaw in Patients With Oral Bisphosphonate Exposure. Lo JC, O'Ryan FS, Gordon NP, Yang J, Hui RL, Martin D, Hutchinson M, Lathon PV, Sanchez G, Silver P, Chandra M, McCloskey CA, Staffa JA, Willy M, Selby JV, Go AS; Predicting Risk of Osteonecrosis of the Jaw with Oral Bisphosphonate Exposure (PROBE) Investigators. J Oral Maxillofac Surg Jun 30 [Epub ahead of print]. ONJ cases occurred in 1/952 respondents with oral bisphosphonate exposure; a similar number had features that did not meet the criteria. Bone turnover markers in postmenopausal breast cancer treated with fulvestrant--a pilot study. Agrawal A, Hannon RA, Cheung KL, Eastell R, Robertson JF. Breast 2009 Jun;18(3): Long-term stability of bone markers may be exploited by early use of fulvestrant. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. Abrahamsen B, Eiken P, Eastell R. J Bone Miner Res Jun;24(6): Subtrochanteric/diaphyseal and classic hip fracture had similar epidemiologies and similar responses to alendronate. The cost-effectiveness of strontium ranelate in the UK for the management of osteoporosis. Borgström F, Ström O, Coelho J, Johansson H, Oden A, McCloskey E, Kanis JA. Osteoporos Int 2009 Jun 10 [Epub ahead of print]. Strontium ranelate is costeffective in older women with established osteoporosis and possibly in younger women with additional clinical risk factors. Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX. Kanis JA, Johansson H, Oden A, McCloskey EV. Bone 2009 Jun;44(6): Bazedoxifene decreased clinical fracture and morphometric vertebral fracture risk in women a FRAX-based fracture probability threshold. Biochemical Markers of Bone Turnover, Hip Bone Loss and Fracture in Older Men: The MrOS Study. Bauer DC, Garnero P, Harrison S, Cauley J, Eastell R, Ensrud K, Orwoll E; For the Osteoporotic Fractures in Men (MrOS) Research Group. J Bone Miner Res 2009 May 19 [Epub ahead of print]. Higher bone turnover was associated with greater loss of bone at the hip, but was not an independent predictor of hip or nonspine fracture. Can fall risk be incorporated into fracture risk assessment algorithms: a pilot study of responsiveness to clodronate. Kayan K, Johansson H, Oden A, Vasireddy S, Pande K, Orgee J, Kanis JA, McCloskey EV. Osteoporos Int 2009 May 13 [Epub ahead of print]. Fall risk did not significantly impact on the anti-fracture efficacy of clodronate. Ten-year fracture probability identifies women who will benefit from clodronate therapy--additional results from a double-blind, placebo-controlled randomised study. McCloskey EV, Johansson H, Oden A, et al. Osteoporos Int 2009 May;20(5): Estimation of 10-year fracture probability by FRAX in elderly women identifies those at high risk of fracture. 5