Effect of a Fracture Liaison Service on the Rate of Subsequent Fracture Among Patients With a Fragility Fracture in the Norwegian Capture the Fracture Initiative (NoFRACT)

This trial protocol of the Norwegian Capture the Fracture Initiative (NoFRACT) intends to use registry data from Norway and a stepped wedge cluster design to investigate the effect of a standardized intervention program on the rate of subsequent fracture among patients with a fragility fracture.


Aspects relating to the research project
The pathogenesis and clinical significance of bone fragility 54 The pathogenesis of fractures is multifactorial; genetics, trauma mechanism, falls and bone strength 55 are all important factors. (19) Women suffer more fractures than men, particularly postmenopausal 56 women, but the risk of recurrent hip fracture is similar given similar remaining life expectancy. (13) 57 However, compared to women, men have higher mortality after a hip fracture, (20) and the 1-year 58 excess mortality post hip fracture was 2.8 and 4.6 increased in women and men, respectively. (21) 59 One year after a hip fracture, one of four patients over 50 years of age were no longer alive. 60 61 Assessment and treatment of persons at high risk of fracture 62 Measurement of femoral neck bone mineral density (BMD) by dual energy X-ray absorptiometry 63 (DXA) is the most common approach used to assess fracture risk and is considered the gold 64 standard surrogate for bone strength. (22;23) However, although a lower BMD is associated with 65 increased risk of fracture, most people with fractures do not have osteoporosis (T score of 2.5 or 66 To address this lack of sensitivity, Fracture Risk Assessment Tool (FRAX) is developed, which 68 calculates the 10-years probability of a major osteoporotic fracture based on clinical risk factors as 69 age, height, weight, smoking, excessive alcohol intake, previous fracture, parental history of hip 70 fracture, glucocorticoid therapy, rheumatoid arthritis and femoral neck BMD. ( This cross-regional cooperative project is a unique opportunity to measure the effect of introducing 112 a standardized intervention program, mainly in terms of possible changes in fracture rates and 113 fracture-associated excess mortality. The effect of this intervention will be measured based on 114 endpoints from national registers (as outlined below). 115

116
The main aim is to assess the effectiveness of introducing a standardized intervention program 117 for treatment of fragility fracture patients measured by changes in recurrent fracture rates and 118 mortality. 119 120 A fracture liaison service (FLS) model of care is widely recommended but data on its effectiveness 121 regarding recurrent fracture risk and fracture related mortality is scarce. We therefore aim to assess 122 the effectiveness of an intervention in terms of introducing a standardized program for assessment 123 and treatment of bone fragility in fracture patients. This FLS program will involve dedicated 124 coordinating nurses at each hospital, who will approach fracture patients, invite them to participate, 125 inform them about the importance of bone fragility, give lifestyle advice concerning physical 126 activity, healthy diet, moderate alcohol intake and smoking cessation, and offer assessment and 127 treatment for osteoporosis if needed. Seven hospitals are Stepped Wedge Cluster Randomized for 128 starting date of introducing a standardized intervention program from 2015 to 2016, with follow-up 129 throughout 2019 (Fig. 1). The effect of the intervention will be measured based on endpoints from 130 national registers. Main outcomes are recurrent fractures (hip, forearm and all fracture types) and 131 post hip fracture mortality. Each hospital will act as its own controls, and provide endpoint data 132 before and after intervention. In the analyses the effect of the standardized intervention program regions of Norway will be assessed in register data before intervention. 147 2. The incidence of fragility fractures (hip, proximal humerus and wrist) will be reduced at hospitals 148 with a standardized intervention program compared to hospitals without. 149 3. The mortality rate after fragility fractures (hip, proximal humerus and wrist) will be reduced at 150 hospitals with a standardized program compared to hospitals without. 151 152 Stepped Wedge Cluster Randomized Controlled Trial 153 In this stepped wedge cluster randomized controlled trial, the hospitals are randomized for the order 154 to start of the study. The intervention was planned to start at 4 months interval for 3 clusters 155 (consisting of 2-3 hospitals, Fig. 1), until all 7 hospitals have received the intervention. A stepped wedge design is similar to a crossover design in terms that the different clusters (groups 173 of hospitals) in turn switch from no standardized program (control) to standardized program but at 174 different time points. The clusters will cross over in only one direction. (40;41) Each hospital will be 175 their own control, and endpoints will be compared before and after the introduction of intervention. 176 This stepped wedge cluster randomization design is particular relevant where it would be 177 considered unethical to not deliver or retract the intervention when it is expected to do more good 178 than harm, as here where the intervention is expected to be included as a future standard routine. 1. Women and men ≥ 50 years of age with a low-trauma vertebral or non-vertebral fracture (except 182 fingers, toes, face and skull) will be approached by the coordinating nurse, and offered information, 183 assessment, lifestyle advice and treatment for bone fragility, preferable while in-patient are at the 184 hospital, or as out-patients, within 6 weeks after the fracture (see algorithm Fig. 2). Lifestyle advice 185 about physical activity, fall prevention, healthy diet, smoking cessation and moderate alcohol 186 intake, will be given, and referral to fall prevention at the hospital or primary care if indicated. 187 All will be offered a DXA scan at hospitals with DXA available (for BMD T-score or FRAX score 228 calculation) except patients with dementia, difficulties laying on the back, or short life expectancy; 229 they will not be scanned by DXA (but have treatment decision made based on clinical assessment 230 and FRAX score calculated without BMD). At hospitals without DXA machine available, FRAX 231 score will be calculated for all fracture patients without BMD measurements. 232 233 9. Patients with fracture of the hip, vertebrae or 2 or more low-trauma fracture do not need DXA for 234 treatment decision, however, a DXA scan for T-score or FRAX score calculation is needed for the 235 decision about AOD treatment of patients with one other low-trauma fracture. 236 237 10. Hip fracture patients will be recommended AOD regardless of FRAX or T-score, and they do 238 not need any DXA scan or FRAX score for treatment decision. Drug of choice i) zoledronic acid 5 239 mg iv x 1/year, to avoid compliance problem, ii) denosumab 60 mg sc/6 month to women > 75 240 years of age if they are not able to use peroral treatment, or iii) alendronate 70 mg po x 1/week. 241 242 11. Patients with vertebral fracture or ≥ 2 low-trauma fracture will similarly be recommended AOD 243 treatment regardless of T-score or FRAX score, as outlined in the treatment algorithm below. 244 Drug of choice i) alendronate 70 mg po x 1/week, ii) zoledronic acid 5 mg iv x 1/year, or iii) 245 denosumab 60 mg sc/6 month. 246 247 12. For patients with one other low-trauma fracture; a DXA scan is recommended, and AOD 248 treatment is recommended if T-score ≤ -1.5 or FRAX score for major fracture ≥ 20%. If kidney 249 function is normal, the first choice of AOD is alendronate 70 po/week, see treatment algorithm. 250 251 13. Patients with spine or femoral neck T-scores ≤ -3.5, > 2 severe vertebral fractures (> 40% 252 compression), and those who suffer a second fracture while using AOD, will be referred for further 253 examination by specialist at the hospital and teriparatide treatment will be considered. 254 255 14. AOD will be prescribed by a hospital physician involved in this project. All patients treated 256 with AOD will be offered a follow-up phone call after 3 months by the nurse and a visit to talk with 257 the nurse after 1 year, to improve the compliance and resilience. 258 259 In brief, at all hospitals, the intervention is a standardized program involving a nurse and physician 260 who offer information, assessment, and treatment if needed in the hospital setting as an integrated 261 part of the fracture treatment. All patients included in this study, will be offered a follow-up 262 appointment to talk with the nurse 1 year after the fracture. The study design is kept simple to make 263 the project realistic and feasible, scientifically, organizationally, in relation to the use of resources. physicians or private x-ray institutes when they fracture. This type of information is available in 281 KUHR. In order to make sure that information on fractures treated outside hospitals is not missed, 282 we want to include KUHR-data. The ICPC-2 diagnosis codes L72-L76 contain relevant information 283 on fractures (Fig. 3). 284 285 Merging and storing of data: Data from the Norwegian Patient Register (NPR), the National 286 Population Registry (from 1 January 2008 to 31 December 2019), and statistics Norway will be 287 combined (Fig. 3). Regarding fractures of the hip, additional information will also be obtained from 288 the Cause of Death Register. The University of Oslo (UiO) has implemented a research platform 289 Services for Sensitive Data (TSD), which meets all requirements in the Norwegian law regarding 290 safe handling and storing of sensitive data. All data will be stored in TSD. 291 292

Statistics 293
In this stepped-wedge CRT, each of the hospitals will act as their own controls, and provide data 294 from before and after intervention. In the analyses the effect of introducing the standardized 295 intervention program will be estimated by comparing data before Norway (UNN, Tromsø). All fracture patients will be offered assessment and treatment as outlined 321 previously. The dedicated FLS nurses will perform weekly systematic searches of all in-patients 322 and out-patients, and approach admitted patients and invite out-patients to participate by letter, SMS and telephone and offer appointment with nurse within 6 weeks. Good routines will be established 324 together with our international collaborators, who have experience from establishing and 325 maintaining such projects. The nurses will provide patients with information about bone fragility, 326 and the impact of their future fracture risk, so they will be well motivated for modifying amendable 327 lifestyle factors such as; physical activity, healthy diet, with sufficient intake of vitamin D and 328 calcium, protein, avoid excess alcohol intake and quit smoking. Follow-up appointment with the 329 nurses after 1 year will be offered for assessment of compliance. A physician will prescribe anti-330 osteoporosis drug (AOD) for those who need it and outlined in the treatment algorithm. 331

2018-2019
Data from registers will be retrieved for the first publications on the incidence of 332 forearm fractures and other low-energy fragility fractures at different hospitals and regions in 333 Norway. The PhD student will take the courses they need for the PhD program. 334 2020 The final papers on the effect of the introduction of the standardized program will be written 335 by the PhD student and researchers. In 2021 the PhD student will defend their theses. 336 337 Research Team 338 The research team has all the qualifications and resources needed to complete the study including 339 equipment, methods and infrastructure, regional, national and international collaborators. Treatment 340 of fracture patients will be coordinated across specialities, as the team includes orthopedic surgeons, 341 endocrinologist, epidemiologists and rheumatologists with longstanding experience in treatment of 342 patients with fractures and/or osteoporosis; some are world capacities in the field. This 343 collaboration will promote national and international network building. The international 344 cooperation will ensure that the intervention will be well planned, organized and executed. 345 Initiatives are taken at seven hospitals, particular from the Norwegian Orthopedic Surgeon Society 346 of Osteoporosis and Bone Health (FOB), and four universities with a range of experts involved: 347 348 Oslo University Hospital, Prof. Lars Nordsletten, orthopedic surgeon (Ullevål), Frede Frihagen, 349 expect this research to provide a basis for ensuring high-quality, safe and effective services for the 394 many fracture patients. The evidence from this project will be used to develop national guidelines 395 for secondary fracture prevention to break the fragility fracture cycle and improve patient care. 396 397 3.2 Relevance and benefit to society 398 Bone fragility is currently largely ignored by treating physicians, both specialists and general 399 practitioners. This project is a unique possibility to test the hypothesis that a new standardized 400 program for bone fragility assessment and treatment will prevent secondary fractures and reduce 401 mortality rates in both genders. We believe this will be useful to establish a clinical management 402 strategy, to correctly target treatment to individuals who need it, to reduce the burden of bone 403 fragility in the society, and promote bone health and life quality by advancing age. We wish 404 through this research to contribute to increased understanding of the importance of bone fragility, 405 and offer assessment and treatment to those who need it, and help focus on osteoporosis. 406 407 3.3 Environmental impact No environmental impact expected as a result of this project. 408 409

Ethical perspectives 410
Approval by the ethics committee has been achieved for linkage of data from national registers for 411 the main study, with exemption from obtaining of consent (REK 2015/334 for the period 2015-412 2025). We will apply for access of the data from each of the national registers. The linkage of the 413 register data will be performed by NPR, who will provide us with anonymous data that will be 414 stored safely at TSD, at the University of Oslo (see method section). 415 416 3.5 Gender issues (Recruitment of women, gender balance and gender perspectives) 417 Of fracture patients 2/3 are women and 1/3 men, but men have higher mortality after a hip fracture. 418 The nurses at each hospital will approach patients of both genders. Analyses will be gender 419 stratified, and women and men will be compared. Moreover, the project will promote the Research 420 Council's general objectives to increase recruitment of female collaborators and improve gender 421 balance in projects, to obtain an equal gender distribution. 422 423 The scientific results will be presented and published in peer-review national journals and highly 426 renowned international journals and at local, national and international meetings. The results will 427 also be presented for the public in local meetings, through media and in cooperation with patient organisations. Authorship for the various scientific papers will be according to the Vancouver 429 protocol. If in doubt about authorship, the project steering committee will decide. 430

Communication with users 431
All patients will be informed about the importance of bone fragility and advised about treatment if 432 needed in a face-to-face setting by the coordinating nurses at each of the study sites. All information 433 important to the participant's health and results of this research will be made available for the 434 participants. The nurses and physicians involved in this project will educate patients, staff members 435 and the general population, present results from successful FLS models in other countries, for 436 prevention of secondary fractures and explain the importance of the current research project. 437 438