Title: Excess risk and predictors of fracture/s following bariatric surgery for obese patients in the NHS: a real-world self-controlled case series and cohort study.
Funder: Department of Health and Social Care

Abstract: BACKGROUND Anecdotal evidence from our clinical practice suggests that patients undergoing bariatric surgery for severe obesity might have an increased fracture risk post-operatively. However, related research is contradictory, with the most relevant UK-based study(1) having found no association when comparing fundamentally different groups: patients undergoing bariatric surgery, and those not receiving such procedure which introduces unmeasured bias into the sample. In addition, there is a need for data on key predictors of post-operative fracture/s, which could be used to target high risk patients for pre-operative assessment/s and/or preventive anti-fracture therapy. AIM/S 1.We will use established methods for the evaluation of drug and vaccine safety (self-controlled case series, SCCS) to assess the risk of fractures in the period/s before and after bariatric surgery in the same group of patients. 2.Secondly, we will determine the key predictors of post-operative fracture, and then combine them to produce a clinical fracture risk prediction tool. PLAN OF INVESTIGATION -Data sources: we will use NHS routinely collected data from anonymised electronic primary care records (Clinical Practice Research Database, CPRD) linked to hospital admissions (Hospital Episode Statistics, HES). -Participants: all patients registered in CPRD with a body mass index (BMI) of 35+ and undergoing bariatric surgery will be eligible. Patients with -Exposure (Aim 1): Bariatric surgery will be identified using READ codes in CPRD(1) and linked procedure (OPCS4) codes in HES. -Predictors of post-operative fracture/s (Aim 2): a pre-specified list will be designed, to include pre-operative factors that can be assessed during routine pre-operative assessment. Expert consensus and literature review will inform this, but it is likely to include: classic bone fragility factors (age, gender, systemic steroid use, BMI, fracture history, smoking, alcohol drinking, history of inflammatory arthritis, secondary osteoporosis), type 2 diabetes and related treatments, other drugs affecting fracture risk, socio-economic deprivation, and available blood tests. -Outcomes: 1.primary outcome will be any osteoporotic fracture/s (excluding skull, face, or digits) in the 5 years following bariatric surgery, with sensitivity analyses using 0-3 and >3 year periods instead(1-3). 2.Secondary outcomes: 1.major fracture (hip, wrist/forearm, spine, and proximal humerus), and 2.peripheral fracture/s (wrist/forearm, ankle, and proximal humerus) in the same time frames(4, 5). All the proposed outcomes will be ascertained using previously validated lists of READ codes(6). -Sample Size: 68 cases would be needed to detect as significant an incidence rate ratio (IRR) of 2 or above in a 2-sided SCCS with alpha risk of 0.05, 80% power, and a 5-year (post-surgery) exposure period (primary analysis). According to feasibility counts from CPRD-HES the number of patients eligible is of 10,989, making an expected 494 cases(1). -Statistical Analyses: Incidence rate ratios (IRR) will be calculated for fracture/s within the &ldquo;exposure&rdquo; (5 years postsurgery) period compared to baseline (presurgery) using SCCS methods. In addition, a cohort design will be used to identify key predictors of 5-year postoperative fracture (Aim 2): 1.logistic regression with bootstrap will be used with automatic (backwards stepwise) selection of key predictors; 2.final predictors will be then combined to derive a prediction tool; 3.which will then be validated using c-statistic (discrimination) and observed/expected plots (calibration). POTENTIAL BENEFITS This research will help clinicians involved in Bariatric Surgery care to 1.understand whether there is a need for concern about bone health post-surgery; and 2.identify patients at high risk of post-operative bone fractures, who could be assessed further (e.g. bone mineral density scans) and/or supplemented (with calcium or vitamin D) to prevent such fractures.

Lay abstract: BACKGROUND: While bariatric surgery is an effective treatment for severe obesity, some research suggests that it might double the risk of bone breaks. However, the data is controversial, and most of the existing studies compare patients undergoing surgery to those not offered such treatments, making the results difficult to interpret. In addition, we do not know which patients who receive bariatric surgery are at highest risk of breaking their bone/s and could be targeted for further bone assessment/s or treatments. The lack of convincing evidence means screening for bone health is not routinely carried out in the NHS. AIMS: We aim to study if there is an increased risk of bone fracture/s following bariatric surgery. In addition, we will look for key factors that can be combined in a risk scoring tool to identify those most likely to suffer such fractures. DESIGN/METHODS: We will use anonymised GP and hospital records to study these associations in real-world clinical practice conditions, and amongst actual NHS patients. According to figures provided by these data sources, >10,900 patients undergoing bariatric surgery for obesity are available for such a study. To avoid the biases mentioned above we will use advanced methods applied in drug and vaccine safety studies (called self-controlled case series ), where the risk of fracture in the periods before and after surgery are compared for each patient. PATIENT/PUBLIC INVOLVEMENT: A public co-applicant will be part of the research team, and a PPI representative will be part of the study steering committee. The local-regional Bariatric Support group has reviewed the research topic and methodology of the proposal and will be involved on the results discussion and dissemination.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;6.4 SURGERY
Health categories: STROKE;CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL;CARDIOVASCULAR;METABOLIC AND ENDOCRINE