Title: Risks and benefits of bisphosphonate use in patients with chronic kidney disease: a population-based cohort study
Funder: Department of Health and Social Care

Abstract: AIMS: One in four women with osteoporosis has moderate chronic kidney disease (CKD)(1). Oral bisphosphonates (BP) are first line anti-osteoporosis therapies, but data on their risks and benefits in CKD patients is scarce. We aim to study, in CKD patients, the association between BP use and: 1.CKD progression (WP1); 2.fracture risk (WP2); 3.hypocalcemia/hypophosphoatemia and adverse events (WP3); and 4.bone mineral density (BMD)(WP4). DESIGN: Population-based cohort studies using routinely collected data. SETTING/DATA SOURCES: Data for WP1-3 will be extracted from the Clinical Practice Research Datalink (CPRD) linked to hospital episode statistics (HES) and the UK Renal Registry (RR). WP4 will use the Odense University Hospital database (Denmark), which includes clinical events, biochemistry, drug use and BMD for all residents in the Funen region who had a BMD scan in 1995-2013. POPULATION: Participants aged 40 years or older, with CKD stage 3B or above (eGFR<45 ml/min/1.73m2). Previous users of anti-osteoporosis medications and those with <2 years follow-up data available will be excluded. EXPOSURE: Incident BP use based on GP prescriptions(UK) or pharmacy dispensations(Denmark). Up to 5 BP non-users will be matched to each user using propensity scores(PS) [see “Other information” for details]. PS is the estimated probability that a patient is a BP user based on his/her clinical characteristics. PS-matching is a proven technique to minimise confounding by indication(2). OUTCOMES: For WP1: CKD progression based on stage progression or requirement of haemodialysis/transplantation (primary outcome) and change in eGFR (secondary outcome). WP2: READ/OXMIS(CPRD) codes will be used to ascertain osteoporotic (all but face/skull/fingers/toes) fracture/s. WP3: ICD10/OPCS codes(HES) will be used to identify:1.acute kidney injury, 2.hospitalization for hypocalcemia/hypophosphataemia, and 3.upper gastro-intestinal events. WP4: annualized hip BMD % change. SAMPLE SIZE (see "Other Information" for details): According to feasibility counts from CPRD, the number of eligible participants is of 204,528, with 34,127 being BP users. These numbers would provide 90% power to detect as significant a =15% fracture reduction, a =10% increase in CKD progression and a =20% excess risk of adverse events associated with BP use. The Danish database includes >35,000 patients. We expect to identify at least 500 CKD patients defined as BP users matched 1:5 to 2,000 non-users, which would provide >80% power to detect as significant a >25% bone loss reduction. STATISTICAL ANALYSES: BP use will be introduced as a time-varying exposure. Cox regression stratified by propensity matched sets will be used to estimate the association between BP use and the study outcomes(WP1/2/3). Linear regression models will be fitted to study the association between BP use and hip BMD in CKD patients(WP4). MILESTONES: Month(M)0:Study coordinator appointed; M3:Statistician appointed+ISAC(CPRD) protocol approval; M6:Data linkage and extraction; M9:Data management; M17:Internal discussion of preliminary results; M21:Internal discussion of final results/dissemination plan; M24:Reporting, dissemination, and study closure. EXPERTISE: CPRD(DPA,MKJ,AJ,CC,NKA,YBS,DD) and RR(AJ,FC,YBS,DA) data analysis/interpretation; Osteoporosis(DPA,MKJ,CC,NKA); renal epidemiology(FC,YBS,AJ); Pharmaco-epidemiology(DPA,MKJ,AJ,CC,NKA); PPI interaction/dissemination(MKJ,FC,DA,A

Lay abstract: With the aging population a growing number of patients are living with kidney disease. Kidney disease is associated with a significantly increased risk of broken bones (fractures) with substantial implications for patients, NHS and society. Although there are effective drugs such as bisphosphonates that reduce the risk of fracture in patients with osteoporosis (brittle bones), these drugs are untested in patients with kidney disease where the biology of the bone disease leading to bone fragility can be different. In addition some data suggests that these first-line bone therapies may worsen kidney function. Indeed, patients with kidney disease were under-represented or excluded from most randomised clinical trials, leaving a gap in the current medical knowledge about the potential benefits and risks of these medications in this growing group of the population. This evidence gap has led some to use untested treatment regimens in an attempt to reduce the risk of fracture. To address this, we propose to use ‘real life’ data as routinely collected in NHS clinical practice including primary and hospital care anonymised records for millions of UK people (the called CPRD/HES database), linked to the UK Renal Registry data, with detailed information on end-stage kidney disease. Finally, a unique Danish dataset including all patients who had a bone density scan in 1995-2013 will be used to study the effect of bisphosphonates on bone density in patients with kidney disease. As this is an observational study and the data have already been routinely collected whenever a patient is seen in any NHS facility, patients will not need to be randomized to receive bisphosphonates or any other treatment including “water pills” (placebo). Therefore, this approach will avoid exposing patients with kidney function impairment to unnecessary risks such as bisphosphonate-related potential adverse events. Advanced statistical methods will be used to match users of bisphosphonates to non-users with similar characteristics in order to provide a fair comparison. The current study will offer relevant information on the risks (side effects and renal disease progression/worsening) and potential benefits (fracture prevention) of the most commonly used treatment for osteoporosis (bisphosphonates) in UK patients with kidney impairment. Importantly, by using routinely collected data we will be able to make sure the study fully represents the general population of patients. This will make our final report a key piece of information for clinicians and patients with kidney impairment considering bisphosphonate therapy across the NHS. The proposed research group has extensive expertise in the analysis and interpretation of CPRD and UK Renal Registry data. Patient representatives have been involved in the design of this study, and will be part of steering group meetings to monitor the smooth progress of this research, which should be finished in a total period of 2 years time.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL;RENAL AND UROGENITAL