Comparative anti-fracture effectiveness of different oral anti-osteoporosis therapies based on “real-world” data: a meta-analysis of propensity-matched cohort findings from the UK Clinical Practice Research Database and the Catalan SIDIAP Database

Purpose This paper aims to compare the clinical effectiveness of oral anti-osteoporosis drugs based on the observed risk of fracture while on treatment in primary care actual practice. Materials and methods We investigated two primary care records databases covering UK National Health Service (Clinical Practice Research Datalink, CPRD) and Catalan healthcare (Information System for Research in Primary Care, SIDIAP) patients during 1995–2014 and 2006–2014, respectivey. Treatment-naive incident users of anti-osteoporosis drugs were included and followed until treatment cessation, switching, death, transfer out, or study completion. We considered hip fracture while on treatment as main outcome and major osteoporotic fractures (hip, clinical spine, wrist, and proximal humerus) as secondary outcome. Users of alendronate (reference group) were compared to those of (1) OBP, (2) strontium ranelate (SR), and (3) selective estrogen receptor modulators (SERMs), after matching on baseline characteristics using propensity scores. Multiple imputation was used to handle missing data on confounders and competing risk modelling for the calculation of relative risk according to therapy. Country-specific data were analyzed separately and meta-analyzed. Results A total of 163,950 UK and 145,236 Catalan patients were identified. Hip (sub-hazard ratio [SHR] [95% CI] 1.04 [0.77–1.40]) and major osteoporotic (SHR [95% CI] 1 [0.78–1.27]) fracture risks were similar among OBP compared to alendronate users. Both hip (SHR [95% CI] 1.26 [1.14–1.39]) and major osteoporotic (SHR [95% CI] 1.06 [1.02–1.12]) fracture risk were higher in SR compared to alendronate users. SERM users had a reduced hip (SHR [95% CI] 0.75 [0.60–0.94]) and major osteoporotic (SHR [95% CI] 0.77 [0.72–0.83]) fracture risk compared to alendronate users. Conclusion We found a 26% excess hip fracture risk among SR compared to matched alendronate users, in line with placebo-controlled RCT findings. Conversely, in a lower risk population, SERM users had a 25% reduced hip fracture risk compared to alendronate users. Head-to-head RCTs are needed to confirm these findings.

[1]  G. Oster,et al.  Effectiveness of bisphosphonate therapy in a community setting. , 2009, Bone.

[2]  C. Cooper,et al.  Fracture risk before and after total hip replacement in patients with osteoarthritis: potential benefits of bisphosphonate use. , 2011, Arthritis and rheumatism.

[3]  A. Westfall,et al.  RisedronatE and ALendronate Intervention over Three Years (REALITY): minimal differences in fracture risk reduction , 2009, Osteoporosis International.

[4]  C. Turner,et al.  Raloxifene preserves bone strength and bone mass in ovariectomized rats. , 1994, Endocrinology.

[5]  Ping Li,et al.  Readers guide to critical appraisal of cohort studies: 3. Analytical strategies to reduce confounding , 2005, BMJ : British Medical Journal.

[6]  R. Burge,et al.  The cost of osteoporotic fractures in the UK: projections for 2000–2020 , 2001 .

[7]  Medicines And Healthcare Products Regulatory Agency , 2020, Definitions.

[8]  E. Badamgarav,et al.  Systematic review and meta-analysis of real-world adherence to drug therapy for osteoporosis. , 2007, Mayo Clinic proceedings.

[9]  Daniel Solomon,et al.  Relative Effectiveness of Osteoporosis Drugs for Preventing Nonvertebral Fracture , 2008, Annals of Internal Medicine.

[10]  L Abenhaim,et al.  The use of a large pharmacoepidemiological database to study exposure to oral corticosteroids and risk of fractures: validation of study population and results , 2000, Pharmacoepidemiology and drug safety.

[11]  D. Torgerson,et al.  The Cost of Treating Osteoporotic Fractures in the United Kingdom Female Population , 1998, Osteoporosis International.

[12]  E. Brankin,et al.  The impact of dosing frequency on compliance and persistence with bisphosphonates among postmenopausal women in the UK: evidence from three databases , 2006, Current medical research and opinion.

[13]  Harry K. Genant,et al.  Reduction of Vertebral Fracture Risk in Postmenopausal Women With Osteoporosis Treated With Raloxifene: Results From a 3-year Randomized Clinical Trial , 2000 .

[14]  Real-Life and RCT Participants: Alendronate Users Versus FITs’ Trial Eligibility Criterion , 2016, Calcified Tissue International.

[15]  S. Cummings,et al.  Design of the Fracture Intervention Trial , 2005, Osteoporosis International.

[16]  P. Roberson,et al.  Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. , 1999, The Journal of clinical investigation.

[17]  C. Longson.  ALENDRONATE, ETIDRONATE, RISEDRONATE, RALOXIFENE AND STRONTIUM RANELATE FOR THE PRIMARY PREVENTION OF OSTEOPOROTIC FRAGILITY FRACTURES IN POSTMENOPAUSAL WOMEN , 2007 .

[18]  C C Glüer,et al.  Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. , 1999, JAMA.

[19]  A. Díez-Pérez,et al.  Validation of fragility fractures in primary care electronic medical records: A population-based study. , 2017, Reumatologia clinica.

[20]  A. Díez-Pérez,et al.  “Burden of osteoporotic fractures in primary health care in Catalonia (Spain): a population-based study” , 2012, BMC Musculoskeletal Disorders.

[21]  Paul G Shekelle,et al.  Comparative Effectiveness of Pharmacologic Treatments to Prevent Fractures , 2014, Annals of Internal Medicine.

[22]  C. Cooper,et al.  Bisphosphonate use and risk of post-operative fracture among patients undergoing a total knee replacement for knee osteoarthritis: a propensity score analysis , 2011, Osteoporosis International.

[23]  Robert Gray,et al.  A Proportional Hazards Model for the Subdistribution of a Competing Risk , 1999 .

[24]  Toshitaka Nakamura,et al.  Clinical Efficacy on Fracture Risk and Safety of 0.5 mg or 1 mg/month Intravenous Ibandronate Versus 2.5 mg/day Oral Risedronate in Patients with Primary Osteoporosis , 2013, Calcified Tissue International.

[25]  P. Rothwell,et al.  External validity of randomised controlled trials: “To whom do the results of this trial apply?” , 2005, The Lancet.

[26]  Strontium ranelate discontinued , 2017, Drug and therapeutics bulletin.

[27]  S. Cummings,et al.  Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. , 2000, The Journal of clinical endocrinology and metabolism.

[28]  T. Spector,et al.  Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies , 2004, The New England journal of medicine.

[29]  Piet Geusens,et al.  Epidemiology of fractures in the United Kingdom 1988-2012: Variation with age, sex, geography, ethnicity and socioeconomic status. , 2016, Bone.

[30]  N. Freemantle,et al.  Results of indirect and mixed treatment comparison of fracture efficacy for osteoporosis treatments: a meta-analysis , 2012, Osteoporosis International.

[31]  Luke Keele,et al.  An overview of rbounds: An R package for Rosenbaum bounds sensitivity analysis with matched data. , 2010 .

[32]  K. Bhaskaran,et al.  Data Resource Profile: Clinical Practice Research Datalink (CPRD) , 2015, International journal of epidemiology.

[33]  Cristina Carbonell Abella,et al.  [Analysis of therapeutic compliance in women with osteoporosis]. , 2011, Reumatologia clinica.

[34]  C. Rey,et al.  Mechanisms of Action and Therapeutic Potential of Strontium in Bone , 2001, Calcified Tissue International.

[35]  Peter C Austin,et al.  The performance of different propensity-score methods for estimating relative risks. , 2008, Journal of clinical epidemiology.

[36]  F. Aversa,et al.  Competing risk analysis using R: an easy guide for clinicians , 2007, Bone Marrow Transplantation.

[37]  P. Tugwell,et al.  Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. , 2008, The Cochrane database of systematic reviews.

[38]  T. Yoneda,et al.  Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo , 1995, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[39]  Harry K. Genant,et al.  Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. , 1993, The American journal of medicine.

[40]  J. Reginster,et al.  Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. , 2005, The Journal of clinical endocrinology and metabolism.

[41]  P. Tugwell,et al.  Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. , 2008, The Cochrane database of systematic reviews.