Fracture prevention in patients with cognitive impairment presenting with a hip fracture: secondary analysis of data from the HORIZON Recurrent Fracture Trial
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Patients with cognitive impairment (CI) often do not receive secondary fracture prevention. Use of zoledronic acid led to a similar reduction in re-fracture risk but the survival benefit was limited to those without CI.
We tested whether the effects of zoledronic acid (Zol) on re-fracture and mortality differed in patients presenting with a hip fracture by cognitive status.
We used data from the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Recurrent Fracture Trial, of yearly intravenous 5 mg Zol vs. placebo in patients presenting with a hip fracture. Primary outcome was new fracture and secondary outcome mortality. Short Portable Mental Status Questionnaire (SPMSQ) with a cut-point of >2 was used to identify CI. Fine–Gray models for competing events were fitted to study the effect of Zol on re-fracture and Cox regression for death. A multiplicative term was introduced to study a potential interaction between treatment and cognitive status on outcomes.
Baseline SPMSQ of 1,966/2,127 (92.4 %) patients was measured. Three hundred fifty (17.8 %) had CI, balanced between treatment arms. In the placebo arm, there was similar fracture incidence between those with and without CI (15.4 vs. 12.3 %, p = 0.26). There was no significant interaction for the effect of CI on Zol and re-fracture (p = 0.66). CI was associated with higher 1-year mortality (12.6 vs. 4.3 %, p < 0.001) and the interaction was bordering significance (interaction, p = 0.066). Zol prolonged survival only in patients with normal cognitive status [HR 0.56 (95 % CI 0.40–0.80)] and not in those with CI [HR 0.90 (95 % CI 0.59–1.38)].
While these results require confirmation, the findings support the use of bisphosphonates in patients with osteoporotic fracture and CI expected to live for more than 6 months.
KeywordsBone Dementia Epidemiology Fractures Mortality Zoledronic acid
We wish to thank the patients, carers and research staff involved in the original trial and Professor A Munoz for his advice on competing risk models.
Conflicts of interest
All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that: (1) DPA and AJ have no conflicts of interest to declare; (2) MKJ, NKA and CC have received honorarium, advisory boards and consortium research grants, respectively, from Novartis, Alliance for Better Health and Lilly; Merck, MSD, Roche, Novartis, Smith and Nephew, Q-MED, Nicox, Servier, GSK, Schering-Plough, Pfizer and Rottapharm; and Alliance for Better Bone Health, Amgen, Novartis, MSD, Servier, Eli Lilly and GSK; (3) Dr. Lyles reports receiving grant support from Novartis, the Alliance for Better Bone Health (Sanofi-Aventis and Procter & Gamble) and Amgen, consulting fees from Novartis, Procter & Gamble, Merck, Amgen, GTx, GlaxoSmithKline, Eli Lilly and Bone Medical, and being listed as an inventor on a US patent application (20050272707) covering methods for preventing or reducing secondary fractures after hip fracture and on another provisional patent application for medication kits and formulations for preventing, treating or reducing secondary fractures after a previous fracture; and (4) their spouses, partners, or children have no financial relationships that may be relevant to the submitted work.
While the parent study was sponsored by Novartis Pharmaceuticals Corporation and Novartis Pharma AG, the origination of the research question, statistical methodology, analysis and interpretation of the data, and authoring of the manuscript were performed independently by the Oxford NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, UK. The pre-submission manuscript was sent to Novartis Pharmaceuticals Corporation for comment.
Informed consent was obtained from subjects, and investigations were approved by an institutional human research committee. The study was conducted according to the ethical principles of the 1989 Declaration of Helsinki and local applicable laws and regulations.
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