Long-Term Randomized Trial of Intensive Versus Symptomatic Management in Paget's Disease of Bone: The PRISM-EZ Study.
It has been suggested that normalization of bone turnover may improve clinical outcome in Paget's disease of bone (PDB) by preventing complications such as fractures and the development of osteoarthritis. Here we investigated the long-term effects of a treatment strategy that aimed to normalize bone turnover in PDB with that of symptomatic treatment. The study group comprised 502 subjects who were enrolled into a 3-year extension of the Paget's Disease: Randomized Trial of Intensive versus Symptomatic Management (PRISM) study. Intensive bisphosphonate therapy was continued in 270 of these subjects with the aim of normalizing bone turnover using zoledronic acid as the treatment of first choice. Symptomatic treatment continued in 232 subjects in whom bisphosphonates were only given for the treatment of bone pain. The primary outcome was fracture and secondary outcomes were orthopedic procedures, quality of life, and bone pain, adjusted for baseline characteristics. Serum total alkaline phosphatase (ALP) concentrations were significantly lower in the intensive group on entry to the study and the differences between groups increased as the study progressed. There were no clinically important differences in quality of life measures or bone pain between the treatment groups. Intensive treatment was associated with a nonsignificant increase in fracture risk (hazard ratio = 1.90; 95% CI, 0.91 to 3.98; p = 0.087), orthopedic procedures (1.81; 95% CI, 0.71 to 4.61; p = 0.214), and serious adverse events (relative risk 1.28; 95% CI, 0.96 to 1.42). We conclude that long-term intensive bisphosphonate therapy confers no clinical benefit over symptomatic therapy and is associated with a nonsignificant increase in the risk of fractures, orthopedic events, and serious adverse events. The results of this study suggest that in patients with established PDB, bisphosphonate therapy should focus on control of symptoms rather than suppression of bone turnover. © 2016 American Society for Bone and Mineral Research.
Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
Adrian
A
Tan
Edinburgh Clinical Trials Unit, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
Kirsteen
K
Goodman
Edinburgh Clinical Trials Unit, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
Allan
A
Walker
Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
Jemma
J
Hudson
Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
Graeme S
GS
MacLennan
Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.|Manchester Royal Infirmary, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
Peter L
PL
Selby
Department of Medicine, University of East Anglia, Norwich, UK.
William D
WD
Fraser
Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.|Edinburgh Clinical Trials Unit, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
Stuart H
SH
Ralston
D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D000700:Analgesics / Q000627:therapeutic use; D004164:Diphosphonates / Q000627:therapeutic use; D005260:Female; D050723:Fractures, Bone / Q000150:complications; D006801:Humans; D008297:Male; D019637:Orthopedic Procedures; D010001:Osteitis Deformans / Q000097:blood / Q000188:drug therapy / Q000628:therapy*; D010146:Pain / Q000188:drug therapy; D011788:Quality of Life
D000700:Analgesics; D004164:Diphosphonates; D000469:Alkaline Phosphatase
BISPHOSPHONATES; CLINICAL TRIAL; PAGET'S DISEASE OF BONE; QUALITY OF LIFE; TREATMENT