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Intensive bisphosphonate therapy no better than symptomatic therapy in Paget's disease
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In adults with Paget’s disease of bone, intensive treatment with bisphosphonate therapy yielded only transient and clinically insignificant benefits for pain and quality-of-life measures vs. symptomatic treatment, according to findings from an extension of the PRISM study.
[Intensive] bisphosphonate therapy to maximally suppress bone turnover in Paget’s disease is of no benefit and probably is harmful,” Stuart H. Ralston, MD, FRCP, FMedSci, FRSE, professor of rheumatology at the MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, told Endocrine Today. “That might be due to oversuppression of bone turnover, as we know that too much bisphosphonate for too long can actually lead to fractures.”
Ralston and colleagues analyzed data from 502 patients enrolled in a 3-year extension of the PRISM study (PRISM-EZ). Patients in the intensive treatment arm received zoledronic acid as the treatment of first choice (n = 213); patients in the symptomatic arm received bisphosphonate therapy only if bone pain due to increased disease was present (n = 191). Both groups received analgesics and nonsteroidal anti-inflammatory drugs as required. Primary outcome was clinical fracture; secondary outcomes included orthopedic procedures, serum total alkaline phosphatase, bone pain and health-related quality of life. The cohort was followed for a mean of 7.3 years over the course of during both PRISM studies.
Researchers observed no sustained between-group differences in quality-of-life measures, as changes favoring the intensive group were observed for year 1 only. Changes in the physical component summary score (mean increase of 1.6) and the arthritis-specific health score (mean increase 2.7) were observed for year 1 only in the intensive treatment group, as were differences in physical function and bodily pain. The proportion of patients with bone pain were not different between groups.
Researchers observed a nonsignificant excess of fractures in the intensive treatment group vs. symptomatic group (22 vs. 12; HR = 1.9; 95% CI, 0.91-3.98), as well as orthopedic procedures (15 vs. 7; HR = 1.81; 95% CI, 0.71-4.61).
In an exploratory analysis evaluating possible associations between bisphosphonate use during PRISM-EZ and skeletal events, researchers found that fractures were more common in patients receiving bisphosphonates in the intensive group (12.7% vs. 3.1%), the symptomatic group (12.7% vs. 0) and in both groups combined (14.1% vs. 1.5%).
“The results reported here do not support the recommendations made by the Endocrine Society guideline group, which suggested that most patients with [Paget’s disease of bone] should be treated with potent bisphosphonates with the aim of restoring [alkaline phosphatase] values to within the lower part of the reference range,” the researchers wrote. “On the contrary, the PRISM-EZ study demonstrates that this strategy is not associated with clinical benefit and might be harmful. Rather, the data from PRISM-EZ suggests that a more appropriate indication for bisphosphonate treatment in [Paget’s disease of bone] is to control bone pain thought to be due to disease activity.”
Ralston said it is important to treat the patient, not the serum level of alkaline phosphatase.
“The study shows that, in patients with well-established disease, you should focus on symptom control,” Ralston said. “What we don’t know is if bisphosphonate treatment in early, asymptomatic disease is beneficial.”
Ralston and colleagues are currently conducting a prospective trial, Zoledronate in the Prevention of Paget's (ZiPP), which aims to determine whether bisphosphonate therapy can prevent Paget's disease in people with SQSTM1 genetic mutations. The ongoing study is expected to run through January 2020, he said. – by Regina Schaffer
For more information:
Stuart H. Ralston, MD, FRCP, FMedSci, FRSE, can be reached at the Centre for Genomic and Experimental Medicine at the University of Edinburgh, EH4 2XU, United Kingdom; email: stuart.ralston@ed.ac.uk.
Disclosure: Ralston reports receiving consultant fees on behalf of his institution from Merck and Novartis and research grants to his institution from Amgen, Eli Lilly and UC. Please see the full study for the other authors’ relevant financial disclosures.
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