Intensive Bisphosphonate Treatment in Paget’s Disease Lacks Clinical Benefit

Patients with Paget’s disease of bone (PDB) who received intensive bisphosphonate therapy aimed at normalizing bone turnover did not receive more clinical benefit than patients with PDB who received bisphosphonates only as symptomatic treatment for bone pain when analgesics were inadequate. Results from the multicenter randomized controlled PRISM-EZ trial were published ahead of print in the Journal of Bone and Mineral Research.¹

In the study, 502 patients with PDB were divided into 2 groups with distinct management strategies. The symptomatic treatment group (n = 232) received medication only in the case of bone pain, using analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs) first, with subsequent bisphosphonates if pain control was not achieved. The intensive treatment group (n = 270) received bisphosphonates sufficient to reduce and maintain serum alkaline phosphatase (ALP) levels within the normal range.

The study population was made up of patients who completed a previous study, Paget’s Disease: Randomized Trial of Intensive versus Symptomatic Management (PRISM). PRISM employed the same treatment strategies but allowed for the use of any licensed bisphosphonate, with a preference for risedronate as first-line treatment. PRISM-EZ used the more potent zoledronic acid as the treatment of choice in the intensive treatment arm. Patients who participated in PRISM-EZ continued with the same treatment group they were originally randomly assigned to in PRISM.

Clinical fractures were chosen as the primary end point; secondary outcomes were orthopedic procedures, serum total alkaline phosphatase (ALP) concentrations, bone pain, and health-related quality of life. Results showed a nonsignificant excess of fractures (adjusted hazard ratio [AHR) 1.90; 95% CI, 0.91 to 3.98; P =.087), orthopedic procedures (AHR 1.81; 95% CI, 0.71 to 4.61; P =.214), and serious adverse events (relative risk 1.28; 95% CI, 0.96 to 1.42) in patients in the intensive group.

No significant difference between the treatment arms was found for quality-of-life measures or bone pain. “We also found that in both treatment groups, patients who suffered fractures were more likely to have received bisphosphonates than those who had not suffered fractures,” the investigators wrote. “Because the number of events was small it is difficult to draw firm conclusions, but the data raise the possibility that prolonged suppression of bone turnover in PDB might increase the risk of fracture.”

The most recent clinical practice guideline from The Endocrine Society and the European Society of Endocrinology, published in 2014, recommended that most patients with active Paget’s disease deemed at risk for future complications be treated with a bisphosphonate.² In an email interview, PRISM-EZ co-investigator Stuart Ralston, MD, told Rheumatology Advisor that this recommendation was not based on the evidence, and instead represented the unsubstantiated opinion of the expert group. “It is quite frequent for patients with PDB to get bisphosphonates since it’s been known for years that they can help bone pain. The issue with the Endo guidelines is that they were implying everyone with PDB should get bisphosphonates with the aim of lowering ALP irrespective of symptoms. The previous evidence never supported that and PRISM-EZ shows the advice is misplaced.”

Summary and Clinical Applicability

“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 investigators concluded. “The results of this study,” they added, “suggest that in patients with established PDB, bisphosphonate therapy should focus on control of symptoms rather than suppression of bone turnover.”

Study Limitations

• Despite the excess of fractures and orthopedic procedures in the intensive group, the number was small and may have been a chance finding.
• Only one-half of patients from PRISM took part in PRISM-EZ.
• Because most patients in the study cohort had already received bisphosphonates and experienced complications from PDB, the findings may not be applicable to bisphosphonate-naïve patients with early PDB.

Disclosures

Dr. Ralston has received consulting fees on behalf of his institution from Novartis and Merck, and research grants to his institution from Amgen, Eli Lilly, and UCB. Dr. Fraser has received consultancy fees from Siemens, Becton Dickinson, and Roche. Dr. Selby has received consultancy fees from Internis.

References

1. Tan A, Goodman K, Walker A, et al. Long-term randomized trial of intensive versus symptomatic management in Paget’s disease of bone: the PRISM-EZ study [published online February 8, 2017]. J Bone Miner Res. doi:10.1002/jbmr.3066
2. Singer FR, Bone HG, Hosking DJ, et al. Paget’s disease of bone: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(12):4408-4422. doi:10.1210/jc.2014-2910

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