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Targeting Paget’s bone symptoms supported in long-term trial

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No need to force alkaline phosphatase down

The PRISM-EZ study is the largest and longest study of PDB and provides important information on its long-term management. The results need to be kept in perspective. All patients were treated; hence, there is no untreated group and the results apply to follow-up therapy only. In this group, repeat therapy for active PDB as measured from serum total alkaline phosphatase (ALP) versus therapy for symptoms did not make a difference in a 3-year follow-up, and the authors recommend treating only when symptoms warrant it. Longer follow-ups would be needed to definitively show a difference in a condition that is present for many years.

Dr. Roy D. Altman

However, the results do suggest that the initial course of therapy may contain the most protection. Forcing the serum total ALP down suggests risks of complications from their data. The Endocrine Society guideline group may wish to modify their guidelines.

Roy D. Altman, MD , is professor emeritus of medicine in the division of rheumatology and immunology at the University of California, Los Angeles. He has no relevant disclosures.



Long-term intensive bisphosphonate treatment of patients with Paget’s disease of bone continued to show no benefit over symptomatic treatment in a 3-year extension trial of the PRISM study, leading investigators in the trial to recommend that treatment guidelines focus more on managing the condition’s symptoms rather than normalizing bone turnover biomarkers in hope of reducing disease complications.

“The Paget’s Disease Randomized Trial of Intensive versus Symptomatic Management (PRISM) study showed that intensive bisphosphonate therapy and symptomatic treatment had similar effects on clinical outcome of PDB [Paget’s disease of bone] with respect to the occurrence of fractures, orthopedic procedures, hearing loss, bone pain, quality of life, and adverse events,” wrote the principal investigator of the PRISM-EZ (extension with zoledronic acid) phase of the trial, Stuart H. Ralston, MD, of the University of Edinburgh (Scotland), and his colleagues.

Dr. Stuart H. Ralston

Dr. Stuart H. Ralston

Dr. Ralston and his coinvestigators invited 949 of the 1,324 PDB patients who took part in the PRISM trial to enroll in the 3-year PRISM-EZ trial, and 502 did, including 232 (48%) patients who completed treatment in the symptomatic arm of PRISM and 270 (54%) who completed treatment in the intensive arm of PRISM (J Bone Miner Res. 2017 Feb 8. doi: 10.1002/jbmr.3066).

Enrollment in the extension trial, which occurred during January 2007-January 2012, meant that patients kept to the same treatment strategies except for those in the intensive arm, who switched to zoledronic acid as the treatment of first choice. Both groups received analgesics and nonsteroidal anti-inflammatory drugs as needed. Patients in the symptomatic arm received bisphosphonate treatment only if they had bone pain thought to be caused by the increased metabolic activity of PDB, whereas those in the intensive arm were prescribed “bisphosphonates as required to suppress and maintain ALP [alkaline phosphatase] concentrations within the normal range,” according to the investigators. Clinical fracture rate was the primary outcome, but Dr. Ralston and his colleagues also compared orthopedic procedures, serum total ALP concentrations, bone pain, and quality of life in both cohorts.

A higher proportion of patients in the intensive group received zoledronic acid than in the symptomatic group (28.1% vs. 10.3%; P less than .001), whereas fewer patients in the intensive group received pamidronate (4.8% vs. 15.5%; P less than .001).

Of 270 in the intensive cohort, 22 (8.1%) experienced fractures, versus 12 (5.2%) of the 232 in the symptomatic cohort, yielding a hazard ratio of 1.90 (95% confidence interval, 0.91-3.98; P = .087). Of those, fractures in the pagetic bone numbered five and two, respectively. A total of 15 (5.6%) intensive treatment subjects and 7 (3.0%) symptomatic treatment subjects required orthopedic surgery, with a hazard ratio of 1.81 (95% CI, 0.71-4.61; P = .214).

This is a high magnification micrograph of Paget's disease of bone. Nephron/Wikimedia Commons/CC-ASA 3.0

This is a high magnification micrograph of Paget's disease of bone.

Adverse events occurred at similar rates, totaling 226 (83.7%) with intensive treatment and 196 (84.5%) with symptom-driven treatment. However, serious adverse events numbered only 87 (32.2%) and 66 (28.4%), respectively, for a relative risk ratio of 1.28 (95% CI; 0.96-1.72). Serum total ALP levels were more often in the normal range, as expected, for patients in the intensive cohort based on having 3 (1.1%) with “very high” levels, 62 (23.8%) with “high” levels, and 100 (38.3%) with “normal” levels, compared with the symptomatic cohort in whom 8 (3.6%) had very high levels, 73 (32.6%) had high levels, and 66 (29.5%) had normal levels.

There were no differences in bodily pain, bone pain, or quality of life at year 3 as reported by patients in both cohorts. While there was a statistically significant difference between intensive and symptomatic treatment in bodily pain, physical component summary score, and arthritis-specific health index scores at year 1 of the trial, the investigators noted that the findings were below the clinically significant five-point threshold and did not persist beyond 1 year.

“The results reported here do not support the recommendations made by the Endocrine Society guideline group, which suggested that most patients with PDB should be treated with potent bisphosphonates with the aim of restoring ALP values to within the lower part of the reference range,” the authors concluded. “On the contrary, the PRISM-EZ study demonstrates that this strategy is not associated with clinical benefit and might be harmful, [so] a more appropriate indication for bisphosphonate treatment in PDB is to control bone pain thought to be due to disease activity.”

The study was funded by grants from Arthritis Research UK and the Paget’s Association. Dr. Ralston reported receiving consultancy fees on behalf of his institution from Novartis and Merck and grant support on behalf of his institution from Amgen, Eli Lilly, and UCB. One coauthor reported receiving consultancy fees from Siemens, Becton Dickinson, and Roche, and another disclosed receiving such fees from Internis.

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