Long‐Term Randomized Trial of Intensive Versus Symptomatic Management in Paget's Disease of Bone: The PRISM‐EZ Study

Abstract

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 progression 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 three-year extension of the Paget's Disease: Randomised Trial of Intensive versus Symptomatic Management (PRISM) study. Intensive bisphosphonate therapy was continued in 270 of these subjects with the aim of normalising serum total alkaline phosphatase (ALP) concentrations using zoledronic acid as the treatment of first-choice. Symptomatic treatment was continued in 232 subjects where bisphosphonates were given only if there was bone pain thought to be caused by PDB. The primary outcome was fracture and secondary outcomes were orthopaedic procedures, quality of life and bone pain, adjusted for baseline characteristics. Serum total 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 non-significant increase in fracture risk (hazard ratio We conclude that long-term intensive bisphosphonate therapy confers no clinical benefit over symptomatic therapy and is associated with a non-significant increase in the risk of fractures, orthopaedic 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.

Diagnosis and Management of Paget's Disease of Bone in Adults: A Clinical Guideline

“…There is no clear evidence regarding the risk of ONJ after use of intravenous bisphosphonates for PDB, although one case was reported in the PRISM-EZ study in a patient who received intensive bisphosphonate therapy. (113) Atypical femoral fractures (AFF) are thought to be a class effect of bisphosphonates; as of 2017, the EMA had received only one report of an AFF in a patient with PDB. The authors of the Cochrane review speculated that the infrequent occurrence of ONJ and AFF in PDB might be related to the fact that patients tend to have intermittent or short-term courses for treatment of the disease.…”

“…The PRISM-extension with zoledronic acid study (PRISM-EZ) employed the same strategy as in PRISM, but zoledronic acid was used as the treatment of first choice in the intensive arm. (113) Patients within PRISM-EZ maintained the same treatment allocation as they had been randomized to in PRISM. The PRISM-EZ study followed 270 patients in the intensive group and 232 in the symptomatic group, providing an average total duration of 7.3 years follow-up since the beginning of the PRISM study.…”

“…Fractures through Pagetic bone occurred in 8 of 661 (1.2%) of the intensive group and 13 of 663 (2.0%) of the symptomatic group (RR ¼ 0.62, 95% CI 0.22-1.60). In the PRISM-EZ trial, (113)…”

Effect of technetium‐99 conjugated with methylene diphosphonate (99Tc‐MDP) on OPG/RANKL/RANK system in vitro

“…It therefore plays an important role in the development of those diseases . Bisphosphonates have obvious curative effects for the treatment of related bone resorption diseases caused by osteoclasts, such as aneurysmal bone cyst, Langerhans cell disease, giant cell tumor, osteoporosis, Paget's disease, Gorham's disease, SAPHO syndrome, osteofibrous hyperplasia, and other bone‐derived tumors . This indicates that bisphosphonates have a therapeutic effect on osteoporosis‐associated bone resorption diseases.…”

Clinical Guidelines on Paget's Disease of Bone

“…Nothing could be further from the truth. Neither symptoms nor complications have been shown to align with biochemical markers of bone turnover in Paget's disease, and, indeed, it has been reported that clinical relapse often occurs after treatment with zoledronic acid in patients who are in “biochemical remission.” With regard to values and preferences, patients are hardly likely to be reassured by the fact that their blood test is normal when they have symptoms that require attention. Another example is conditional recommendation 3.6, which stated that “we suggest treatment with a bisphosphonate in patients with Paget's disease and congestive heart failure” supported by low‐quality evidence.…”