Treating Paget's Disease—Why and How Much?

Paget’s disease of bone (PDB) is a benign chronic focal disorder of older people. Affected bones have greatly accelerated bone turnover, a chaotic structure, and are highly vascular. People with PDB are commonly asymtomatic but can also suffer chronic bone pain. Affected bones may become enlarged and deformed, and they are also liable to fracture. The long-term complications of the disease, which may take many years to evolve, include secondary osteoarthritis and, if the skull is affected, deafness and a need for larger hats. Rarely, thedisease undergoesmalignant transformation to osteosarcoma. Bone turnover markers, such as plasma alkaline phosphatase (ALP), are variably increased, depending on the extent of skeletal involvement and disease activity. The etiology of PDB and many aspects of its pathogenesis and natural history remain mysterious, but there have been remarkable developments in treatment, based on the availability of agents that can suppress the accelerated bone turnover. The first effective therapy for this hitherto intractable andoften disabling disorderwas calcitonin, introduced in 1968. Calcitonin’s effects were, however, incomplete and short-lived, and it was rapidly superseded by bisphosphonates, with etidronate being first used in 1973. Over the following 40 years, bisphosphonates of progressively greater potency and duration of action have been developed and introduced into clinical practice. In many parts of the world, potent bisphosphonates such as zoledronate, with their effectiveness attestedbydata from randomized clinical trials, havebecome the de facto agents of choice for treating PDB. There is good evidence that suppressing bone turnover with bisphosphonate treatment improves pagetic bone pain, heals lytic lesions, reduces bone turnover, and restores more normal bone structure. It is probable that they are also effective in the rare complication of paraparesis due to vertebral involvement. However, there is much less certainty as to whether complications such as fracture, deformity, osteoarthritis, and deafness can be prevented by the long-term suppression of abnormal bone turnover. It was in this context that theMulticentre Randomised Controlled Trial of Symptomatic versus Intensive Bisphosphonate Therapy for Paget’s Disease (PRISM) study was conceived in 2001. The stated aim of the PRISM trial was to examine whether intensive therapy with potent bisphosphonates, sufficient to give long-term suppression of bone turnover, would be superior to symptomatic treatment in improving clinical outcome and preventing complications of Paget’s disease. In the “symptomatic treatment only” arm of the study, researchers were encouraged to give analgesia or NSAIDs for symptoms and only if this strategy was insufficient to control pain to use short courses of lowormedium-potency oral bisphosphonates. In the “intensive treatment” arm, treatment with an intravenous bisphosphonate (pamidronate) was given irrespective of symptoms, with the aim of keeping bone turnover suppressed (as assessed by plasma ALP measurements). The 1324 participants were followed for a median 3 years. The results showed that, as expected, bone turnover was somewhat lower in those receiving intensive bisphosphonate treatment, but there was no observable effect on fracture, the need for orthopedic surgery, audiometry, quality of life, or bone pain (although the symptomatic treatment group did take more analgesia). The researchers concluded that striving to maintain normal ALP levels through intensive bisphosphonate treatment offered no clinical benefit above a “symptom only” approach. The trial was subject to a number of criticisms. First, it was designed and powered to compare the two regimens’ effectiveness based on the total number of fractures, not specifically fractures occurring in pagetic bone (the latter were less frequent in the intensive group). Second, the original protocol’s aim of determining if there was radiologic evidence of osteoarthritis developing or progressing in the hips or kneeswas not reported; instead, the authors reported the “need for orthopedic surgery” (mainly hip or knee arthroplasty), but did not specify whether pagetic bone was involved. Third, a high proportion of the subjects (70%) in PRISM had already been treated with bisphosphonates before the study began, so the trial could not be taken as a guide to managing treatment-na€ıve patients. Finally, the trial was too short in duration to assess realistically the rate of development of chronic complications. In response to the latter point, Tan and colleagues, in the current issue of JBMR, present a follow-up study (PRISM-EZ) of 38% of the original cohort (502 subjects) from the PRISM study, who continued in their original allocated treatmentgroups for a further 3 years, to an average follow-upof 7.3 years. The subjects in the follow-up study were drawn from the younger part of the original cohort, but nonethelesswereonaverage76 years old at entry into theextension study, andmost had disease of limited extent (two-thirds had only 1 or 2 bones involved). A surprisingly high proportion (53%) were said tohave “bonedeformity,”but it isnot clearhowthiswasdetermined. The majority of subjects in the “symptom only” arm were treated with bisphosphonates at some stage: 59% had received bisphosphonates before and 66% during PRISM; 39% received bisphosphonate treatment for PDB (most commonly pamidronate