Guidelines for the Diagnosis and Management of Paget's Disease: A UK Perspective

Since its foundation in 1973, The National Association for the Relief of Paget's Disease (NARPD) has dealt with numerous questions from its members and other people suffering with Paget's disease. One of the most common questions raised in the United Kingdom has been how to deal with a doctor or other health care professional who either does not believe that Paget's disease is a serious clinical problem or who does not believe that treatment for the condition is warranted. To address these issues, the NARPD decided to develop clinical guidelines for the diagnosis and management of Paget's disease. These guidelines were developed as a joint venture with the Bone and Tooth Society (now Bone Research Society) by a small writing group comprising Dr Peter Selby (chair), Professor Stuart Ralston, Dr Michael Davie, and Dr Michael Stone. Although previous UK clinical practice had been to develop guidelines on a consensual basis, the climate has changed, initially under pressure from the Scottish Intercollegiate Guidelines Network (SIGN)1 and then on a United Kingdom-wide basis with the development of the National Institute for Health and Clinical Excellence (NICE),2 so that evidence-based guidance is now necessary to influence the clinical governance. The framework for evidence-based guidance has been codified in a similar manner to the way in which the structure of clinical trials has been laid down by the CONSORT collaboration.3 This has been laid out in the internationally agreed AGREE collaboration.4 This requires clinical guidelines to satisfy several criteria. These include the following: (1) clarity of scope and purpose; (2) stake holder involvement; (3) a rigorous development process using systematic searches for evidence with explicit criteria for selecting evidence and formulating the recommendations; (4) clarity of presentation; (5) consideration of potential barriers to application; and (6) editorial independence. The NARPD, in conjunction with the writing group, sought to ensure that these areas were all addressed in the development of these guidelines. To do this, a systematic review of the Paget's disease literature was undertaken, and relevant English language papers were considered by the group. The way in which recommendations were formulated on the basis of clinical evidence was according to the methods applied both by SIGN and NICE (Table 1). The recommendations produced can be summarized as follows, although for full recommendations and the grading of the evidence underlying the recommendations, the reader is referred to the published guidelines document.5 The diagnosis of Paget's disease is primarily a radiological diagnosis, and at least one skeletal site should have plain X-rays taken to establish the diagnosis. Any painful areas should be examined using plain radiographs. Full skeletal survey is generally not appropriate, but it is appropriate to offer skeletal scintigraphy to assess the extent of skeletal involvement. For most cases, total alkaline phosphatase is sufficient for monitoring the activity of the disease, but in patients with pre-existing liver disease or plasma alkaline phosphatase activity within the normal range, bone-specific alkaline phosphatase is recommended. Histological diagnosis is rarely necessary. Primary treatment is suppression of bone turnover using bisphosphonates. At the time of writing, oral tiludronate or risedronate or intravenous pamidronate were the recommended agents. Zoledronic acid was not available for treatment of Paget's disease at the time the guidelines were written and so is not considered in this document but will form part of any revision. Oral etidronate was specifically not recommended. Calcitonin, plicamycin, and a variety of other agents not licensed in Paget's disease were also specifically not recommended in routine management. The primary indication for treatment was bone pain, where there is good evidence of treatment effect. Although there is less evidence of treatment effect for many of the other commonly accepted indications for treatment of Paget's disease, it was felt that it was reasonable to offer treatment for patients with asymptomatic disease of the skull base because there was some evidence to suggest this might halt the progression of deafness, but that once the deafness had supervened, no treatment could reverse the hearing loss. In most cases, this can be undertaken using total alkaline phosphatase activity, although in those patients where the use of bone-specific alkaline phosphatase was recommended (see above), this should be used to monitor treatment. It is generally accepted that a fall of 25% in the biochemical marker indicates a significant response to treatment; however, there is no evidence to support what the actual goal of treatment should be. There is evidence of the effectiveness of retreating patients who have relapsed after treatment with a bisphosphonates. Retreatment should not be offered until at least 6 months after the initial treatment course. It can be offered to patients with recurrent symptoms or an increase in alkaline phosphatase activity (total or bone-specific-see above) of 25% above nadir. Compared with the more traditional consensus-based approach to guideline development, our process has resulted in a robust, evidence-based set of guidance for the treatment of patients with Paget's disease. This ensures their acceptability by funding and reimbursement agencies that are not willing to resource health care for those people in whom there is no evidence of clinical effectiveness. Conversely, they do not offer guidance in those areas where there is no clinical evidence. As a result of this, many patients who would have received treatment as a result of more consensual guidance would be denied treatment by slavish adherence to these guidelines. In most cases, this is not caused by evidence of lack of effect of treatment but merely that there is no evidence one way or the other in that particular circumstance. Clearly, any such guidance should not be taken as denying the possibility of a treating physician doing what is considered best for their patients, but unfortunately, this is the way in which such guidance is often interpreted by funding bodies. However, the very fact that the guideline development process has shown these areas of uncertainty in the evidence base underpinning the management of Paget's disease has been an important stimulus in its own right. It was as a result of the systematic review of evidence undertaken to inform this guideline development process that these areas of uncertainty were brought to light. The appropriate response to such uncertainty in the clinical field is to develop further evidence to inform that situation. The gaps that were identified in the evidence regarding treatment of Paget's disease led members of the guideline writing group to address this Paget's PRISM study, which aims to determine the effectiveness of intensive treatment of Paget's disease in preventing long-term complications of the condition. Thus, it can be seen that, although an evidence-based approach to guideline development in patients with Paget's disease may be seen as precluding treatment from some patients in which it has been generally accepted that treatment is beneficial, the approach has benefits in terms of supplying a rigorous justification for treating those patients where there is evidence of treatment benefit and also as a spur to further clinical study to justify those areas where clinical uncertainty has been identified.