Clinical Guidelines on Paget's Disease of Bone

To the Editor

As authors of the recently published clinical guideline on the diagnosis and management of Paget's disease1 we were delighted to see that our article was thought by the Editors of JBMR to be of sufficient interest to warrant an editorial.2 However, we were astonished to read in the editorial that “the new PDB guideline is a review more than a clinically relevant guideline” apparently because we did not make recommendations where there was a lack of evidence, unlike the 2014 Endocrine Society Guideline.3

It's certainly true that the two guidelines differed in approach. Ours primarily focused on patient relevant outcomes such as pain, fractures, deformity, quality of life, and deafness, whereas the Endocrine Society document primarily focused on biochemical markers and other surrogate endpoints. They also differed in methodology and in the interpretation of the strength of evidence that was available. A summary is provided in Table 1. Of the many differences, one of the most striking is the strength of evidence assigned to support recommendations. This is due to the fact that the Endocrine Society Guideline assigned strengths of evidence that were out of keeping with the GRADE framework in many instances. Some recommendations were also made that lacked an evidence base as has previously been pointed out.4

For example, recommendation 2.6 in the Endocrine Society document stated that “biochemical follow-up should be used as a more objective indicator of relapse than symptoms” with moderate quality of evidence. This implies that there is evidence from randomized controlled trials (RCTs) and/or strong evidence from unbiased observational studies to show that there is alignment between biochemical markers of bone turnover and clinical outcome in Paget's disease. 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,5, 6 and, indeed, it has been reported that clinical relapse often occurs after treatment with zoledronic acid in patients who are in “biochemical remission.”7 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. This suggests that there is evidence from observational studies, from RCTs with serious flaws, or indirect evidence to show that bisphosphonate therapy is effective in treating heart failure in Paget's disease. There is actually no evidence for this recommendation whatsoever. The supporting literature cited was a study of calcitonin on cardiac output in 6 patients with Paget's disease who did not have congestive cardiac failure.8 We very much hope that physicians would ignore this advice and use diuretics, ACE inhibitors, or beta-blockers in patients with Paget's disease of bone who have congestive cardiac failure according to standard clinical practice.

The GRADE framework provides a transparent and structured approach to reviewing evidence and making recommendations so that they can be trusted by clinicians and patients alike. There is no place within this framework for expert opinion making recommendations without an evidence base. That is why we did not make a recommendation when we identified gaps in the evidence. Our view was that it is best to recognize these gaps so that they can be addressed by future research. Such research is perfectly feasible with imaginative study designs given that Paget's disease is not a rare condition in many countries.9

Professor Langdahl argues that even in the absence of evidence, knowledge of bone physiology and pharmacology might allow an experienced clinician to guess about the likely effect of treatment on clinical outcome in Paget's disease. This is simply not true. There is no way that the effects of treatment on outcomes such as progression of osteoarthritis, bone deformity, or progression of deafness can be predicted on this basis. Answers to those questions require clinical trials or well-designed cohort studies. We would all like to believe that normalizing bone turnover with the powerful bisphosphonates that we now have available can prevent complications and favorably modify clinical outcome in Paget's disease, but there is no evidence to demonstrate that they do so.10 On the contrary, the evidence available from randomized controlled trials suggests that trying to normalize bone turnover with intensive bisphosphonate therapy carries no greater benefit than symptom-directed treatment6 and in the longer term might even be detrimental for some outcomes.5 The situation could well be different in people with very early Paget's disease, but a randomized placebo-controlled trial is already in progress that will help to address this issue (the ZiPP study; ISRCTN 1161677011) and allow a recommendation to be made.

An example of the limitations of expert opinion and non-evidence-based treatment in another focal bone disease was recently provided by the study of Florenzano and colleagues,12 which coincidentally appeared in the same issue of JBMR as the new Paget's disease guideline. These authors reported that the commonly used practice of giving bisphosphonate therapy to children with fibrous dysplasia in an attempt to modify natural history of the disease had no demonstrable effect on disease progression or disease burden, contrary to what one might expect from knowledge of bone physiology and pharmacology.

Following treatment recommendations that are not evidence-based might make doctors feel better because they think they are “doing something,” but such an approach carries the risk of not making things better and causing patients harm. Clinicians that choose to pursue an empirical approach to treatment for outcomes for which there is no evidence of benefit in Paget's disease should do so only after they make it crystal clear to the patient that they are using guesswork to guide their decisions and explain that the treatment on offer may not be beneficial and could be harmful.