This is an interesting paper which documents the prevalence of scintigraphic pagetic lesions in individuals identified as having SQSTM1 mutations. My comments are minor, as follows:
1. The authors have used what appears to be a unique way of reporting serum alkaline phosphatase activity. It appears in the abstract without explanation, so will not be understandable to the casual reader. This needs to be corrected. In the body of the manuscript, the description of its derivation is incomplete, and would not permit a reader to reproduce the calculations. Is it a linear scale with the upper end of each hospital’s reference range given a value of 1.0? If so, what is the reference point for “0”: is it a value of 0 or is it the lower end of the reference range? Writing this as an equation would eliminate any residual uncertainty. Have the authors used reference ranges for serum alkaline phosphatase which are age- and sex-appropriate? Postmenopausal women have a higher upper limit of normal than do younger women or men.
2. In the Abstract at line 35, reference is made to “biochemical markers”. It should be clarified that these are biochemical markers of bone turnover.
3. The statement on page 10 of 19 at line 26 that “we did not observe a delayed onset of pdb …” is not really accurate. As they go on to state, these individuals had not been diagnosed with Paget's prior to the study, and may well have not been diagnosed for many years if the study had not taken place, so in the absence of the study diagnosis may well have bene later than in their parents. Therefore, they should simply state the facts, as they do in the Abstract, and not attempt to extrapolate beyond the data.
4. The paragraph beginning at line 52 on that page implies that potent bisphosphonates are only effective in managing pagetic pain and suppression of bone turnover. This is not a widely held view, and overlooks evidence that scintigraphy, radiology and histomorphometry are all returned to normal with these interventions, and quality of life improved. This paragraph appears to be an attempt to promote the guidelines recently constructed by some of these authors against those published by the US Endocrine Society several years ago. This is not an argument that needs to take place in the context of the present paper, and the entire paragraph is probably best deleted.
5. In the final sentence of the Discussion, it is suggested that the study will yield new insights into the effects of zoledronic acid in modifying the natural history of Paget’s disease. This seems somewhat optimistic in the context of a trial that appears to only include 20 patients with Paget’s disease. The power of such a small study to demonstrate differences in complications must be open to question, so a more cautious concluding statement would be appropriate.

The authors have addressed my questions satisfactorily