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For Peer Review Only Expert Opinion On Pharmacotherapy For Peer Review Only Please download and read the instructions before proceeding to the peer review Management of Severe Osteoporosis Journal: Expert Opinion On Pharmacotherapy Manuscript ID EOOP-2015-0304.R1 Manuscript Type: Review severe osteoporosis, management of severe osteoporosis, treatment of Keywords: high risk osteoporotic patients, pharmacological therapy of severe osteoporosis URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 1 of 111 Expert Opinion On Pharmacotherapy 1 2 3 Reviewer Comments: 4 5 6 Referee 1: 7 8 9 This review focuses on recognition and treatment of severe osteoporosis. The high risk patients have 10 11 been defined according to author opinion and appropriate treatment to reduce their fracture risk was 12 13 revised. 14 For Peer Review Only 15 16 Several points need to be clarified: 17 18 1) Page 3; I have some concerns about the definition of severe osteoporosis and the categorization 19 20 provided by the author. In fact, at point 3, “pre-menopausal women or young men with lower extremity 21 22 fractures” are included in the group of “Osteoporosis associated with systemic diseases that are also 23 24 25 associated with low bone formation and turnover”, but it is not clear which systemic diseases the author 26 27 refers to. Moreover, chronic kidney disease are considered to be associated with low bone formation 28 29 and turnover, but this is not always the case, since in chronic kidney disease a large spectrum of 30 31 32 different bone involvement can be observed, including high bone turnover. Moreover, regarding 33 34 multiple myeloma and MGUS, multiple factors that either increase osteoclast-mediated bone loss or 35 36 suppress osteoblast-mediated bone formation have been described, but this does not imply low bone 37 38 39 turnover (see Drake MT, J Bone Miner Res, 2014). 40 41 2) Page 8 lines-55-58. The sentence seems to affirm that “first line” vs “second line” therapies are 42 43 exclusively based on health-economics; put this way, this statement appear to be rather simplistic and I 44 45 believe that reasons related to efficacy, safety, potency may concur to discriminate a first vs. a second 46 47 48 line therapy. Please, clarify. 49 50 3) Page 9, lines 39-47. This paragraph seems too generic. I do not believe that in considering parenteral 51 52 therapy for osteoporosis zoledronate, ibandronate, denosumab and teriparatide are alternative choices 53 54 55 to be put at the same level. 56 57 4) Page 11, lines 43-45. The author writes that “There is no greater risk for a second fracture once the 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 2 of 111 1 2 3 first fracture has occurred”; this is probably a mistake, since this is contrary to what known and also to 4 5 6 what is stated by the author himself several times in the text – please correct. 7 8 5) Page 11, lines 45-53. This statement is too strong. It is obvious that an intravenous route of 9 10 administration ensures that the drug is delivered to the site of action, but this applies to all drugs. The 11 12 13 sentence regarding oral bisphosphonates that “their absorbability is so erratic and uncertain” is an 14 For Peer Review Only 15 author’s opinion and this should be outlined. To my knowledge, there are no clinical trials comparing 16 17 oral and intravenous bisphosphonates in terms of how predictable are of their serum levels – please 18 19 provide supporting evidence for your statement or revise your paper appropriately. 20 21 22 6) Page 17, lines 41. Figure X regarding Cathepsin K is lacking – please ensure all figures are provided/ or 23 24 correctly cited throughout the text. 25 26 7) There are several typing errors and errors in grammar throughout the text, please carefully review 27 28 29 your paper to address these mistakes. 30 31 8) Some references mentioned in the text are incomplete and not listed in the references section, please 32 33 carefully review your paper and address these changes 34 35 36 37 38 Referee 2: 39 40 In this paper, the treatment of severe osteoporosis is reviewed. The topic is of interest, particularly at a 41 42 time when secondary fracture prevention is becoming a management priority. 43 44 45 1. The review is very US centred, please can the author provide information regarding Europe and the 46 47 Rest of World management 48 49 2. May be the WHO definition of severe osteoporosis could be extended in the future, by including other 50 51 52 risk factors. It would be interesting to know the author’s opinion with this respect – please discuss 53 54 3. « IOF and NBHA » should be read instead of the opposite (p 3). 55 56 4. p 7, line 17, the sentence should be rewritten, to provide clarity to the reader 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 3 of 111 Expert Opinion On Pharmacotherapy 1 2 3 5. p 8, medical societies other than ACR have also taken positions regarding GIOP, please discuss. 4 5 6 6. Please comment that the FDA, EMA and other agencies also have registration guidelines. 7 8 7. p 9, the registration of generics is based on similar PK and PD, and not necessarily on BMD efficacy 9 10 similarity. Could the author verify this point? 11 12 13 8. p 11, ibandronate is not registered for non-vertebral fracture. This should be specified. 14 For Peer Review Only 15 9. The spelling of denosumab should be corrected. 16 17 10. p 16, the right reference is likely Seeman and Martin, and not Eisman and Seeman, please can the 18 19 author review and correct as appropriate. 20 21 22 11. How could a wide use of bone turnover markers contribute to a better management of severe 23 24 osteoporosis? Please discuss. 25 26 12. p 20, depending on the experimental system, areal BMD could account for up to 80% of bone 27 28 29 strength variance. The 50% mentioned is not the rule, please correct. 30 31 13. How does the drug efficacy review specifically pertain to severe osteoporosis and not to 32 33 osteoporosis in general? Please make sure this is clear to the reader 34 35 36 37 38 39 40 Referee 3: 41 42 1. The review seems inaccurate, there are a lot of typos and copy and paste errors, see for example line 43 44 45 19: "Finally, the number one cause of the loss of independence in" - please carefully review your paper 46 47 for quality of English language and grammar. 48 49 2. The figures are of low quality and need to be improved before publication 50 51 52 3. Figure X cited within the text does not exist, please cite the correct figure 53 54 4. Table II is not cited, please add a citation. 55 56 5. Reference citations within the text are inaccurate, please carefully review and make changes where 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 4 of 111 1 2 3 necessary. 4 5 6 6. The author does not consider SERMs in the treatment of severe osteoporosis – please can authors 7 8 provide discussion on SERMs. 9 10 11 12 13 Editorial Comments: 14 For Peer Review Only 15 1. Please number your section headings and subheadings. 16 17 2. Small figures should be 300 dpi and large figures should be 72 dpi. 18 19 3. Please provide a copy of permission to use for each of your figures and tables from previous 20 21 22 publications 23 24 4. Please provide an article highlights box, in the form of a bulleted list of five or six statements, covering 25 26 the key aspects of your paper. 27 28 29 5. Please use “et al.” in place of fourth and subsequent authors in the reference list, and delete periods 30 31 from the end of each reference in the list. 32 33 6. Please provide a few reference annotations (*=of importance, **= of considerable importance, 34 35 36 followed by a brief sentence explaining why the reference is considered to be of interest). 37 38 39 40 41 42 Response to reviewer comments: 43 44 45 Reviewer #1 : Thank you. 46 47 48 I have removed the reference to pre-menopausal women with lower extremity fractures. For general 49 50 information, while these young otherwise healthy patients with spontaneous mid-shaft femur fractures 51 52 do represent a form of severe disease (and on bone biopsy do have very low bone formation) as 53 54 published by The Columbia University (NYC) group (Cohen A et al), and, whom I myself have 6 such 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 5 of 111 Expert Opinion On Pharmacotherapy 1 2 3 patients with similar fractures and histomorphometric findings, I am also sensitive to overstating a very 4 5 6 rare condition. 7 8 9 I have also clarified what, in my opinion constitutes “severe” osteoporosis. 10 11 12 As a nephrologist, this author is well aware of the spectrum of bone turnover in chronic kidney disease 13 14 (CKD) but the statementFor under Peer item #3 was specificaReviewlly discussing low Only bone turnover. 15 16 17 Finally, I have added reference to the osteoblast dysfunction in multiple myeloma and MGUS, including 18 19 Dr.
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