Costantini et al write about early onset osteoporosis (EOOP), a group of conditions of diverse origins. Their aim is to "guide through the various steps in the clinical and genetic diagnostics of EOOP" and "to provide clarity to diagnostic approaches and elucidate the clinical, genetic, a bone tissue features of EOOP", while admittedly focusing on several monogenic for of EOOP. The manuscript addresses an interesting and important topic that deserves more clarification. The writing is generally clear.

While the authors briefly describe EOOP as being quite heterogeneous, including childhood forms as well as forms in young men and women, they spend essentially no time considering this heterogeneity, the broad scope of EOOP or the challenges it presents to clinicians. Rather, they concentrate a few specific and quite unusual genetic causes. While their summary of these few causes is interesting, it seems quite inappropriate to call this a review of EOOP. Rather, it includes a brief review of several of the more rare, monogenic causes of osteoporosis. By undertaking the review of these few monogenic disorders, the overall issue of EOOP is not effectively addressed.

One of their intents is to clarify the clinical and diagnostic approaches to EOOP. As above, they spend little time considering EOOP apart from the several monogenic disorders they have chosen to cover. The brief, general discussion of genetic diagnostic methods is not tailored to either the problem of EOOP or to the specific genetic causes they concentrate upon, so is not particularly helpful. They don't consider thorny issues in EOOP. For instance, in what patients is a bone biopsy helpful, in exactly what patients should genetic testing be performed and what panels should be used, and practically when should exome sequencing be considered (among a variety of others)? As they conclude, there is little if no experience in the treatment of the rare genetic disorders they chose to concentrate on and a review of treatment approaches of EOOP is not attempted. In essence, the review is not particularly helpful from a clinical perspective.

The section on bone tissue abnormalities is potentially interesting in a research setting, especially if it were to provide insight concerning the biology of the underlying disorders being considered. But their discussion is based on only 2 patients (one with OI and another with a WNT1 variant). Certainly, those 2 patients can't be considered representative of EOOP! While the authors state that "bone biopsies gives valuable information to....distinguish EOOP from other bone fragility disorders,..." they present no documentation for the statement or how to use bone biopsy information in the context of either EOOP of the genetic disorders they consider.

Page 6 line 22. Immediately before, the authors appropriately point out that the diagnosis of osteoporosis in children is not well established. Yet, here they present fairly rigid definitions based on a specific fracture history and BMD criteria. I would urge them to be less dogmatic with these criteria and rather to suggest that clinicians consider the suggested criteria, recognizing that there are, to date, no hard and fast, well established criteria.

Page 6 line 22. Since osteomalacia can present with low BMD and fractures, it would be ideal to mention that osteomalacia must be considered before the diagnosis of osteoporosis is made.

The attempt to use the information on WNT1, PLS3 and SGMS2 variants to understand EOOP is not successful. With major changes, perhaps this could be transformed into a review of those three genes and bone disorders that result from their genetic variants?

Constantini et al. have revised their review of EOOP, and it is considerably improved. The clarification of the intent of the manuscript, and the more obvious focus on the monogenic causes of EOOP, are important changes. The review serves as a useful consideration of the monogenic causes of EOOP on the background of the larger group of patients with the disorder.

I have one remaining concern and suggestion. While the authors appropriately discuss the value of bone biopsies in understanding the pathophysiology of the monogenic disorders, it seems that the clinical role of bone biopsy in EOOP remains unclear and problematic. In this reviewer’s experience and understanding of the literature, among all the patients <50 yrs with osteoporosis, many have secondary causes, a small fraction has identifiable genetic causes, and many have idiopathic disease. Of those few with genetic causes (that are not OI) would the authors suggest they all have bone biopsies, and if so, why? And, do the authors suggest that bone biopsies should be done in all of the large group of patients with idiopathic disease? It would appear so, since they state that biopsies are indicated when “the cause of the osteoporosis or fractures is unclear, when the presentation is unusual or fractures continue despite therapy”. If this is their intent, and since this is a potentially a very large number of patients, they should be clear how the information will be used and that those uses are solidly justified. For instance, is it known that the results of bone biopsies are really useful in determining effective therapy in this group? That has not been the case in other forms of osteoporosis. In the general field of osteoporosis, the clinical role of bone biopsy has become quite restricted, and if the authors are arguing that it has a much larger role in this patient group, they should present a stronger justification.

Costantini et al have revised the manuscript. Although somewhat more clear about the role of bone biopsy, there continues to be ambivalence, and statements are still included that are difficult to support. In Section 6 a statement was added that bone biopsies are not easily available, but foregoing statements in the paragraph are still not easy to defend and imply that biopsies are useful in the clinical management of EOOP. For instance, in the text that starts “In other forms of primary EOOL the analysis of a bone biopsy ……” there are suggestions of the usefulness of biopsies. Can they support the claim that bone biopsy is “indicated”? That it is important to do a bone biopsy to differentiate low and high turnover states, especially when bone turnover markers are available? Their own case 1 illustrates a situation in which the low bone turnover state could not be interpreted clinically. Can they back up the claim that bone biopsy can, or should, help to evaluate treatment effects? Later in the section the text “….in the future be translated to general management guidelines in the specified monogenic forms of EOOP, as already is the case with OI.” In fact, I don’t know that biopsies have any role in the management of OI. I suggest they remove discussions of the clinical usefulness of bone biopsies, and limit the consideration of bone biopsies to the purely research situations in which they might contribute to understanding basic disease causation.