Fractures at Diagnosis in Infants and Children With Osteogenesis Imperfecta.

To the Editor: We welcome the opportunity to provide a response to Dr Paterson’s letter1 in which he raised some concerns regarding a recent publication we coauthored.2 We would like to take this opportunity to address the concerns raised by Dr Paterson and to provide some broader context for the issues at hand. Dr Paterson raised 2 concerns about our recent study in which medical records of infants and children with a known diagnosis of osteogenesis imperfecta (OI) were reviewed to assess the number and location of fractures at the time of initial diagnosis. The 2 concerns raised by Dr Paterson stem from a misunderstanding of our study’s purpose and our conclusions. We would like to address each concern raised by Dr Paterson individually. First, Dr Paterson expressed a concern regarding a surveillance bias embedded in our study. His concerns were that we could possibly have underascertained the presence of rib fractures by not reviewing the primary radiographs; particularly in children with a known diagnosis of OI. As we noted in our limitations, we endorsed caution given the possibility of fractures being present which were simply not identified or even radiographed. A Referral Bias is when the evaluation of a cohort under study is particular to a specific local practice pattern. A Surveillance Bias (or Sample Bias) is when the cohort under study does not adequately reflect the spectrum of disease within the target population. These are 2 of the many potential sources of bias in clinical research designs. We recognize that Dr Paterson is quite familiar with the issue of Referral Bias and Surveillance Bias as much of his work promoting temporary brittle bone disease (TBBD) has suffered from them. As we were quite aware of a potential of either a Referral Bias or Surveillance Bias, we urged caution in overinterpreting our conclusions and recommended that similar studies be carried out by other independent investigators on other cohorts of children with OI. We agree that infants or children with a known diagnosis of OI will likely have a limited radiographic evaluation to minimize lifetime radiation exposure. To overcome this, we were interested in the presence of fractures in infants or children before their diagnosis of OI, thus they would likely have similar imaging patterns as other children without a subsequent diagnosis of OI. We were not interested in lifetime fracture patterns as the limited imaging would likely result in a Study Examination Bias or Image-based Selection Bias. Dr Paterson’s concern about rib fractures being present at birth as a result of bone fragility from OI, and the inclusion of the chest radiograph demonstrating this point, are somewhat baffling. First, we agree that rib fractures can occur in children with OI as a result of birth. In fact, in our paper we clearly demonstrate that within our cohort we identified 22% (15 of 68) of our subjects had rib fractures, and that 87% of those with rib fractures were identified at birth (ie, neonates). This reinforces the idea that birth is a physically brutal process and that for infants with skeletal fragility, birth is a significant stress on their skeleton. The physical forces associated with birth support the idea that infants who develop skeletal fractures during early infancy, but not from birth itself, likely do not have significant bone fragility present at birth. This is further evidence against the TBBD theory embraced by Dr Paterson. In addition, Dr Paterson uses a chest radiograph of a neonate (which he apparently used in a prior publication) with OI type III to support his contention that rib fractures “may occur spontaneously. ” It is well described, even by Dr Paterson himself,4 that neonates with OI type III have significant skeletal fragility and that fractures at birth (in utero or as part of the birth process) are common. As this neonate had multiple fractures in various stages of healing on a radiograph obtained at birth, it does not present a compelling example of a “spontaneous” rib fractures or a potential misdiagnosis of physical abuse. The second concern expressed in Dr Paterson’s letter is that we did not include other potential sources of bone fragility as a cause of fractures within our cohort. Dr Paterson simply misunderstands our study design. As a retrospect chart review, our case designation was infants or children with a diagnosis of OI, and we were interested in their fracture number and pattern. Our primary aim was not to look for all potential sources of bone fragility in infants and children, but simply to describe the fracture number and pattern in infants and children at the time they were diagnosed with OI. The conclusions from our paper are limited to the potential diagnosis of OI and it would be improper for us to extrapolate our data to other disease conditions. This question of alternative explanations for fractures in infants raises an underlying issue. It is specious to report that “rib fractures during infancy have a wide differential diagnosis. ” Outside of the neonatal period there is quite a narrow differential diagnosis for rib fractures in infants. Dr Paterson has endorsed many alternative causes for fractures in infancy, including osteopenia of prematurity, vitamin D deficiency, and OI, with the most notable being TBBD. While osteopenia of prematurity, vitamin D deficiency, and OI can be a source of bone fragility in a very small number of infants or children, TBBD remains an implausible entity. As many children with seemingly unexplained fractures are parties in a judicial process assessing the potential for physical abuse, it is The authors declare no conflicts of interest. LETTER TO THE EDITOR