Simple quantification of bone disorganization from routine x-rays allows identification and monitoring of the severity of bone disease in patients with hypophosphatasia.

Abstract

Objective-As BMD and bone structural assessment are typically within normal range in patients with hypophosphatasia (HPP), a critical unmet challenge remains the lack of a tool to accurately quantify the severity of bone disease in these patients. In HPP, as there is loss of function mutations in tissue non-specific alkaline phosphatase (TSNAP). It is reasonable to assume that this leads to impair ability to properly organise (arrange, align) bone. A disorganised bone is abnormally shaped (deformed), damage-prone, and fragile (1) - All features of HPP. Hence, we hypothesized that measurement of the extent of bone disorganization provides a mean for identifying patients with HPP and quantifying the severity of the disease. Methods-We studied 6 adult patients with HPP and 30 age-, and sex-matched controls, mean age 48 Yrs (IQR 23-53). The extent of disorganization and features of the most misarranged areas were assessed on femoral X-rays using a novel validated tool (ALIGNOGRAM) (2). Results- Bone Material was markedly (~3-fold) more disorganized in HPP; Mean Disorganization Values (DVs) (+/-SEM) were 3.17 1.1(IQR=2.37-4.03) in HPP vs 1.1(IQR=0.83- 1.14) in controls, respectively P<0.0001) (Fig). There were many abrupt spiky peaks with excessively high DVs. These allowed us to identify relatively transverse subtle bands (barely visible unless detected by the tool). These bands were either small lucent lines suggestive of micro (early-stage) fractures, or opaque lines corresponding to micro-sclerosis (Fig, panel A). No strikingly disorganized areas were detected in controls ((Fig, panel B).). Similar findings were observed for the external shape with a periosteal surface 3-fold more disorganized in patients with HPP. Conclusion- Disorganization (misarrangement) is a distinct cause of bone diseases; this abnormality should be considered, especially when traditional parameters such as BMD or bone architecture are normal. Indeed, disorganized bone is a quantifiable feature of HPP. Moreover, this measurement can be done from standard X-RAYS readily available worldwide. This may offer a way for easy, early routine identification of HPP patients in clinical and research settings; and perhaps better monitoring of response to therapy. Detection of microfractures (early stage) or tiny looser zones barely visible to the naked observed in these patients offers the opportunity for early intervention, which may revolutionize HPP treatment. Larger studies are underway.