The frequency of severe type HPP, mostly the perinatal and infantile types, has been estimated to be 1 per 150,000 in Japan and North America, and 1 per 300,000 in European countries [27–30]. However, the frequency of heterozygous HPP is estimated to be 1 per 6370 in European countries [4,31]. In the present study, patients with odonto type HPP made up half of the total patients and had mostly dominant inheritance . It is estimated that many patients with odonto type remain undiagnosed. There was no significant difference in serum ALP values at diagnosis between odonto type and childhood type HPP . Additionally, dental manifestations were the first symptoms of HPP in three cases of infantile and childhood type HPP in this study. HPP is known to be a progressive disease. Patients diagnosed with odonto type HPP with only dental manifestations sometimes transition to childhood type or adult type HPP with bone symptoms as they grow up [2,13,14,24]. Early diagnosis and management of growth and development are important for HPP patients. Dentists are in a position to make an early diagnosis based on the early exfoliation of the primary incisors.
This is the first study to devise a method for quantitatively evaluating alveolar bone mineralization in orthopantomographic images taken in HPP patients. To achieve this goal, it is important to know the standard values for alveolar bone mineralization in systemically healthy subjects. Therefore, we collected data from systemically healthy subjects who came to our clinic for dental treatment or periodical examinations. When healthy patients required orthopantomographic images for treatment of dental caries, periodontal disease, or occlusal problems, the images were taken with a special step wedge constructed for the present study. Orthopantomographic images were obtained from 200 systemically healthy subjects aged 2–15 years to compare with those of 17 HPP patients.
A novel method was devised to quantitatively evaluate pixel values in orthopantomographic images using the step wedge as a reference. Different quantitative and qualitative indices calculated on orthopantomography have been proposed to screen for reduced skeletal bone mineral density (BMD) in osteoporosis [32,33]. BMD was predicted by quantitative analysis of the trabecular pattern on dental radiographs by Geraets et al. . A systematic review of the linear and quantitative orthopantomographic measures to assess the accuracy of these indices was performed by Calciolari et al. . They described limitations related to differences in the experience and agreement between different operators and the different image quality and magnification of the orthopantomography. They also concluded that standardized orthopantomography and controlling for magnification and distortion are needed in detecting reduced skeletal bone density. The indicator we developed solves the problem of orthopantomography not having quantitative gray values like those of multi-detector computed tomography images by attaching a simple indicator to the chinrest.
The corrected pixel values in the systemically healthy subjects were significantly lower in the younger group than in those aged 14–15 years and increased with age. We chose the distal side of the mandibular left second premolar tooth germ in the primary or mixed dentition or the root apex of the second premolar in the permanent dentition as the measurement point for quantification of the corrected pixel values. Stable values were obtained in this study because this region is little affected by changes in the dentition. Several studies have evaluated BMD using mandibular cortical width in children with osteogenesis imperfecta, which is the most common skeletal disease reported in children [34,35]. Our method can be applied in future studies to measure the condition of the mandible in bone diseases that are accompanied by dental symptoms, such as osteogenesis imperfecta or X-linked hypophosphatemia.
Studies involving quantitative evaluations with orthopantomography for clinical osteoporosis screening have used the mandibular cortical index and the mandibular inferior cortical width below the mental foramen [36,37]. Evaluation of the alveolar trabecular bone pattern of the mandible using orthopantomography and intraoral radiography has also been reported . It has also been reported that the density and fractal analysis of orthopantomography can be used to detect osteoporosis . These studies used aluminum balls of different diameters to standardize brightness. Because these methods do not fully consider the change in brightness caused by overlapping soft tissues, we attempted to devise a modified quantitative evaluation method using orthopantomography.
A significant positive correlation was found between chronological age and dental age in systemically healthy subjects. Dental age corresponds to the formation of the permanent tooth germs, which is an important index for assessing tooth mineralization. However, the actual dental age calculated in the present study should be regarded as lower than the chronological age in each case. This is because no data has been collected from Japanese children in recent times; therefore, we used data obtained from Scandinavian children 50 years ago  when measuring dental age in our clinical practice. The gap between chronological and dental ages in systemically healthy subjects may have been a result of the use of dental ages of different races or eras. A positive correlation was also found between dental age and corrected pixel values in the systemically healthy subjects, indicating that corrected pixel values increase with dental age because both the tooth and the bone are calcified tissues.
Patients with odonto type HPP, the mildest form of HPP with only dental symptoms, exhibit relatively higher serum ALP values than the other types of HPP except for childhood type HPP, including perinatal severe, perinatal benign, and infantile type HPP . Early exfoliation of primary teeth, which is the main dental manifestation, is caused by disturbed cementum formation [7,8,11]. Because HPP is a progressive disease, bone symptoms may appear as patients grow up [2,13,14,24]. The corrected pixel values of three-quarters of the odonto type patients were lower than the mean values of the systemically healthy subjects in this study, suggesting that early exfoliation of primary teeth could be caused not only by disturbed cementum formation, but also by hypomineralization of alveolar bone. This finding also demonstrates that the reduction in ALP activity influences the mandibular bone of odonto type patients who do not have skeletal bone symptoms or signs. Taken together, the lower corrected pixel values in odonto type patients is a possible indicator of disease progression from the dental region to the whole body. Additionally, the values may be a criterion for estimating the prognosis of odonto type HPP.
One-third of the HPP patients treated with ERT recorded higher corrected pixel values than the systemically healthy subject group of the same age. Serum ALP values at birth in perinatal severe type HPP patients were almost 0, and they cannot survive without treatment due to respiratory failure caused by severe bone hypomineralization . Their corrected pixel values were close to those of systemically healthy subjects, indicating that ERT reduces hypomineralization in mandibular bone to the same extent as skeletal bone.
The dental ages of HPP patients were lower than those of the systemically healthy subjects, indicating that tooth development in HPP patients could be slower than that of systemically healthy children. No studies were found investigating tooth formation speed as a dental manifestation of HPP patients. We previously reported in a nationwide survey that hypomineralization of enamel and dentine was detected in HPP patients, especially in those with severe type HPP . Delayed tooth formation is a novel dental finding in the HPP patients observed in the present study. We consider that low serum ALP values influence not only bone hypomineralization but also tooth hypomineralization in HPP patients. The dental age of all HPP patients treated with ERT was lower than the mean dental age of the systemically healthy subjects, suggesting that ERT may not reduce tooth hypomineralization to the same extent as skeletal bone hypomineralization. A limitation of this study is that it is a cross-sectional study of a rare disease. A longitudinal study of HPP patients is necessary to study the effect of ERT in the oral region, and more cases should be included to confirm any statistically significant differences.
A major limitation of the study is the small number of HPP patients included because of the rarity of this disease. In the present study, only 17 HPP patients were included, which was not sufficient for statistical analysis. However, compared with the systemically healthy subject groups of the same age, the corrected pixel values of three-quarters of the odonto type patients were lower, and those of one-third of the HPP patients treated with ERT were higher. These tendencies may be proved to be statistically significant with the accumulation of many more cases in the future.
We devised an innovative method of using orthopantomography for quantitative assessment of alveolar bone mineralization. This method revealed that odonto type HPP is sometimes accompanied by hypomineralization of the alveolar bone and teeth, and that ERT is effective in reducing hypomineralization of the alveolar bone in HPP patients.