Bisphosphonate Therapy and Tooth Development in Children and Adolescents with Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a heterogeneous connective tissue disorder [1].The disease is usually inherited in an autosomal dominant manner, although new mutations are common. In 85–90% of the cases, the mutations are located in the COL1A1 and COL1A2 genes in chromosomes 17 and 7, respectively [2]. In recent years, several other genes have been associated with the disease [3], and there are now more than 1500 known mutations in over 20 different genes. New mutations are being detected and reported over time, and their effects on tissue structure and biomechanics studied [4‐6]. The clinical manifestations may include bone fragility, skeletal deformities, growth and hearing deficiencies, joint instability due to laxity of ligaments, coagulation and bleeding disturbances, skeletal pain, blue sclerae, dentinogenesis imperfecta (DGI), and other dental development disorders [2, 3, 5, 7‐10], of which tooth agenesis is the most frequent [11]. The most commonly used classification of OI is based on clinical, radiological, and hereditary findings: type I (mild OI with blue sclera), type II (pre- or perinatal lethal), type III (severely deforming), and type IV (variable but often moderate severity, and white sclerae after infancy) [10].

The core feature of OI therapy is fracture prevention. Treatment with bisphosphonates (BPs) is today the gold standard treatment for children with OI [12]. Alendronate, risedronate, pamidronate, and zoledronate are today the most commonly bisphosphonates used for treatment in individuals with OI although in children intravenous pamidronate or zoledronate are most frequently used. They act mainly by inhibiting osteoclast function. Intravenous BPs have proven to decrease bone pain and improve muscle strength and mobility. It increases cortical thickness, vertebral size and architecture and bone mineral density and thereby decreased fracture incidence [13‐17]. Treatment with pamidronate infusions started 1991 in Sweden and it was initially given to adolescents with severe OI but later also to younger children with the more severe phenotypes of OI, types III and IV. Later on, it was also given to individuals with milder phenotype but with vertebral compressions, repeated bone fractures, and pain. Before 1991 treatment with physiotherapy, orthotics, orthopedic surgery, and intravenous calcitonin were the only available treatment options [14].

Tooth eruption involves bone resorption and deposition [18], and it is well known that osteoclasts are important for tooth eruption and for resorption of the primary teeth [19]. Two human studies [20, 21] on how BP therapy affects tooth development reported conflicting results. Kamoun-Goldrat et al. [20] claimed that the therapy was associated with delayed tooth eruption, while Vourimies et al. [21] found age-appropriate dental development.

The present study evaluated the effect of BP therapy on the maturation and eruption of permanent teeth in a cohort of 45 children and adolescents with OI, whose ages ranged from newborn to 12 years at the start of therapy, and who had undergone treatment for at least 1 year. Healthy children and adolescents and children and adolescents with OI who had not had treatment with BPs acted as controls. The hypotheses were that BP treatment delays dental maturity, dental age, and tooth eruption when treatment begins in early childhood.

The main findings in the present study are that the dental age and dental maturity of individuals treated with BPs are significantly lower when compared to patients with OI who had not been treated with BPs and healthy controls. Furthermore, tooth eruption was significantly delayed in children treated with BPs. In both control groups, maturity was accelerated in correlation with Demirjian’s dental scores [22]; but in contrast to Vuorimies et al. [21], we found no difference in dental maturity between the two control groups. When analyzing the different types of OI, we found that the dental maturation was significantly delayed in patients with OI types III and IV compared with healthy controls.

The system used to assess dental age in this study was the worldwide used assessment system of Demirjian et al. [22]. In many countries, dental maturity of Caucasian children has been found to be earlier than in the Demirjian assessment system [25‐29], and dental age might be overestimated [30]. In 1998, a report described a trend towards earlier dental maturation in orthodontic patients between the 1970s and 1990s [31]. Another study showed that root maturation in children in a modern sample was advanced compared with children in a historic sample of 50 years before [32]. Jääsaari et al. [33] found that dental maturity of Finnish 6–12-year-old children was advanced by 0.6–1.0 years compared with chronological age and suggested that the advancement in dental maturity might be associated with higher energy intake. Earlier puberty has also been observed in girls and boys over the last century. The reasons for these changes are unknown but may be explained by environmental and social factors [34]. Genetic, hormonal, and environmental interactions as well as epigenetic and nutritional factors may also be involved in dental development.

We found that individuals treated with BPs demonstrated a significantly lower dental age and dental maturity when compared with OI patients not treated with BPs and healthy controls. This is in contrast to Vourimies et al. [21], who found no significance difference between chronological and dental age in their study group (only five subjects had been treated with BPs before the age of 2 years). One explanation for our results might be the higher number of children below 2 years of age who had been treated with BPs in the present study.

At present, the nitrogen-containing BPs pamidronate and zoledronate are the most commonly used for intravenous medication of children with OI. They have different in vitro potencies, with pamidronate having the lowest relative potency of 100, and zoledronic acid, the highest with a relative potency 10,000. In our study, only intravenous pamidronate was administrated. In the two human studies of Kamoun-Goldrat et al. [20] and Vourimies et al. [21], the age of the population, medical treatment, evaluation methods, and results differed. The ages of the 33 children and adolescents in the Kamoun-Goldrat et al. study [20] ranged from 6.2 to 14.6 years at the start of BP therapy; the researchers did not report which BP was being used. The ages of the 22 children and adolescents in the Vourimies et al. study [21] ranged from 0.1 to 13.0 years at the start of therapy; this research group used various types of BPs such as intravenous pamidronate and zoledronic acid, and oral administration of risedronate.

Resorption of the roots of primary teeth is needed for a permanent tooth to erupt. For that process to be possible, alveolar bone resorption must occur and a biological process for the tooth to move in the pathway must be possible [19]. BPs act by inhibiting osteoclast function and thereby decrease bone resorption. This effect on bone density persists for years since the half-life of BPs is a decade [2]. Since tooth eruption involves bone resorption and deposition [18, 35], osteoclasts are important for tooth eruption and for resorption of primary teeth [19]. BP-induced decreases in osteoclast activity may affect tooth development. We assessed eruption based on the results of Haavikko [23] because we used the same criteria for eruption in the panoramic radiographs. This study was published as early as 1970. Parner et al. [36] concluded that the emergence of permanent teeth was not subject to acceleration between 1969 and 1996 and, consequently, the study by Haavikko is still relevant. Parner et al. recorded a tooth as erupted when any part of it had emerged through the gingiva. Vuorimies et al. [21] related the number of erupted teeth to the study by Nyström et al. [37]. In their study, they recorded a tooth as erupted when any part of it had emerged through the gingiva while Vourimies et al. [21] recorded it as erupted also when it had radiographically pierced the alveolar bone, which makes a correlation unsure. In the present study, we demonstrate a significantly delayed tooth eruption in children with OI who had been treated with BPs compared with those who had not and healthy controls. We also found a significantly delayed tooth eruption among boys with OI treated with BP, compared the two control groups, which was not seen among girls.

Regarding eruption, Kamoun-Goldrat et al. [20] examined their subjects only by visual inspection of all four quadrants and the number of delayed teeth was determined using the classical data of Hurme [41] where a tooth was described as delayed if it had not emerged in the age range given by Hurme. Although they did not report type of OI, we assume that the majority had OI type III as they had been treated with BPs. We reported earlier [11] that tooth agenesis occurs more often in OI type III-affected individuals, 47%, compared with OI types I (12%) and IV (13%). Thus, as Vuorimies et al. [21] also discussed, the effect on tooth eruption in patients who had received BP therapy is likely overestimated. Vourimies et al. studied only the left mandibular teeth and used as reference values published norms for the timing of tooth eruption [37]. Our results differed from the results reported by Vourimies et al. One explanation might the higher number of individuals in all groups in our study. Furthermore, 14 children in the present study had started BP therapy before the age of 2 years compared to five in the former (personal communication).

The prevalence of DGI in OI type I varies from 8 to 40% [7, 8, 38‐40]. In the present study, DGI was found in 10% and it was more frequent in children treated with BPs (21%), than in those not treated (8%). Normally, DGI is less frequent in patients with OI type I compared with patients with OI type III/IV which is also demonstrated in the present study. The difference seen in patients with OI type I treated with BP compared with those not treated is most probably just a coincidence. Hypothetically, as teeth affected with DGI have more calcified tissue to be resorbed, this could delay tooth eruption. We found no difference in eruption between teeth with and without DGI.

Surprisingly, the eruption was significantly delayed in the healthy controls compared with the patients with OI type I treated with BPs. The high variation in number of erupted teeth in the healthy controls was probably a contributing factor. We found a delay in dental maturation in children treated before two years of age (Figs. 1 and 2) and as only three children with OI type I started BPs therapy before 2 years of age, the BP therapy was not reflected here.

In conclusion, BP therapy in OI patients seems to lower the dental age, and delay the dental maturity and tooth eruption. BP administration before 2 years of age might be a contributing factor.