Osteogenesis imperfecta is a hereditary disorder that results from a genetic defect in the synthesis of type-I-collagen. This genetic defect results in a typical phenotype with increased bone fragility, short stature, blue sclera and abnormal tooth growth.1–4
Sillence et al.4
classified the OI into four different types ranging from a mild form to a lethal form, according to their appearance. OI type I is a mild form with only a few fractures in childhood, blue sclera and a good mobility. OI type II is the most serve form with multiple perinatal fractures and normally lethal course. Types III and IV are accompanied by increased bone fragility, with or without blue sclera and are clinically difficult to treat because of multiple deformities and a high rate of immobility.4,33
Bisphosphonates with their influence on bone turnover have been established in osteoporotic disorders and in the treatment of osteogenesis imperfecta. The benefits of bisphosphonate treatment, especially with pamidronate, have been demonstrated in several studies. There was an increase in bone density, a decreased fracture rate, a normalization of bone turnover markers and a subjective reduction of bone pain seen with an improvement in mobility.26–29,34–37
In the present study we retrospectively analyzed the data of 27 patients who were treated with intravenous ibandronate for at least 1.5 years. To our knowledge only one previous study also focused on the benefits of this kind of bisphosphonate in children with osteogenesis imperfect.30
Bone alkaline phosphatase and osteocalcin have been concluded to be the most valuable bone markers for bone formation, whereas urinary deoxypyridinoline (DPD) and the cross-linked telopeptides of type-I-collagen are most valuable markers for bone resorption.38
One of the main problems of the present study is that the bone turnover markers were not compared with an age-gender-matched group of healthy children. Most children with OI are smaller and lighter when compared with children of the same age and a correlation between the levels of bone turnover markers and body size and weight has been reported.39
Because of these findings and because of the mean age of our patients, we did not compare initial bone turnover markers with the few and still incompletely published paediatric reference intervals.38,40,41
Nevertheless, we evaluated bone turnover markers before starting therapy with ibandronate and monitored changes during treatment. Most patients demonstrated elevated serum and urinary markers for bone formation and bone resorption, which implies that there is an increased turnover in patients with OI. We were able to detect statistically significant changes with a normalisation of the different bone markers during the therapy. There was decrease in total alkaline phosphatase (bone formation), in the ratio of urinary deoxypyridinoline/urinary creatinine (bone resorption) and the ratio of urinary pyridinoline/creatinine (bone resorption). In our opinion, these markers are suitable to detect the benefits of ibandronate therapy. These findings support the results by Aström et al.
, where serum alkaline phosphatase (ALP) and urinary DPD were also seen as most informative in the observation of treatment benefit, although they used pamidronate in their study.25
However Braga et al.
reported serum bone ALP, urinary DPD and collagen-type I Ntelopeptides (NTX) as being the best for clinical separation.42
On the other hand there might be the possibility of a type I failure while detecting a decrease in the ratio of urinary deoxypyridinoline/urinary creatinine and the ratio of urinary pyridinoline/creatinine caused by the small sample size.
We did not detect an increased bone ALP or statistically significant changes in bone ALP which might be caused by a type II failure because of the small sample size.
Bone densitometry in infants and especially in patients with a pathological bone structure such as in patients with OI is difficult. DXA is the most commonly used method and a lot of studies have shown an increase in bone mineral density during the therapy with bisphosphonates especially with pamidronate.28,29,34,35
To our knowledge this is the first study using BUA for monitoring bone density during bisphosphonate treatment. We used BUA for measurement of bone density to avoid radiation exposure during follow-up especially in children and to minimize measuring time. Different studies have demonstrated the high sensitivity of this technique when measuring bone density.43–45
We were able to show a statistically significant increase in bone density, which is consistent with previous studies.28,29,34,35
We note several limitations of the present study. The most important limitation was that we performed a retrospective analysis of patient data. Therefore we analyzed a very heterogeneous patient collective especially in regard to the age. For the same reason there was a lack of information about different bone turnover markers such as osteocalcin. Most patients were tested for the most important bone turnover markers during therapy, such as alkaline phosphatase, deoxypyridinoline or pyridinoline and we were therefore unable to perform a statistical analysis of most parameters retrospectively. On the other hand in our opinion the patients which have been included into the study represented there age-group sufficiently.
Secondly we did not analyse clinical features such as bone fracture rate, mobility, pain during the treatment with ibandronate and have not differentiated between OI Type I/III/IV when analyzing the effects of ibandronate. Further studies should focus on these topics.
Thirdly, we analysed bone density by using broadband ultrasound attenuation and the region of interest was plotted free hand, so the interobserver quality seems to be low. However, this was only performed by one observer (author II) in a standard manner so that there was a high conformity.