The effect of systemically and locally administered clodronate on bone quality
Year: 2014
Type: dissertation
Abstract: The effect of systemically and locally administered clodronate on bone quality The aims of this study were to evaluate the effect of clodronate, given systemically or locally, on the quality of bone and to develop a combination product including clodronate and bioactive glass for local administration in the treatment of periodontitis. The beneficial effects of clodronate on bone are known. Clodronate inhibits osteoclasts in bone and reduces bone turnover. It is used in breast cancer patients with non-osseous metastases to reduce the osteolytic complications and bone metastases. It is widely investigated e.g., in healthy women reducing bone loss. The first aim of this thesis was to investigate whether these established effects are similar in women with primary operable breast cancer. Since skeletal bone loss and alveolar bone loss in periodontitis share common mechanisms, the effect of clodronate upon dental application was of interest. Systemic bone conditions impact the periodontium and systemically administered clodronate positively affects the peridontium, but also side effects such as diarrhea, rash and osteonecrosis of the jaw can be problematic. However, clodronate is poorly absorbed from gastrointestinal (GI) tract and the oral bioavailability of clodronate is low. Therefore, systemically administered oral dose of clodronate needs to be high to achieve a therapeutic effect, which in turn leads to increased adverse events. Therefore, the challenge in developing novel drug delivery systems for clodronate is to achieve improved bioavailability and safety. The aim of the second part of this thesis was to develop a new delivery system that would reach the target site in the periodontium, while limiting unwanted side effects and reducing the required dose through local administration. In the first part of this study, the loss of bone mineral density (BMD) was studied in patients with primary operable breast cancer given either clodronate or placebo. Oral clodronate appears to reduce the loss of bone in these patients. In premenopausal patients clodronate significantly reduced the loss of bone after one year and in postmenopausal patients clodronate increased the spinal BMD. Patients receiving clodronate had significantly more incidences of diarrhea than those receiving placebo. This indicates that clodronate is poorly absorbed from GI tract thus causing irritation to the intestine. In addition, the development of bone metastases was compared with patients with primary operable breast cancer given either clodronate or placebo. Clodronate given to these patients was shown to reduce the occurrence of bone metastases. Additionally, there was a significant reduction in mortality. In the second part of the study, a novel combination product of bioactive glass (BAG, SiO2 53%, Na2O 23%, CaO 20% and P2O5 4% (w/w %)) and clodronate was investigated. Firstly, preformulation studies were performed. Clodronate was found to promote the activity of the BAG and a calcium clodronate precipitate formed. Additionally, the bioactivity lasted longer in the combination product than in BAG alone. The optimal ratio for bioactive glass and clodronate and optimal particle size for BAG for local treatment of periodontitis was investigated and selected based on bioactivity of the BAG, safest pH profile of the combination product, as well as highest possible amount of clodronate to achieve the enhanced bioactivity for the BAG. The combination product chosen was 1 g BAG with a particle size of 0.5-0.8 mm and 200 mg of clodronate premoisturized with saline. Finally, the selected combination product was compared to the BAG alone in the treatment of the periodontitis maintenance phase in a pilot study with ten study subjects. Based on the clinical signs and symptoms of inflammation or infection at the site (evaluated by the investigator) and overall satisfaction the combination product is at least as good as bioactive glass alone. Of the two bone remodeling biomarkers (osteoprotegerin and osteocalcin) selected for the study, only osteoprotegerin data indicate that the effect of the novel combination product is beneficial. Osteoprotegerin levels decreased in both combination product and BAG alone treated teeth but less in the combination product treated teeth. However, due to the short time period of investigation as well as the limited number of subjects and treated teeth, the result for bone quality remains only indicative. The positive effect of the combination product on tooth sensitivity may bring additional benefits in comparison to the use of BAG alone in periodontal maintenance therapy.
Source: Työväentutkimus Vuosikirja
Author: Kirsi Rosenqvist
Language: English
Topic: Bone health and treatments
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2165490942