Treatment of bone metastases by combining low intensity ultrasound and bisphosphonates – MOTUS

Low intensity ultrasound was used to generate hyperthermia in combination with a bisphosphonate (zoledronic acid). A single dose of zoledronic acid corresponding to a clinical dose was combined with a single or daily application of ultrasound. Results were compared with vehicle, ultrasound alone and zoledronic acid alone. Thermal effects were created using a plane transducer operating at a frequency of 2.9 MHz and delivering 7 acoustic watts (free field acoustic power) in continuous mode in order to increase the bioavailability of zoledronate. Ultrasound treatments lasted 30 minutes. A single dose of zoledronate was injected and combined with a daily application (30 minutes) of pulsed or continuous ultrasound for fifteen days. These treatment strategies were compared with vehicle, ultrasound alone and zoledronate alone. Efficacy of treatments was measured by radiography, histology and histomorphometry. Serum was used to measure the activity of bone resorption and bone formation.

In a recent study we have compared eight different treatment strategies to optimize skeletal tumor growth inhibition in a mouse model of bone metastasis. Radiographic analysis on the day before starting treatments revealed that tumour-bearing mice had homogeneous osteolytic lesions. The average osteolytic surface was 0.58 ± 0.15 mm2, no statistical differences were observed between groups at day 17.
Radiographic analysis on day 32 after tumor cell injection revealed that tumour-bearing mice treated with a single dose of zoledronic acid had osteolytic lesions that were 55% (p <0.01) smaller than those of tumor-bearing mice treated with the vehicle. Tumour-bearing mice treated daily with C-US had similar osteolytic lesions compared to mice treated with the vehicle (p=0.65). A single injection of ZOL immediately followed by only one treatment of continuous ultrasound did not affect osteolytic lesions comparing to ZOL group (p=0.30). Importantly, we found that tumor-bearing mice treated daily with C-US and a single dose of zoledronic acid had osteolytic lesions that were 81% (p<0.01) and 58% smaller (p<0.01), respectively, than those of vehicle-treated animals and ZOL-treated mice. Another important conclusion of this preliminary work is that we used clinical doses of bisphosphonates and ultrasounds, suggesting that clinical application of such therapy is conceivable.

Further investigations are therefore needed to understand the physical and/or biological phenomena responsible for this antitumor effect, and then optimize this novel treatment strategy. A clinical use of this method is not conceivable without this understanding.

1. Low Intensity Ultrasound Substantially Improves the Efficacy of Bisphosphonate Zoledronic Acid in the Treatment of Breast Cancer Bone Metastases in Animals. 2011. 11th International Symposium on Therapeutic Ultrasound, New-York, USA
2. Efficacy of Bisphosphonate Zoledronic Acid is Substantially Improved by Low Intensity Ultrasound in the Treatment of Breast Cancer Bone Metastases in Animals. 2011. International Conference on Cancer-Induced Bone Disease, Chicago, USA
3. Low Intensity Ultrasound associated with Bisphosphonate Zoledronic Acid Decrease Osteolytic Lesions in Breast Cancer Bone Metastases. 2012. 12th International Symposium on Therapeutic Ultrasound, Heidelberg, Germany.
4. Low Intensity Ultrasound Enhances the Bioavailability of a Bisphosphonate Zoledronate in a Breast Cancer Bone Metastases Animal Model. 2012. IEEE Ultrasonic Symposium, Desden, Germany
5. Zoledronic acid combined with an Ultrasound treatment Achieves Antitumoral Effect in Breast Cancer Bone Metastases. 2012. International Conference on Cancer-Induced Bone Disease, Lyon, France

Breast cancers are prone to metastasize to bone and around 70-80% of patients with advanced disease exhibit bone metastases. These skeletal lesions can be fatal or may rapidly impede the quality of life of patients by causing pathological fractures, hypercalcemia, nerve compression and loss of mobility. Most of these patients will also experience substantial, life-altering cancer-induced bone pain. Therefore bone metastases from breast cancer represent a major problem of public health.
Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and have demonstrated clinical utility in the palliative treatment of patients with bone metastases. There is now extensive in vivo preclinical evidence that bisphosphonates can reduce skeletal tumor burden and inhibit the formation of bone metastases in animal models. In addition, bisphosphonates appear to have direct antitumor effects but with doses that are not compatible with clinical use.
It may be relevant to combine the action of bisphosphonates with a physical agent. Indeed, ultrasound treatment has been proposed by several authors to enhance the repair of long bone injury. In addition, other studies indicate that combined treatment using chemotherapy and HIFU has a synergistic effect on solid tumors progression through a prolonged slowing of tumour growth, suggesting that such combined therapy could be useful. The use these osteogenic effects with or without the action of drug for tumor growth inhibition or anti-tumor effects in bones has never been suggested.
In a preliminary unpublished study we have observed that the treatment of metastatic animals with a bisphosphonate in combination with ultrasound not only inhibits bone destruction but also exhibits antitumor effects, suggesting that such a therapeutic strategy might be a promising approach for treating bone metastasis from breast cancer. However, the reasons why such a treatment strategy combining a bisphosphonate with ultrasound reduces skeletal tumor growth are unknown. Further investigations are therefore needed to understand the physical and/or biological phenomena responsible for this antitumor effect, and then optimize this novel treatment strategy. A clinical use of this method is not conceivable without this understanding.
Thus, it is important to determine if a clinically relevant combination of ultrasound producing mechanical and/or thermal effects in combination with a relevant dosing regimen of bisphosphonate can achieve meaningful antitumor effects in animal models of bone metastasis. We will use a mouse model of human breast cancer bone metastasis to examine the effects of different treatment strategies combining ultrasound and different dosing regimens of a bisphosphonate (zoledronic acid) on osteolysis and skeletal tumor growth.
This project requires knowledge and expertise in very different areas. The excellence of the partnership lies therefore in the complementarities of the partners' expertise which integrate various scientific disciplines (as different as physics, biology, bone physiopathology and oncology) and technical skills (ultrasound, pharmacology, animal experimentation, noninvasive imaging methodologies). Such a diversity of the contributions by the two partners is relatively rare. The two partners involved in this project is the unit 556 of INSERM specialised in the therapeutic applications of ultrasound and the unit 664 of INSERM specialised in the mechanisms and treatments of bone metastases from solid tumours. Grouping knowledge and expertise of two INSERM laboratories in such a project is an opportunity to allow the development of very innovative treatment strategies in order to fight bone metatastasis.