Spinal metastasis commonly occurs in advanced breast cancer. Treatment is often multimodal including radiation therapy (RT), bisphosphonates (BPs), and surgery, yet alternative minimally invasive local treatments are needed. Photodynamic therapy (PDT) has been shown to ablate tumor cells and enhance bone formation secondary to metastatic breast cancer, demonstrating potential as a treatment for spinal metastasis. Combined with previous BP treatment, bone formation was further enhanced by PDT. This study aimed to determine the effects of PDT in combination with previous RT on healthy and metastatically involved vertebrae. Forty-six athymic rats underwent RT (4 Gy on day-7), twenty-three of them were inoculated with MT-1 human breast cancer cells on day 0. Thirteen healthy and ten metastatically involved rats underwent PDT treatment on day 14. All rats were sacrificed on day 21. L2 vertebrae were analyzed using μCT imaging, mechanical testing, and histological methods. In healthy vertebrae, while modest increases in trabecular structure were found in RT + PDT compared to RT only, mechanical stability was negatively affected. The 4 Gy RT dose was found to ablate all tumor cells and prevent further vertebral metastasis. As such, in metastatically involved rats, no differences in stereological or mechanical properties were detected. RT + PDT and RT-only treatment resulted in greatly improved vertebral structural and mechanical properties versus untreated or PDT-only treatment in metastatically involved rats, due to early tumor destruction in RT-treated groups. Increased amounts of woven bone and osteoid volume were found in PDT-treated vertebrae. Further investigation is needed to understand if structural improvements seen in RT + PDT treatment can translate into longer-term improvements in strength to support the potential of PDT as a viable adjuvant treatment for spinal metastasis postradiation.

Photodynamic therapy (PDT) has been shown to ablate tumors within vertebral bone and yield short-term improvements in vertebral architecture and biomechanical strength, in particular when combined with bisphosphonate (BP) treatment. Longer-term outcomes of PDT combined with current treatments for skeletal metastases are essential to understand its therapeutic potential. The objective of this study is to evaluate the response of vertebrae to PDT after a longer (6-week) time period, alone and combined with previous BP or radiation treatment (RT). Sixty-three female rnu/rnu rats were randomized to six treatment groups: untreated control, BP-only, RT-only, PDT-only, combined BP þ PDT and combined RT þ PDT. L2 vertebrae were structurally analyzed through mCTbased analysis, axial compressive load-to-failure testing and histological analysis of morphology, osteoid formation and osteoclast activity. Combined BP þ PDT treatment yielded the largest improvements in bone architecture with combined RT þ PDT treatment yielding similar findings, but of a lesser magnitude. Mechanically, ultimate force and stress were correlated to stereological parameters that demonstrated a positive structural effect from combinatory treatment. Increased osteoid formation was observed in both combination therapies without any significant differences in osteoclast activity. Overall, multimodality treatment demonstrated a sustained positive effect on vertebral structural integrity, motivating PDT as a minimally-invasive adjuvant treatment for spinal metastases. This can lead to skeletal related events, including pathologic fracture.3 While improvements in cancer treatments help to prolong the survival of patients, this provides more time for metastases to develop, 1 potentially increasing spinal metastasis incidence.4 Current treatment strategies for spinal metastasis are multimodal using systemic chemotherapy and bisphosphonates (BPs) in combination with local treatments such as radiation therapy (RT).5 BPs are a clinical standard of care for reducing the number of skeletal complications in patients with metastatic bone disease, 6 through the inhibition of osteoclast function and induction of apoptosis. While BPs have been established as an effective treatment for improving bone strength and structure, evidence for anti-tumor effects have been equivocal. [7][8][9] RT is a current standard of care for the treatment of spinal metastasis and is widely used for palliation of pain, with up to 80% of patients reporting benefit. 10 However, there is considerable variation in tumor response due to variation in radiation sensitivity and RT repeated exposure may contribute to tumor radio-resistance and radio-toxicity of adjacent healthy tissues (e.g., the spinal cord).11 Yet overall, tumor response remains variable despite current treatments, motivating the need for novel approaches or combination therapies to treat metastases while preserving skeletal structural integrity and surrounding healthy tissues.Photodynamic therapy (PDT) is a novel, m...

The widespread use of systemic and local therapies aimed at spinal metastatic lesions secondary to breast cancer has increased the incidence of mixed osteolytic/osteoblastic patterns of bony disease. The complex structure of these lesions requires novel therapeutic approaches to both reduce tumor burden and restore structural stability. In photodynamic therapy (PDT), a minimally invasive approach can be used to employ light to activate a photosensitizing agent that preferentially accumulates in tumor tissue, leading to cell toxicity and death. Previous work in an osteolytic rat model (MT-1) demonstrated that PDT effectively ablates tumor and improves vertebral structural properties. The aim of this study was to assess the efficacy of PDT in a rat model of mixed osteolytic/osteoblastic spinal metastases. Mixed spinal metastases were generated through intracardiac injection of Ace-1 canine prostate cancer cells into female athymic rats (day 0). A single PDT treatment was applied to lumbar vertebra L2 of tumor-bearing and healthy control rats (day 14). PDT-treated and untreated control rats were euthanized and excised spines imaged with μCT to assess bone quality (day 21). Spines were mechanically tested or histologically processed to assess mechanical integrity, tumor burden, and remodelling properties. Untreated tumor-bearing vertebrae showed large areas of osteolysis and areas of immature, new bone formation. The overall bone quality resulting from these lesions consisted of decreased structural properties but without a significant reduction in mechanical integrity. PDT was shown to significantly decrease tumor burden and osteoclastic activity, thereby improving vertebral bone structural properties. While non-tumor-bearing vertebrae exhibited significantly more new bone formation following PDT, the already heightened level of new bone formation in the mixed tumor-bearing vertebrae was not further increased. As such, the effect of PDT on mixed metastases may be more influenced by suppression of osteoclastic resorption as opposed to the triggering of new bone formation.