Currently sacrectomy is a standard approach for sacral chordoma. Promising results have been reported when using high-dose radiation as an adjuvant treatment. The effects of high-dose radiation using protons and photons on bone are relatively unexplored, but a high risk of insufficiency fractures has been reported . We aimed to assess the effects of high-dose radiation on the trabecular density of bone in the sacrum using CT-derived HU. We observed a decrease in trabecular bone density of radiated bone in patients with sacral chordoma using retrospectively collected CT scans. Using a reference value outside of the radiation field for each patient, we were able to control for heterogeneity between the pre- and postradiation CT scans. Some patients—such as those undergoing sacrectomy—will receive radiation doses even greater than the dose we studied here. That being said, it is especially important to consider the loss of trabecular bone density.
This study has several limitations. First is the use of clinical CT scans in which images were obtained using different imaging and contrast protocols. Changes in HU measurement cannot completely be attributed to radiation, but also the differences in the methods used to obtain the images. This explains the increase in HU outside the radiation field, an area where no change is expected. We also measured a difference in HU inside the radiation field; interestingly, this was not an increase but a decrease in HU. This means that even with the increase in HU caused by a difference in scanning protocol, the decrease in HU inside the radiation field was big enough that a decrease was still measured. Nevertheless, we accounted for differences in voltages used by converting HU values using a conversion formula (shown in Appendix, Supplemental Digital Content 1). We normalized HU values to a reference value outside of the radiation field for each patient and tested a difference in ratios rather than the absolute HU values. Ideally, the pre- and postradiation would have been done using the same scanner and scanning protocol. However, the method we used did allow us to isolate the change in HU not caused by the difference in scanner or scanning protocol. In this case, the most likely factor causing the decrease in density in between the two CT scans was the radiation. Second, we were not able to calibrate our measurements to bone mineral density because phantoms are not routinely used for clinical CT scans. This makes it difficult to compare our results with studies reporting on bone mineral density (ie, studies using DEXA scans or phantoms). In routine clinic, no phantoms or DEXA scans are used. Our study does present a method that allows using routinely made scans for measuring bone density and might be of value as a first step in recognizing potential clinical problems, in this case the high rate of insufficiency fractures observed in patients treated for sacral chordoma.
In addition, almost half of the patients treated for the diagnosis of interest were not included because a pre- or postradiation CT scan was not available. This might introduce selection bias, although this is unlikely because scans were not missing because of any specific patient or treatment characteristic. Rather, practical issues with obtaining the old scans prevented us from including these patients. Fourth, the sacral level that was used to measure density was dependent on the level of the tumor. Although not all sacral vertebrae have the same density , they have similar biology and were therefore grouped together. We did not compare different levels within one patient; we were able to measure the exact same location within one patient before and after radiation. Last, not all patients received a similar amount of proton and photon radiation. We were therefore not able to analyze the effect of photon or proton radiation separately. Most likely a combination of both protons and photons will be used in the foreseeable future given the rarity of proton centers. We did however make sure patients received a similar total dose of radiation. Potentially the effect of photon radiation on bone might be greater because proton radiation can be delivered with more precision as a result of its biologic behavior .
Our results show that the high-dose combined proton and photon radiotherapy decreases trabecular bone mineral density within a matter of weeks. When comparing our raw results with reference values , it becomes clear that the bone inside the radiation field changed from being within the range of normal bone (mean 133 ± 38 HU) to within the lower range of osteoporotic bone (101 ± 25 HU). Outside the radiation field the bone stayed within the range of normal bone. A recent study looking at bone mineral density changes of thoracic and lumbar vertebral bodies in patients treated with chemoradiation (using chemotherapy and photons only) for abdominal tumors found similar results . The authors reported decreased bone mineral density after 4 to 8 months and after 9 to 12 months. However, gemcitabine was used in 57% of the patients in their study. Gemcitabine has been associated with myelosuppression [11, 35, 36]. A recent animal study reported myelosuppressive therapies to increase inflammation and directly contribute to bone loss , indicating a potential contribution of the chemotherapy to the decreased bone mineral density. Although the authors state that they controlled for this by performing the same measurement in patients treated with chemotherapy alone (and found no difference), they do not state which chemotherapies were given to the control group. In addition, the effect of the combination of radiation and chemotherapy on bone is unknown.
A cross-sectional study of 19 patients treated with surgical excision and radiotherapy for soft tissue extremity sarcomas had bone density measured using a DEXA scan. The authors concluded that radiation does not routinely decrease bone density . These results have to be interpreted with care because no preradiation scans were done. Results were based on comparisons with the contralateral limb depending on the site of radiation. Furthermore, the bones included were not homogenous and included only long bones, which have more cortical bone (nine femura, three humerii, four radii, and three tibiae) and are less sensitive to damage or we are less able to detect a change in bone density when compared with trabecular bone .
Based on recent animal studies, fragility of radiated bone is attributed to early postradiation activation of existing osteoclasts resulting in a decrease of the trabecular bone and thus the trabecular bone mineral density. Trabecular bone that is lost after early radiation-induced resorption is not regenerated as a result of the lack of a scaffold to guide osteoblasts . Osteoclast progenitors reside in marrow and are known to be radiosensitive. Depletion of osteoclast progenitors may be attributed to long-term decreased loss of osteoclasts [16, 31, 40]. This may ultimately lead to uncoupling of the bone resorption and formation. This allows long-term unopposed appositional bone growth, which eventually may lead to increased bone mineral density of trabecular and cortical bone combined, cortical thickening, decreased remodeling, and accumulation of poor-quality matrix . Historically it is suggested that bone loss is mediated by the damage done to mesenchymal stem cells resulting from radiation [8, 9]. Osteoblasts are short-lived cells that need constant replenishing; damage to their mesenchymal progenitors may result in long-term bone damage. These are all mechanisms for radiation to contribute to bone fragility and an increased fracture risk. The question arises whether preventive stabilization is necessary. At our institution, lumbosacral reconstruction is routinely done in patients with an osteotomy higher than at the S2 to S3 level in patients who received high-dose radiation. Despite this, insufficiency fractures in patients with reconstructions are still seen. To more definitively determine whether preventive stabilization is necessary, studies should be done to determine whether the remaining bone is strong enough for screws to hold and also to look at bone quality over the longer term after high-dose radiation to the sacrum. In the osteoporosis literature, surgical techniques have been described, mentioning that osteoporotic bone quality might lead to the risk of screw loosening [23, 30]. This being said, osteoporosis and radiation-induced loss of bone are a result of different pathophysiologies and comparisons should be made with care.
This study sheds light on the short-term effect of the radiation, but not on the long-term results. It has been suggested that at higher dosages, the lack of osteoclasts results in uncoupling of the bone resorption and formation. This allows long-term unopposed appositional bone growth, which eventually may lead to increased bone mineral density of trabecular and cortical bone combined, decreased remodeling, and accumulation of poor-quality matrix . The poor-quality bone may not be well suited for fixation.
We observed that trabecular bone density decreased after high-dose radiation therapy in a small group of patients with sacral chordoma; specifically, trabecular density decreased within weeks of the end of radiation in patients who received a dosage of 50.4 Gy. High-dose radiation is increasingly gaining acceptance for treating malignancy of the sacrum; these results should be taken into consideration when planning treatment involving high-dose radiation. To fully comprehend the effect of high-dose radiation on bone and be able to guide clinical care, long-term prospective studies using calibrated CT scanners and preferably bone biopsies need to be conducted.
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