1 Introduction

Cancer patients today face more favorable survival prognoses largely in part due to the availability of a broader variety of multidisciplinary treatment options for various cancers. Despite this, bone metastasis persists as a problem faced universally by patients with advanced cancers, and effective treatment remains elusive. Cancer patients have difficulty maintaining their activities of daily living (ADL) and quality of life (QOL) after developing bone metastases, and these patients are often referred to orthopedic surgery. Problems related to diminished ADL and QOL due to skeletal-related events (SRE) such as fractures and paralysis present difficulties, particularly for patients who have developed spinal metastasis.

Administration of denosumab has been reported in recent years to be associated with a decrease in the frequency of SREs in many types of cancer, and denosumab is gaining recognition as a standard therapy for the prevention of SREs. For example, a report discussing the results of a large-scale prospective study stated that administration of denosumab (anti-receptor activator of the nuclear factor-kappaB ligand antibody (anti-RANKL antibody)) to prostate cancer patients reduced the frequency of SREs and also improved disease-free survival and life prognosis.¹ Numerous studies in the field of oncology characteristically use disease-free survival and life prognosis as endpoints.^2,3 However, in cases of metastasis of cancer to bone tissues, determining the therapeutic effects of the treatments on bone is also considered to be important.

Although metastases of malignant cancers to bone tissue may be roughly classified into osteosclerotic and osteolytic lesions, bone turnover by osteoclasts plays an important role regardless of the type of lesion present.⁴ As such, bone resorption marker values tend to rise regardless of whether a lesion is osteosclerotic or osteolytic.⁵

Bone metabolism markers are used as a method of monitoring the effect of treatment on bone lesions; serum tartrate-resistant acidic phosphatase (TRAP-5b) value as a marker of bone resorption and serum bone alkaline phosphatase (BAP) value as a marker of bone formation are widely adopted in clinical environments. Bone metabolism markers can be assessed rapidly, easily, and repeatedly, and are considered to offer high clinical utility.

Our hypothesis is that this change in bone metabolism marker values over time is one of the methods for evaluating the effect of treatment on bone tissue in cases of spinal metastasis. In this study, we measured serum TRAP-5b and BAP values as bone metabolism markers prior to denosumab administration and 6 months afterward.

2 Subjects and methods

The subjects were 28 patients investigated prospectively at Aichi Medical University from December 2017 to December 2018. The subjects were 13 men and 15 women with a mean age of 65.6 years (35–85 years). The primary tumors in these subjects were 7 cases of breast cancer, 6 cases of colon cancer, 5 cases of prostate cancer, 4 cases of lung cancer, 2 cases of renal cancer, and 4 cases of other forms of cancer. In terms of the characteristics of the bone metastasis, there were 9 cases of bone metastasis in the osteosclerotic lesion group and 19 cases in the osteolytic lesion group. The mean follow-up period was 11 months (6–36 months). All of the cases were followed-up over 6 months. As the treatment strategy followed by the department managing the patient's primary cancer can often change depending on the presence of bone metastasis, computed tomography (CT)-guided bone biopsies are performed as necessary, to enable a histological definitive diagnosis of cancer bone metastases.

Single 120 mg doses of denosumab were administered at 4-week intervals, and serum TRAP-5b and BAP values were measured as bone metabolism markers prior to administration and 6 months afterward. Following measurement, TRAP-5b and BAP values before and after denosumab intervention in the osteolytic and osteosclerotic lesion groups were assessed.

For statistical analysis, the Wilcoxon signed rank sum test was used to determine whether the bone metabolism marker values decreased following intervention significantly. The level of statistical significance was set at p < 0.05.

This study received the approval of the Aichi Medical University School of Medicine Ethical Review Board.

3 Results

At initial examination of the 28 spinal metastatic patients investigated, there were 9 cases of bone metastasis in the osteosclerotic lesion group and 19 cases in the osteolytic lesion group. We conducted a comparative study of TRAP-5b and BAP values in the osteolytic and osteosclerotic lesion groups before and after denosumab intervention with denosumab.

Measured TRAP-5b values were found to be significantly decreased in comparison with pre-intervention values in both the osteosclerotic and osteolytic lesion groups 6 months after intervention (Wilcoxon signed rank sum test results: osteosclerotic lesion group: p = 0.0039, osteolytic lesion group: p = 0.0001) (Fig. 1). BAP values in the osteolytic lesion group decreased significantly at 6 months after denosumab intervention compared to pre-intervention values. Although no significant difference was seen with the osteosclerotic lesion group, the mean actual value was found to be lower (Wilcoxon signed rank sum test results: osteosclerotic lesion group: p = 0.1289, osteolytic lesion group: p = 0.0244) (Fig. 2).

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Fig. 1 TRAP-5b values in the osteolytic and osteosclerotic lesion groups before and after denosumab.

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Fig. 2 BAP values in the osteolytic and osteosclerotic lesion groups before and after denosumab.

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4 Discussion

In this study, TRAP-5b values were significantly decreased as a result of denosumab intervention in both the osteosclerotic and osteolytic lesion groups, suggesting a potential effect of denosumab on bone tissue.

There are a lot of reports about the relationship between metastasis of cancer to bone tissue and bone metabolism marker values. For example, there are some reports on the relationship between actual measured bone metabolism marker values and cases with and without bone metastasis. In breast cancer cases with bone metastases, TRAP-5b values, BAP values, and urinary N-terminal telopeptide (NTx) values were found to be significantly higher in comparison with cases without bone metastasis.⁶ In lung cancer cases with bone metastases, TRAP-5b values, BAP values, and type I collagen (1CTP) values were also found to be significantly higher compared with lung cancer cases without bone metastasis. Further, cases with multiple bone metastases exhibited significantly higher TRAP-5b values, BAP values, and 1CTP values when compared to cases with solitary bone metastasis.⁷ These reports indicate that the actual bone metabolism marker values are indicative of the presence or absence of metastasis.

We did not consider bone metabolism marker values in cases without bone metastasis in this study. However, we believe that the changes over time in bone metabolism marker values following treatment administration in bone metastasis cases is especially important.

Both bone formation marker values and bone resorption marker values were significantly higher in prostate cancer patients with bone metastasis compared to patients without bone metastases. Both the bone formation and bone resorption marker values significantly decreased after treatment compared with marker values measures before and 2 weeks after administration of zoledronic acid.⁴ These reports indicate that assessing changes in actual bone metabolism marker values over time can serve as a method for evaluating the effect of treatment on bone tissues.

A limitation of this study was the potential of the influence of numerous confounding variables in consideration of the small number of cases examined, the types of cancers represented by these cases, and the variation in treatment histories, and as a result the true impact of denosumab intervention may not be fully reflected.

According to the results of this study, bone metabolism marker values may be a viable tool for therapeutic evaluation of bone tissues in cancer cases with bone metastasis. In the future, it will be necessary to investigate and consider treatments addressing the primary tumor and adjuvant treatments in the same manner.

5 Conclusion

Based on the results of the present study, this change in bone metabolism marker values over time is one of the methods for evaluating the effect of treatment on bone tissue in cases of spinal metastasis. We think that there is a possibility bone metabolism marker values over time is a useful assessment method in improving quality of life in the final stages of cancer.

Sources of funding

The authors report no conflict of interest concerning the materials or methods used in this study, nor in the findings specified in this paper.