Introduction
Bone metastases (BM) are a serious complication of several late-stage malignancies. In particular, breast and prostate cancers, which account for the majority of tumors in adult females and males, respectively, exhibit a marked tendency to colonize the skeleton, with up to 65–75% of patients experiencing bone disease when in stage IV [
1]. In addition, a not negligible proportion of subjects suffering from thyroid, lung and renal cancer may develop BM during the course of their disease [
2,
3].
Depending on the primary tumor and according to the radiographic features of the lesions, BM can be classified as either osteolytic or osteoblastic. When bone resorption prevails, as often observed in lung and renal cell carcinoma patients, focal bone destruction occurs, leading to the establishment of “lytic” lesions. On the other hand, BM characterized by enhanced osteoblastic activity, as in prostate cancer, appear osteosclerotic (also known as “osteoblastic”) [
4]. However, even if one component seems to prevail over the other, bone resorption and osteogenesis are usually both accelerated within BM, and mixed lesions can be observed, especially in metastatic breast cancer patients [
4].
Due to the considerable morbidity of skeletal metastases, their timely diagnosis and periodic monitoring are crucial. Current guidelines define plain X-ray, computerized tomography (CT) and radionuclide bone scan as the gold standard techniques for BM detection [
5], whereas the interest toward whole-body magnetic resonance imaging (MRI) and positron emission tomography (PET) scan with different radiotracers is increasing [
5‐
7]. However, rather than depicting the cancer cell foci, these techniques show the stromal reaction within the bone marrow, for which their sensitivity in detecting early-stage BM may be poor. In addition, skeletal lesions change during anti-cancer and anti-resorptive treatments, further complicating their monitoring over time [
2].
In an attempt to overcome the limitations of current imaging techniques, which also include radiation exposure, economic burden for national health systems and/or financial toxicity for individual patients, few studies attempted to evaluate the role of dual-energy X-ray absorptiometry (DXA) in monitoring BM response to anti-cancer treatment, with promising results [
8,
9].
Several efforts have also been made to evaluate the potential role of bone turnover markers (BTM), which are susceptible to non-invasive measurement in blood and urine [
10‐
12], as a surrogate for radiological imaging [
12‐
15], and/or as prognostic biomarkers in patients with metastatic bone disease [
16‐
20]. However, conflicting results emerged from such studies, with high inter- and intra-individual variability representing a substantial limitation to their routine use [
11].
In this single-center experience, we assessed whether the coupled use of DXA and BTM measurement could enable early identification of BM progression in a heterogeneous cohort of patients with skeletal metastases from solid malignancies receiving zoledronate during the anti-tumor treatment.
Discussion
BM are a common complication of solid tumors, accounting for substantial morbidity and mortality, as well as socioeconomic costs. One of the major clinical issues related to BM is the lack of specific biomarkers for early diagnosis and treatment monitoring [
2,
31]. To our knowledge, this is the first study to assess the role of integrated BTMs and DXA scan in predicting the efficacy of zoledronate in terms of bone disease control and prevention of SREs in a heterogeneous and “real-world” cohort of cancer patients.
BTMs have been already investigated as potential biomarkers of BM, and a correlation between BTMs and the extent of metastatic bone disease as well as the risk of SREs has been described [
32]. Consistent with prior observations [
33‐
35], we found that baseline levels of the bone resorption markers CTX and NTX significantly correlated with the extent of skeletal disease in our cohort. While intra- and inter-individual variability negatively affect the reliability of urine BTMs, thus limiting their routine clinical use, we note that only serum measurements were used in our study in order to overcome the need of creatinine correction [
12] and minimize the assay variability [
26]. In agreement with previous reports [
13,
25], a significant reduction of CTX and NTX was observed during the first 6 months of zoledronate treatment. However, no association was found between longitudinal changes of these markers (reduction or increase) and skeletal progression by MDA criteria or SRE occurrence.
Among osteoblast-derived proteins, OC and OPG showed an opposite direction in terms of over time change during bisphosphonate treatment in our study. Nevertheless, both the decrease in OC and the increase in OPG are not surprising findings. OC is the most abundant non-collagenous protein in bone and is released into systemic circulation during bone resorption [
36], a process known to be negatively modulated by zoledronate. On the other hand, OPG is a marker of osteoblast differentiation [
37], which is fostered by bisphosphonates [
38,
39]. In our cohort, low levels of both OC and OPG predicted early skeletal progression, especially in patients with lytic BM. On the other hand, a progressive increase in OPG concentration during zoledronate treatment predicted a reduced probability of SREs. To the best of our knowledge, this is the first evidence of such a clinical value of OPG and deserves further investigation in a wider patient cohort.
The role of DXA in predicting BM response to zoledronate has been poorly investigated so far. Sporadic reports [
40‐
42] have described the ability of DXA scan (performed to rule out osteoporosis in patients without an established diagnosis of cancer or in the setting of cancer treatment-induced bone loss, CTIBL) to reveal the presence of skeletal lesions, subsequently diagnosed as BM. In a previous report, Shapiro et al. [
8] prospectively evaluated the role of DXA in monitoring BM response to anti-cancer treatment in 9 patients with breast cancer. The over time change of skeletal metastasis BMD was shown to correlate with the findings from standard imaging modalities, such as X-rays and CT scan, and a significant association was observed between BMD increase and response to treatment.
In line with prior evidence [
9,
43‐
45], the BMD of osteolytic lesions was significantly lower than that of osteosclerotic metastases in our study. Moreover, as expected, lumbar, femur and target lesion BMD as well as lumbar and femur T-score significantly increased during zoledronate treatment. While longitudinal changes of either BMD or T-score failed to predict BM progression or SRE occurrence, the presence of two abnormal DXA parameters at baseline (low lumbar T-score and low femur BMD) was associated with higher risk of on-study SREs. Such a correlation suggests that a routine densitometric assessment of bone metastatic patients at baseline could be useful for stratifying their risk of skeletal complications and plan appropriate therapeutic strategies. Indeed, pre-existing osteopenic/osteoporotic conditions might further increase bone fragility in patients with BM.
It has to be noted that a variable (between 3 and 40%) degree of discordance between lumbar spine and femur DXA parameters has been described in the literature [
46‐
48], due to physiological and anatomical differences, as well as potential artifactual and technical issues; this might explain why only two DXA parameters correlated, in our series, with the risk of SREs, while the remaining did not.
Although intriguing, these findings might have been biased by the heterogeneity of our “real-world” patient cohort and need further confirmation in wider, more homogeneous series.
Our analysis did not show any correlation between BTMs or densitometric parameters and OS, but the heterogeneity of the cohort, coupled with that of administered anti-tumor treatments, might have confounded our results.
Our work has other limitations. First, the small sample size limits the power of our analyses, hindering definitive conclusions on the role of BTMs and densitometric parameters in monitoring the activity of zoledronate. Second, the heterogeneity of the cohort (in terms of cancer diagnosis, tumor molecular features, age of the patients, smoking habits, administered anti-tumor treatments, etc.) may bias our results, introducing uncontrolled confounding factors.
Nevertheless, our cohort mirrors a “real-world” scenario, providing information that are directly applicable to the routine clinical practice. In addition, patients with a personal history of hormone treatment (which is a well-established modifier of bone turnover) [
21] were excluded from our study to reduce the risk of pre-existing iatrogenic bone health alterations (i.e. CTIBL). As for the hormone anti-cancer therapies administered between T0 and T1, instead, we did not expect them to have relevant impact on bone turnover during zoledronate treatment, since several clinical trials have described that up-front concomitant administration of the bisphosphonate reduces the risk of bone loss, even when the 6-monthly schedule of the drug is applied, as in the setting of CTIBL prevention [
49‐
53]. Moreover, over time comparisons within the same patient should be less dependent on the aforementioned confounders, having an internal baseline control.
In conclusion, improvement of densitometric parameters or BTMs during the first 6 months of zoledronate treatment is not necessarily associated with a reduced risk of bone disease progression. Low baseline concentrations of OC and OPG as well as low baseline T-score and BMD might predict the occurrence of SREs. Therefore, integration of BTM dosage and DXA evaluation at diagnosis of BM may be helpful in better stratifying the risk of SREs. Future studies in larger, more homogeneous cohorts of patients should evaluate whether the increase in OPG levels during zoledronate therapy may truly predict a reduced risk of SREs.
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