Analysis of factors related to osteoporotic vertebral fracture in prostate cancer patients

Osteoporotic fracture is one of the main causes of disability and death in elderly patients. With the increasing social age of the population, the prevalence of osteoporosis has significantly increased. In the past, the diagnostic and treatment modalities for osteoporosis focused more on female patients than male patients. However, men over the age of 50 years have a lifetime risk of osteoporotic fracture of 13%, similar to the lifetime risk of prostate cancer [1]. Since the discovery of the effect of castration (surgery-based or drugs-based) on prostate cancer in 1941, androgen deprivation therapy (ADT) has become one of the cornerstones of prostate cancer treatment. ADT not only reduces the recurrence rate of prostate cancer patients but also prolongs their lives [2]. Due to the improved detection rate and treatment of prostate cancer, more patients are receiving ADT than ever before; however, the course of treatment is longer than ever before [3]. ADT reduces estrogen and testosterone levels by disrupting the hypothalamic-pituitary–gonadal axis. However, its mechanism of action also leads to a range of side effects, such as sexual dysfunction, hot flashes, cognitive decline, insulin resistance, anemia, ischemic heart disease, muscle atrophy, and increased bone resorption [4]. Increased bone resorption leads to decreased bone mineral density (BMD) and bone structural damage, leading to an increased risk of osteoporotic fracture. Previous studies have reported that the reduction of BMD after the first year of ADT is in the range of 2–8% [5]. With subsequent ADT, BMD will still be lost at a rate of 2–4.5% per year. Long-term ADT has significant negative effects on the bone health of prostate cancer patients [6]. The purpose of this study was to explore the changes in osteoporotic vertebral fracture rate and related influencing factors in prostate patients before and after they received ADT. With this information, the patients can be better advised to prevent therapeutic bone loss and reduce the rate of vertebral fractures through adequate lifestyle changes and medication. Thus, our results will be instrumental in improving the quality of life of prostate cancer patients postoperatively.

In this study, the vertebral fracture rate of the pre-treatment group was found to be significantly lower than that of the control group. This finding might be attributed to the high androgen level of prostate cancer patients. There are abundant levels of androgen receptor (AR), estrogen receptor α (ERα), and estrogen receptor β (ERβ) on the surface of osteoblasts, osteoblasts, and osteoclasts in the human body. Androgen and estrogen play a regulatory role in bone formation and absorption by acting on the abovementioned receptors. Androgens impact the function of osteoblasts through receptors, including the proliferation, synthesis, and secretion of various growth factors and cytokines of osteoblasts, and the production of bone matrix proteins (collagen, osteocalcin, and osteoblast), which play a role in regulating and balancing bone metabolism. Both testosterone and dihydrotestosterone can suppress bone resorption by inhibiting bone resorption stimulators, such as parathyroid hormone (PTH), interleukin 1 (IL1), and interleukin 6 (IL6). In addition, testosterone can promote the secretion of calcitonin, suppressing the activity of osteoclasts. The decrease in calcitonin levels post-castration may also be responsible for the increased activity of osteoclasts. Osteoporosis is a kind of bone disease wherein the patient is prone to fractures due to a decrease in bone mass and the destruction of the fine structure of bone tissue. In prostate cancer patients, androgen promotes the growth of prostate cancer cells. Both surgery-based and drug-based castrations reduce the level of androgen in the body. Although androgen reduction can prolong the life span of patients and reduce the risk of advanced prostate cancer, it also leads to the loss of the regulating effect of androgen on bone formation and bone resorption, eventually causing osteoporotic fractures. The results of this study corroborated this phenomenon. The vertebral fracture rate of the post-treatment group was significantly higher than that in the pre-treatment group. In our previous research on osteoporotic fracture-related factors, we found that treatment time was a risk factor for vertebral fractures in breast cancer patients, and the risk of vertebral fractures in patients being treated for > 2 years increases by 2.736 times. However, there was no significant difference in the vertebral fracture rates between the post-treatment group and the control group, as well as between the prostate cancer patients being treated for > 2 years and those treated for < 2 years. This finding may be attributed to the short duration of ADT treatment for most patients in the case group. In a large study on long-term ADT therapy, the prevalence of osteoporosis was found to be 35% at the beginning, which increased to 43% after 2 years and 81% after 10 years of ADT [8]. Further, in the post-treatment group, univariate analysis showed that age, PSA levels, and treatment parameters significantly correlated with the vertebral fracture rate. However, in the multivariate analysis, only age was found to be significantly associated with vertebral fracture rate. This finding might be attributed to the small sample size or because there is certain collinearity between the selected independent variables.

Prostate cancer patients are prone to bone metastasis, which can cause different degrees of dysfunction, resulting in bone pain, bone fractures, pathological fractures, and other complications. The mechanism underlying bone metastasis development in prostate cancer patients is still unclear; however, it is suspected to be related to direct tumor expansion, retrograde venous flow, and tumor embolism. The most common sites of bone metastasis in prostate cancer patients are pelvis, spine, and ribs. Bone metastasis to the spine can also cause vertebral compression fractures. Lateral radiographs of the thoracolumbar spine can be used to determine whether the vertebral fracture is osteogenic and, thus, can help rule out osteoporotic or metastatic fractures. Clinically, 99 mTc-MDP bone imaging is one of the important modalities used for the diagnosis of bone metastases in prostate cancer patients. However, because prostate cancer patients are older and their own lesions, such as osteoporosis and degeneration, can lead to a positive bone scan and reduced specificity, it is often necessary to combine other imaging methods for bone scan diagnosis. Magnetic resonance imaging (MRI) also plays an important role in the detection of bone metastases in prostate cancer patients. In particular, 3D whole-body MRT1-weighted sequential imaging has better diagnostic performance than planar MRI for bone metastases. Currently, the gold standard for the diagnosis of osteoporosis is still the determination of BMD using dual-energy X-ray absorptiometry (DXA). In previous studies, we found that BMD measurement, combined with vertebral fracture assessment (VFA), in postmenopausal women can help detect occult vertebral fractures and improve the clinical diagnosis of osteoporosis [9]. A recent epidemiological survey also showed that, according to the DXA bone density test results, the prevalence rate of osteoporosis in Chinese men over 50 years old was 6.46% [10]. In addition, osteoporotic fractures occur in one out of five men over 50 years old. Also, the consequences of osteoporotic fractures are more serious in men, with significantly higher disability and fatality rates than in women [11, 12]. However, at present, DXA is not popular, and clinicians do not pay much attention to it. Another survey found that the awareness rate of osteoporosis in men over 20 years old was only 10.5%, while 25% of the men were subjected to the BMD test. Only 7% of people over 50 years old were aware of osteoporosis, and only 3.2% of men had their bone density tested. Of the 100 prostate cancer patients, only 25% were ever subjected to a DXA test. Of those 25 patients, 56% had osteoporosis, 28% had low bone mass, and only 16 percent had normal bone density. Genant’s semi-quantitative assessment is the basis for standardized interpretation of the severity of vertebral fractures. It is a simple and effective method for detecting vertebral fractures. Early detection of vertebral fractures can help improve the diagnosis and prognosis of osteoporosis [7]. In the 2020 guidelines of the American Association of Clinical Endocrinologists (AACE), osteoporosis is described as “a silent bone disease” that is preventable and treatable. Lumbar (thoracic) lateral vertebral imaging or DXA VFA evaluation is recommended when the T value of BMD is < − 1.0, and at least one of the following conditions exists: ① Age: ≥ 70 years old female or ≥ 80 years old male; ② Height: Previous reduction > 4 cm; ③ History of vertebral fracture: Self-reported but not treated; ④ Glucocorticoid: ≥ 5 mg prednisone daily for ≥ 3 months [13]. Prostate cancer patients treated with ADT are at risk for osteoporotic fractures. Lateral chest radiography is a routine examination method for inpatients. Radiologists can use lateral chest radiographs to preliminarily assess a vertebral condition, thus prompting clinicians to pay attention to the bone health of patients receiving ADT treatment and for further diagnosis and treatment.

This study also has some limitations. First, the evaluation of vertebral fractures was based on Genant’s semi-quantitative method. Although it is currently a commonly used diagnostic method, the influence of the evaluator’s subjectivity cannot be excluded. Second, this study did not include other osteoporosis-related factors, such as smoking, drinking, obesity, and lack of exercise. Third, the small sample size might lead to statistical bias. Although this study has some deficiencies, it also provides a reference value for future research directions.

The incidence of osteoporotic vertebral fracture in prostate cancer patients before treatment was lower than that in the normal population. However, this incidence increases significantly after treatment, primarily due to age, PSA level, and treatment parameters. Osteoporotic fractures are an important complication of ADT. To prevent these fractures, all patients subjected to ADT should be closely monitored for bone health by lumbar (thoracic) lateral imaging or VFA with DXA. Their monitoring might help reduce the incidence of fractures through lifestyle and necessary pharmacological interventions, thereby improving the quality of life of the patients.