前列腺癌ADT相关骨质疏松症的机制及防治进展

前列腺癌是男性最常见的癌症及主要死因之一。从20世纪40年代开始人们认识到前列腺癌对雄激素具有高度依赖的特点后,雄激素剥夺治疗（androgen deprivation therapy,ADT）现已成为局限性、复发性和转移性前列腺癌治疗的标准治疗方案。但ADT在治疗前列腺癌的同时却会出现骨质疏松等副作用。就骨质疏松而言,大部分前列腺癌患者在接受ADT前已患有骨质疏松症,接受ADT会使其原有骨质疏松症状加剧,在另一方面又增加了患者骨折的风险。因此探讨ADT相关性骨质疏松发病机制及防治进展已成为前列腺癌内分泌治疗及骨质疏松临床诊疗研究的重点。本文总结了前列腺癌ADT相关骨质疏松近几年来一系列研究成果,就其发病机制及防治进展作以下综述,如ADT相关骨质疏松症中雄激素的作用机制、ADT的药物种类及其作用机制和ADT相关骨质疏松症的研究,为医务工作者们了解前列腺癌ADT相关性骨质疏松发病机制及防治进展提供参考。     

Alendronate decreases the fracture risk in patients with prostate cancer on androgen‐deprivation therapy and with severe osteopenia or osteoporosis

OBJECTIVE

To evaluate changes in bone mass and fracture risk in patients with prostate cancer on androgen‐deprivation therapy (ADT) and with a basal T‐score of >?2.0, who were treated with an oral bisphosphonate, as such patients treated with ADT are at increased risk of bone loss and bone fracture.

PATIENTS AND METHODS

We selected 61 patients with prostate cancer treated with ADT; 31 were treated with oral alendronate 70 mg once‐weekly and a control group of 30 were not. At baseline and 12 months we measured bone mineral density (BMD) of the lumbar spine, femoral neck and total hip by dual‐energy X‐ray absorptiometry. All patients had severe osteopenia or osteoporosis at baseline. The risk of femoral neck fracture was calculated at baseline and 12 months (Z‐score 2.7).

RESULTS

Patients treated with alendronate had a significant increase in BMD at the lumbar spine and femoral neck after 1 year of follow‐up, with mean (sd ) values of 1.06 (0.26) vs 1.01 (0.21) g/cm² at baseline (P < 0.001), and 0.75 (0.07) vs 0.73 (0.07) g/cm² (P = 0.03), respectively, while the control group had a significant loss of BMD at the total hip of 0.79 (0.14) vs 0.81 (0.13) g/cm² (P = 0.03). BMD was significantly improved at the three locations in patients treated with alendronate compared with the control group, with differences at the lumbar spine, femoral neck and total hip of 0.05 (0.07) vs 0.01 (0.10) (P = 0.001), 0.01 (0.04) vs ?0.002 (0.03) (P = 0.04) and 0.01 (0.04) vs ?0.01 (0.02) g/cm², respectively (P = 0.001). Patients treated with alendronate had a significant decrease in the fracture risk at the femoral neck, by ?0.54 (1.29) (P = 0.04) after 1 year of follow‐up.

CONCLUSIONS

Treatment with once‐weekly 70 mg alendronate significantly improved the BMD at the lumbar spine and femoral neck in patients with prostate cancer with severe osteopenia or osteoporosis and on ADT, and significantly decreased the risk of femoral neck fracture.     

雄激素剥夺治疗前列腺癌引起的骨代谢变化

雄激素剥夺治疗(androgen deprivation therapy,ADT)是治疗转移性前列腺癌(PCa)的基石,显著延长了PCa患者生存期.然而在ADT治疗的PCa患者中,每年平均骨密度下降2％～10％,导致骨折发病率、相关发病率和死亡率增加,应该引起临床医师的注意.这种骨代谢状态,目前认为主要是雄激素、雌激素...     

Frequency of zoledronic acid to prevent further bone loss in osteoporotic patients undergoing androgen deprivation therapy for prostate cancer

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVE

To evaluate the efficacy of zoledronic acid (ZA) in osteoporotic patients with prostate cancer receiving either luteinizing hormone‐releasing hormone agonists (LHRHA, which accelerate bone loss) or bicalutamide (which preserves bone mineral density, BMD) as androgen‐deprivation therapy is the mainstay of treatment for advanced prostate cancer, and many patients are osteoporotic at presentation, with others becoming so on treatment.

PATIENTS AND METHODS

Fifty‐eight osteoporotic men with non‐metastatic prostate cancer were followed for 3 years. Patients were randomly assigned to receive either LHRHA (29) or bicalutamide (29). All received 4 mg ZA 3‐monthly for 1 year. BMD was measured by dual energy X‐ray absorptiometry at four times: 1 year before ZA; immediately before ZA; after five infusions; and 1 year afterwards. Bone turnover markers (BTMs) were measured at 3‐monthly intervals on ZA and 1 year later. All patients had radiography of the thoracolumbar spine at baseline and after ZA.

RESULTS

Patients on LHRHA showed a 4.9% decrease in BMD before ZA, a 1.6% increase after ZA and a 3.0% decrease 1 year later, compared to 2.0% increase, 7.8% increase and 1.9% decrease, respectively, in those on bicalutamide. BTMs decreased significantly after ZA. Seven patients (12%) had vertebral fractures at baseline, with none deteriorating at 1 year; two (3.5%) developed mandibular osteonecrosis.

CONCLUSION

Before ZA, BMD decreased on LHRHA, but was maintained on bicalutamide. Treatment with 3‐monthly ZA increased BMD and suppressed BTMs in osteoporotic patients both on LHRHA and bicalutamide, but to a greater extent in the latter. However, 1 year after the last infusion, BMD declined, suggesting that annual administration is inadequate in these patients. The optimum frequency might be related to BMD at time of bisphosphonate initiation.     

去势治疗对前列腺癌患者骨密度的影响

目的 :探讨去势治疗对前列腺癌患者骨密度 (BMD)的影响。　方法 :4 9例完成BMD测定的前列腺癌患者分为 2组 :非去势组 2 1例 ,在去势治疗前即已完成BMD测定 ;去势组 2 8例 ,均为去势治疗 1年以上者。BMD测定采用双能X线吸收法 (DEXA法 ) ,测定部位为腰椎 (L2～ 4)和股骨颈。为校正年龄、性别和体重因素对BMD的影响 ,与年龄、种族等相配对的Z评分被用于结果评估。　结果 :13例 (6 2 % )非去势组患者和 2 3例 (82 % )去势组患者均存在不同程度的BMD水平下降。在非去势组 ,腰椎 (L2～ 4)Z评分为 - (0 .9± 0 .7)分 ,股骨颈Z评分为 - (0 .6± 0 .5 )分 ;而在去势组 ,腰椎 (L2～ 4)Z评分为 - (1.8± 1.1)分 ,股骨颈Z评分为 - (1.6± 1.0 )分。与非去势组相比 ,去势组患者BMD水平明显偏低 ,差异有显著性 (P <0 .0 1)。　结论 :去势治疗前 ,前列腺癌患者常伴有不同程度的骨量减少和骨质疏松 ,去势治疗与前列腺癌患者BMD水平下降明显相关。在对前列腺癌患者采用去势治疗之前 ,BMD测定是必要的。     

Preserving bone health in patients with hormone‐sensitive prostate cancer: the role of bisphosphonates

Men with prostate cancer initiating androgen‐deprivation therapy (ADT) may have multiple factors that threaten their skeletal health, including increased fracture risk from bone loss during ADT and the propensity to develop bone metastases, which may lead to skeletal‐related events (SREs). Bisphosphonates have utility in oncology for patients with bone metastases to prevent bone loss during hormonal therapy and in the benign setting to treat osteoporosis. These agents have an emerging role in patients with hormone‐sensitive prostate cancer (HSPC). Etidronate, alendronate, pamidronate, and zoledronic acid have all shown efficacy in preventing ADT‐related bone loss. Alendronate and zoledronic acid have also been shown to increase bone mineral density vs baseline during ADT. Patients with bone metastases from HSPC who received 4 mg zoledronic acid every 3 or 4 weeks had a low incidence of skeletal complications, although controlled study data have not been reported. Bisphosphonate treatment in men with HSPC may be effective for the prevention of ADT‐related bone loss, underscoring the importance of treating early to avoid SREs and potentially delay disease progression to metastatic bone disease.     

Preventive effect of risedronate on bone loss in men receiving androgen-deprivation therapy for prostate cancer

AIM: Androgen-deprivation therapy for prostate cancer decreases bone mineral density and increases the risk of fracture. The effect of risedronate, a potent third-generation oral bisphosphonate, on bone loss during androgen deprivation therapy was investigated. METHODS: Sixty-one prostate cancer patients with a mean age (+/- SD) of 79 +/- 6 years who had received androgen deprivation therapy for 42 +/- 29 months were enrolled, and were treated with 2.5 mg of risedronate daily for six months. Bone mineral density was measured at the femoral neck, lumbar spine, and ultradistal radius by dual energy X-ray absorptiometry. The percent change of bone mineral density after treatment with risedronate was calculated as the primary efficacy variable. Urinary N-telopeptide of type I collagen was measured as a bone resorption marker. RESULTS: Bone mineral density remained stable in the femoral neck and radius during risedronate therapy. In contrast, the bone mineral density of the lumbar spine showed a significant increase from 1069 +/- 488 mg/cm(2)-1112 +/- 497 mg/cm(2) (P < 0.001), representing a gain of 4.9 +/- 8.9%. Urinary N-telopeptide of type I collagen decreased significantly (P < 0.001) after three months of risedronate treatment. CONCLUSIONS: Risedronate could prevent and reverse bone loss in men receiving androgen deprivation therapy for prostate cancer by inhibiting bone resorption.     

Effect of androgen deprivation therapy on bone mineral density in prostate cancer patients

Aim: To evaluate the effect of androgen deprivation therapy (ADT) on bone mineral density (BMD) in prostate cancer patients. Methods: Forty-nine prostate cancer patients with their BMD determined were divided into two groups: the non-treated group included 21 patients before the commencement of ADT and the treated group, 28 patients, who had received ADT for more than 1 year. BMD was measured by dual energy X-ray absorptiometry (DEXA) in the lumbar spine (L2-4) and femoral neck. Results: Thirteen (62 %) non-treated and 23 (82 %) treated patients fulfilled the BMD criteria for osteopenia or osteoporosis. Z scores for age-matched control in lumbar spine and femoral neck were -0.9 ± 0.7 and -0.6 ± 0.5, respectively, in the treated group, and -1.8 ± 1.1 and-1.6 ± 1.0 , respectively, in the non-treated group, the differences between the two groups were highly significant (P<0.01). Conclusion: Prostate cancer patients who received ADT for more than 1 year had a significantly lower BMD in the lumbar spine a     

Risedronate prevents early bone loss and increased bone turnover in the first 6 months of luteinizing hormone‐releasing hormone‐agonist therapy for prostate cancer

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVE

To determine whether increased bone loss and bone turnover during the first 6 months of therapy for prostate cancer with luteinizing hormone‐releasing hormone (LHRH)‐agonist therapy could be prevented by bisphosphonate therapy with risedronate 35 mg/week, as prostate cancer is commonly treated with LHRH agonists and this often leads to rapid bone loss within the first 6 months of therapy.

PATIENTS AND METHODS

A 6‐month randomized, double‐blind, placebo‐controlled trial was conducted, including 40 men aged ≥55 years receiving LHRH‐agonist treatment for 6 months for locally advanced prostate cancer. Bone mineral density (BMD) of the lumbar spine, femoral neck, and total hip was measured every 6 months. In addition, bone turnover markers including N‐telopeptide, serum C‐telopeptide and procollagen peptide, and 25‐OH vitamin D and intact parathyroid hormone were measured at baseline and at 6 months.

RESULTS

After 6 months of LHRH‐agonist therapy, the control group had a significant decline at the spine and hip BMD sites; however, the risedronate group had no bone loss at the hip and an increase at the lumber spine. Markers of bone turnover were increased significantly in the control group but unchanged in the risedronate group.

CONCLUSIONS

LHRH‐agonist treatment for locally advanced prostate cancer produces increased bone turnover and rapid bone loss within the initial 6 months of therapy, and this can be prevented by weekly risedronate treatment.     

最大限度雄激素阻断治疗前列腺癌对患者骨密度的影响

目的:探讨最大限度雄激素阻断(MAB)治疗对前列腺癌患者骨密度的影响。方法:对40例因前列腺癌行MAB治疗的患者进行调查,治疗时间7～12个月,分别于治疗前后检测血清前列腺特异性抗原(PSA)、睾酮及血钙、血磷、24 h尿钙、尿磷、碱性磷酸酶、甲状旁腺激素、血常规及肝肾功能,双能X线吸收法测定腰椎、股骨颈骨密度,并进行疼痛评分,比较MAB治疗前后各项指标差异。结果:前列腺癌患者治疗前5例(12.5%)腰椎骨量减少,8例(20.0%)腰椎骨质疏松;13例(32.5%)左股骨颈骨量减少,15例(37.5%)左股骨颈骨质疏松。MAB治疗前患者血清PSA为(52.9±69.9)μg/L,睾酮为(18.9±6.5)nmol/L,治疗后PSA为(1.5±1.6)μg/L,睾酮为(1.9±1.3)nmol/L,与治疗前比较均显著下降(P<0.05)。治疗前血钙为(2.5±0.2)mmol/L,血磷为(1.2±0.2)mmol/L,尿钙为(3.1±1.4)mmol/L,尿磷为(11.5±8.1)mmol/L,治疗后血钙为(2.5±0.1)mmol/L,血磷为(1.2±0.1)mmol/L,尿钙为(2.8±1.2)mmol/L,尿磷为(9.9±4.0)mmol/L,两者比较差异均无统计学意义(P>0.05)。治疗前后碱性磷酸酶、甲状旁腺激素、血常规、肝肾功能差异均无统计学意义(P>0.05)。治疗前腰椎和股骨颈骨密度分别为(1.1±0.1)g/cm2和(0.8±0.2)g/cm2,疼痛评分为(0.6±0.2)分,治疗后腰椎和股骨颈骨密度分别为(1.1±0.2)g/cm2和(0.8±0.1)g/cm2,疼痛评分为(0.7±0.1)分,与治疗前比较差异均无统计学意义(P>0.05)。结论:7～12个月MAB治疗对前列腺癌患者骨密度无明显影响,安全有效,但治疗前应注意监测患者骨密度。     

Immediate dual energy X-ray absorptiometry reveals a high incidence of osteoporosis in patients with advanced prostate cancer before hormonal manipulation

OBJECTIVE: To examine the incidence of osteoporosis in patients with advanced prostate cancer (using forearm densitometry) before commencing androgen deprivation therapy (ADT), as osteoporotic fractures are more frequent in patients with prostate cancer who have undergone either medical or surgical castration, because of rapid loss of bone mass. PATIENTS AND METHODS: In all, 174 patients (mean age 74.6 years, range 46-90) with advanced prostate cancer presented over 2 years. Their forearm bone densitometry values were compared with those from 106 age-matched controls (mean age 74.3 years, range 66-90). RESULTS: Of the 174 patients, 73 (42%) were osteoporotic (t score 相似文献   

Hormone therapy for prostate cancer and the risk of stroke: a 5-year follow-up study

Study Type – Therapy (outcomes) Level of Evidence 2c What's known on the subject? and What does the study add? Numerous studies have consistently reported that long‐term use of ADT for PC may increase the risk of fractures, metabolic syndrome and cardiovascular diseases. There was no significant difference in risk of stroke between ethnic Chinese PC patients who did and did not receive ADT.

OBJECTIVE

• ? To examine the 5‐year risk of stroke among patients with prostate cancer (PC) receiving androgen deprivation therapy (ADT) in Taiwan, using a population‐based dataset.

PATIENTS AND METHODS

• ? This prospective case–control study used data sourced from the Longitudinal Health Insurance Database.
• ? The study included 365 patients with PC; 64 (17.6%) received ADT for more than 1 month.
• ? Cox proportional hazards regression was used to evaluate the association between ADT and the risk of stroke during the subsequent 5‐year follow‐up period, after adjusting for sociodemographic characteristics and hypertension, diabetes, coronary heart disease, heart failure, atrial fibrillation and hyperlipidaemia.

RESULTS

• ? In the total sample of 365 patients with PC, 68 (18.6%) patients had strokes during the 5‐year follow‐up period. These included 11 patients with PC who received ADT (17.2% of all patients who received ADT) and 57 patients who did not receive ADT (18.9% of patients who did not receive ADT).
• ? After adjusting for potential confounders, no significant difference in the hazard of stroke was found between patients with PC who did and did not receive ADT (hazard ratio, 1.09; 95% confidence interval, 0.80–1.50).

CONCLUSION

• ? There was no significant difference in the risk of stroke between ethnic Chinese patients with PC who did and did not receive ADT, after adjusting for potential confounders.

     

Use of androgen deprivation therapy in prostate cancer: indications and prevalence

Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease. Controversies remain, however, surrounding the optimal timing, duration and schedule of these hormonal approaches. Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer. This review highlights the various androgen-directed treatment options available to men with prostate cancer, their specific indications and the evidence supporting each approach, as well as patterns of use of hormonal therapies.     

Adverse effects of androgen deprivation therapy in men with prostate cancer: a focus on metabolic and cardiovascular complications

Prostate cancer (PCa) is the most common malignancy in men. Prostate being an androgen responsive tissue, androgen deprivation therapy (ADT) is used in the management of locally advanced (improves survival) and metastatic (improves pain and quality of life) PCa. Over the past two decades, the use of ADT has significantly increased as it is also being used in patients with localized disease and those experiencing biochemical recurrences, though without any evidence of survival advantage. Hypogonadism resulting from ADT is associated with decreased muscle mass and strength, increased fat mass, sexual dysfunction, vasomotor symptoms, decreased quality of life, anemia and bone loss. Insulin resistance, diabetes and cardiovascular disease have recently been added to the list of these complications. As the majority of men with PCa die of conditions other than their primary malignancy, recognition and management of these adverse effects is paramount. Here we review data evaluating metabolic and cardiovascular complications of ADT.     

去势抵抗性前列腺癌新型内分泌治疗耐药机制研究进展

前列腺癌是男性泌尿生殖系统最常见的恶性肿瘤之一,雄激素在其发生发展中都扮演着重要角色。经去势治疗(ADT)后绝大多数前列腺癌都会进展成为去势抵抗性前列腺癌(CRPC)。肾上腺来源的雄激素和(或)雄激素受体(AR)的改变(包括AR基因扩增)驱动了瘤内雄激素的合成,进而重新雄激素轴信号通路。目前,阿比特龙、恩扎鲁胺等抗雄激素治疗药物都是CRPC患者的一线治疗用药。但是,治疗一段时间后患者仍然会出现耐药和疾病进展。因此,明确CRPC患者抗雄激素治疗耐药机制可以为克服CRPC治疗耐药和改善CRPC患者的预后提供契机。     

Prognostic significance of genetic polymorphisms in disease progression and survival in prostate cancer after androgen deprivation therapy

It is believed that androgens and their receptors regulate normal prostate growth and mediate prostate cancer development. Androgen deprivation therapy is the most commonly used treatment for advanced prostate cancer. Although the therapy is initially effective, progression of the disease to castration-resistant prostate cancer is almost inevitable, leading to treatment failure. Despite the existence of current clinical parameters, new biomarkers are urgently needed to improve the prognosis. Some molecules and DNA-based genetic biomarkers are under investigation as potential prognostic factors. The advancement in molecular cytogenetic research, such as genome-wide association for single-nucleotide polymorphisms, has made possible the detection of genetic mutations. In this study, a literature search from August 1985 to April 2013 was performed through the PubMed database using the keywords “genetic polymorphisms”, “prostate cancer” and “androgen deprivation therapy”. The results revealed that several genome-wide association studies (such as rs16901979, rs7931342, HSD17B4, rs6162 in the CYP17A1, rs4243229 and rs7201637 in the HSD17B2, rs1062577 in the ESR1, SLCO1B3, SLCO2B1, rs2939244 in the ARRDC3, rs9508016 in the FLT1, rs6504145 in the SKAP1, rs7830611 in the FBXO32, rs9508016 in the FLT1, rs12529 in the AKR1C3, rs16934641 in the BNC2, rs3763763 in the TACC2, rs2051778 in the ALPK1, and rs3763763 in the TACC2, AR, ESR1, and ESR2) and single-nucleotide polymorphisms in important pathways (such as androgen signal, biosynthesis, metabolism, androgen receptor binding site, response element, androgen receptor CAG repeat polymorphism length, and estrogen receptor-binding sites) involved in prostate cancer occurrence and mechanism could serve as candidate biomarkers for the early detection of castration-resistant prostate cancer after androgen deprivation therapy. Additional investigations are required to decipher precisely the gene combinations and personalize the management of prostate cancer.     

Obesity is associated with castration-resistant disease and metastasis in men treated with androgen deprivation therapy after radical prostatectomy: results from the SEARCH database

Study Type – Prognosis (cohort series) Level of Evidence 2a What's known on the subject? and What does the study add? The incidence and prevalence of obesity in the USA and Europe is increasing. Higher body mass index is associated with a lower risk of overall prostate cancer diagnosis but also with an increased risk of high grade prostate cancer. Obese men undergoing primary therapy with radical prostatectomy or external beam radiation are more likely to experience a biochemical recurrence after treatment compared with normal weight men. Finally, obesity is associated with increased prostate‐cancer‐specific mortality. We hypothesized that obese men on androgen deprivation therapy may be at increased risk for prostate cancer progression. Previous studies have shown that obese men have lower levels of testosterone compared with normal weight men. Additionally, one previous study found that obese men have higher levels of testosterone on androgen deprivation therapy. Men with higher levels of testosterone on androgen deprivation therapy are at increased risk of prostate cancer progression. We found that men with higher body mass index were at increased risk of progression to castration‐resistant prostate cancer, development of metastases and prostate‐cancer‐specific mortality. When we adjusted for various clinicopathological characteristics, obese men were at increased risk of progression to castration‐resistant prostate cancer and development of metastases. The results of our study help generate hypotheses for further study regarding the mechanisms between obesity and aggressive prostate cancer.

OBJECTIVE

• ? To investigate whether obesity predicts poor outcomes in men starting androgen deprivation therapy (ADT) before metastasis, since previous studies found worse outcomes after surgery and radiation for obese men.

METHODS

• ? A retrospective review was carried out of 287 men in the SEARCH database treated with radical prostatectomy between 1988 and 2009.
• ? Body mass index (BMI) was categorized to <25, 25–29.9 and ≥30 kg/m2.
• ? Proportional hazards models were used to test the association between BMI and time to castration‐resistant prostate cancer (PC), metastases and PC‐specific mortality adjusting for demographic and clinicopathological data.

RESULTS

• ? During a median 73‐month follow‐up after radical prostatectomy, 403 men (14%) received early ADT.
• ? Among 287 men with complete data, median BMI was 28.3 kg/m2.
• ? Median follow‐up from the start of ADT was 52 months during which 44 men developed castration‐resistant PC, 34 developed metastases and 24 died from PC.
• ? In multivariate analysis, higher BMI was associated with a trend for greater risk of progression to castration‐resistant PC (P= 0.063), a more than threefold increased risk of developing metastases (P= 0.027) and a trend toward worse PC‐specific mortality (P= 0.119).
• ? Prognostic biomarkers did not differ between BMI groups.

CONCLUSIONS

• ? Among men treated with early ADT, our results suggest that obese men may have increased risk of PC progression.
• ? These data support the general hypothesis that obesity is associated with aggressive PC, although validation of these findings and further study of the mechanisms linking obesity and poor PC outcomes are required.