Management of treatment-related osteoporosis in men with prostate cancer

Osteoporosis is an important and preventable adverse effect of androgen deprivation therapy for prostate cancer. Androgen deprivation therapy by either bilateral orchiectomies or administration of a gonadotropin-releasing hormone agonist decreases bone mineral density and increases fracture risk. Treatment-related osteoporosis can be prevented by intermittent administration of either intravenous pamidronate or zoledronic acid. Pamidronate (60 mg intravenously every 3 months) prevents bone loss during androgen deprivation therapy. Zoledronic acid (4 mg intravenously every 3 months) not only prevents bone loss but also increases bone mineral density. Alendronate and other oral bisphosphonates may be effective but have not been evaluated in men with castrate testosterone levels. Oestrogen replacement therapy and treatment with selective ooestrogen receptor modulators may prevent bone loss during androgen deprivation therapy. Bicalutamide (150 mg daily) monotherapy increases serum ooestrogen levels and maintains bone mineral density.     

Osteoclast-targeted therapy for prostate cancer

Opinion statement Skeletal complications are a major cause of morbidity in men with metastatic prostate cancer. Bone metastases cause pain, fractures, spinal-cord compression, and ineffec-tive hematopoiesis. Men without bone metastases are also at risk for skeletal complications. Androgen deprivation therapy (ADT), the mainstay of treatment for metastatic prostate cancer and a routine part of the management for many men with nonmetastatic prostate cancer, decreases bone mineral density, and increases fracture risk. Pathological osteoclast activation plays a central role in both disease and treatment-related skeletal morbidity. Bisphosphonates, potent inhibitors of osteoclast activity, are now an important part of the management for many men with prostate cancer. Zoledronic acid, a potent intravenous bisphosphonate, decreases the risk of skeletal complications in men with hormone-refractory prostate cancer and bone metastases. Zoledronic acid and pamidronate preserve bone mineral density in men receiving ADT for nonmetastatic prostate cancer. Ongoing clinical trials will evaluate the role of osteoclast-targeted therapy in other settings including prevention of treatment-related fractures, prevention of bone metastases in men with high-risk nonmetastatic prostate cancer, and prevention of skeletal complications in men with hormone-sensi-tive metastatic disease.     

Changes in bone mineral density and body composition during initial and long-term gonadotropin-releasing hormone agonist treatment for prostate carcinoma

BACKGROUND: Initial treatment with a gonadotropin-releasing hormone (GnRH) agonist increases fat mass, decreases lean body mass, and decreases bone mineral density (BMD) in men with prostate carcinoma. To the authors' knowledge, little is known regarding either the long-term effects of treatment or predictors of treatment-related changes in BMD and body composition. METHODS: The authors analyzed prospective 12-month data from 65 men during initial and long-term GnRH agonist treatment for prostate carcinoma. Relationships between baseline characteristics (age, treatment duration, body mass index, and baseline values for outcome of interest) and changes in lean mass, fat mass, and BMD were assessed using univariate and multivariate regression models. RESULTS: Mean BMD of total hip decreased by 1.9 +/- 2.7%, lean body mass decreased by 2.0 +/- 3.3%, and fat mass increased by 6.6 +/- 9.4% at 12 months (P < 0.001 for each comparison). Twenty-three men (35%) had received treatment with a GnRH agonist before study entry, and the mean (+/- standard deviation) duration of previous treatment was 35 +/- 41 months. Longer duration of previous GnRH agonist treatment was found to independently predict less fat accumulation and less loss of lean body mass in multivariate models. In contrast, the duration of GnRH agonist treatment did not significantly predict changes in BMD. Other covariates did not appear to predict changes in body composition or BMD consistently. CONCLUSIONS: The results of the current study showed that fat mass increased and lean body mass decreased mostly during initial GnRH agonist therapy whereas BMD decreased steadily during initial and long-term treatment.     

Management of complications of prostate cancer treatment.

Prostate cancer is the most commonly diagnosed noncutaneous cancer in men in the United States. Treatment of men with prostate cancer commonly involves surgical, radiation, or hormone therapy. Most men with prostate cancer live for many years after diagnosis and may never suffer morbidity or mortality attributable to prostate cancer. The short-term and long-term adverse consequences of therapy are, therefore, of great importance. Adverse effects of radical prostatectomy include immediate postoperative complications and long-term urinary and sexual complications. External beam or interstitial radiation therapy in men with localized prostate cancer may lead to urinary, gastrointestinal, and sexual complications. Improvements in surgical and radiation techniques have reduced the incidence of many of these complications. Hormone treatment typically consists of androgen deprivation therapy, and consequences of such therapy may include vasomotor flushing, anemia, and bone density loss. Numerous clinical trials have studied the role of bone antiresorptive therapy for prevention of bone density loss and fractures. Other long-term consequences of androgen deprivation therapy may include adverse body composition changes and increased risk of insulin resistance, diabetes, and cardiovascular disease. Ongoing and planned clinical trials will continue to address strategies to prevent treatment-related side effects and improve quality of life for men with prostate cancer.     

双磷酸盐对接受去势治疗的激素敏感型前列腺癌患者防治骨质丢失的研究进展

前列腺癌（prostate cancer,PC）可以通过多个途径增加患者的骨质丢失,破坏骨完整性。去势治疗（androgen deprivation therapy,ADT）为激素敏感型晚期PC的标准治疗手段,但ADT可以加速患者的骨质丢失,增加骨相关事件（skeletal related events,SREs）的发生率。随机对照临床研究已经证实双磷酸盐类药物可以防治接受ADT的激素敏感型PC患者的骨质丢失,增加其骨密度,减少或延缓SREs的发生,提高患者的生活质量。     

Androgen deprivation therapy as adjuvant/neoadjuvant to radiotherapy for high-risk localised and locally advanced prostate cancer: recent developments

Androgen deprivation therapy (ADT) has traditionally formed the mainstay of treatment for advanced/metastatic prostate cancer (PCa); however, it is now also having an increasingly important role in earlier stages of disease. Indeed, in patients with locally advanced or high-risk localised disease, the addition of neoadjuvant and adjuvant hormone therapy is now considered the standard of care for those men treated with radical radiotherapy. Although luteinising hormone-releasing hormone (LHRH) agonists have been used for many years as ADT, they may be associated with clinical flare and testosterone breakthrough. Newer hormonal agents continue to be developed, such as gonadotropin-releasing hormone antagonists, which reduce testosterone and prostate-specific antigen levels more rapidly than LHRH agonists, without testosterone flare. This review examines ADT use in combination with radiotherapy to improve outcomes in localised or locally advanced disease, and examines some of the latest developments in hormonal therapy for PCa.     

双磷酸盐治疗和预防前列腺癌骨相关事件研究进展

前列腺癌（prostate cancer,PC）癌细胞转移到骨后,首先激活破骨细胞进而使成骨细胞活性增加形成前列腺癌骨转移病灶,导致一系列骨相关事件（skeletal related events,SREs）的发生。去势治疗（androgen deprivation therapy,ADT）可以加速激素敏感型PC患者的骨质丢失,增加SREs的发生。随机对照临床研究证实双磷酸盐类药物不仅对激素抗拒型PC或激素敏感型PC骨转移治疗有效,能够缓解骨痛,增加患者骨密度,减少SREs的发生,而且对接受ADT的激素敏感型PC患者也可以预防骨质丢失,减少或延缓SREs的发生。此外,双磷酸盐类药物可以治疗高钙血症,提高骨转移患者的生活质量。     

Contribution of androgen deprivation therapy to elevated osteoclast activity in men with metastatic prostate cancer.

PURPOSE: Biochemical markers of both osteoblast and osteoclast activity are elevated in men with osteoblastic metastases from prostate cancer. Androgen deprivation therapy (ADT), the mainstay of therapy for advanced prostate cancer, increases markers of osteoblast and osteoclast activity, even in the absence of bone metastases. Little is known about the relative contributions of ADT and skeletal metastases to elevated bone turnover in men with prostate cancer. EXPERIMENTAL DESIGN: To evaluate the relative contributions of ADT and skeletal metastases to osteoblast and osteoclast activity, we performed a cross-sectional study in three groups of men with advanced prostate cancer: (a) hormone-na?ve men without bone metastases; (b) castrate men without bone metastases; and (c) castrate men with bone metastases. The primary study end points were serum levels of bone-specific alkaline phosphatase (BSAP), a marker of osteoblast activity, and N-telopeptide (NTX), a marker of osteoclast activity. RESULTS: Serum levels of both BSAP and NTX were significantly higher in groups of castrate men (groups 2 and 3) than in hormone-na?ve men (group 1; P < 0.01 for all comparisons). Among castrate men, serum BSAP was significantly higher in men with bone metastases than in men without bone metastases (P = 0.01). In contrast, serum levels of NTX were similar in groups 2 and 3 (P = 0.33). CONCLUSIONS: The unintended effects of ADT on the skeleton are sufficient to explain increased osteoclast activity in castrate men with bone metastases. These results may have important implications for the optimal timing and schedule of osteoclast-targeted therapy in men with advanced prostate cancer.     

Single infusion of zoledronic acid to prevent androgen deprivation therapy‐induced bone loss in men with hormone‐naive prostate carcinoma

BACKGROUND:

Androgen‐deprivation therapy (ADT) decreases bone mineral density (BMD) and increases fracture risk in patients with prostate carcinoma. The authors investigated the effectiveness of a single infusion of zoledronic acid initiated subsequent to ADT on BMD with hormone‐naive prostate carcinoma.

METHODS:

Forty men received either a single infusion of zoledronic acid (4 mg intravenously on Day 1) or no infusion during ADT. BMD of the proximal femur and posteroanterior lumbar spine was measured by dual‐energy x‐ray absorptiometry and urinary N‐telopeptide (u‐NTx) at 6 and 12 months.

RESULTS:

At baseline, the overall BMDs demonstrated no significant difference in lumbar spine and hip regions. At 6months, mean (±standard error) BMD of the posteroanterior lumbar spine decreased 4.6% ± 1.0% in control patients and increased 5.1% ± 1.2% in patients receiving zoledronic acid, a significant difference (P = .0002). At 12 months, the change in BMD between the 2 groups was statistically significantly different at the lumbar region (P = .0004), indicating that zoledronate preserved BMD. For u‐NTx, bone turnover was statistically significantly decreased in the zoledronate group compared with controls at 6 months (P < .0001), but returned to pretreatment levels at 12 months in the zoledronate group.

CONCLUSIONS:

Bone loss begins at 6 months with ADT. A single infusion of zoledronic acid in patients receiving ADT reduces bone mineral loss and maintains BMD at least at 12 months during ADT. Further study is needed to determine the best dosing schedule to prevent ADT‐induced bone loss in men with hormone‐naive prostate carcinoma. Cancer 2009. © 2009 American Cancer Society.     

Changes in body composition during hormonal therapy for prostate cancer

Androgens are important determinants of body composition in men. Androgen-deprivation therapy, the mainstay of treatment for advanced prostate cancer, increases fat mass and decreases lean body mass. These adverse changes in body composition may contribute to treatment-related fatigue, fracture risk, insulin resistance, and increased cardiovascular disease risk. Potential strategies to treat or prevent these adverse body composition changes include exercise training, alternative forms of hormonal therapy, and insulin-sensitizing agents.     

Concept and viability of androgen annihilation for advanced prostate cancer

There remains no standard of care for patients with a rising prostate‐specific antigen level after radical prostatectomy or radiotherapy but who have no radiographic metastases, even though this is the second largest group of patients with prostate cancer (CaP) in the United States. Androgen deprivation therapy (ADT) may cure some men with advanced CaP based on single‐institution series and a randomized clinical trial of immediate versus delayed ADT for men found to have pelvic lymph node metastasis at the time of radical prostatectomy. ADT may be more effective when initiated for minimal disease burden, which can be detected using PSA after radical prostatectomy or radiotherapy, and if more complete disruption of the androgen axis using newer agents decreases the chance that androgen‐sensitive cells survive to adapt to a low‐androgen environment. Androgens may be “annihilated” simultaneously using a luteinizing hormone‐releasing hormone antagonist or agonist to inhibit testicular production of testosterone, a P45017A1 (CYP17A1) inhibitor to diminish metabolism of testosterone via the adrenal pathway and dihydrotestosterone (DHT) via the backdoor pathway, a 5α‐reductase (SRD5A) inhibitor to diminish testosterone reduction to DHT and backdoor metabolism of progesterone substrates to DHT, and a newer antiandrogen to compete better with DHT for the androgen receptor ligand‐binding domain. Early initiation of androgen annihilation for induction as part of planned intermittent ADT should be safe, may reduce tumor burden below a threshold that allows eradication by the immune system, and may cure many men who have failed definitive local therapy. Cancer 2014;120:2628–2637 . © 2014 American Cancer Society.     

Low bone density and high percentage of body fat among men who were treated with androgen deprivation therapy for prostate carcinoma

BACKGROUND: Men with prostate carcinoma who are treated with androgen deprivation therapy (ADT) are reported to be at an increased risk of bone loss and weight changes due to the sudden disruption of hormonal levels. In the current case-control study, the authors examined the prevalence and magnitude of low bone density and obesity among men with prostate carcinoma who were treated with ADT. METHODS: Sixty-two men with prostate carcinoma who had been receiving ADT for 1-5 years were included as cases. Healthy men (n = 47) with a prostate specific antigen level < 4.0 ng/mL were recruited as controls. Body composition and bone mineral density (BMD) were measured using dual-energy X-ray absorptiometry. The average age was 74.3 years for the cases and 72.8 years for the controls. RESULTS: The results of the current study demonstrate that prostate carcinoma cases had significantly higher body weight (86.5 kg vs. 80.6 kg), a higher percentage of body fat (30% vs. 26%), and a lower total body BMD (1.12 mg/cm(2) vs. 1.17mg/ cm(2)) compared with controls (P < 0.05). Cases were more likely to be obese (27.4% vs 43%) and have low BMD at trochanter (32.3% vs. 10.6%), intertrochanter (48.4% vs. 29.8%), and total hip measurements (50.0% vs. 25.3%). CONCLUSIONS: The results of the current study indicate that men with prostate carcinoma who are treated with ADT have a significantly increased risk of low bone density and obesity.     

Bone mineral density in Jamaican men on androgen deprivation therapy for prostate cancer

Background

Androgen deprivation therapy (ADT) has been reported to reduce the bone mineral density (BMD) in men with prostate cancer (CaP). However, Afro-Caribbeans are under-represented in most studies. The aim was to determine the effect of androgen deprivation therapy (ADT) on the bone mineral density (BMD) of men with prostate cancer in Jamaica.

Methods

The study consisted of 346 Jamaican men, over 40 years of age: 133 ADT treated CaP cases (group 1), 43 hormone-naïve CaP controls (group 2) and 170 hormone naïve controls without CaP (group 3). Exclusion criteria included metastatic disease, bisphosphonate therapy or metabolic disease affecting BMD. BMD was measured with a calcaneal ultrasound and expressed in S.D. units relative to young adult men (T score), according to the World Health Organization definition. Patient weight, height and BMI were assessed.

Results

Mean ± sd, age of patients in group 1 (75± 7.4 yrs) was significantly greater than groups 2 and 3 (67 ± 8.1 yrs; 65±12.0 yrs). There was no significant difference in weight and BMI between the 3 groups. . The types of ADT (% of cases, median duration in months with IQR) included LHRH (Luteinizing hormone releasing hormone) analogues (28.6%, 17.9, IQR 20.4), oestrogens (9.8%, 60.5, IQR 45.6) anti-androgens (11.3%, 3.3, IQR 15.2) and orchiectomy (15.7%, 43.4, IQR 63.9). Unadjusted t score of group 1, mean ± sd, (-1.6± 1.5) was significantly less than group 2 (-0.9±1.1) and group 3 (-0.7±1.4), p <0.001. Ninety three (69.9%), 20 (45%) and 75 (42%) of patients in groups 1, 2 and 3 respectively were classified as either osteopenic or osteoporotic (p<0.001). Adjusting for age, there was a significant difference in t scores between groups 1 and 2 as well as between groups 1 and 3 (p<0.001). Compared with oestrogen therapy and adjusting for duration of therapy, the odds of low bone mineral density (osteopenia or osteoporosis) with LHRH analogue was 4.5 (95%CI, 14.3 to 3.4); with anti-androgens was 5.9 (95%CI, 32.7 to 5); with orchiectomy was 7.3 (95%CI, 30 to 5.8) and multiple drugs was 9.2 ((95%CI, 31 to 7.1).

Conclusions

ADT is associated with lower BMD in Jamaican men on hormonal therapy for prostate cancer.

     

Recent trend of androgen deprivation therapy in newly diagnosed prostate cancer patients: Comparing between high- and middle-income Asian countries

The number of newly diagnosed prostate cancer cases varies across Asia, with higher mortality-to-incidence ratio reported in developing nations. Androgen deprivation therapy (ADT), alone or in combination, remains the mainstay of first-line treatment for advanced prostate cancer. Key findings of extensive research and randomized controlled trials have shaped current clinical practice and influenced clinical guideline recommendations. We describe here the recent trend of ADT in newly diagnosed prostate cancer for Asia focusing on Japan (high-income country) and Malaysia (middle-income country) based on the Asian Prostate Cancer (A-CaP) Study. The combination of radiotherapy and ADT or ADT alone was common in patients with intermediate-to-high risk localized and locally advanced disease. For metastatic prostate cancer, maximum androgen blockade (gonadotrophin-releasing hormone [GnRH] agonist/antagonist plus antiandrogen) was prevalent among the Japanese patients while primary ADT alone with GnRH agonist/antagonist was widely practiced in the Malaysian cohort. Upfront combined therapy (ADT plus docetaxel or androgen receptor pathway inhibitor) has significantly improved the outcomes of patients with metastatic castration-naïve prostate cancer. Its application, however, remains low in our cohorts due to patients’ financial capacity and national health insurance coverage. Early detection remains the cornerstone in prostate cancer control to improve treatment outcome and patient survival.     

Bone density testing among prostate cancer survivors treated with androgen‐deprivation therapy

BACKGROUND.

Androgen‐deprivation therapy (ADT) causes bone loss and fractures. Guidelines recommend bone density testing before and during ADT to characterize fracture risk. The authors of the current report assessed bone density testing among men who received ADT for ≥ 1 year.

METHODS.

Surveillance, Epidemiology, and End Results/Medicare data were used to identify 28,960 men aged > 65 years with local/regional prostate cancer diagnosed from 2001 to 2007 who were followed through 2009 and who received ≥ 1 year of continuous ADT. Bone density testing was documented in the 18‐month period beginning 6 months before ADT initiation. Logistic regression was used to identify the factors associated with bone density testing.

RESULTS.

Among men who received ≥ 1 year of ADT, 10.2% had a bone density assessment from 6 months before starting ADT through 1 year after. Bone density testing increased over time (14.5% of men who initiated ADT in 2007‐2008 vs 6% of men who initiated ADT in 2001‐2002; odds ratio for 2007‐2008 vs 2001‐2002, 2.29; 95% confidence interval, 1.83‐2.85). Less bone density testing was observed among men aged ≥ 85 years versus men ages 66 to 69 years (odds ratio, 0.76; 95% confidence interval, 0.65‐0.89), among black men versus white men (odds ratio, 0.72; 95% confidence interval, 0.61‐0.86), and among men in areas with lower educational attainment (P < .001). Men who visited a medical oncologist and/or a primary care provider in addition to a urologist had higher odds of testing than men who only consulted a urologist (P < .001).

CONCLUSIONS.

Few men who received ADT for prostate cancer underwent bone density testing, particularly older men, black men, and those living in areas with low educational attainment. Visiting a medical oncologist was associated with increased odds of testing. Interventions are needed to increase bone density testing among men who receive long‐term ADT. Data on bone density testing for nonmilitary populations of prostate cancer survivors in the United States who have received long‐term androgen‐deprivation therapy (ADT) have not been published. The current analysis of Surveillance, Epidemiology, and End Results/Medicare data suggests that few prostate cancer survivors who receive long‐term ADT undergo bone density testing; and several key populations, including African Americans and older men, have considerably lower rates of bone density screening. Cancer 2013. © 2012 American Cancer Society.     

Complications of androgen deprivation therapy in men with prostate cancer

Androgen deprivation therapy (ADT) is indicated for the treatment of metastatic prostate cancer and locally advanced disease. In addition to sexual side effects, long-term ADT results in several other changes, including hot flashes; gynecomastia; changes in body composition, metabolism, and the cardiovascular system; osteoporosis; anemia; psychiatric and cognitive problems; and fatigue and diminished quality of life. This review discusses these complications of ADT and treatments aimed at reducing them. It is important for clinicians to anticipate these effects and to initiate measures to prevent or minimize them in order to maintain quality of life in prostate cancer survivors.     

前列腺癌雄激素剥夺治疗的新思路——睾酮最大控制临床研究新进展

前列腺癌是常见的男性恶性肿瘤之一,其发病率位居男性恶性肿瘤第二位。前列腺癌的发病率居于所有男性恶性肿瘤首位。中国男性的前列腺癌发病率低于欧美国家,但随着生活方式、饮食习惯的西化以及人均寿命延长,前列腺癌的发病率也呈现逐年升高的趋势。雄激素受体（androgen receptor,AR）在前列腺癌的发生、发展过程中扮演着重要角色,抑制AR信号转导通路是前列腺癌治疗的基础,比如在去势抵抗性前列腺癌（castration-resistant prostate cancer,CRPC）治疗中,使用AR拮抗剂能够竞争性结合AR并阻断内源性雄激素的结合,从而干扰雄激素依赖的细胞下游反应,阻止前列腺癌的进展。雄激素剥夺治疗（androgen deprivation therapy,ADT）是前列腺癌治疗的基石,国内专家共识中前列腺癌去势治疗有效定义的睾酮（testosterone,T）水平为低于50 ng/dL。随着研究的深入,越来越多的研究表明T低于20 ng/dL的患者临床预后更佳：T ＜ 20 ng/dL时可以诱导包括雄激素敏感和部分雄激素不敏感亚群细胞的死亡,在治疗间隙细胞增殖时可以获得雄激素高度敏感的细胞群,从而延长了去势抵抗的时间。如果不能达到T ＜ 20 ng/dL,可能会导致部分雄激素不敏感的亚群持续存在,这些亚群在再次治疗后会快速增殖,加速肿瘤向去势抵抗发展。目前控制T水平的促性腺激素释放激素激动剂（gonadotropin-releasing hormone agonist,GnRHa）的有效性和安全性在研究中和临床上均得到了明确的验证,在药物层面上提供了控制T ＜ 20 ng/dL的临床可行性。通过总结T水平与ADT新进展,探讨最大限度控制T水平与前列腺癌治疗中患者受益、药物疗效及安全性的关系。     

Androgen deprivation and thromboembolic events in men with prostate cancer

BACKGROUND:

Androgen deprivation therapy (ADT) improves prostate cancer outcomes in specific clinical settings, but is associated with adverse effects, including cardiac complications and possibly thromboembolic complications. The objective of this study was to estimate the impact of ADT on thromboembolic events (TEs) in a population‐based cohort.

METHODS:

In the linked Surveillance, Epidemiology and End Results–Medicare database, we identified men older than 65 who were diagnosed with nonmetastatic prostate cancer between 1999 and 2005. Medical or surgical ADT was identified by Medicare claims for gonadotropin‐releasing hormone agonists or bilateral orchiectomy at any time following diagnosis. TEs included deep venous thrombosis, pulmonary embolism, and arterial embolism. The impact of ADT on the risk of any TE and on total number of events was estimated, controlling for patient and tumor characteristics.

RESULTS:

Of 154,611 patients with prostate cancer, 58,466 (38%) received ADT. During a median follow‐up of 52 months, 15,950 men had at least 1 TE, including 8829 (55%) who had ADT and 7121 (45%) with no ADT. ADT was associated with increased risk of a TE (adjusted hazard ratio = 1.56; 95% confidence interval, 1.50‐1.61; P < .0001), and duration of ADT was associated with the total number of events (P < .0001).

CONCLUSIONS:

In this population‐based cohort, ADT was associated with increased risk of a TE, and longer durations of ADT were associated with more TEs. Men with intermediate‐ and low‐risk prostate cancer should be assessed for TE risk factors before starting ADT and counseled regarding the risks and benefits of this therapy. Cancer 2011. © 2011 American Cancer Society.