Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer

CONTEXT: Although androgen deprivation therapy (ADT) for prostate cancer is associated with bone loss, little is known about when this bone loss occurs. OBJECTIVE: We postulated that men on ADT would experience the greatest bone loss acutely after initiation of ADT. DESIGN AND SETTING: We conducted a 12-month prospective study at an academic medical center. PATIENTS OR OTHER PARTICIPANTS: We studied 152 men with prostate cancer (30 with acute ADT, < 6 months; 50 with chronic ADT, > or = 6 months; and 72 with no ADT) and 43 healthy age-matched controls. MAIN OUTCOME MEASURES: We assessed bone mineral density (BMD) of the hip, wrist, total body, and spine; body composition; and markers of bone turnover. RESULTS: After 12 months, men receiving acute ADT had a significant reduction in BMD of 2.5 +/- 0.6% at the total hip, 2.4 +/- 1.0% at the trochanter, 2.6 +/- 0.5% at the total radius, 3.3 +/- 0.5% at the total body, and 4.0 +/- 1.5% at the posteroanterior spine (all P < 0.05). Men with chronic ADT had a 2.0 +/- 0.6% reduction in BMD at the total radius (P < 0.05). Healthy controls and men with prostate cancer not receiving ADT had no significant reduction in BMD. Both use and duration of ADT were associated with change in bone mass at the hip (P < 0.05). Men receiving acute ADT had a 10.4 +/- 1.7% increase in total body fat and a 3.5 +/- 0.5% reduction in total body lean mass at 12 months, whereas body composition did not change in men with prostate cancer on chronic ADT or in healthy controls (P < 0.05). Markers of bone formation and resorption were elevated in men receiving acute ADT after 6 and 12 months compared with the other men with prostate cancer and controls (P < 0.05). Men in the highest tertile of bone turnover markers at 6 months had the greatest loss of bone density at 12 months. CONCLUSIONS: Men with prostate cancer who are initiating ADT have a 5- to 10-fold increased loss of bone density at multiple skeletal sites compared with either healthy controls or men with prostate cancer who are not on ADT, placing them at increased risk of fracture. Bone loss is maximal in the first year after initiation of ADT, suggesting initiation of early preventive therapy.     

性激素阻断治疗对前列腺癌患者骨代谢及骨量的影响

目的探讨药物去势方法治疗老年人前列腺癌对患者骨代谢和骨量的影响。方法以确诊的老年前列腺癌患者36例作为观察组（前列腺癌组），无前列腺癌及影响骨代谢疾病的老年男性13例作为对照组。前列腺癌组分别在诺雷德（Goserelin）去势前和去势后12个月测定2～4腰椎、左股骨颈、大转子、Ward’s三角和全髋的骨密度，并检测血中的骨特异性碱性磷酸酶（BALP）、骨钙素（BGP）、甲状旁腺素（PTH）、Ⅰ型前胶原末端肽（CICP）、抗酒石酸酸性磷酸酶（TRACP）及尿吡啶啉（PYD）、脱氧吡啶啉（DPD）、Ⅰ型胶原C端交联物（Cros）、尿钙／尿肌酐比值（Ca／Cr）等骨代谢指标，对照组同期检测上述项目。结果前列腺癌组在Goserelin去势前和对照组相比，骨密度和骨代谢各项指标差异无统计学意义（P〉0．05）；前列腺癌组经过Goserelin 12个月的治疗后，血雄激素和雌激素等性激素水平都显著性降低（P均〈0．01）；血BALP、尿DPD、Cros、Ca／Cr明显增高，全髋、左股骨颈、Ward’s三角3个部位的骨量丢失显著，变化率与对照组比较差异有统计学意义（均为P〈0．05）。结论前列腺癌患者接受Goserelin去势治疗后发生明显的骨转换增加和骨量丢失，与体内雄激素和雌激素水平极度降低有关，故对于这些患者监测骨密度和骨代谢指标有利于早期发现Goserelin去势治疗后发生的骨质疏松，并及时给予治疗。     

The effect of androgen on bone metabolism

Although androgens are thought to be important for skeletal maintenance, little is known about the mechanisms involved. In osteoporotic animal studies, androgens directly stimulate bone formation, and increase periosteal bone mass in cortical bone. These effects are reflected to a major gender difference in bone size. Recently, attempts have been made to develop selective androgen receptor modulators (SARMs) that have tissue selective androgenic activity in bone and muscle with less side effects on prostate to cause prostate hypertrophy or cancer.     

An aged rat model of partial androgen deficiency: prevention of both loss of bone and lean body mass by low-dose androgen replacement

The aim of this study was to evaluate the effects of different doses of androgen replacement, both on body composition and bone, in an aged male orchidectomized rat model. Testosterone was administered by 0.5, 1, and 2.5-cm sc SILASTIC implants (release of, respectively, 11.5, 23, and 55 microg/day) to aged (12 months old, +/- 550 g) male orchidectomized Wistar rats during a 15-week experimental period. T 0.5 only partially prevented decrease of ventral prostate and seminal vesicle weight, compared with an intact group that received an empty implant (Intact). The 1-cm implant (T 1) completely prevented decrease of both seminal vesicles and ventral prostate weight. The 2.5-cm implant (T 2.5) was clearly supraphysiological, as demonstrated by significant hypertrophy of both androgen-sensitive organs. Serum testosterone was lower in T 0.5 and T 1 (0.38 +/- 0.06 ng/ml and 0.92 +/- 0.06 ng/ml, respectively) and higher in T 2.5 (2.4 +/- 0.28. ng/ml), compared with both Intact (1.6 +/- 0.23 ng/ml) and the baseline group(1.6 +/- 0.11 ng/ml). As expected, orchidectomized rats that received an empty SILASTIC implant had significantly lower bone mineral content (-7.9%), apparent density (-5.7%), and lean body mass (-10.8%), as measured by dual-energy x-ray absorptiometry, without significant changes in body weight and fat mass, compared with Intact. Also, cancellous (-50.3%) and cortical (-1.8%) volumetric density, as measured by peripheral quantitative computed tomography, were decreased in the tibia. Bone turnover, as measured by serum osteocalcin and urinary deoxypyridinoline excretion, was increased in orchidectomized rats that received an empty SILASTIC implant. T 0.5 prevented all changes, not only in bone mineral content, density, and turnover but also in lean body mass. Moreover, there were no significant differences, for all these parameters, between the different doses of testosterone replacement. In conclusion, low-dose androgen replacement does not lead to lower bone mineral density, higher bone turnover, and lower lean body mass in aged male rats, whereas complete androgen deficiency does. Therefore, the threshold concentration of testosterone necessary for prevention of both bone and lean body mass loss in aged male rats is clearly lower than for prostate and seminal vesicles.     

The influence of androgen deprivation therapy on metabolism in patients with prostate cancer

The effects of androgen deprivation therapy (ADT) include not only suppression of tumor growth, but also adverse effects on various bodily functions. The aim of this study was to determine the metabolic effects of ADT in patients with nonmetastatic prostate cancer. Forty-nine men with prostate cancer were treated with ADT before beginning radical therapy for 6 months. Body weight, peripheral red blood cell counts, hemoglobin, hematocrit, fasting blood sugar, serum total cholesterol, blood urea nitrogen, uric acid, compensated calcium, inorganic phosphorus, bone-specific alkaline phosphatase, urinary deoxypyridinoline, and radial bone density determined using dual energy x-ray absorptiometry were examined before and 6 months after ADT treatment. Body weight (P = 0.037) and the levels of fasting blood sugar (P = 0.014), serum total cholesterol (P = 0.017), blood urea nitrogen (P = 0.030), compensated calcium (P < 0.001), inorganic phosphorus (P < 0.001), bone-specific alkaline phosphatase (P < 0.001), and compensated urinary deoxypyridinoline (P < 0.001) increased significantly. Peripheral red blood cell counts (P < 0.001), hemoglobin level (P < 0.001), hematocrit (P < 0.001), uric acid (P < 0.001), and radial bone density (P = 0.023) decreased significantly. These effects of ADT on various bodily functions warrant systematic study in clinical trials. We should be aware of the far-reaching consequences of ADT and incorporate strategies for preventing and managing adverse effects into routine practice.     

Outcomes and predictive factors for biochemical relapse following primary androgen deprivation therapy in men with bone scan negative prostate cancer

Purpose  

Primary androgen deprivation therapy (PADT) is an important treatment modality for men with localized or locally advanced prostate cancer and without bone metastasis. There is, however, a lack of data on the biochemical relapse (BR) outcomes in these patients. Here, we studied the outcome of a contemporary series of men treated by PADT and investigated predictive risk factors for BR.     

Effect of reversible androgen deprivation on hemoglobin and serum immunoreactive erythropoietin in men.

To examine the role of testosterone in the maintenance of hemoglobin levels, we studied the effect of reversible androgen deprivation on hemoglobin, serum immunoreactive erythropoietin, and serum testosterone in seven men treated with a luteinizing hormone-releasing factor (LHRH) agonist for 6 months and then followed for an additional 6 months. The mean serum testosterone level was 4.35 +/- 1.05 ng/ml initially and it decreased to castrate levels in all patients by 6 months. After stopping therapy, there was a rapid increase in serum testosterone such that by 12 months the mean concentration was normal. The pretreatment hemoglobin was 15.2 +/- 0.9 g/dl (mean +/- SD); after 6 months of androgen deprivation it had fallen to 14.1 +/- 0.4 g/dl (P less than 0.05). Six months after stopping therapy, the hemoglobin rose to pre-treatment levels. Before treatment, serum immunoreactive erythropoietin was 9.5 +/- 4.6 mu/ml (mean +/- SD) and did not change significantly during or after the 6 month period of androgen deprivation. No significant inhibition of burst-forming unit-erythroid (BFU-E) or colony-forming unit-granulocyte macrophage (CFU-GM) was observed at the serum level of nafarelin acetate obtainable in vivo. These data suggest that, within the normal range of hemoglobin in men, androgens are a determinant of the red cell mass.     

Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats

The partial agonist activity of a selective androgen receptor modulator (SARM) in the prostate was demonstrated in orchidectomized rats. In the current study, we characterized the full agonist activity of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (a structurally related SARM referred to in other publications and hereafter as S-4) in skeletal muscle, bone, and pituitary of castrated male rats. Twelve weeks after castration, animals were treated with S-4 (3 or 10 mg/kg), dihydrotestosterone (DHT) (3 mg/kg), or vehicle for 8 wk. S-4 (3 and 10 mg/kg) restored soleus muscle mass and strength and levator ani muscle mass to that seen in intact animals. Similar changes were also observed in DHT-treated (3 mg/kg) animals. Compared with the anabolic effects observed in muscle, DHT (3 mg/kg) stimulated prostate and seminal vesicle weights more than 2-fold greater than that observed in intact controls, whereas S-4 (3 mg/kg) returned these androgenic organs to only 16 and 17%, respectively, of the control levels. S-4 (3 and 10 mg/kg) and DHT (3 mg/kg) restored castration-induced loss in lean body mass. Furthermore, S-4 treatment caused a significantly larger increase in total body bone mineral density than DHT. S-4 (3 and 10 mg/kg) also demonstrated agonist activity in the pituitary and significantly decreased plasma LH and FSH levels in castrated animals in a dose-dependent manner. In summary, the strong anabolic effects of S-4 in skeletal muscle, bone, and pituitary were achieved with minimal pharmacologic effect in the prostate. The tissue-selective pharmacologic activity of SARMs provides obvious advantages over steroidal androgen therapy and demonstrates the promising therapeutic utility that this new class of drugs may hold.     

European consensus on grading bone marrow fibrosis and assessment of cellularity

Quantification of characteristic bone marrow biopsy features includes basic parameters such as cellularity and fiber content. These are important to assess the dynamics of disease processes with a significant impact on risk stratification, survival patterns and, especially, therapy-related changes. A panel of experienced European pathologists and a foreign expert evaluated, at a multi-headed microscope, a large number of representative slides of trephine biopsies from patients with myelofibrosis in an attempt to reach a consensus on how to grade cellularity and fibrosis. This included a critical evaluation of previously described scoring systems. During the microscopic analysis and subsequent discussion and voting, the importance of age-dependent decrease in cellularity was recognized. Grading of myelofibrosis was simplified by using four easily reproducible categories including differentiation between reticulin and collagen. A consensus was reached that the density of fibers must be assessed in relation to the hematopoietic tissue. This feature is especially important in order to avoid a false impression of a reduced fiber content in fatty and/or edematous bone marrow samples after treatment. The consensus for measuring myelofibrosis by clear and reproducible guidelines achieved by our group should allow for precise grading during the disease process and after therapy.     

Preliminary report: effect of adrenal androgen and estrogen on bone maturation and bone mineral density

To clarify the independent physiological roles of adrenal androgen and estrogen on bone growth, we compared the lumbar spine bone mineral density (BMD) in prepubertal girls with virilizing congenital adrenal hyperplasia (CAH) (n = 17) and girls with central precocious puberty (CPP) (n = 18). When BMD was analyzed according to chronologic age, no significant differences were found between CPP and CAH patients. However, when adjusted to bone age, BMD was statistically higher in CAH than in CPP subjects. This finding suggests that adrenal androgen, as well as estrogen, plays an important role in increasing BMD. Adrenal androgen may act on bone not only as androgen, but as estrogen after having been metabolized into an aromatized bone-active compound in peripheral tissues, such as bone and fat. Therefore, adrenal androgen may have a more important role in increasing BMD than previously realized.     

Deficiency in androgens and upregulation of insulin-like growth factor-1 are involved in high bone turnover in men receiving androgen deprivation therapy for prostate cancer

ObjectiveThis study was performed to elucidate the mechanism of high bone turnover during androgen deprivation therapy (ADT) in terms of osteogenic endocrine activity by testosterone, adrenal androgens, and insulin-like growth factor-1 (IGF-I), and to identify markers reflecting the bone mineral density (BMD) during ADT.DesignBMD and samples of blood and urine were studied before and after 6 months of ADT in 70 patients with localized prostate cancer.ResultsBefore ADT, serum free-testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and IGF-I levels were correlated with BMD (rs = 0.344, p = 0.004; rs = 0.264, p = 0.027; rs = 0.329, p = 0.005; rs = 0.300, p = 0.012, respectively). The serum IGF-I level was independently correlated with the pretreatment BMD (Multivariate p = 0.001). These relationships disappeared after ADT (p = 0.519, 0.316, 0.116, and 0.597, respectively). After ADT, serum levels of free-testosterone decreased (7.9 to 0.2 pg/mL), and DHEA-S and androstenedione were also reduced (3.6 to 2.3 μmol/L and 5.6 to 2.9 nmol/L, respectively) (p < 0.001 in all). In contrast, IGF-I levels were elevated after ADT by 11.6% (19.9 to 22.3 nmol/L, p < 0.001). Delta-values of IGF-I (post- minus pretreatment levels, mean: + 2.2, ranged between ? 7.1 and + 15.3) were inversely correlated with the pretreatment (rs = ? 0.333 p = 0.005) and post-treatment (rs = ? 0.408, p = 0.001) BMD. After ADT, the serum IGF-I level was closely correlated with the serum level of the bone formation marker bone-specific alkaline phosphatase (BAP) (rs = 0.328, p = 0.006), and delta-IGF-I and delta-BAP showed a close positive correlation (rs = 0.388, p = 0.001). The post-treatment BMD was correlated only with the urine deoxypyridinoline (DPD) concentration (rs = ? 0.302, p = 0.024) among the bone formation/resorption markers including serum/urine N-telopeptide.ConclusionsSerum IGF-I levels increased during ADT in men with a low BMD. Coupled with reduced androgen levels, elevated IGF-I levels, which were positively correlated with BAP during ADT, possibly explain the mechanism of ADT-related high bone turnover. The increase of IGF-I is more prominent in men whose BMD is already low at the baseline, and urine DPD might be a marker that reflects BMD during ADT.     

自噬对炎症性牙槽骨吸收作用的研究进展

牙周炎是牙周致病菌引发的、以牙周支持组织(尤其是骨组织)进行吸收为临床表现的慢性炎症性疾病。近年来研究发现自噬及其相关蛋白通过参与调控细胞因子和炎性小体来影响炎症进程。同时自噬及其相关蛋白作用于骨组织细胞,尤其是参与破骨细胞的形成、分化和功能发挥。该文从自噬与牙周炎症、骨组织细胞的相互作用关系以及相关研究进展作一综述,旨在阐述自噬在牙周炎导致的骨吸收进程中的作用,为牙周炎的临床治疗提供新的靶点。     

Preventive effect of estrogen on postmenopausal bone loss.

Follow-up studies of bone mineral content in the radius were done in 82 postmenopausal women 4 to 10 years after the first examination. These patients were subdivided into four groups depending on the type of menopause (artificial or natural) and estrogen administration (treated or untreated). Bone mineral mass and combined cortical thickness decreased significantly in both groups of untreated women. Both mineral loss per year for the untreated women was -9.1 mg/sq cm for castrates and -6.9 mg/sq cm for those with a natural menopause. In neither group was the rate of loss correlated with age. The change in bone mineral mass per year in the estrogen-treated subjects (mean +3.25 mg/sq cm) differed significantly from that of untreated subjects (mean -7.99 mg/sq cm). The findings suggest that postmenopausal osteoporosis could be prevented by estrogen treatment.