:: Asian Journal of Andrology ::

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

Jun-Hong Deng, Liu-Ping Yang, Liang-Sheng Wang, De-Fan Zhou

Department of Urology, First Municipal People's Hospital, Guangzhou 510180, China

Asian J Androl 2004 Mar; 6: 75-77

Keywords: prostate cancer; androgen deprivation therapy; osteoporosis; osteopenia

Abstract

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 -0.90.7 and -0.60.5, 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 and femoral neck than those before the beginning of ADT.

1 Introduction

There has been a gradual increase in the incidence of prostate cancer around the world since the 1960's. While androgen deprivation therapy (ADT) is an effective measure to control advanced prostate cancer, the development of osteoporosis in patients treated with ADT has not aroused general attention until recent years [1]. Ross and Small indicated very recently that osteoporosis was an important and debilitating side effect of ADT, but the precise estimates of its incidence and importance have not been fully elucidated [2]. To further the understanding of bone metabolism in the setting of ADT, we observed the bone mineral density (BMD) in prostate cancer patients before and after ADT.

2 Materials and methods

2.1 Patients

A total of 49 patients diagnosed as prostate cancer stage C or D with their BMD accessed were enrolled into this study between October 1999 and December 2002. Patients with a documented secondary cause of osteoporosis, such as primary hypogonadism, hyper-thyroidism, hyperparathyroidism and hypercortisolism, and systemic steroid use were excluded. The patients were divided into two groups: the non-treated group (n=21) before the commencement of ADT and the treated group (n=28) had received ADT for more than 1 year.

The baseline data for the patients are summarized in Table 1. No statistically significant differences were found between the two groups in age, body weight, and serum calcium level (P>0.05), but significant differences were observed in serum levels of PSA and testosterone (P<0.01).

Table 1. Baseline data of patients. PSA=prostate specific antigen. Data in meanSD, if applicable. Value in parentheses is the interquartile range. ^bP<0.01, compared with non-treated group.

	Non-treated (n=21)	Treated (n=28)
Median age (yr)	71 (65-83)	73 (64-85)
Mean weight (kg)	65.8 (55-72)	63.9 (53-71)
Median ADT duration (month)	0	27 (14-48 )
Serum PSA (ng/mL)	21.431.2	4.67.3b
Serum testosterone (ng/dL)	457115	6736^b
Serum calcium (mmol/L)	2.380.38	2.450.43

2.2 Imaging studies

The BMD (g/cm2) was determined at the lumbar spine (L2-4) and femoral neck using dual energy X-ray absorptiometry (DEXA). As the BMD may decrease with increasing age, the Z score with age-adjustment was applied [1]. The age-matched Z-score values derived from the Taipei population were supplied by Lunar ExpertTM (Part Number 17177) as an attachment in the inner software of the Lunar machine (Lunar Expert, USA). The BMD values for healthy adult men provided by Lunar Expert equipment (version. 5/98B, Taipei, China) were used as the reference standard. According to the World Health Organization, the t score at the site with the greatest decrease in BMD was used to classify patients into normal (-1.0 SD), osteopenic (between -1.0 and -2.5 SD) and osteoporotic (< -2.5 SD) groups.

2.3 Laboratory analysis

The serum calcium was determined with the Vitros System 250 (Ortho-clinical Diagnostics. Inc., USA), the serum testosterone with the IMMULITE automated chemoluminescent immunoassay analyzer (DPC, USA) and the serum prostate-specific antigen (PSA) with the Hybritech assay using a Microparticle Enzyme Immunoassy system (AXSYM, USA).

2.4 Statistical analysis

Data were expressed as meanSD. Probabilities were determined with the chi-square test or t test under the null hypothesis. P<0.05 was considered significant.

3 Results

3.1 General information

All the patients completed the study protocol. Surgical orchiectomy was performed in 25 of the 28 treated patients and the remaining 3, who refused the operation, were treated with a luteinizing hormone-releasing hormone agonist. The duration of ADT ranged from 14 to 48 (median: 27) months. None received oral nonsteroidal antiandrogen agent (e.g., flutamide). No fracture occurred in either group.

3.2 Bone densitometry

In the non-treated patients, 7 (33 %) had evidence of osteopenia and 6 (29 %) had BMD levels consistent with osteoporosis. In comparison, 10 (36 %) and 13 (46 %) of the men in the treated (n=28) met with the BMD criteria for osteopenia and osteoporosis, respectively (Table 2). Although there were more patients with osteopenia and osteoporosis in the ADT group, the difference was statistically insignificant. According to the age-adjusted model, the BMD in lumbar spine and femoral neck were significant lower in the treated than those in the non-treated group (P<0.01).

Table 2. Patients with osteopenia and osteoporosis according to BMD measurement. BMD=bone mineral density.

	Non-treated (n=21)	Treated (n=28)
Normal bone density	8 (38 %)	5 (18 %)^a
Osteopenia	7 (33 %)	10 (36 %)
Osteoporosis	6 (29 %)	13 (46 %)

4 Discussion

Recently, many investigators have focused on the problem of osteoporosis in prostate cancer patients treated with ADT [1-4]. The testosterone effect on bone formation is complex and not completely understood. It probably involves direct stimulation of the androgen receptor on the osteoblasts, estrogenic intermediaries, and down regulation of growth factors such as transforming growth factor-b [4]. In the present study, most patients had pre-existing osteopenia and osteoporosis, which were exaggerated by ADT. In consistent with our results, Daniell et al [5] and Smith [6] indicated that in older men without prostate cancer, low serum testosterone levels were closely associated with the risk of osteoporosis, while in patients with advanced prostate cancer, the incidence of low BMD was much higher; so further loss of BMD from ADT may put these men at an even greater risk of fracture.

Whether ADT actually increases the number of osteoporosis and osteoporotic fractures in men with prostate cancer is uncertain. In a study of men with non-stage A prostate cancer reported by Daniell [7], 13 castrated men and only 1 non-castrated men experienced fracture. The overall incidence of osteoporotic fractures in men with non-stage A prostate cancer was estimated to be 4.3 % and nearly one quarter of these fractures were attributed to ADT. A significant loss of BMD in lumber and femoral neck were detected, but significant differences in the proportion of men with osteoporosis and osteopenia were not seen [7]. Similar results were reported by Townsend et al [8]. In a long-term study by Kiratli et al [4], there was a progressive bone loss with increasing duration of medical ADT and it was exaggerated by surgical castration. In our study, 10 (36 %) and 13 (46 %) of the men in the ADT group met with the BMD criteria for osteopenia and osteoporosis, respec-tively. Although significant differences in the proportion of the two groups were not seen, the BMD in lumbar spine and femoral neck were significantly lower in the ADT than those in the non-ADT group after adjusted for age, race and weight (Z score, Table 3). It appears that BMD loss is accelerated in men undergoing ADT for prostate cancer [9]. In conclusion, preexisting osteopenia and osteoporosis are common in men with prostate cancer before initiation of ADT. ADT is associated with bone loss and the evaluation of BMD is necessary before and after ADT in prostate cancer patients.

Table 3. Z score. Data in meanSD. ^bP<0.01, compared with non-treated group.

	Non-treated (n=28)	Treated (n=21)
Lumbar spine	-0.60.5	-0.90.7^b
Femoral neck	-1.61.0	-1.81.1^b

References

[1] Wei JT, Gross M, Jaffe CA, Gravlin K, Lahaie M, Faerber GJ, et al. Androgen deprivation therapy for prostate cancer results in significant loss of bone density. Urology 1999; 54: 607-11.
[2] Ross RW, Small EJ. Osteoporosis in men treated with androgen deprivation therapy for prostate cancer. J Urol 2002; 167:1952-6.
[3] Berruti A, Dogliotti L, Tucci M, Tarabuzzi R, Fontana D, Angeli A. Metabolic bone disease induced by prostate cancer: rationale for the use of bisphosphonates. J Urol 2001; 166:2023-31.
[4] Kiratli BJ, Srinivas S, Perkash I, Terris MK. Progressive decrease in bone density over 10 years of androgen deprivation therapy in patients with prostate cancer. Urology 2001; 57: 127-32.
[5] Daniell HW, Dunn SR, Ferguson DW, Lomas G, Niazi Z, Stratte PT. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 2000; 163: 181-6.
[6] Smith MR. Osteoporosis during androgen deprivation therapy for prostate cancer. Urology 2002; 60 (3 Suppl 1): 75-85.
[7] Daniell H. Osteoporosis after orchiectomy for prostate cancer. J Urol 1997; 157: 439-44.
[8] Townsend MF, Sanders WH, Northway RO, Graham SD Jr. Bone fractures associated with lutenizing hormone-releasing hormone agonists used in the treatment of prostate carcinima. Cancer 1997; 79: 545-50.
[9] Smith MR, Eastham J, Gleason DM, Shasha D, Tchekmedyian S, Zinner N. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 2003; 169:2008-12.

Correspondence to: Dr Liu-Ping Yang, Department of Urology, First Municipal People's Hospital, Guangzhou 510180, China.
E-mail: YLP38@hotmail.com
Received 2003-03-03 Accepted 2003-11-28