Bone mineral density in hypogonadal men remains low after long-term testosterone replacement

Kazuhiro Ishizaka¹, Masahito Suzuki², Yukio Kageyama², Kazunori Kihara², Ken-Ichiro Yoshida³

Asian J Androl  2002 Jun; 4:  117-121             

Keywords: bone mineral density; male hypogonadism; androgen replacement therapy

Abstract

Aim: In 11 congenital hypogonadal men, the bone mineral density (BMD) values were determined to assess the effect of long-term androgen replacement therapy (ART) on skeletal integrity. Methods: Eleven congenital hypogonadal men, including 8 isolated gonadotropin deficiency patients, 2 Kallmann's syndrome and 1 vanishing testes syndrome were recruited and treated with 250 mg of testosterone enanthate intramuscularly every 4 weeks for 7-43 years (meanSD: 21.513 years). In these patients and a group of 10 healthy young men (controls), the whole and trabecular BMDs were examined at the distal end of radius by means of a peripheral quantitative computerized tomography device. Results: The whole radial BMD in hypogonadal men was significantly less in the patients than in the healthy men (498115 and 725134 mg/cm³, respectively; P<0.01); the trabecular BMD was also lower in the hypogonadal men (19980 and 37589 mg/cm³; P< 0.01). The whole radial BMD values in 10 of 11 hypogonadal men were at least 1 SD below the mean value for healthy young men; 2 hypogonadal men had BMD values more than 2.5 SD lower than the healthy mean. Additionally, the whole radial BMD showed a significant negative correlation with the patient's age at the initiation of ART (r = 0.748, P<0.01). The serum level of bone-specific alkaline phosphatase and the urinary level of deoxypyridinoline were not significantly different between the two groups. Conclusion: Osteopenia persists in the hypogonadal men after long-term ART, suggesting that such patients have a persistent defect in bone development not alleviated by androgen replacement.

Bone is a major target tissue for sex hormones, that facilitate bone growth until epiphyseal closure and help to regulate bone mass throughout the adulthood [1]. In contrast, hypogonadism results in reduced bone mineral density (BMD) [2], which has recently received much attention due to the increase of fragility fracture as BMD declines in men [3] and postmenopausal women [4]. Although in hypogonadal men, BMD may reach age-matched standard within 3 years of androgen replacement therapy (ART) [5], this was not the case with every patient [6] and some studies have altogether failed to show the effectiveness of the therapy [7,8]. It was found that in boys with isolated gonadotropin deficiency, a disease thought to be congenital, ART for up to 7 years resulted in increased bone mass and body height to the average range, but the BMD remained low up to the adulthood [7]. Another study showed that the BMD gain in GnRH-deficient men treated with ART was greater in skeletally immature men than in men with fused epiphyses [8]. Consequently, it is thought that a deficiency of gonadal steroids at a critical time in bone maturation, as the early infantile or pubertal periods, might irreversibly inhibit the peak bone mass gain [7]. It was observed that in hypogonadal men once a BMD gain is achieved after the initiation of therapy, long-term androgen replacement maintains this BMD [5]. However, it is not clear whether the BMD of patients irresponsive to the initial therapy can be increased by prolonged ART.

In the present study, the BMD of congenital hypo-gonadal men subjected to long-term ART was deter-mined, employing the peripheral quantitative computerized tomography (pQCT), a sensitive and reproducible approach [9].

2 Materials and methods

Eleven Japanese hypogonadal males, aged 42.315.8 years (meanSD, range: 27-63 years) and having received effective androgen substitution therapy, were enrolled with written informed consent. Two patients had Kallmann's syndrome, 8 an isolated gonadotropin deficiency and 1 vanishing testes syndrome. No one had a history of hyperparathyroidism, Cushings syndrome, and liver, renal or other chronic diseases. Nobody had received corticosteroids, anticonvulsants, calcium or vitamin D supplements, and all patients had serum levels of calcium and inorganic phosphate within the healthy control range. No one was involved in regular vigorous exercise. The average body mass index (BMI) for this group was 23.33.1 (range: 18.5-27.2).

Ten healthy men, aged 24.60.7 years (range: 24-26), were selected as the controls; they had a history of normal pubertal development without apparent diseases and the use of medications. The BMI was 22.42.9 (range: 19.0-27.6).

The study was approved by the Ethical Committee in the Institute.

2.2 Androgen replacement

For the hypogonadal subjects, ART was started at an age of 22.6 ?8.3 years (range: 14-43), and continued for 21.513 years (range: 7-43). Testosterone enanthate (TE) 250 mg (Enarmone Depot 250; Teikoku Hormone Manufacturing; Tokyo, Japan) was injected intramuscularly every 4 weeks. In a few younger patients, the therapy was commenced with human chorionic gonadotropin or a lower dose of TE, which was then increased to the regular dose of 250 mg.

The serum total and free testosterone (T), FSH, LH and estradiol-17b concentrations were determined by radioimmunoassay, employing total T kit, free T kit (Nippon DPC Corp., Japan), LH-kit, FSH-kit (Daiichi Radioisotope Laboratory. Ld., Japan) and estradiol kit (Nippon DPC Corp.).

2.4 Determination of BMD and biochemical markers for bone turnover

The whole and trabecular BMD (in g/cm³) was examined at the distal end of radius with a Densiscan-1000 pQCT (ScancoMedical AG; Bassersdolf, Switzerland). Since the device does not offer a universal database for young adults or an age-matched reference applicable to Japanese men, the BMD of 10 healthy Japanese young men were determined to provide the young adult mean (YAM). The YAM was also used as the peak adult bone mass (PABM, in g/cm³) to calculate the T score [10] by means of the following equation: T score = (measured BMD - PABM mean) / PABM SD. The bone turnover markers, including the serum level of bone-specific alkaline phosphatase (AKP) and the urinary level of deoxypyridinoline (DPD), were also measured by enzyme-immunoassay (EIA) with Alkphase B and PYRLINKSTM-D EIA kits (Quidel Co. San Diego, USA), respectively.

Data are presented as meanSD unless otherwise specified. The Student's t-test was used to analyze the significance of difference between groups. Multiple linear regression analysis was used to test the correlation between BMD and the following variables: serum T, serum estradiol-17b, age, age at initiation of therapy and duration of therapy. The software package StatView version 4.01 (Abacus Concepts Inc., Berkeley, USA ) was used for the calculation.

In 10 hypogonadotropic hypogonadism patients, the average serum LH level was 1.01.0 (range: 0.2-2.9) mIU/mL, and the FSH, 1.81.2 (range: 0.9-4.6) mIU/mL. In the patient with vanishing testes syndrome, the values were 9.5 mIU/mL for FSH and 57.9 mIU/mL for LH. In the 11 patients, the serum levels of total T, free T, estradiol-17b, and prolactine just prior to the next injection were 1.10.9 (range: 0.1-3.0) ng/mL, 2.11.7 (range: 1.2-5.6) pg/mL, 46.021.1 (range: 25-85) pg/mL and 6.13.4 (range: 2.3-11.4) ng/mL, respectively.

3.2 Radial BMD

v 1 indicates the whole radial BMD, which was significantly lower in the hypogonadal men than in the healthy controls (498115 vs 725134 mg/cm³, P < 0.01). Only one hypogonadal patient had a whole radial BMD within 1 SD below the mean for healthy men. In the remaining 10 patients, the BMD was more than 1 SD below the healthy mean and in 2 of them, it was more than 2.5 SD below the healthy mean. The average T score for the hypogonadal men was -1.70.9 (range: -3.6 to -0.7). Figure 2 shows the trabecular BMD, which was also significantly lower in the hypogonadal men than in the healthy controls (19980 vs 37589 mg/cm³, P < 0.01). As with the whole BMD, in only 1 hyopogonadal man the trabecular BMD was within 1 SD below the healthy mean. In the remaining 10 patients the trabecular BMD was more than 1 SD below the healthy mean and in 2 of them it was more than 2.5 SD below the healthy mean. The T score was -2.00.9 (range: -3.7 to -0.54). In both the hypogonadal and healthy men, the trabecular BMD showed a significant correlation with the whole BMD values (r = 0.769, P < 0.01 and r=0.855, P<0.01, respectively). The T score is lower for the trabecular BMD than for the whole BMD in 8 of 11 patients, but the difference is statistically insignificant.

As shown in Figure 3, there is a negative correlation between the whole radial bone BMD and the patient's age at the beginning of ART (r = 0.748, P < 0.01), i.e., the younger the patient was at the start of therapy, the greater was the amount of bone mass. The trabecular BMD also showed a negative correlation (r = 0.763, P < 0.01) with the age (data not shown). In contrast, the patient's age at the time of BMD measurement, the duration of ART, the serum total T, free T and estradiol-17b levels had no correlation with the BMD.

Figure 1. Whole bone mineral density in radius of 11 hypogonadal patients and 10 healthy young men. Solid horizontal lines: group means, dotted lines: -1 SD or -2.5 SD boundaries from healthy mean. Mean values of two groups were significantly different (P < 0.01, Student's t-test).
Figure 2. Trabecular bone mineral density in radius of 11 hypogonadal men and 10 healthy young men. Solid lines: group means, dotted lines: -1 SD or -2.5 SD boundaries from healthy mean. Mean values of two groups were significantly different (P < 0.01, Student's t-test).
Figure 3. Correlation between whole bone mineral density in radius and patient's age at beginning of replacement therapy.

Serum levels of bone-specific AKP ranged from 16.1 to 34.9 (normal: 13.0-33.9) with a mean of 24.87.7 IU/L. The ratio of the concentration of urinary DPD to that of urinary creatinine (Cr) ranged from 2.8 to 5.9 (normal: 2.1-5.4) with a mean of 4.61.0 mmol DPD/mmol Cr. Two hypogonadal men had the AKP slightly above the normal range (34.6 and 34.9 IU/L) and another patient had the DPD/Cr ratio slightly above the normal range (5.9 mmol DPD/mmol Cr). The serum calcium, albumin and inorganic phosphate levels were within the normal range in all the subjects.

The World Health Organization has developed widely used criteria for interpreting BMD measurement [11]. Patients with BMD between 1 and 2.5 SD below the YAM are considered osteopenic and those with BMD more than 2.5 SD below the YAM, osteoporotic. According to these criteria, 77 % of the patients in the present study have osteopenia and 11 %, osteoporosis. It is not clear whether hypogonadal men undergoing ART will achieve the same BMD gain as the postmenopausal women after estrogen replacement. The present study indicates that hypogonadal men remain osteopenic even after long-term ART. Ten of the 11 hypogonadal men had BMD values at least 1 SD below the YAM value. Although a few patients were at their fifth and sixth decades, when bone loss is supposed to begin [12], this 1 SD or greater decrease in radial BMD is far greater than that estimated for age-matched reference range with single-photon absorptiometry [2]. Furthermore, in these patients the BMD was not correlated with age, suggesting that the low BMD values are not simply the result of aging.

In the present study the low BMD in hypogonadal men during long-term ART is probably a result of insufficient accumulation of bone mass during the initial period of therapy rather than a rapid loss of bone mass, because their bone turnover markers were within the normal range. Results of previous studies show that BMD rapidly increases during the first few years of treatment with a concomitant decrease in bone resorption marker levels and increase in osteoblastic markers [13] both in hypogonadal men [5,13] and postmenopausal women [14]. This initial increase in BMD is maintained during long-term therapy [5]. It is thought that the BMD of the patients in the present study increased slightly after the initiation of therapy but remained in the subnormal range.

This inability to achieve normal BMD in hypogonadal men might be the result of inhibited bone development [7] that cannot be corrected by prolonged ART. Further-more, men with a history of delayed puberty also have lower peak BMD than normal men [15]. These findings suggest that osteopenia resulting from androgen deficiency at the critical developmental time might not be reversible [8]. The only patient with the BMD within 1 SD below the YAM was started on ART at 16 years of age. Promising as these findings may be, additional studies are necessary to confirm this hypothesis, because the pubertal growth response is determined by an intricate interaction of gonadal steroids, growth hormone and insulin-like growth factor-I together with other endocrine, paracrine, and autocrine factors. Additionally, the final development of androgen-dependent tissues might be determined by the response occurring during previous periods that requires proper androgen exposure. Such a phenomenon has been reproduced experimentally in murine seminal gland [16] and canine prostatic tissue [17].

It may be argued that different treatment regimens or preparations of testosterone might be responsible for the differing effects of ART on BMD. In a long-term replacement study where BMD within the agematched reference range was achieved, most patients were injected TE 250 mg every 3 weeks [5]. However, the rates of BMD gain between patients treated with 250 mg of a T ester mixture every 3 weeks [18] or every 4 weeks [19] were reported to be comparable. In one patient in the present study, the serum T level was low-normal (3.0 ng/mL) just prior to the next injection and his BMD value was also low (below 1 SD of the YAM). Therefore, to maintain only the normal T level during the therapy might not be sufficient for hypogonadal men to achieve the age-matched BMD level. The advantage of transdermal treatment on BMD, which delivers a more physiologically consistent T level, remains unclear [13].

The pQCT allowing the measurement of both the cortical and trabecular BMD, has been encouraged, because it lessens or prevents the likelihood of underscoring the BMD, as the response of the cortical and the trabecular bone to ART may be different [2]. In this study it is not settled which bone is more sensitive for the detection of osteopenia.

In hypogonadal men, the clinical significance of this low BMD has not been established. It has been reported that in fracture patients, the average BMD in women is lower than in men [3]. In postmenopausal women and elderly men, a 1 SD reduction in BMD is associated with an average of 1.5-fold relative increase in the general fracture risk [20]. More research is also required to examine the effects of bisphosphanates, calcium and vitamin D supplementation, exercise, and calcitonin therapy (which has been clearly demonstrated effective in women) on male hypogonadism treated with androgens [21].

In conclusion, osteopenia persists in the hypogonadal men after long-term ART, suggesting that such patients have a persistent defect in bone development not alleviated by androgen replacement.

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Correspondence to: Kazuhiro Ishizaka, M.D., Department of Urology, Kanto Central Hospital, 6-25-1 Kamiyoga, Setagaya-ku, Tokyo 158-8531, Japan.
Tel: +81-3-3429 1171, Fax: +81-3-3426 0326
E-mail: kazzie@parkcity.ne.jp
Received 2002-05-27      Accepted 2002-06-03