Effects of androgen substitution on bone tissue

The effects of androgen replacement on bone mass have been addressed by several studies. An early report on results in a mixed group of 36 hypogonadal men demonstrated a significant increase of spinal bone density assessed by radiological methods dual-energy X-ray absorptiometry (DXA) and quantitative computer tomography (QCT) during 12 to 18 months of therapy. Corresponding results were seen in 37 men with primary and in 35 men with secondary hypogonadism. Bone density of the spine as determined by QCT increased particularly in those patients who had lower bone density at the start of the study and those who had not received gonadal steroid therapy. A more detailed approach in 32 of these patients demonstrated that this increase was due to gain of both trabecular and cortical bone tissue, while the vertebral bodyarea did not increase (Leifke etal. 1998). In a prospective multicenter trial using different transdermal testosterone preparations in 227 men with hypogonadism of heterogeneous origin (about 60% of these men with prior testosterone treatment), significant increases both in spinal and hip bone density as detem-ined by DXA were seen (Wang et al. 2001). The importance of baseline androgen concentrations on the outcome of testosterone replacement in respect to increment of bone density is stressed by a study in 108 men older than 65 years receiving either placebo or transdermal testosterone. Androgen concentrations were not a selection criterion and significant changes in terms of higher bone density as assessed by DXA occurred only in the hypogonadal men. Bone density of the eugonadal men was not influenced by testosterone administration, quite in agreement with models of non-linear testosterone effects on bone tissue (see above, Fig. 7.2) (Snyder et al. 1999). Corresponding results are also reported from a similar study in 44 men older than 65 years in a placebo-controlled study (Kenny etal. 2001).

The above-mentioned methods to assess bone density apply radiation and are costly, thus limiting their widespread and repeated use. The feasibility of inexpensive nonradiation methods applied by portable devices using quantitative ultrasound (QUS) to measure transmission speed in bone tissue has also been demonstrated. The feasibility of using phalangeal QUS in comparison to radiological methods for the assessment of fracture risk and monitoring changes in bone density during hormone substitution therapy or bisphosphonate medication was demonstrated in a large study involving more than 10,000 women (Wuster etal. 2000).

Concerning men, a detailed cross-sectional approach involving 521 men (226 healthy controls, 156 hypogonadal men and 141 men receiving testosterone substitution for at least two years) compared this method to QCT of the lumbar spine and showed differences between the respective patient groups (Zitzmann et al. 2002). In comparison to QCT, patients with a lumbar content of hydroxylapatite of <100 mg/cm3 were reliably identified by phalangeal QUS (cutoff level 1965 m/sec which is a T score of -3.5 based on eugonadal subjects). The receiver operating characteristics showed an area under the curve of 0.94 (sensitivity 94%, specificity 92%, p < 0.0001). Since the association was non-linear, QCT values within the normal range could not be predicted by pQUS. A treatment effect was visible over the complete age range of 20 to 70 years of substituted patients. In comparison to the eugonadal men, substituted individuals had an overall significantly lower bone density (p < 0.004), which was caused by differences in the age groups <50 years, but patients receiving substitution therapy had a significantly higher bone density in comparison to hypogonadal patients in all age groups (p < 0.0001). Significant differences of bone density were seen in all patient subgroups comparing untreated hypogonadal men to substituted individuals of the respective diagnosis (non-Klinefelter patients with primary hypogonadism, Klinefelter patients, idio-pathic hypogonadotropic hypogonadal men, subjects with postpubertal onset of secondary hypogonadism or late-onset hypogonadism, respectively, with p < 0.001 for every subgroup). Age, treatment modality and duration of treatment did not have a significant influence on the effect of substitution (p = 0.13, p = 0.96, and p = 0.24, respectively), but levels of substituted testosterone showed a trend toward a positive association with bone density (p = 0.07) (Zitzmann etal. 2002).

In a longitudinal section of this study involving 54 men, a general improvement of bone density occurred (p < 0.0001). Those patients with initially lower bone density gained significantly more bone density (p < 0.001); this also applies to initially lower testosterone levels (p = 0.03). Putative influences on results by age, diagnosis, treatment modality, duration of treatment and gained testosterone levels were not significant (p = 0.43, p = 0.88, p = 0.18, p = 0.15, and p = 0.65, respectively), although initial bone density and testosterone levels showed a trend toward lower values in subjects with secondary hypogonadism in comparison to those with primary hypogonadism (p = 0.07) (Zitzmann etal. 2002).

These results suggest that bone density of androgen-deficient men is improved by testosterone therapy but may not reach the level of age-matched healthy eugonadal controls, especially in those patients with congenital disorders of hypogonadism, hence impaired pubertal skeletal maturation. This is confirmed by a smaller study in 33 secondary and 20 primary hypogonadal men using DXA (Schubert et al. 2003).

The potent synthetic androgen 7a-methyl-19-nortestosterone (MENT), which is resistant to 5a-reductase but is a substrate for aromatase and may therefore offer selective sparing of the prostate gland while supporting other androgen-dependent tissues, was tested in 16 hypogonadal men (Anderson et al. 2003). A prostatesparing effect could, as intended, be demonstrated. Nevertheless, while androgen-dependent functions such as erythropoeisis (see Chapter 9) and psychosocial implications were adequately restored by MENT, a decrease in spinal bone mass was observed. Simultaneously, serum markers of bone formation decreased, while urinary excretion of bone resorption indicators increased. As it has been demonstrated that 5a-reduced androgens do not play a major role in bone metabolism, results point towards the importance of sufficient aromatization to maintain bone mass. It is suggested that aromatization-endproducts of MENT are less potent activators of estrogen receptors than estradiol itseslf (Anderson etal. 2003).

In conclusion, testosterone substitution in hypogonadal men restores bone mass. To this end, aromatization to estradiol is paramount in addition to intrinsic androgen activities.

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