Low bone mineral density is associated with hypogonadism and cranial irradiation in male childhood cancer survivors

Survival rate for childhood cancer has improved considerably during the last decades and is now approximately 80% in Europe [1]. Potential long-term adverse consequences from cancer treatment have therefore become increasingly important. Depending on organ system, the time elapsed from cancer treatment to clinical symptoms may be extended, and this is in particular true for skeletal effects. Low bone mineral density (BMD) and osteoporosis often develop over many years. Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength, predisposing to an increased fracture risk. There is no method for measuring overall bone strength, but BMD serves as a proxy [2], since a decreased BMD correlates with increased fracture risk [3]. Although fragility fractures are less prevalent in men than in women, men have higher rates of fracture-related mortality [4]. Because of the morbidity and mortality associated with osteoporotic fractures, it is desirable to identify those at risk of osteoporosis so that preventive measures can be taken.

Among adult childhood cancer survivors (CCS), almost 40% in the large St Jude Lifetime Cohort Study had low BMD in total body or lumbar spine [5]. Hypogonadism has been stated to be a risk factor of low BMD in CCS [6‐8]. Available studies reporting on the association between hypogonadism and BMD in CCS are based on a low number of subjects [9‐11], mixing both male and female CCS [8, 10‐12] or lacking controls [8, 9, 11], making conclusions regarding possible association between hypogonadism and BMD in adult male CCS difficult.

To address these shortcomings, we investigated 125 male CCS after a mean follow-up of 24.3 years and a corresponding number of age-matched controls from the general population. Our aims were (1) to investigate differences in BMD and the risk of low BMD in male CCS compared with controls and (2) to elucidate possible associations between BMD and biochemical signs of hypogonadism, previous cancer treatment and type of cancer.

This study is based on a cohort of male CCS invited 13 years ago (2005–2006) to participate in a study on reproductive function [13]. However, all the data presented in the current study was collected during 2010–2012, when we asked the patients and controls to re-visit our research unit and undergo investigations related to skeletal health under standardized conditions (see below).

Sixteen CCS (13%) presented with low S-testosterone levels and two (1.6%) were categorized as hypogonadal due to isolated elevated S-LH. Seventeen controls (14%) exhibited low S-testosterone, and none with isolated elevated S-LH or TRT.

The most important finding from this study is that BMD among male childhood cancer survivors does not significantly differ from age-matched controls. However, among untreated hypogonadal CCS, BMD was lower both at the hip and lumbar spine compared with eugonadal CCS. This was also expressed as a higher risk of low hip BMD, i.e. hip BMD below the normal range, in this group. Childhood cancer survivors treated with radiotherapy to the brain had lower BMD both at the total hip and lumbar spine compared with controls, this difference being robust for adjustment for hypogonadism.

The fact that no difference was seen for the entire group of CCS compared with controls was probably because not all CCS in our cohort had received extensive cancer treatment (Online Resource, “Childhood cancer survivors, therapeutic subgroups”). Previous studies reporting on reduced BMD in CCS are often based on CCS treated for a specific diagnosis such as acute lymphoblastic leukaemia (ALL) [21‐23] or sarcoma [24]. Patients with ALL are extensively treated with chemotherapy, including high-dose methotrexate, in addition to high cumulative doses of corticosteroids. Patients with Ewing’s sarcoma and osteosarcoma are treated with intense chemotherapy and surgery, with or without radiotherapy [25].

In comparison with the St Jude Lifetime Cohort Study (SJLIFE) where 39% of CCS had total body or lumbar spine BMD Z-score < − 1, [5], the proportion with low lumbar spine BMD was lower in our cohort (22%). Among SJLIFE patients treated with hypothalamic-pituitary irradiation, 54% had total body or lumbar spine BMD Z-score < − 1, compared with 30% with low lumbar spine BMD in our CCS cohort. However, half of the participants in the SJLIFE were female, and this might, at least in part, explain these differences. In survivors of ALL, the negative impact of cranial irradiation on BMD was reported to be more pronounced in females than in males [26], and men also have a higher increase in BMD following growth hormone replacement than women [27].

Untreated hypogonadism in male CCS was associated with lower BMD at the total hip and lumbar spine, as well as an increased risk of low BMD at the total hip. Testosterone deficiency is a risk factor for low BMD and osteoporosis in elderly men [28], whereas less in known about the association younger men. In a study by Kacker et al., testosterone deficiency was associated with low BMD in men below 50 years with sexual dysfunction or infertility; 38% having T-scores below − 1 at the hip or spine [29]. This is similar to the 39% prevalence low hip BMD among our hypogonadal untreated CCS.

To the best of our knowledge, only two studies have reported on the association between gonadal function and BMD in adult male CCS. Holmes et al. reported a positive correlation between S-testosterone and BMD in lumbar spine and femoral neck in 29 men with azoospermia treated for Hodgkin disease [9]. S-testosterone was within normal range for most subjects, with mean (SD) 15.2 ± 1.1 nmol/L, and S-LH was in the upper normal range with mean (SD) 9.7 ± 0.7 IU/L; hence, many of the subjects probably had mild compensated hypogonadism. In a study of male CCS treated for haematological malignancy, Howell et al. [30] reported lower femoral neck BMD in CCS with elevated S-LH and low or low normal S-testosterone, compared with equally treated CCS presenting with normal S-LH and S-testosterone levels. The two latter studies indicate, in line with our findings, that mild hypogonadism can negatively affect BMD in male CCS.

In CCS treated with cranial irradiation, we found lower BMD at the total hip and lumbar spine, which is in line with previous studies [7, 8, 26]. Cranial irradiation in children is a known risk factor for later pituitary malfunctions [31], among others, growth hormone deficiency (GHD) and hypogonadism. Adults with untreated adult-onset GHD have decreased BMD, and adults with childhood-onset GHD have in some, but not all, studies been reported to have lower BMD than controls [32]. Bone mineral density increases after more than 1 year of growth hormone replacement in adults with GHD [27]. The statistically significant associations found in our study were robust for adjustment for hypogonadism and growth hormone replacement. We used the latter as a proxy for GHD as our study was not designed for evaluating growth hormone status, e.g. we did not perform provocative testing for GHD. It is possible that we were unable to adjust for the real impact of GHD on BMD, due to potential undiagnosed and untreated GHD in our cohort. The normal stature of our CCS compared with Swedish men of similar age indicates there is no symptomatic childhood-onset GHD [33]. Therefore, it is unlikely that BMD is underestimated in the CCS—an otherwise potential problem when BMD is measured in children [34]. However, the finding of lower BMD in CCS treated with cranial irradiation indicates that factors other than hypogonadism may play a role in the development of low BMD in male CCS.

Alkylating agents have been suggested as a risk factor for low BMD in CCS by causing hypogonadism [7], but are not defined as risk factors for reduced BMD by The North American Children’s Oncology Group [6]. For male CCS, cumulative cyclophosphamide dose > 20,000 mg/m² is a risk factor for testosterone deficiency/insufficiency [6]. Median CED in our cohort of CCS treated with chemotherapy without radiotherapy was well below 20,000 mg/m², which might explain why we did not find any effect of treatment with alkylating agents on BMD. This is supported by den Hoed et al., finding no increased risk of low BMD at median 17 years after treatment with ifosfamide or cyclophosphamide [35]. Likewise, median methotrexate dose was 11 g/m² in our cohort, well below the > 40 g/m² associated with decreased BMD [21].

CCS treated for lymphoma had borderline decreased risk of low lumbar spine BMD compared with controls. As concerning haematological malignancies in childhood, children diagnosed with ALL have been reported to have reduced BMD at diagnosis, with a further decrease during therapy [22, 23]. Reduced BMD associated with cranial irradiation has been reported in survivors of ALL [36, 37], a median of 8 and 11.5 years after therapy, respectively. However, recovery of BMD in ALL survivors has also been reported, with 67% of subjects with previous BMD Z-score ≤ − 2 improving at least one standard deviation at a median of 8.5 years later [26]. As our follow-up time was a mean of 24 years, our results can hypothetically reflect such a recovery of BMD, and/or the observed lower risk could be a chance finding.

One of the limitations is the lack of data on duration of TRT and a relatively low statistical power of this part of our calculations. Thus, we cannot conclude if androgen replacement prevents or reverses lowering of BMD in hypogonadal CCS. The effect of TRT on BMD has been debated, and two previous meta-analyses showed only a moderate increase in lumbar BMD but no statistically significant effect on femoral neck BMD after TRT for up to 36 months [38, 39]. However, both meta-analyses included studies on subjects with normal basal testosterone levels, and many studies had only up to 12 months of follow-up. Subsequently, TRT has been found to increase BMD in hypogonadal men at the hip [40] or hip and lumbar spine [41, 42], after treatment for 12 [40, 41] or 36 months [42]. The effect on BMD of TRT for longer than 36 months is not known. Fracture information was not systematically collected in the study, which might have been relevant for assessment of vertebral fractures in particular. However, we do not regard this as a major limitation, since only a single patient had undergone spinal surgery for a vertebral compression and in addition, VFA available for a large portion of the patients identified only one case of vertebral deformity.

An additional limitation is the lack of information regarding lifestyle factors other than smoking, such as physical activity and dietary intake of calcium and vitamin D, factors known to affect BMD [2]. Low participation rate among the controls might also lead to selection bias, with potential overrepresentation of subjects with previous fractures or a family history of osteoporosis. Such a selection bias would, if present, tend to decrease the difference in BMD between controls and patients. Also, the within-patient group comparisons as hypogonadal vs. eugonadal are not dependent on selection of controls. Our data on the number of children among participants and non-participants do not indicate selection of controls due to impairment of reproductive function, but potential selection bias concerning BMD cannot be assessed.

The study has also some obvious strengths. Inclusion of age-matched controls allowed us to draw more valid conclusions as considers the bone status of CCS in relation to that in the general population. The size of our patient cohort made it possible to compare eugonadal and hypogonadal men. The diagnosis of hypogonadism was based on hormone values measured in blood samples obtained under standardized and proper conditions—fasting, before 10 am. Although only 125 of the original cohort of 427 CCS were included in the current study, the distribution between those having children and childless men was similar in participants and the remaining eligible patients, which indicated a reduced risk of selection bias related to reproductive function.

Due to their novelty, our findings have some important implications in relation to management of male CCS. A significant proportion of CCS are hypogonadal and are, therefore, at increased risk of having secondarily reduced BMD. According to The Endocrine Society’s Clinical Guidelines regarding osteoporosis in men, DXA is suggested in hypogonadal men aged 50–69, and testosterone replacement is suggested for men with borderline high risk of fracture and symptomatic testosterone deficiency (S-testosterone < 6.9 nmol/L), or S-testosterone < 6.9 nmol/L and high risk of fracture but contraindications to approved osteoporosis therapy [43]. More than 75% of our hypogonadal untreated CCS had S-testosterone above this level; hence, our data suggest that BMD is also affected in younger hypogonadal CCS with only moderately lowered S-testosterone.

In conclusion, it is reassuring that BMD was not significantly decreased in the entire group of childhood cancer survivors. However, those presenting with biochemical hypogonadism—representing a significant proportion of this patient group—are at increased risk of impaired bone health. The same was true to some extent for CCS receiving cranial irradiation, and in those men, other factors than low testosterone levels seem to be of significance for the risk of decreased BMD. Taking into consideration the relatively young age of these patients and the age-related decline in testosterone values, DXA should be considered in male cancer survivors with untreated biochemical hypogonadism or previous treatment with cranial irradiation.