Abstract:
Introduction
Klinefelter’s syndrome (KS) is a sex chromosomal disorder where males have one or more than one extra X-chromosome resulting in a different karyotype, the most common karyotype being 47,XXY. KS was first described in 1942 by Harry Klinefelter, with affecting approximately 1 in 600 males it is the most common chromosomal syndrome disorder (Anders Bojesen, Juul, & Gravholt, 2003). Symptoms of KS differ in expression but the most common ones are: male hypogonadism, small testis, increased stature, infertility and gyneacomastia (Lanfranco, Kamischke, Zitzmann, & Nieschlag, 2004). Next to these symptoms low bone mineral density (BMD) is also found in KS patients. Because sex steroid hormones are known to have an important role in the bone metabolism, low testosterone (T) levels are implied to cause the low BMD in KS patients but controversial data is found (Foresta, Ruzza, Mioni, Meneghello, & Baccichetti, 1983; Horowitz et al., 1992; Kübler, Schulz, Cordes, Beyer, & Krause, 1992). Because of the controversial data scientist are searching for other causes of low BMD in KS patients as presented in this study. Low BMD is linked to osteoporosis, which is most common in postmenopausal women, but is also seen in males with hypogonadism. The standard method for diagnosis of osteoporosis is Dual-energy X-ray absorptiometry (DEXA-scan), DEXA-scan results of KS-patients are unfortunately scarce (De Rosa et al., 2001; Luisetto et al., 1995; F. H. Wong, Pun, & Wang, 1993). Some studies already associated KS with osteoporosis but more evidence is necessary (Breuil & Euller-Ziegler, 2001; Horowitz et al., 1992; Kübler et al., 1992). No treatment in KS patients is focussed on the possibility of KS patient being at risk for osteoporosis at the moment. The aim of this study is to examine the role of T on BMD in KS patients. Also examined are other causes for low BMD in KS patients and the risk of osteoporosis and fractures.
Methods:
For the search in June 2016 the Pubmed central database was consulted. The primary search consisted of the following search terms: Klinefelter syndrome, bone mineral density, testosterone. The search was then extended with mesh and tiab terms to make sure no articles where missed. For klinefelter syndrome [mesh] the term XXY syndrome [tiab] was added, for the term bone density [mesh] the terms bone mineral density [tiab] and BMD [tiab] were added and for the term testosterone[mesh] the terms 7-beta-Hydroxy-4-Androsten-3-one [tiab] and 17 beta Hydroxy 4 Androsten 3 one [tiab] where added. This search gave 25 results. Articles were excluded on:
Date of release being before 2000 (n=8)
Being a review (n=1),
Article was only available in Japanese (n=1)
Being a case report (n=1)
No focus on testosterone in relation to BMD (n= 3)
No focus on BMD (n=1)
After using the exclusion criteria there where ten articles left all focussing either on the relationship of testosterone and bone mineral density in KS patients, osteoporosis in KS patients or other explanations for low BMD in KS patients.
Search Add to builder Query Items found Time
#5 Add Search ((((klinefelter syndrome [mesh] OR klinefelter syndrome [tiab] OR XXY syndrome [tiab]))) AND (testosterone [mesh] OR 17-beta-Hydroxy-4-Androsten-3-one [tiab] OR 17 beta Hydroxy 4 Androsten 3 one [tiab])) AND ((bone density [Mesh] OR bone density [tiab] OR bone mineral density[tiab] OR BMD[tiab])) 25
06:17:09
#4 Add Search (bone density [Mesh] OR bone density [tiab] OR bone mineral density[tiab] OR BMD[tiab]) 59213
06:16:56
#3 Add Search (((klinefelter syndrome [mesh] OR klinefelter syndrome [tiab] OR XXY syndrome [tiab]))) AND (testosterone [mesh] OR 17-beta-Hydroxy-4-Androsten-3-one [tiab] OR 17 beta Hydroxy 4 Androsten 3 one [tiab]) 500
05:55:38
#2 Add Search testosterone [mesh] OR 17-beta-Hydroxy-4-Androsten-3-one [tiab] OR 17 beta Hydroxy 4 Androsten 3 one [tiab] 64542
05:55:23
#1 Add Search (klinefelter syndrome [mesh] OR klinefelter syndrome [tiab] OR XXY syndrome [tiab]) 3947
05:54:57
Table 1. Search done in the Pubmed central database
Results
Testosterone levels and BMD in Klinefelter’s Syndrome patients
Different studies focussed on the association between testosterone levels and BMD in KS patients but found contradictory results. One study shows a significant correlation between baseline testosterone levels and BMD (Seo, Lee, Oh, & Joo, 2007). In this study 40 KS patients with a mean age of 32.05 years and a SD of 3.10 where compared with 20 age-matched controls. 33 of the 40 KS patients had normal serum testosterone levels (>3.0 ng/mL) and seven had low serum testosterone levels (<3.0 ng/mL). BMD was examined at the femoral neck, ward’s triangle and lumbar spine using DEXA-scan. A statistically significant linear correlation was found between baseline T level and BMD of the lumbar spine and Ward’s triangle. There was only a weak correlation was found looking at the femoral neck BMD. Four studies show no relationship between testosterone levels and BMD in KS patients (A. Bojesen et al., 2011; A. Ferlin et al., 2015; Alberto Ferlin et al., 2011; van den Bergh, 2001). In the first study 127 KS patients with a mean age of 31.5 and a SD of 8.5 where studied. 71 patients had reduced plasma T levels and 49 had normal plasma T levels. BMD was measured in the femoral neck and lumbar spine using DEXA-scan. There was no difference in BMD in the femoral neck and lumbar spine in KS patients with reduced and normal plasma T levels (A. Ferlin et al., 2015). In the second study 112 KS patients with a mean age of 32.2 and a SD of 8.2 where examined. 41 KS patients had normal T levels and 71 patients had low T levels. BMD was measured in de femoral neck and the lumbar spine using DEXA-scan. Comparing groups with low and normal T there was no difference in BMD (Alberto Ferlin et al., 2011). In the third study 70 KS patients where studied. BMD was measured at the lumbar spine, the femoral neck and trochanteric region (hip) and the right forearm. There was no significantly correlation between T levels in KS patients and BMD (A. Bojesen et al., 2011). The fourth study examined 52 KS patients. In this study BMD was measured at the left femoral neck, the total hip and the posterior and anterior lumbar spine using DEXA-scan. 29 per cent of the KS patients had a serum T below normal. Results show that there is no difference in BMD of patients with normal serum T or a low serum T (van den Bergh, 2001).
Testosterone treatment and BMD in Klinefelter’s syndrome patients
Contradictory results are also found comparing different studies researching the testosterone treatment in KS patients. In these different studies the main outcome is BMD. Four studies show no significant difference in BMD looking at T treated and untreated KS patients (A. Bojesen et al., 2011; A. Ferlin et al., 2015; Shanbhogue et al., 2015; van den Bergh, 2001). In the first study 70 KS patients where examined. BMD was measured at the lumber spine, the femoral neck and trochanteric region (hip) and the right forearm. Although it was not the primary goal of this study to research the effectiveness of testosterone treatment, they found only minimal differences in BMD between treated KS patients and untreated KS patients (A. Bojesen et al., 2011). The second study was done on 127 KS patients with a mean age of 31.5 years and a SD of 8.5. DEXA-scan was used to measure the BMD of the femoral neck and lumbar spine. KS patients received T supplementation when T levels where <8 nmol/l or between 8 and 12 nmol/l and patients had hypogonadal symptoms (39 patients). There was no difference in BMD of the femoral neck and lumbar spine before and after the T treatment in the KS patients (A. Ferlin et al., 2015). In the third study 31 KS patients where examined, 21 of them where on long term T supplementation at the moment of the study, four of them where on treatment for less then two years, four of them have never het T treatment and the remaining two have been on T treatment for less then two years in the past, but are currently not getting any treatment. BMD was measured at the lumbar spine and total hip using DEXA-scan. Results show no difference in lumbar spine and total hip BMD comparing the treated and untreated KS patients. When the lumbar spine and total hip BMD is related to the duration of the T treatment there is also no significant difference shown(Shanbhogue et al., 2015). The fourth study examined 52 KS patients with a mean age of 39.1 years and a SD of 12.4. 14 patients started their T therapy before the age of 20 years, 38 started their T therapy after the age of 20 years. The mean period of the T treatment was 9.2 years with a SD of 8.2. BMD was measured at the left femoral neck, the total hip and the posterior and anterior lumbar spine. Results show that long term T treatment has no effect on BMD. Also different types of T treatment had no relation with BMD and duration of the T treatment had no association with the BMD either (van den Bergh, 2001). There are also studies who found a increased BMD in KS patients treated with T (Jo, Lee, Joo, & Seo, 2013; S. C. Wong et al., 2015). One of the two studies showing increased BMD after treatment examined 18 Korean KS patients with a 30-44 age range. All of the KS patients never had any treatment with medication known to affect the skeleton. All subjects where treated with long-acting T injections at week 0, week 6 and every 12 weeks after that. BMD was measured at the lumbar spine, femoral neck and Ward’s triangle using DEXA-scan. T treatment was minimal or not effective in the femoral neck and Ward’s triangle but was definitely effective in the lumbar spine. In the lumbar spine there was a significant difference between the BMD before and after treatment (Jo et al., 2013). The second study had a study population of 20 patients with 12 of them being KS patients. The subjects where compared to a group of age-matched controls of the same racial background. All of the KS patients started with T treatment before the age of 16. BMD was measured at the radius and the tibia using DEXA-scan and pQCT. BMD of KS patients treated with T from adolescence did not differ between subjects and controls using DEXA-scan. Only at the tibia there was a slight difference in BMD between subjects and controls using pQTC (S. C. Wong et al., 2015).
KS and osteoporosis
Four studies show the frequency of osteoporosis and osteopenia in KS patients with two of them also giving the frequency of fractures. The first study examined 26 adult KS patients and compared them with 39 age-matched healthy subjects. Two KS patients and one control had osteoporosis. Osteopenia was seen in six patients and 12 controls. The KS patients had no history of any fractures. The conclusion of this study was that osteoporosis is not a constant feature in KS patients (Hiéronimus et al., 2011). The second study examined 112 KS patients and 51 controls. Of the 112 KS patients, 39 had osteopenia and 8 had osteoporosis. The frequency of osteopenia and osteoporosis is not given for the control group (Alberto Ferlin et al., 2011). The third study shows the results of 127 KS patients and 60 age-matched controls. Out of the 127 KS patients, 10 had osteoporosis and 50 had osteopenia. The frequency of osteopenia and osteoporosis of the control group is not shown (A. Ferlin et al., 2015). The fourth study examined 52 KS patients all treated with T. Of the 52 patients 24 patients had osteopenia and 5 patients had osteoporosis. The BMD was measured at the spine and hip but no fractures where reported here.
Other causes for low BMD in KS patients
Because the relation between T and BMD in KS patients is unclear, several studies are done to research other causes for low BMD in KS patients:
Role of androgen receptor gene CAG polymorphism
In a study done to examine the role of the androgen receptor gene CAG polymorphism, 112 KS patients diagnosed in there adulthood where studied. They where compared to 51 age-matched healthy controls. Blood samples where taken to analyse the AR CAG triplet polymorphism. BMD was determined using DEXA-scan. Short CAG repeats where less in activated than long ones in KS patients, but this was not significant. Also the mean weight of the CAG repeats was compared between the KS and controls and gave no significant difference. When comparing both the length of the CAG-repeat and the weight with T levels and BDM, there was no significant difference in weight and length of the CAG repeat when comparing normal and low T levels or BMD. (Alberto Ferlin et al., 2011)
Role of INSL3
The role of INSL3 was studied using a population containing 70 KS patients all above the age of 18 who where one-to-one age-matched with healthy controls. Of the 70 KS patients 35 of them where treated with T at the time of the study. To measure the INSL3 a time-resolved fluoroimmunoassay was used on blood drawn at 8 o’clock in the morning after fasting over night. BMD was measured with DEXA-scan. T, free T and INSL3 where significantly lower in KS patients compared to the healthy controls. Comparing INSL3 to osteocalcin there was a positive correlation found among untreated KS patients. No correlation was found between INSL3 and BMD. (Overvad, Bay, Bojesen, & Gravholt, 2014)
Role of muscle strength and resorptive markers
To determine the role of muscle strength and resorptive markers on BMD, 70 KS patients and 71 age-matched controls where studied. Muscle strength was determined assessing the strength of the right biceps and quadriceps using a dynamometer. BMD was measured using DEXA-scan. Bone markers measured where: bone ALP (bone-specific alkaline phosphatase), NTX(N-terminal cross-linking telopeptide of type 1 collagen), ICTP(P-C-telopeptide fragments of type 1 collagen), PIIINP( P-procollagen III-amino-terminal propeptide), P-osteocalcin and PINP(P-procollagen I-amino-terminal propeptide). All bonemarkers where measured differently. Except for PINP, which was significantly higher in KS patients, no difference in bone markers where found between KS patients and healthy controls. ALP, 1CTP, P1NP and NTX were the bone markers significantly correlated to BMD. Muscle strength is significantly lower in KS patients compared to controls. When muscle strength is compared to BMD, it is shown to be a predictor of BMD. In this study T level is no predictor of BMD as described before.(A. Bojesen et al., 2011)
Role of vitamin D levels and supplementation
The influence of vitamin D levels and supplementation of vitamin D on BMD in KS patients is examined studying 127 KS patients and 60 age-matched healthy controls. BMD was measured using DEXA-scan. 25-hydroxyvitamin D levels where measured between November and February in all subjects. 25-hydroxyvitamin D was significantly lower in the KS patients group compared to the controls. Also a positive correlation was seen between levels of 25-hydroxyvitamin D and BMD. 25-hydroxyvitamin D supplementation increased BMD significantly. In this study there was no relation seen between T level or treatment and BMD as described before. (A. Ferlin et al., 2015)
Testosterone levels
Article Mean BMD (g/〖cm〗^2)
Lumbar spine Femoral neck Ward’s triangle
Low T Normal T P Low T Normal T P Low T Normal T P
(Seo et al., 2007)
0.850 0.875 <0.001 0.710 0.800 0.003 0.520 0.660 <0.001
(A. Ferlin et al., 2015)
0.99 1.00 – 0.99 1.01 – – – –
(Alberto Ferlin et al., 2011)
Data not shown – – – – – – –
(van den Bergh, 2001)
Data not shown – – – – – – –
(A. Bojesen et al., 2011)
Data not shown – – – – – – –
Testosterone treatment
Article Mean BMD (g/〖cm〗^2)
Lumbar spine Femoral neck Ward’s triangle
Untreated Treated P Untreated Treated P Untreated Treated P
(Alberto Ferlin et al., 2011)
1.07 1.06 – 1.01 1.00 – – – –
(Shanbhogue et al., 2015)
– – 0.1 – – – – – 0.27
(van den Bergh, 2001)
Data not shown – – – – – – –
(A. Bojesen et al., 2011)
Data not shown – – – – – – –
(Jo et al., 2013)
0.908 0.967 <0.001 0.807 0.812 0.42 0.683 0.668 0.50
(S. C. Wong et al., 2015)
Data not available – – – – – – –
Discussion
Results show controversial data about T levels and T treatment affecting BMD. Looking at T levels, only one study implies that T levels affect BMD and four studies show no effect at all. Looking at T treatment, two studies show a significant difference in BMD after T treatment but four show no significant increase in BMD after T treatment. Considering other causes of low BMD in KS patients only vitamin D and muscle strength show a relation. Osteoporosis and fractures are present in KS patients but the one study making a conclusion, state that it’s not a constant feature.
Studies concerning the relation between T levels and BMD where not in agreement. Differences between the studies might be explained by difference in main aim. The study that found a positive correlation was completely focussed on the relationship between T levels and BMD, whereas the studies finding no correlation had other main aims. The studies who found no significant correlations where bigger studies with study populations being 52,70, 112 and 127 KS patient who where examined. The only study finding a correlation only studied 40 KS patients, all of them being Korean.(Seo et al., 2007). Because there are differences between study population and main aim of the study, a big study with different ethnicities needs to be done to examine the relation between T levels and BMD.
Studies concerning T treatment and it’s effect on BMD had also contradictory outcomes. Variations in outcome might be related to the difference in T treatment between the studies. One study made a T treatment plan where they treated untreated adult KS patients with T injections for 42 weeks (Jo et al., 2013). Another study treating untreated KS patients assessed 127 patients. But did not only treated patients with T but also with vitamin D, the patients treated with vitamin D where not included but it means not all 127 subject where used to examine the results of T treatment. Their T treatment protocol showed that only patients with low T levels where treated. After the T treatment protocol was implied, only 12 KS patients treated with T where assessed after 2 years of treatment (A. Ferlin et al., 2015). Two other studies all examined patients who already had T treatment, this was not executed by the studies and the patients received different T treatment for different periods of time (A. Bojesen et al., 2011; Shanbhogue et al., 2015). Another study treated KS patients that where not treated before but the types of treatment where different. (S. C. Wong et al., 2015) The last study had 14 patients starting T treatment before the age of 20 and 38 starting T treatment after the age of 20. The duration of the T treatment was different in the patients, another difference was the T treatment itself, some where treated orally, some intramuscularly and some used both (van den Bergh, 2001). All this information about the T treatments used in the different studies show that it is difficult to compare the studies because they are not using the same treatment methods. In all studies except for one T treatment was started at adulthood. One study started T treatment before the age of 16 hoped to get the same peak bone mass as controls without KS. This study found no differences in BMD between the KS patients treated with T and controls, except for a mild reduction in thickness and cortical area at the tibia (S. C. Wong et al., 2015). Another difference between this study and the others is location of the BMD measurements. This study measured BMD at the tibia and radius where other studies measure BMD at the femoral neck, lumbar spine and Ward’s triangle. More and bigger studies about T treatment starting at an early age needs to be done with BMD measured at the femoral neck, lumbar spine and Ward’s triangle to support the data found.
Only few recent articles show the frequency of osteopenia and osteoporosis. Most of them are not focussed on osteoporosis and show only the frequency, they don’t compare this with the frequency in healthy controls. The only study with the main focus on osteoporosis had a small study population of 26 KS patients. This study concluded that osteoporosis is not a constant feature in KS (Hiéronimus et al., 2011). There is not enough data to conclude osteoporosis is not a constant feature in KS and if there is a higher fracture risk for KS patients. Because a considerable number of studies found a lower BMD in KS patients compared to controls, more studies investigating a relationship between osteoporosis and KS is necessary. If osteoporosis is more common in KS patients, treatment can be given to KS patients in time to prevent a higher risk of fractures.
Four studies examined other causes for low BMD in KS patients. Two studies proved CAG polymorphism and INSL3 are no reason for low BMD in KS patients. These where the only studies done about the subject so lack of data makes it hard to compare them with other studies. (Alberto Ferlin et al., 2011; Overvad et al., 2014).
The study about vitamin D was a big study examining 127 KS patients where T treatment is compared to vitamin D treatment. The study shows a significant increase in BMD after vitamin D treatment, and no increase in BMD after T treatment. The study has a good design but because it is the only study more proof is necessary. If vitamin D has such a big result on BMD in KS patients as this study shows, KS patients benefit from treatment with vitamin D (A. Ferlin et al., 2015).
This study shows the most recent studies concerning BMD in KS patients. The articles where difficult to compare because the study designs, treatments and outcomes where very different. More research needs to be done to determine the role of T in KS concerning the low BMD. Also osteoporosis and fracture risk are not well described in the literature. Treatment of KS patients is not well described and T treatment is not consequently done. If there is more data available a good treatment plan for KS patients can be made.
Conclusion:
Most results show that T levels do not influence en predict BMD in KS patients. T treatment is most effective when started before the age of 16, when started later results are contradictory. Vitamin D is shown to have an more important role in BMD than T and needs to be studied more. When accessing osteoporosis and fractures in KS patients, osteoporosis is present in KS patients but fractures are not examined enough as an outcome to draw any conclusions about this. More and bigger studies need to be done to determine the relation between KS and osteoporosis also looking at fracture risk.
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