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ARTICLE
Relationship Between Osteoporosis and Serum Sclerostin Levels in Kidney Transplant Recipients

Objectives: Sclerostin, a peptide secreted primarily by osteocytes, suppresses osteoblast maturation, thus reducing bone formation. Here, we evaluated the relationship between sclerostin levels and osteo­porosis in kidney transplant recipients.

Materials and Methods: This cross-sectional study included 78 kidney transplant recipients > 18 years old and at least 6 months posttransplant. In our center, unrelated living-donor kidney transplants are not performed. Patients with parathyroid adenoma or parathyroidectomy history were excluded. Lumbar and femoral neck bone mineral densities and T and Z scores were obtained by dual-energy X-ray absorptiometry; results were used to divide patients into osteoporotic and nonosteoporotic groups. Serum sclerostin was measured by enzyme-linked immunosorbent assay.

Results: Of total patients, 43% had osteoporosis, mean age was 40.8 years, and 70% were male. Groups had similar ages, male-female distribution, time post­transplant, cumulative corticosteroid dose, estimated glomerular filtration rates, and 25-hydroxyvitamin D2 levels (P > .05). The osteoporotic group had lower sclerostin (405.9 ± 234.9 vs 521.7 ± 233.5 ng/dL; P = .035) and higher intact parathyroid hormone levels (110.9 ± 68.0 vs 84.8 ± 41.4 pg/mL; P = .04) than the nonosteoporotic group. Sclerostin levels were not correlated with cumulative corticosteroid dose, intact parathyroid hormone, bone mineral density, and T scores at any site but were weakly negatively correlated with age (P = .04, r = -0.25). In multiple regression analyses, only intact parathyroid hormone had negative effects on lumbar bone mineral density (P = .02) and T scores (P = .036). Serum sclerostin levels, age, and cumulative corticosteroid dose did not affect lumbar or hip bone mineral density and T scores (P > .05).

Conclusions: Sclerostin levels were low in our osteoporotic patients; therefore, sclerostin may not be a contributing factor to osteoporosis development. Because sclerostin is an osteocyte-derived peptide, its serum levels only reflect total osteocyte number and bone mass.


Key words : Bone mineral density, 25-Hydroxyvitamin D2, Renal transplantation

Introduction

Kidney transplant is the best choice for treatment of chronic renal failure. However, graft dysfunction, cardiovascular diseases, infections, malignancies, and musculoskeletal problems can emerge during short-term and long-term follow-up after kidney transplant. Along with effects on graft and patient survival rates, osteoporosis has become an issue that is more often encountered, especially over long-term follow-up of these patients. Unfortunately, osteo­porosis is often neglected in kidney transplant recipients. Although the main risk factors for development of osteoporosis in healthy populations are advanced age and postmenopausal estrogen deficiency,1 additional risk factors are shown after kidney transplant. These additional risk factors include immunosuppressive drugs (especially corticosteroids), total corticosteroid dose, diabetes mellitus, femal sex, inadequate calcium intake, physical inactivity, hypogonadism, pretransplant parathyroid hormone levels, pretransplant renal replacement treatment duration, and time elapsed after renal transplant.2

Bone metabolism is quite complicated in kidney transplant patients. Bone pathologies associated with chronic kidney disease (CKD) in the pretransplant period, persistent hyperparathyroidism in the post­transplant period, and new-onset hyperpara­thyroidism caused by decreased renal function in the late post­transplant period all contribute to bone pathologies.

Sclerostin is a 213-amino acid glycoprotein, which is encoded by the SOST gene and released primarily from osteocytes.3 Sclerosteosis and van Buchem disease are characterized by the gradual development of hyperostosis in patients with a genetic deficiency of sclerostin due to SOST gene mutations.4,5 Sclerostin inhibits the Wnt signaling pathway (which promotes terminal maturation of osteoblasts and prevents their apoptosis) by binding to LRP5/6. Thus, this results in inadequate bone formation.6 For this reason, the relationship between sclerostin and osteoporosis has been the subject of studies in the general osteoporosis population and in CKD patients.7-9 There are few studies examining sclerostin levels after kidney transplant, but no study exists that has investigated possible relationship between sclerostin and osteoporosis in kidney transplant recipients.10-12 The aim of our study was to investigate the relationship between osteoporosis and serum sclerostin levels in kidney transplant recipients.

Materials and Methods

Ethical approval
This study was approved by the Local Ethics Committee of Kahramanmaras Sutcu Imam University (Decision No: 04 and Decision Date: 17/05/2017) and were in accordance with the 1964 Helsinki Declaration and its later amendments. Informed consent was obtained from all participants included in the study.

Study population
This cross-sectional study was conducted between June 1 and October 1, 2017 in Kahramanmaras Sutcu Imam University Medical Faculty Hospital (Kahramanmaras, Turkey). Over the study period, 94 patients over 18 years of age had undergone renal transplant and were at least 6 months posttransplant. In our transplant center, we do not perform kidney transplant procedures from living unrelated kidney donors, and only living related donations and deceased donations are used for transplant.

The greatest bone loss related to intense corticosteroid use after kidney transplant occurs during the first 6 months, and bone pathologies such as hyperparathyroid or adynamic bone diseases related to CKD pretransplant are possible confounding factors. To reduce the effects of these factors on bone health and to reveal a natural relationship between osteoporosis and sclerostin levels, patients with these factors within the first 6 months after kidney transplant were excluded from our study. We also excluded those with parathyroid adenoma, those who had undergone parathy­roidectomy surgery, and those who received vitamin D, cinecalcet, or antiosteoporotic therapy. Therefore, of 94 patients, 12 patients with impaired renal function posttransplant who developed CKD and with estimated glomerular filtration rate (eGFR) of less than 40 mL/min/1.73 m2 were excluded from our study to exclude the effects of CKD mineral bone disorder. Four patients who had intact parathyroid hormone (iPTH) > 300 pg/mL were also excluded from the study due to a possible unrecognized parathyroid adenoma. In total, 78 patients met the inclusion criteria.

Causes of CKD, elapsed time after kidney transplant, age, sex, immunosuppressive drugs that were used, presence of diabetes and hypertension, smoking status, and other demographic data were obtained from the database at our center.

We used total usage duration and average daily dose of immunosuppressive drugs to calculate the total dose used after renal transplant for each drug.

Bone density measurement and diagnosis of osteoporosis
Bone mineral density (BMD) of patients was measured from lumbar spine 1-4 and left femoral neck by the dual-energy X-ray absorptiometry (DEXA) method using the Hologic QDR 4500 fan beam scanner device (Bedford, MA, USA). The mean BMDs, T scores, and Z scores of the lumbar spine and femoral neck were obtained. Patients were divided into 2 groups: those with and those without osteoporosis.

The diagnosis of osteoporosis was made accor­ding to the criteria of the World Health Organization and the International Society for Clinical Densitometry.13,14 According to these criteria, postmenopausal women and men older than 50 years with T-score result of -2.5 or lower according to DEXA are classified as having osteoporosis, and those with a T-score result greater than -2.5 are classified as nonosteoporotic. However, T scores cannot be used to define osteoporosis in premenopausal women and men younger than 50 years of age. These individuals are defined as “below the expected range for age” when they have a Z score of -2.0 or lower according to DEXA results.14 Therefore, in our study, for renal transplant recipients who were either premenopausal women or men younger than 50 years of age, we decided to include them in our osteoporosis group if they had a Z score of -2.0 or lower, whereas those with a Z score of greater than -2.0 were included in the nonos­teoporosis group.

Laboratory values and serum sclerostin measurements
Blood urea nitrogen, creatinine, calcium, phosphorus, albumin, potassium, alkaline phosphatase (ALP), and iPTH levels were measured in blood samples taken after an 8-hour fast in the morning using the Advia 1800 Fully Automated Clinical Chemistry Analyzer (Bayer, Berlin, Germany). Levels of 25-hydroxyvitamin D2 [25(OH)D2] were measured in blood samples taken into EDTA tubes using the ultra-high-performance liquid chromatography instrument (Thermo Fisher Scientific Inc., Rockford, IL, USA). Blood samples (2 mL) taken simultaneously were centrifuged at 5000 revolutions/minute for 3 minutes to be used for the measurement of serum sclerostin level. The separated serum was stored at -80°C. After all samples were collected, they were defrosted simultaneously and were studied using the human SOST (sclerostin) enzyme-linked immunosorbent assay kit (Elabscience, Houston, TX, USA) on an enzyme-linked immunosorbent assay device (Thermo Fisher Scientific). The intra- and interassay coefficient variability of the kit was 5.32, and the average recovery was 91%. The eGFR value was calculated for each patient using the Modification of Diet in Renal Disease-4 equation. Blood sampling for serum sclerostin level, 25(OH)D2, and other laboratory measurements were taken between 8:00 and 9:00 AM in the morning of the day when bone measurements were made.

Statistical analyses
Categorical data obtained by counting are expressed as number and percent of patients. Continuous variables obtained by measurement are expressed as means and standard deviation. Statistical evaluation was performed using the SPSS software package (SPSS 16.0, SPSS Inc., Chicago, IL, USA). For comparison of patients with and without osteoporosis, the chi-square test was used for categorical data. Although we used t tests to compare noncategorical data if parameters were normally distributed, the Mann-Whitney U test was used to compare noncategorical data if parameters were not normally distributed. Correlations between sclerostin level, BMD, T score, Z score, and other parameters were assessed by Pearson and Spearman correlation analyses and partial correlation analyses. Multiple regression analysis was performed by the enter method to assess factors affecting the lumbar and hip BMD scores. P < .05 was considered statistically significant.

Results

Total patient population
The demographic and laboratory data of 78 kidney transplant patients included in the study are shown in Table 1. The mean age of patients was 40.8 ± 12.6 years, and 70% of the patients were male. Of female patients, 42% were postmenopausal. The mean elapsed time after renal transplant was 56.2 ± 31.4 months. Of the total patients, 43.6% were included in the osteoporosis group. The mean sclerostin level was 474.4 ± 243.5 ng/dL, and the mean 25(OH)D2 level was 25.4 ± 13.3 ng/mL. The mean eGFR was 81.5 ± 23.2 mL/min/1.73 m2, and the mean iPTH level was 94.2 ± 54.5 pg/mL. The mean lumbar and hip BMD results were 0.890 ± 0.172 g/cm2 and 0.820 ± 0.187 g/cm2, respectively. Cumulative corticosteroid dose was calculated as 8450 ± 4751 mg, and cumulative tacrolimus dose was calculated as 2751 ± 2009 mg. Other than corticosteroids and mycophenolate, 89% of patients were taking tacrolimus, 6% were taking cyclosporine, and the remaining 5% were taking mammalian target of rapamycin inhibitors. Eight of the patients (10%) were smokers.

Comparison of patients with and without osteoporosis
In the osteoporosis group, the mean lumbar BMD and T-score values were 0.755 ± 0.09 g/cm2 and -2.9 ± 0.8, respectively, and the mean femoral neck BMD and T-score values were 0.675 ± 0.122 g/cm2 and -2.0 ± 0.8, respectively. In the nonosteoporosis group, the mean lumbar BMD and T-score values were 0.994 ± 0.143 g/cm2 and -0.7 ± 1.2, respectively, and the mean femoral neck BMD and T-score values were 0.932 ± 0.148 g/cm2 and -0.3 ± 0.9, respectively. There were no significant differences between groups in terms of male-female distribution, mean age, elapsed time from renal transplant, cumulative corticosteroid and tacrolimus doses, eGFR, albumin, calcium, phosphorus, and ALP values (P > .05 for all) (Table 2). Although the mean serum 25(OH)D2 level was slightly lower in the osteoporosis group than in the nonosteoporosis group, this difference was not statistically significant (24.13 ± 14.63 vs 27.60 ± 12.28 ng/mL; P = .26). Mean serum sclerostin level was significantly lower in the osteoporosis group than in the nonosteoporosis group (405.9 ± 234.9 vs 521.7 ± 233.5 ng/dL; P = .035); however, mean serum iPTH level was significantly higher in the osteoporosis group than in the nonosteoporosis group (110.9 ± 68.0 vs 84.8 ± 41.4 pg/mL; P = .04). Comparisons of demographic and laboratory data of both groups are summarized in Table 2 and Figure 1.

In our simple correlation analysis, serum sclerostin levels were not correlated with iPTH, 25(OH)D2 levels, cumulative corticosteroid dose, elapsed time from renal transplant, eGFR, and lumbar/hip BMD or T-score values (P > .05). Serum sclerostin levels were weakly positively correlated with age (P = .04, r = 0.22) and lumbar Z-score (P = .024, r = 0.23) (Table 3). After age and serum iPTH levels that may affect serum sclerostin levels were adjusted, the correlation between serum sclerostin level and Z score disappeared (data not shown).

In multiple regression analysis, when the factors affecting lumbar and femoral neck BMD were examined, we observed that serum sclerostin level, age, and total corticosteroid dose did not affect lumbar or femoral neck T scores or BMD (Table 4). Only serum iPTH levels had a negative effect on lumbar BMD (P = .02 and 95% confidence interval, -0.002 to 0.000) and T score (P = .036 and 95% confidence interval, -0.13 to 0.000) (Table 4 and Figure 2).

Discussion

In this cross-sectional study, we examined the possible relationship between serum sclerostin levels and osteoporosis in kidney transplant recipients. We found that serum sclerostin levels were lower in patients with osteoporosis than in patients without osteoporosis. We suggest that sclerostin is not an independent risk factor for the development of osteoporosis.

The frequency of osteoporosis in renal transplant patients ranges from 15% to 56%.15 These patients lose most of their bone mass in the first year after renal transplant.16 Additional risk factors like corticosteroid use, aside from age, sex, and hormonal status, contribute to the development of osteoporosis in these patients. The incidence of osteoporosis in our study was 43%. Both of our patient groups (osteoporosis and nonosteoporosis groups) were similar in terms of age, male-female distribution, total corticosteroid and tacrolimus doses, and calcium, phosphorus, ALP, and 25(OH)D2 levels. However, we found that, although mean serum sclerostin level was significantly lower in the osteoporosis group than in the nonosteoporosis group, the mean serum iPTH level was significantly higher in the osteoporosis group than in the nonosteoporosis group.

There are few studies examining the relationship between osteoporosis and sclerostin levels in kidney transplant patients. Bonani and associates10 found that serum sclerostin levels decreased significantly after renal transplant but increased again over time in 42 kidney transplant patients. The group did not demonstrate any associations between pretransplant or posttransplant sclerostin levels and BMD scores and commented that pretransplant and posttransplant sclerostin levels were not associated with BMD. In a study from Evenepoel and associates11 comparing 50 kidney transplant patients with 50 CKD patients, sclerostin levels decreased by almost 60% after renal transplant but increased again over time. These studies did not have a design that was aimed to examine a possible relationship between oste­oporosis and sclerostin. According to our information, our study is the first to investigate the relationship between osteoporosis and sclerostin in renal transplant patients.

The possible relationship between osteoporosis and sclerostin has been investigated in various other conditions, such as diabetes mellitus and CKDs. For the first time, Mödder and associates17 showed that sclerostin levels correlated with total body bone mineral content, especially in elderly patients, in a population-based study of 318 men and 362 women (including premenopausal and postmenopausal women) between 21 and 97 years old. In a study from Ardawi and associates18 that followed 707 postmenopausal women for 5.2 years, lumbar and hip BMD values were negatively correlated with sclerostin levels and the relative risk for fractures was > 7-fold among postmenopausal women for each 1 standard deviation increment increase in sclerostin levels. However, other studies have shown that lumbar and hip BMD values were positively correlated with sclerostin levels. In a study from Garnero and associates19 involving 572 postmenopausal women, patients with higher sclerostin levels had higher BMD values with no increase in fracture risk. Amrein and colleagues20 found that sclerostin levels were positively correlated with BMD and bone mineral content in healthy men and premenopausal women, whereas Lapauw and colleagues21 demonstrated that sclerostin levels in men with idiopathic osteoporosis were lower than in healthy men, with sclerostin levels again positively correlated with BMD. In 513 Korean postmenopausal women, sclerostin levels and BMD were found to be lower in patients with osteoporotic fracture.22 Polyzos and associates showed that sclerostin levels increased with risedronate therapy in postmenopausal women with osteoporosis.23 In our study, sclerostin levels did not correlate with hip or lumbar BMD and T scores but were positively correlated with Z scores in both measurement regions. After we adjusted for age and iPTH, factors that affect both BMD and serum sclerostin levels, the correlation between serum sclerostin levels and Z scores disappeared. In general, most studies have shown that, as bone density decreases, serum sclerostin also decreases.

Sclerostin is a peptide that is released mainly from osteocytes; it inhibits osteoblast maturation and leads to osteoblast apoptosis through the Wnt/β-catenin pathway. Because of this feature, we may expect that sclerostin contributes to osteoporosis by reducing bone formation, and thus it should be higher in patients with osteoporosis. Contrary to this expectation, we observed that serum sclerostin levels were lower in renal transplant patients with osteoporosis than in renal transplant patients without osteoporosis. This result is consistent with the studies summarized above. When the possible causative factors were examined, the parameters sclerostin, age, total corticosteroid dose, time elapsed after renal transplant, and eGFR had no effect on lumbar BMD. Only iPTH levels were found to have a negative effect on lumbar BMD. In light of previous results and our findings, we suggest that sclerostin levels are a reflection of low bone mass due to osteoporosis rather than a contributing factor to the development of osteoporosis. Because sclerostin is released primarily from osteocytes, serum sclerostin levels may be an indirect indicator of the total number of osteocytes.

It is known that sclerostin levels are influenced by various parameters. Previous studies have shown that sclerostin levels increase with age and that expression of sclerostin decreases with increased parathyroid hormone levels.17,18,24-28 Consistent with the literature, our study showed that sclerostin levels were weakly positively correlated with age, and we found no significant relationship between iPTH and sclerostin levels. Sclerostin is a small molecule (22 kDa) that can be easily filtered through the glomeruli.24 It is known that sclerostin levels increase as GFR decreases in CKD patients.29,30 Bonani and associates10 showed that baseline sclerostin levels decreased from 62 to 21 pmol/L after transplant in kidney transplant patients and that sclerostin levels began to increase again in accordance with GFR decreasing over time after renal transplant. In our study, we observed no significant relationship between eGFR and sclerostin levels.

During our literature search, we did not see any other study showing that sclerostin levels are lower in renal transplant patients with osteoporosis. However, our study had several limitations. First, this was a cross-sectional study conducted with a limited number of patients. Serum sclerostin levels were measured only once for each patient, which may have lead to some bias resulting from measurement errors. Most of our patients were relatively younger, and 70% were male. The definition of osteoporosis is clear in postmenopausal women and men older than 50 years, but it is not clear in premenopausal women and men younger than 50 years. Because of this uncertainty, we used a Z score of -2.0 or lower according to the International Society for Clinical Densitometry recommendation for the definition of osteoporosis in premenopausal women and men younger than 50 years in our study. This is a controversial issue, and different class­ifications can lead to changes in the results. Although we did not have any patients with known osteoporotic fractures, the fact that we did not screen our patients for osteoporotic fractures radiographically could be another limitation to this study. On the other hand, it is known that lumbar DEXA measurements are adversely affected by vascular calcification and lumbar degenerative changes, which can lead to errors in the diagnosis of osteoporosis. Despite these limitations, a DEXA measurement remains the most commonly used method for diagnosing osteoporosis. In studies conducted in recent years, DEXA measurements have been shown to predict fracture risk in kidney transplant patients and patients with CKD, with KDIGO guidelines also undergoing changes in the CKD-mineral bone disorder guideline for 2017.31 Although patients who had at least 6 months of follow-up after renal transplant were included in our study to reduce the effect of pretransplant bone pathologies, posttransplant bone pathologies are also quite complicated and can continue for several years after transplant.32 The most common posttransplant bone pathology is adynamic bone disease,33 which may affect serum sclerostin levels.

Conclusions

We observed that serum sclerostin levels were lower in kidney transplant patients with osteoporosis. However, this result was not supported by adequate preliminary data, and further studies are needed on this subject.


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DOI : 10.6002/ect.2019.0022


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From the 1Internal Medicine Department, the 2Nephrology Department, and the 3Biochemistry Department, Kahramanmaras Sutcu Imam University Faculty of Medicine, Kahramanmaras, Turkey
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare. The results presented in this paper have not been published previously in whole or part, except in abstract form.
Corresponding author: Orcun Altunoren, Kahramanmaras Sutcu Imam University Faculty of Medicine, Nephrology Department, Kahramanmaras, Turkey
Phone: +90 5326946517
E-mail: orcunaltunoren@hotmail.com