Insufficient bone and high sclerostin in non-functioning pituitary adenoma Is it non-functioning?

doi:10.21203/rs.3.rs-1541581/v1

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Insufficient bone and high sclerostin in non-functioning pituitary adenoma Is it non-functioning?

https://doi.org/10.21203/rs.3.rs-1541581/v1

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Purpose: Sclerostin reduces bone formation by inhibiting the Wnt signaling pathway in bone tissue. This study evaluated the serum sclerostin level in non-functioning pituitary adenoma (NFPA) patients and analyzed its relationship with bone metabolism.

Method: The data of the patients who applied to the Dicle University Endocrinology, diagnosed with non-functioning pituitary adenoma, and the control group consisting of healthy individuals were included in the study. Serum sclerostin levels and DXA analysis parameters were evaluated and compared with healthy control groups.

Results: The study consisted of 39 patients (F / M: 27/12) with NFPA (patient group) and 43 control groups (F / M: 26/17). There was no difference in terms of gender, age, height, weight and serum calcium, phosphorus, creatinine, 25-OH vitamin D, parathyroid hormone levels. Serum sclerostin levels (32.31 ± 1.53 ng / ml) in the patient group was found to be significantly higher than the control group (22.45 ± 8.9 ng / ml) (p <0.001). BMD (Patients groups vs control group); total lumbar BMD (0.951-1.56 gr / cm2) (p <0.001), femoral neck BMD (0.752-1.15 g / cm2) (p <0.001), femoral total BMD (0.995- 1.63 gr / cm2) (p <0.001), were found to be statistically significantly lower.

Conclusion: This study provides the first evidence that serum sclerostin levels were increased in non-functioning pituitary adenomas, which showed that bone parameters were negatively affected.

Non-functioning pituitary adenoma

sclerostin

BMD

Non-functioning pituitary adenomas (NFPAs) are benign pituitary neoplasms that do not cause hormonal hypersecretion. They cover up to about half of pituitary adenomas and have a prevalence of 0.7-4 per million in the population. They are mostly seen in the fourth decade. Most NFPAs are asymptomatic. Large ones can cause significant hypothalamic/pituitary dysfunction and visual field distortion (1).

The bones are negatively affected by the deficiency (GH, FSH, LH) and excess (Acromegaly, cushing's, prolactinoma) anterior pituitary hormones (2). The status of bone parameters in patients with non-functioning pituitary adenomas with normal pituitary functions is not clear in the literature.

The Wnt signaling pathway plays an essential role in osteoblast differentiation, proliferation, and activation. Sclerostin, encoded by the SOST gene and synthesized by osteocytes, is a Wnt antagonist. In addition, sclerostin also increases osteoclast activity. High levels of sclerostin negatively affect bone. Therefore, sclerostin antibodies have been used to treat osteoporosis in recent years (3).

This study aimed to investigate serum sclerostin levels in patients with non-functioning pituitary adenoma compared to healthy controls and patients with non-functioning pituitary adenoma to assess the potential relationship between sclerostin and BMD.

Study design

This prospective observational study of patients with non-functioning pituitary adenoma attended the outpatient clinic of Endocrinology at Dicle University between September 2016 and August 2020.

All participants were informed about the study protocol and written informed consent was obtained from each individual before enrollment in the study. The study was approved by the Dicle University School of Medicine Ethical Committee (Approval Number: 2019/273). Our study procedure was performed according to the principles of the Declaration of Helsinki.

Non-functioning pituitary adenoma patients

Patients with non-functioning pituitary adenomas (NFHA) were defined as patients who were not hormonally active, those who did not have clinical symptoms and signs of amenorrhea-galactorrhea, growth hormone (GH), cortisol or thyroid hormone excess and had normal laboratory data. These patients also had normal pituitary functions, TSH levels, PTH levels, renal function, hepatic function, and 25-OH vitamin D levels.

Healthy controls

A healthy control group consists of the same age and a similar number of genders. The control group consisted of subjects who applied to our outpatient clinic due to any complaints and were found healthy.

All controls had a normal gonadal status, average serum calcium concentration, bone turnover, and renal function. None of the control subjects were treated with bisphosphonates or glucocorticoids.

Sclerostin

Serum sclerostin levels were measured using a fluorescent ELISA (human sclerostin; sclerostin reference range: 0.2–60 ng/mL, intra-assay coefficient of variation < 10%, inter-assay coefficient of variation < 12%, assay sensitivity, 0.175 ng/mL (catalog no: 201-12-5418; Sunred Biological Technology Co., Ltd, Shanghai, China). The assay was performed according to the manufacturer's instructions. The results are expressed in nanograms per milliliter.

Bone mineral density measurements

Dual-energy X-ray absorptiometry (DXA) was used to determine the bone mineral density (BMD). DXA measured the lumbar spine (L1–L4) in the anteroposterior (AP) projection and the three sites of the right and left hip (femoral neck, Ward's triangle, and trochanter) using Lunar, DPX-L.

According to the classical WHO criteria, Osteopenia was defined as a value for BMD more than 1.0, but less than 2.5 SD below the young adult reference mean (T score less than − 1 and more significant than − 2.5 SD).

Osteoporosis was defined as a value for BMD 2.5 or more standard deviation below the young adult reference mean (T score less than or equal to − 2.5 SD).

Statistical analysis

Continuous variables were summarized using descriptive statistics presented as mean and standard deviation (SD). Categorical variables were summarized using counts and percentages.

Because the sclerostin data were not normally distributed, nonparametric tests were used for the analysis. The Mann Whitney U test was used to compare sclerostin levels between groups. Spearman's correlation analysis was also performed on non-normally distributed and ordinal variables. A P value < 0.05 was considered to indicate statistical significance.

A total of 82 patients were included in the study. Thirty-nine patients were in the non-functioning pituitary adenoma group (F/M: 27/12); The control group included 43 patients (F/M: 26/17). There was no difference in age, gender, calcium, phosphorus, creatinine, parathormone, and 25-OH vitamin D between the non-functioning pituitary adenoma and the control groups. BMI was slightly higher in the control group and was statistically significant (p < 0.05). (Table 1).

The serum sclerostin level of our cases did not show a normal distribution, so the Mann-Whitney U test was used to compare the patient and control groups. While the serum sclerostin level of the patient group was 32,31 ± 1,53 ng/ml, the serum sclerostin level of the control group was measured as 22,45 ± 8,9 ng/ml (p < 0,01). (Table 2).

DXA parameters such as total lumbar BMD, femoral neck BMD, and femur total BMD were compared with the Mann-Whitney U test since it did not provide a normal distribution for the groups. Total lumbar BMD, femoral neck BMD, and total femoral BMD were lower in the non-functional pituitary group and were found to be statistically significant(p < 0,01) (Table 3).

This study found that the serum sclerostin level in patients with non-functioning pituitary adenoma was significantly higher than in the healthy population. In parallel with this, we found that all non-functioning pituitary adenoma bone parameters were significantly lower than those of the control group. That indicates that non-functioning pituitary adenomas increase serum sclerostin by an unclear mechanism and that sclerostin damages bone by known mechanisms (osteoblast inhibition and osteoclast activation).

Sclerostin discovery with diseases called sclerosteosis and van Buchem, which are characterized by excessive bone formation. In the studies conducted in the following years, it was determined that there was an inactivating mutation in the SOST gene in these diseases, resulting in the absence or deficiency of sclerostin. Sclerostin prevents osteoblast activation. At the same time, increased sclerostin decreases osteoprotegerin, leaving RANKL exposed and increasing osteoclastogenesis. Thus, sclerostin damages the bone by decreasing osteoblastogenesis and increasing osteoclastogenesis (4, 5).

The Wnt pathway is essential in bone remodeling. Bone formation increases in Wnt activation. Bone destruction is reduced. Sclerostin is an endogenous natural inhibitor of the Wnt pathway. Therefore, a sclerostin antagonist has been developed for the treatment of osteoporosis. This molecule is romosozumab, a human monoclonal antibody developed against sclerostin. Romosozumab increases bone formation and decreases bone resorption (6).

Serum sclerostin level decreases with vitamin D replacement (7).

Although the bone mineral density is normal in acromegalic patients, bone fractures occur. In a study, serum sclerostin levels were found to be high in active acromegalic patients (8).

Intermittent or continuous infusion of parathormone and serum sclerostin levels decrease primary hyperparathyroidism (9).

The incidence of partial pituitary insufficiency in non-functioning pituitary adenomas is present in almost half of the patients. The most common growth hormone deficiency is observed, followed by gonadotropin deficiency (10, 11). The hormonal profile of all patients included in our study was evaluated as usual. However, we may not have detected mild insufficiency. That may indicate that growth hormone deficiency and gonadotropin deficiency adversely affect the bone parameters of our patients.

Kuo et al. They. Investigated bone markers and BMD in 89 patients with chronic kidney disease-related mineral and bone disease who received peritoneal dialysis. That study found positive correlations with serum sclerostin level, male gender, high weight, tall height, serum 25(OH)vitamin D level, creatinine, hemoglobin, glucose level, vertebral BMD, vertebra T, and Z scores, and negatively correlated with PTH level (12). In addition, the positive correlation between serum sclerostin level height and BMD in this study; It seems to contradict the work of Cosman et al. In the study of Cosman et al.; In women with post-menopausal osteoporosis who received anti-sclerostin treatment (Romosozumab), a low rate of vertebral fracture was found, and it was reported that the BMD-reducing effect of sclerostin was supported by this (13). In our study, in patients with NFHA, serum sclerostin level was higher than in the healthy control group, and our bone parameters were found to be lower in the NFHA group than in the control group. This supported the effect of serum sclerostin levels on reducing BMD, but in our study, Kuo et al. As determined, No correlation was found between serum sclerostin levels and BMD, T, and Z scores. When we evaluate the factors affecting this, Kua et al. Grouped the serum sclerostin level above and below the median value. They correlated the bone parameters with the serum sclerostin level above the median value. While performing the correlation test in our study, such a limit value was not considered, and such a grouping was not made.

Czajkowska et al. 31 perimenopausal, 54 post-menopausal patients; investigated estrone, testosterone, andrestenedione, DHEA-S, osteocalcin, β-CTX (cross-linked C telopeptide of type 1 collagen), 25(OH)vit D and serum sclerostin level. Estrone and total testosterone were measured high in the perimenopausal group, and plasma osteocalcin and β-CTX levels, which are markers of bone resorption, were found to be higher in the post-menopausal group. However, they found serum sclerostin levels and 25-(OH) Vit D levels similar in both groups. They found no correlation between serum sclerostin levels and all investigated parameters (14). In our study, although the serum sclerostin level was measured higher and the bone parameters were lower than the control group, There was no correlation between serum sclerostin level and bone parameters. In our study, individuals with normal serum hormone and mineral parameters were evaluated; however, bone resorption markers such as plasma osteocalcin and β-CTX level were not examined. Therefore, according to our study results, we think the relationship between serum sclerostin level and bone formation-resorption in NFHA patients is more complicated. Studies with more comprehensive parameters, perhaps serum cytokine levels, and more extensive case series will explain the different results between clinics on this subject.

The strengths of our study are that it is the first study in the literature to show the relationship between non-functioning pituitary adenoma and sclerostin, the patient population has normal pituitary hormones, the patient population has normal calcium, phosphorus, parathormone, 25-OH vitamin D levels, and the tertiary endocrine center patient population data.

The main limitation of our study is the small number of patients due to the rarity of non-functioning pituitary adenomas.

In conclusion, increased serum sclerostin levels in non-functioning pituitary adenomas negatively affect bone parameters. This study will lead to further studies on the etiopathogenesis of increased sclerostin in non-functioning pituitary adenomas.

Contributions

All authors contributed to the study conception and design. The study was conceptualized and supervised by Z.P. and A.K.T. Material preparation, data collection and analysis were performed by D.V.Y., Z.P., Ş.A.T., B.T., and A.K.T. The first draft of the manuscript was written by Z.P., D.V.Y. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Zafer Pekkolay MD.

Funding

Conflict of interest

The authors declare that a conflict of interests does not exist.

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Table 1

Demographic/laboratory characteristics of non-functioning pituitary adenoma patients and healthy controls
	NFPA	Control	P value
n	39	43
Gender(F/M)	(27/12)	(26/17)	> 0.05*
Age (Mean ± SD)(years)	36,1 ± 12,2	35,8 ± 12,1	> 0.05^*
BMI (kg/m²)	22,3 ± 2,4	23,1 ± 3,1	0.047*
Calcium(mg/dl)	9,32 ± 0,48	9,43 ± 0,42	> 0.05*
Phosphorus(mg/dl)	3,3 ± 0,4	3,3 ± 0,3	> 0.05¶
Creatinine(mg/dl)	0,68 ± 0,1	0,65 ± 0,2	> 0.05¶
25-OH vitamin D(ng/ml)	19,05 ± 6,2	16,9 ± 7,4	> 0.05¶
PTH (pg/ml)	48,2 ± 13,8	44,03 ± 14,1	> 0.05¶
NFPA: Non-functioning pituitary adenoma, *student t, ¶ Mann-Whitney U

Table 2

Serum sclerostin level
	NFPA	Control	P value
Serum sclerostin(ng/ml) median(min.-max.)	28,53(13,01–78,5)	20,03 (11,05–59,45)	< 0.01¶
NFPA: Non-functioning pituitary adenoma, ¶ Mann-Whitney U

Table 3

Comparison of bone mineral density values of NFPA and control group
	NFPA	Control	P value
Total lumbal BMD(g/cm²)	0,951(0,58 − 1,24)	1,56(0,91 − 2,99)	< 0.001¶
Femur Neck BMD(g/cm²)	0,752(0,55 − 1,0)	1,15(0,69 − 2,73)	< 0.001¶
Total Femur BMD(g/cm²)	0,995(0,594-1,234)	1,63(0,87 − 2,9)	< 0.001¶
NFPA: Non-functioning pituitary adenoma, ¶ Mann-Whitney U

No competing interests reported.

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Insufficient bone and high sclerostin in non-functioning pituitary adenoma Is it non-functioning?

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