Osteoporosis and Fractures in Patients with Acromegaly: A Two-Center Cross-Sectional Study

doi:10.21203/rs.3.rs-4821632/v1

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Osteoporosis and Fractures in Patients with Acromegaly: A Two-Center Cross-Sectional Study

https://doi.org/10.21203/rs.3.rs-4821632/v1

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Purpose

This cross-sectional study aimed to assess the prevalence of vertebral fragility fractures, non-vertebral fragility fractures, hip fragility fractures, and osteoporosis in patients diagnosed with acromegaly.

Methods

Data were collected on age, sex, body mass index (BMI), time from diagnosis of acromegaly, insulin-like growth factor (IGF-1) levels, disease control, pharmacological management, risk factors for osteoporosis, vertebral fragility fractures, non-vertebral fragility fractures, hip fragility fractures, and osteoporosis.

Results

A total of 124 patients with acromegaly were included (67 men and 57 women). The mean age at diagnosis was 44 ± 12 years; the mean time from diagnosis was 12 ± 8 years; and the mean BMI was 27 ± 4 kg/m². Fragility fractures were found in 27 patients (21%). There were no significant differences in the presence of osteoporosis or fragility fractures according to age, sex, BMI, duration of acromegaly, or IGF-1 levels at diagnosis. A higher percentage of patients with osteoporosis were treated with somatostatin analogs compared to those without osteoporosis (46% vs. 15%; p < 0.05)

Conclusion

A high prevalence of osteoporosis and fragility fractures was found in patients with acromegaly, regardless of age, sex, BMI, time from diagnosis, IGF-1 levels, and disease control. More patients with osteoporosis were treated with somatostatin analogs compared to those without osteoporosis. Taken together, our results suggest that the severity of the disease and the need for second-line therapies, may be associated with the increased risk of osteoporosis.

Acromegaly

bone density

spinal fractures

osteoporosis

pituitary gland

Growth Hormone-Secreting Pituitary Adenoma

Acromegaly is a chronic disease associated with excess of growth hormone (GH) and insulin like growth factor-1 (IGF-1), as well as the consecutive effects of the excess of these hormones in body tissues. Both the lack and excess of GH have been associated with alterations in bone structure and strength, leading to a higher risk of osteoporosis and fractures in patients with acromegaly [1–3]. This risk remains increased regardless of whether patients achieve adequate control of acromegaly [3–5].

Acromegaly has been associated with increased bone resorption and formation, with a predominance of bone resorption during disease activity. IGF-1 stimulates osteoblasts and osteoclast, although the mechanism by which it stimulates osteoclasts is not entirely clear. It has been observed that osteoclasts express IGF-1 receptors. Some hypotheses suggest that GH/IGF-1 stimulates cytokines involved in the regulation of osteoclasts and a mechanism mediated by the RANK-L system. These factors lead to an elevated risk of fractures, despite normal or increased bone mineral density (BMD). [5–7]. A disrupted calcium and phosphate metabolism is an additional factor, driven by hyperparathyroidism in some patients and the activation of 1α-hydroxylase by GH, leading to an initial increase in 1,25-dihydroxyvitamin D, followed by a decrease after the control of acromegaly. However, it is not clear to what extent these alterations contribute to the bone impairment in patients with acromegaly. [5].

Acromegaly primarily affects trabecular bone, making alternative diagnostic methods such as the trabecular bone score more suitable for assessing bone microarchitecture [8–15]. Cross-sectional studies have reported a significantly higher prevalence of radiographic vertebral fractures in patients with acromegaly (ranging from 39–59%) compared to the general population [11–14].

Studies have also demonstrated the significant impact of acromegaly on hip bone quality. However, a comparison between patients with acromegaly and those with GH deficiency has revealed a higher degree of hip bone abnormalities in the latter group. Multiple studies have reported impaired trabecular bone formation and altered cortical thickness in patients with GH deficiency, leading to alterations in hip bone structure and strength [15–17]. Although the increased cortical thickness observed in acromegaly might be a protective factor against fractures, the reduction in cortical thickness following the control of acromegaly appears to contribute to the increased fracture risk [15].

Patients with acromegaly often have other risk factors for osteoporosis, such as glucocorticoid use for secondary adrenal insufficiency, type 2 diabetes mellitus, and hypogonadism. Similar to patients with acromegaly, multiple studies have demonstrated that patients with type 2 diabetes mellitus, hypogonadism, and glucocorticoid users have a higher risk of vertebral fractures, which, in some cases, is independent of BMD impairment. [7, 18–22].

The majority of studies have focused on the presence of vertebral fractures, but little research has been conducted on non-vertebral fractures and hip fractures in patients with acromegaly. We found a single recently published cohort study by Kwon et al., in which they assessed both vertebral and hip fractures in patients with acromegaly [23]. Their findings revealed a significantly higher risk for both types of fractures, with a particularly elevated risk for hip fractures.

Regarding the risk factors for fractures in patients with acromegaly, in patients with controlled disease, the presence of previous vertebral fractures, hypogonadism, and decreased femoral neck BMD during follow-up can be predictive of future fractures [24]. Additional risk factors for vertebral fractures in acromegaly include active biochemical disease, prolonged disease duration, delayed diagnosis, and decreased BMD of the femoral neck [25]. We did not find specific risk factors for non-vertebral and hip fractures in the literature pertaining to the population with acromegaly.

Although acromegaly had previously been considered a potential bone-neutral or even protective factor against fractures by increasing bone formation [26, 27], multiple studies have subsequently demonstrated a higher prevalence of vertebral fractures in patients with acromegaly [28–32]. A recently published study aimed to establish an association between acromegaly and vertebral deformities rather than a higher incidence of vertebral fractures [33]. The difficulty in distinguishing between vertebral deformities and fractures arises from the challenges associated with diagnosing vertebral fractures. Accurate diagnosis requires vertebral morphometry and the expert interpretation of imaging studies by radiologists to prevent misdiagnosis of vertebral deformities as fractures. However, moderate and severe vertebral fractures are more easily identified [34–37]. The semiquantitative Genant’s method has been widely used for diagnosing and grading vertebral fractures [11].

A recent meta-analysis confirmed that acromegaly is associated with a higher risk of vertebral fractures due to deterioration in bone microarchitecture [38]. There is a lack of similar evidence in both quality and quantity regarding non-vertebral and hip fractures. In this cross-sectional study of patients with acromegaly, we aimed to describe the prevalence of vertebral fractures, non-vertebral fractures, hip fractures and osteoporosis in patients with acromegaly.

Study Design and Setting

This retrospective descriptive study with an analytical component was conducted at two centers: the Endocrinology Department of the Central Military Hospital and Centros Médicos Colsanitas in Bogotá, Colombia. A total of 124 patients diagnosed with acromegaly were evaluated.

Participants

The study included patients with a history of acromegaly, diagnosed based on elevated IGF-1 levels adjusted for age and sex, and the GH glucose suppression test, as described by the Endocrine Society Guidelines [39]. Participants received follow-up care through a health insurer at multiple care centers across the country between 2000 and 2023.

Data Collection

Data from medical records were collected on variables such as age, sex, body mass index (BMI), time since diagnosis of acromegaly, and IGF-1 levels measured using the immunoassay from Immunodiagnostic Systems, IDS-iSYS. Disease control was defined as a normal IFG-1 value for sex and age, assessed by an endocrinologist.

Definitions

Osteoporosis and Fragility Fractures: Definitions were based on criteria from the World Health Organization (WHO), the International Society for Clinical Densitometry (ISCD), and the National Osteoporosis Foundation. Osteoporosis was diagnosed in postmenopausal women and men aged 50 years and older when their bone mineral density (BMD) was 2.5 standard deviations (SD) or more below the average value for young, healthy women (a T-score of <−2.5 SD). It could also be diagnosed in the presence of a hip fracture, with or without BMD testing, or a fragility fracture in the presence of low bone mass (osteopenia) confirmed by dual-energy X-ray absorptiometry (DXA). For premenopausal women and men under 50 years of age, Z-scores of −2.0 or lower indicated low bone mineral density for their chronological age.

Fragility Fractures: Defined as fractures occurring due to low-energy trauma, such as a fall from standing height or less, involving skeletal sites including the hip, spine, forearm, humerus, femur, and pelvis.

Fracture Identification

A comprehensive search of clinical records was conducted to identify non-vertebral and hip fractures. Clinical and radiological vertebral fractures were identified using vertebral radiography, magnetic resonance imaging, computed tomography, densitometry, or radiographic morphometry. Patients with traumatic fractures were excluded from the study.

Ethical Approval

Approval for the study was obtained from the Institutional Ethics Review Boards of the Hospital Militar Central and Fundacion Universitaria Sanitas (record number 011-20).

Statistical Analysis

Descriptive Statistics: Data were expressed as mean ± SD or median with ranges according to the results of the Shapiro–Wilk test. Categorical variables were compared using Fisher’s test. Nonparametric data were analyzed using the Mann–Whitney U test. Relationships between variables were determined using Spearman correlation analysis. A p-value of <0.05 indicated statistical significance.

Sociodemographic and Clinical Variables: Analyzed using univariate analysis according to the nature of the variable. Categorical variables were expressed as absolute and relative frequencies, while continuous variables were expressed as measures of central tendency and dispersion, depending on the normality pattern established through graphical evaluations (e.g., Kernel density estimation) and statistical tests (e.g., Shapiro–Wilk test).

Bivariate Analysis: Conducted according to sex, age, disease progression time, BMI, and other relevant factors. Formal parametric or nonparametric tests were used based on the distribution and assumptions of the data and comparisons

Patient Demographics

A total of 124 patients were evaluated, comprising 67 men and 57 women. The mean age at diagnosis of acromegaly was 44 ± 12 years. The mean time from diagnosis of acromegaly was 12 ± 8.8 years, and the mean BMI was 27 ± 4.1 kg/m² (Table 1). Patients with and without osteoporosis had mean ages of 56 ± 14.6 and 53 ± 17.4 years, respectively, with no significant difference in age distribution between the two groups (Table 2).

Osteoporosis Prevalence

Osteoporosis was diagnosed in 27 patients (21%) based on BMD criteria. The prevalence of osteoporosis was 21% (13 cases) in men and 22% (14 cases) in women, with no significant difference between genders. Among the female patients, 6 were postmenopausal at the time of acromegaly diagnosis, and 8 were postmenopausal at the time of osteoporosis diagnosis.

The mean time from diagnosis of acromegaly was 12 ± 8.8 years. The mean time from diagnosis in patients without and with osteoporosis was 13 ± 11.9 and 11 ± 8.5 years, respectively, with no significant difference between the groups (Table 2). Patients without and with osteoporosis had mean BMIs of 29 ± 5.1 and 27 ± 4 kg/m², respectively, with the difference not being statistically significant (P = 0.076).

Treatment with Somatostatin Analogs

Among the patients with osteoporosis, 46% were treated with a first-generation somatostatin analog (octreotide or lanreotide). In contrast, 15% of patients without osteoporosis received the same treatment. The Chi-square test revealed a statistically significant association between the use of somatostatin analogs and the diagnosis of osteoporosis (P = 0.035).

Acromegaly activity

For IGF-1 levels at diagnosis, patients without and with osteoporosis had median values of 624 ng/mL and 413 ng/mL, respectively. Comparison of the medians using the Wilcoxon or Mann-Whitney test indicated no statistically significant difference between the two groups. Among the patient population, 51 patients (41%) had active acromegaly, while 73 patients (58%) had controlled acromegaly. The prevalence of osteoporosis was 22% in patients with active acromegaly and 21% in those with controlled acromegaly, with no significant difference between the groups.

Bone Mineral Density (BMD)

Complete BMD data were obtained from 22 patients. The mean BMD in the lumbar spine was 0.904 ± 0.204 g/cm³ (mean T-score: −2.2; mean Z-score: −0.2). The mean femoral neck density was 0.771 ± 0.767 g/cm³ (mean T-score: ±0.9; mean Z-score: −0.3). The mean total hip density was 0.778 ± 0.250 g/cm² (mean T-score: −1.4; mean Z-score: −0.3).

Fragility Fractures

Fragility fractures were identified in 27 patients (21%), with vertebral fractures in 4 patients (3%) and non-vertebral fractures in 23 patients (18%). Among patients with and without fragility fractures, 19% and 22% had active disease, respectively, with no significant difference between the groups. The mean age of patients with and without fragility fractures was 56 ± 18.3 and 55 ± 14.4 years, respectively, with no significant difference (P = 0.7519).

The mean evolution time for patients with and without fragility fractures was 12 ± 10.8 and 11.9 ± 8.7 years, respectively, with no significant difference observed (Table 3). The average BMI of patients with and without fragility fractures was 26 ± 4.3 and 27 ± 4.3 kg/m², respectively, with no statistically significant difference (P = 0.6753).

The median IGF-1 levels in patients with and without fragility fractures were 429 ng/mL and 454 ng/mL, respectively, with no statistically significant difference (P = 0.5898). Among patients without fractures, 67% received lanreotide or octreotide, compared to 42% among those with fragility fractures. The Fisher's exact test revealed no statistically significant difference between the groups (P = 0.712) (Table 3).

Patients with acromegaly experience various systemic complications due to prolonged exposure of tissues to high levels of GH and IGF-1. This excess leads to significant changes in bone quality, structure, and strength, characterized by increased bone formation and resorption, with a predominance of the latter, as well as altered calcium metabolism. Consequently, there is a decline in bone microarchitecture and an elevated risk of fractures, particularly vertebral fractures, even in patients with normal bone mineral density (BMD).

Our study found a considerably high prevalence of fragility fractures among patients with acromegaly, independent of age, sex, BMI, time of evolution of acromegaly, IGF-1 levels at the time of diagnosis, and the control of the disease. However, a significant difference was observed between patients treated with somatostatin analogs. According to our findings, somatostatin analog therapy was positively correlated with the presence of osteoporosis.

Multiple studies have demonstrated that acromegaly has profound effects on the quality of the hip bone, causing impaired trabecular bone formation and increased cortical thickness. Consequently, these changes lead to alterations in the bone structure of the hip [15–17]. The majority of studies have focused on the risk of vertebral fractures, while few have investigated hip and non-vertebral fractures, as well as the risk factors for these fractures, in patients with acromegaly. A recent study found that patients with acromegaly have an increased risk of hip fractures, which is even higher than the risk of clinically apparent vertebral fractures [23]. We observed a high prevalence of non-vertebral fragility fractures, including hip fractures, along with a decreased femoral neck BMD. It is crucial to ascertain the prevalence and risk factors for hip and non-vertebral fractures in the population with acromegaly. However, the limited sample size poses challenges in conducting comprehensive analyses in this regard. Further studies are needed to evaluate the prevalence and risk factors for hip and non-vertebral fractures in this patient group.

Regarding vertebral fractures acromegaly was once considered a potential bone neutral or even protective factor against fractures by increasing bone formation [26, 27]. Nevertheless, multiple studies have subsequently shown a high prevalence of vertebral fractures in patient with acromegaly, with prevalence rates ranging from 10% to more than 50% in certain patients [25–29]. There was a low prevalence of vertebral fractures compared to previous studies, likely because clinically or radiologically diagnosed vertebral fractures were included, but without a systematic and active search using a specific imaging technique.

A limitation in the diagnosis of vertebral fractures in clinical practice includes the lack of a satisfactory gold standard criteria for its diagnosis. While morphometric assessment from radiographs seems to be the most accepted, magnetic resonance imaging has shown good accuracy. The use of conventional radiography can lead to a lack of vertebral fracture diagnoses in several patients. Additionally, morphometry assessment of radiographic images needs a trained radiologist to avoid misdiagnosing vertebral fractures as vertebral deformities frequently found in patients with osteoporosis [33, 39–44].

Our study revealed a significant correlation between the treatment with somatostatin analogs and the occurrence of osteoporosis, but did not find a significant correlation with fragility fractures. Chiloiro et al's study suggests a possible higher risk of vertebral fractures in patients treated with pegvisomant compared to pasireotide [45]. Our findings indicate that the severity of the disease and the need for second-line therapies, rather than a specific medication for acromegaly, may be associated with the increased risk of osteoporosis. However, it is important to note that despite the description of somatostatin receptors in rodent bone since the 1990s, limited research has been conducted on somatostatin receptors and the effect of somatostatin analogs on bone. A recent study has demonstrated that octreotide may have a direct effect on bone by inhibiting osteoblast proliferation and promoting apoptosis [46, 47].

Regarding additional risk factors for osteoporosis and fractures, patients with acromegaly often have multiple risk factors such as glucocorticoid use for secondary adrenal insufficiency, type 2 diabetes mellitus, and hypogonadism. Patients with type 2 diabetes mellitus, hypogonadism, and glucocorticoid users have a higher risk of vertebral fractures, which, in some cases, is independent of BMD impairment. [7, 18–22]. A large proportion of patients with acromegaly exhibit hypogonadism either due to GH excess or acromegaly treatment, especially after pituitary radiation [29]. It is crucial to consider that type 2 diabetes mellitus, hypogonadism, and glucocorticoid use can have a negative impact on trabecular bone and serve as risk factors for reduced bone mineral density (BMD) and an elevated risk of fractures, particularly vertebral fractures. Our study revealed a high prevalence of comorbidities associated with higher prevalence of osteoporosis and fractures. Type 2 diabetes, hypogonadism, and adrenal insufficiency were found in 23%, 9%, and 16% of patients, respectively. This indicates that more than half of the patients have significant risk factors for vertebral fractures and osteoporosis. Therefore, the impairment of femoral neck bone mineral density (BMD) and the presence of non-vertebral fractures, as indicators of cortical bone involvement, may serve as potential risk factors for future fractures in patients with acromegaly.

This study has certain limitations. Due to its observational nature, we were unable to establish a causal relationship between acromegaly, osteoporosis, and fractures. Our results were based on clinical records and depended on the availability of data registered in the patients records and images available from the insurer. None of the patients underwent systematic screening for osteoporosis and fractures, and there was heterogeneity in the type of imaging performed with variable sensitivities and specificities.

The current study found a high prevalence of osteoporosis and non-vertebral fragility fractures in patients with acromegaly, independent of age, sex, BMI, time from diagnosis, IGF-1 level, and disease control and regardless of the presence of independent risk factors. Somatostatin analog therapy in patients with acromegaly was associated with a higher risk for having osteoporosis. Taken together, our results suggest that the severity of the disease and the need for second-line therapies, rather than a specific medication for acromegaly, may be associated with the increased risk of osteoporosis. However, further studies are required to assess the effect of somatostatin analogs on bone metabolism.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors

Author contribution statement

Conceptualization: Mauricio Alvarez, Juliana Rincon, Oswaldo Rincon, Methodology: Mauricio Alvarez, Juliana Rincon, Formal analysis and investigation: Mauricio Alvarez, Juliana Rincon,; Writing - original draft preparation: Mauricio Alvarez, Juliana Rincon, Mercedes Ulloa, Monica Bernal Writing - review and editing: Alvarado Alejandra, Rincon Oswaldo, Mejía Liliana, Bernal Mónica, Ulloa María, Galvis Alba, Rincon Juliana Supervision: Mauricio Alvarez, Oswaldo Rincon.

Ethical Approval and Consent to Participate

Approval for the study was obtained from the Institutional Ethics Review Boards of the Hospital Militar Central and Fundacion Universitaria Sanitas (record number 011-20). All participants provided written informed consent before their inclusion in the study.

Consent for Publication

All authors have read and approved the final manuscript, and give their consent for its publication.

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Conflict of Interest

The authors declare that they have no competing interests.

Acknowledgments

We would like to thank the Hospital Militar Central and Fundacion Universitaria Sanitas for their support and for providing the necessary resources for this study. Special thanks to the study participants and the research staff for their invaluable contributions.

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Table 1 to 3 are available in the Supplementary Files section.

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Osteoporosis and Fractures in Patients with Acromegaly: A Two-Center Cross-Sectional Study

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