Psychotropic drugs in patients with Cushing’s disease before diagnosis and at long-term follow-up

Posted on February 27, 2021 by MaryO

The Journal of Clinical Endocrinology & Metabolism, dgab079, https://doi.org/10.1210/clinem/dgab079

Abstract

Context

Psychiatric symptoms are common in Cushing’s disease (CD) and seem only partly reversible following treatment.

Objective

To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up.

Design

Nationwide longitudinal register-based study.

Setting

University Hospitals in Sweden.

Subjects

CD patients diagnosed between 1990 and 2018 (N=372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed.

Main outcome measures

Data from the Swedish Prescribed Drug Register and the Patient Register.

Results

In the 5-year period before, and at diagnosis, use of antidepressants (OR 2.2[95%CI 1.3-3.7] and 2.3[1.6-3.5]), anxiolytics (2.9[1.6-5.3] and 3.9[2.3-6.6]) and sleeping pills (2.1[1.2-3.7] and 3.8[2.4-5.9]) was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants (2.4[1.5-3.9]) and sleeping pills (3.1[1.9-5.3]). Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (IQR 8.1-10.4) had higher use of antidepressants (OR 2.0[1.1-3.8]) and sleeping pills (2.4[1.3-4.7]), but not of drugs for hypertension.

Conclusions

Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health.

Cushing’s syndrome, hypercortisolism, neuropsychiatry, depression, sleeping disorder
Issue Section:

Clinical Research Article

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The Effect of Biochemical Remission on Bone Metabolism in Cushing’s Syndrome: A 2‐Year Follow‐Up Study

Posted on February 25, 2021 by MaryO

https://doi.org/10.1002/jbmr.4033

 

ABSTRACT

Endogenous Cushing’s syndrome (CS) is a rare cause of secondary osteoporosis. The long‐term consequences for bone metabolism after successful surgical treatment remain largely unknown. We assessed bone mineral density and fracture rates in 89 patients with confirmed Cushing’s syndrome at the time of diagnosis and 2 years after successful tumor resection. We determined five bone turnover markers at the time of diagnosis, 1 and 2 years postoperatively. The bone turnover markers osteocalcin, intact procollagen‐IN‐propeptide (PINP), alkaline bone phosphatase, CTX‐I, and TrAcP 5b were measured in plasma or serum by chemiluminescent immunoassays. For comparison, 71 sex‐, age‐, and body mass index (BMI)‐matched patients in whom Cushing’s syndrome had been excluded were studied. None of the patients received specific osteoanabolic treatment. At time of diagnosis, 69% of the patients had low bone mass (mean T‐score = −1.4 ± 1.1). Two years after successful surgery, the T‐score had improved in 78% of patients (mean T‐score 2 years postoperatively −1.0 ± 0.9). The bone formation markers osteocalcin and intact PINP were significantly decreased at time of diagnosis (p ≤ 0.001 and p = 0.03, respectively), and the bone resorption marker CTX‐I and TrAcP 5b increased. Postoperatively, the bone formation markers showed a three‐ to fourfold increase 1 year postoperatively, with a moderate decline thereafter. The bone resorption markers showed a similar but less pronounced course. This study shows that the phase immediately after surgical remission from endogenous CS is characterized by a high rate of bone turnover resulting in a striking net increase in bone mineral density in the majority of patients. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Introduction

Cushing’s syndrome (CS) is a rare disease with approximately 0.7 to 2.4 new cases per 1 million per year.1 Osteoporosis and osteopenia are typical comorbidities of patients with endogenous and exogenous CS. Depending on the study, 60% to 80% of patients have evidence for a reduced bone mineral density2 characteristically affecting the entire skeleton.3 About 5% of all cases of secondary osteoporosis are caused by hypercortisolism.4 However, data from prospective, well‐powered studies are rare, and few risk factors that would predict bone health have been identified so far. Guidelines for the management of osteoporosis due to endogenous CS are still missing.5 In terms of risk assessment, the subtype of CS does not seem to influence osteoporosis risk,6 whereas the morning cortisol levels are negatively correlated with lumbar bone mineral density.6 The duration of endogenous Cushing’s syndrome (or the duration of exogenous replacement therapy after successful surgery) obviously affects bone mineral density.7 Whether the T‐score is the best predictor for fracture risk is not quite clear.2

Another area of uncertainty is the natural course of osteoporosis and bone turnover markers once the diagnosis of Cushing’s syndrome has been established. A number of studies have addressed this topic, but the interpretation of the results is hampered because of limited patient numbers, concomitant osteoanabolic treatment, or both.8–10 In‐depth insight on bone remodeling in CS might come from bone turnover marker studies. For example, the bone formation marker osteocalcin is suppressed in untreated CS,3 a consistent observation making it useful as a diagnostic marker for CS.2

Based on the paucity of data, the lack of evidence for treatment guidelines, and the pressing open questions regarding risk assessment and management of osteoporosis, we performed a sufficiently powered study to analyze the natural course of bone turnover and bone mineral density in a monocentric cohort of patients with endogenous Cushing’s syndrome. To the best of our knowledge, this is the first such study, and the data obtained will be instrumental for clinicians who care for patients with Cushing’s syndrome.

Materials and Methods

Patients

This study was performed as part of the prospective German Cushing registry, which has included 450 consecutive patients referred to our department for suspected CS since 2012. Structure and general characteristics of the registry have been described in detail previously.11–14 All patients included in the registry underwent a standardized biochemical screening and clinical examination at time of diagnosis and a yearly follow‐up after treatment to treat comorbidities and diagnose recurrence of the disease early.

In all patients, standard screening for CS with a 1 mg low‐dose overnight dexamethasone suppression test (LDDST), collection of 24‐hour urine (UFC), and sampling of midnight salivary cortisol were performed. When the diagnosis of CS was confirmed, further subtyping was based on plasma adrenocorticotropic hormone (ACTH), corticotropin‐releasing hormone (CRH) test, high‐dose dexamethasone suppression test, imaging, and inferior petrosal sinus sampling (in case of ACTH dependence). Final diagnosis was CS in 156 patients and exclusion of CS in the remaining 294 patients. Patients with excluded CS were a quite heterogenic group with lead symptoms such as obesity (73%), arterial hypertension (50%), or hirsutism (33%). Final diagnoses in these subjects were metabolic syndrome, polycystic ovary syndrome (PCOS), obesity, depression, or primary hyperaldosteronism. Patient selection is shown in Fig. 1.

image
Figure 1

Open in figure viewerPowerPoint
Patient selection. *Very young age; patient conducted densitometry in a different clinic/outpatient clinic; patient refused densitometry. CS = Cushing’s syndrome; BMD = bone mineral density; BMI = body mass index. Bold text indicates actual cohort of the study.

In our analysis, we excluded patients for whom no densitometry data were available (n = 63) and patients receiving pharmacologic treatment for osteoporosis following diagnosis (n = 4). Densitometry data were not available for multiple reasons (very young age, external densitometry in a different clinic, missing consent to perform densitometry).

We matched the remaining 89 patients with 71 controls subjects selected from those subjects in whom CS was excluded. Matching was done according to sex, age, and body mass index (BMI). None of the patients and controls received specific osteoanabolic or antiresorptive treatment, but 47% of patients with CS received vitamin D supplementation after remission. At time of diagnosis, 11% of controls and 17% of patients with CS received vitamin D supplementation.

Methods

In patients with confirmed CS, a bone mineral densitometry was conducted. Bone mineral density (BMD) was determined at the lumbar spine and the femur (neck and total femur).

If a reduced bone mineral density was diagnosed, a follow‐up densitometry was performed 2 years after surgery. If bone mineral density was normal initially or during follow‐up, only one further densitometry was performed 2 or 3 years after initial diagnosis. An improvement or decrease of bone mineral density was defined according to the least significant change (LSC = 2.8 × 1.8%).15 Accordingly, an alteration of more than 5.04% of BMD was rated as significant. A detailed fracture history was taken and X‐ray of the spine was performed when clinical suspicion for fractures was high.

In all patients, blood samples (serum and plasma) were taken at time of diagnosis and also 1 and 2 years after successful transsphenoidal surgery or adrenalectomy. Blood was taken in the fasting state between 8:00 and 10:00 a.m. Samples were centrifuged within 20 minutes at 4°C and stored at −80° until assayed. Three bone formation markers and two bone resorption markers were measured: osteocalcin, intact procollagen I‐N‐propeptide (PINP), and bone alkaline phosphatase (BAP) as bone formation markers, and CrossLaps (CTX‐I) and tartrate‐resistant acid phosphatase (5b TrAcP5b) as bone resorption marker, on basis of published data demonstrating their usefulness in CS and primary osteoporosis.2, 16

Samples were measured at the Endocrine Laboratory of the Department of Internal Medicine IV on the iSYS automated analyzer (IDS‐iSYS, Boldon, UK) by well‐validated assays.17, 18 Published, method‐specific reference intervals are available from a large healthy population.19, 20 For the determination of osteocalcin, an N‐MID assay was used, as pre‐analytics are less critical in this assay.21 TrAcp 5b is a new marker, which, in contrast to CTX‐1, can also reliably be measured in the non‐fasting state.22

Statistical analysis

In a priori power analysis, we calculated that a total sample size of 102 would be sufficient to identify significant differences between groups, assuming a medium effect size (0.5), a power of 1 – β = 0.80 and a type I error of α = 0.05, with 51 subjects having Cushing’s syndrome and 51 subjects being control subjects after excluding Cushing’s syndrome.

For statistical analysis, SPSS 25 (IBM Corp., Armonk, NY, USA) was used. Clinical characteristics are shown as mean and standard deviation when data is normal distributed; otherwise as median and ranges. Because of the lack of normal distribution of bone turnover markers, nonparametric tests were used to test differences between groups. Differences between bone turnover markers at different times were tested by Friedman test. Multiple regression analysis was used to investigate differences between CS and the control group regarding bone turnover markers adjusted for sex, age, and BMI. Any p values < 0.05 were considered to indicate statistical significance.

Results

Patient characteristics

The clinical and biochemical characteristics of the patient sample are summarized in Table 1. Sixty‐five percent of patients had pituitary CS, 28% adrenal, and 7% suffered from ectopic CS. Patients and controls were well‐matched regarding sex, age, and vitamin D levels and supplementation, but differed in terms of diabetes prevalence.

Table 1. Clinical and Biochemical Baseline Characteristics of Patients with Cushing’s Syndrome (CS) and Control Subjects in Whom CS Has Been Excluded
CS at time of diagnosis (n = 89) CS excluded (n = 71) p Value
Sex 66 women (74%), 23 men (26%) 53 women (75%), 18 men (25%) 0.94
Age (years) 44 ± 13 43 ± 14 0.56
BMI 30 ± 7 31 ± 6 0.11
Vitamin D (ng/mL) 24 ± 10 24 ± 12 0.59
Vitamin D supplementation 17% 11% 0.37
Diabetes mellitus 30% (26) 11% (7) 0.007
Morning serum cortisol (μg/dL) 18 (11.7–24.9) 8.4 (5.9–11.6) ≤0.001
LDDST (μg/dL) 14.7 (7.7–23.7) 1.0 (0.8–1.2) ≤0.001
UFC (μg/24 h) 587 (331–843) 140 (78–216) ≤0.001
ACTH (pg/mL) 47 (9–76) 13 (9–18) ≤0.001
Late‐night salivary cortisol (ng/mL) 7.9 (3.3–11.8) 1.2 (0.6–1.8) ≤0.001
Bone turnover markers
Osteocalcin (ng/mL) 8 (5–13) 13 (10–17) <0.001
PINP (ng/mL) 35 (29–62) 52 (35–73) 0.025
BAP (μg/L) 23 (16–31) 17 (14–24) 0.006
CTX‐I (ng/mL) 0.28 (0.17–0.42) 0.23 (0.12–0.32) 0.033
TrAcP (U/L) 2.3 (1.7–3.4) 1.9 (1.3–2.4) 0.009
  • Date are shown as mean ± standard deviation or median and ranges.
  • BMI = body mass index; LDDST = low‐dose dexamethasone suppression test; UFC = urinary free cortisol; ACTH = adrenocorticotropic hormone; PINP = intact procollagen I‐N‐propeptide; BAP = bone alkaline phosphatase; CTX‐I = CrossLaps; TrAcP = tartrate‐resistant acid phosphatase. Bold numbers indicate statistical significance.

Baseline evaluation

At time of diagnosis, the mean levels of bone formation markers osteocalcin and intact PINP were significantly decreased compared with the controls, and the bone formation marker bone alkaline phosphatase was increased (Table 1; Fig. 2). Both bone degradation markers CTX and TrAcP were increased (Table 1). Taken together, this demonstrates increased bone resorption and decreased bone formation in florid CS. Results of multiple linear regression analysis comparing Cushing’s syndrome patients and controls are shown in Table 2. Bone markers were similar in patients with a reduced bone mass versus those with a normal bone mass (data not shown).

image
Figure 2

Open in figure viewerPowerPoint
Bone turnover markers and bone mineral density at baseline and 1 and 2 years after remission. Boxplot = median and ranges of bone turnover marker in patients with Cushing’s syndrome.Gray box = median and ranges of bone turnover markers in the control group.PINP = procollagen I‐N‐propeptide; BAP = bone alkaline phosphatase; TrAcP = tartrate‐resistant acid phosphatase; CTX‐I = CrossLaps.
Table 2. Results of Multiple Linear Regression Analysis Comparing Cushing’s Syndrome Patients Versus Controls
Dependent variable Standardized regression coefficient and p value for group variable
Unadjusted Adjusted for age, sex, and BMI
Osteocalcin (ng/mL) −0.392, 0.006 −0.375, 0.010
PINP (ng/mL) −0.215, 0.204 −0.256, 0.145
BAP (μg/L) 0.404, 0.001 0.470, <0.001
CTX‐I (ng/mL) 0.111, 0.366 0.065, 0.616
TrAcP (U/L) 0.227, 0.014 0.186, 0.069
  • PINP = procollagen I‐N‐propeptide; BAP = bone alkaline phosphatase; CTX‐I = CrossLaps; TrAcP = tartrate‐resistant acid phosphatase. Bold numbers indicate statistical significance.

Overall, bone mineral density was decreased with an average lowest T‐score of −1.4 (±1.1). BMD was significantly lower (p = 0.001) at the femoral neck (T‐score = −0.9 ± 1.0) and the spine (T‐score = −1.0 ± 1.5) compared with the total femur (T‐score = −0.5 ± 1.2). Twenty‐eight patients (32%) had a normal bone mineral density, 46 (52%) osteopenia, and the other 15 patients (17%) osteoporosis with a T‐score lower than −2.5.

Seventeen of the patients (19%) had a history of low‐trauma osteoporotic fractures (9 vertebral fractures, 8 nonvertebral fractures). The fractures took place shortly before diagnosis (58%) or more than 2 years before diagnosis of the CS (42%). Patients with osteoporotic fractures had a significantly lower T‐score than patients without fractures (T‐score = −1.9 ± 0.8 versus −1.3 ± 1.1, p = 0.03) but did not differ in the values of the bone turnover markers or standard biochemical screening. Subtype, age, or BMI also did not differ between groups. However, men were significantly at higher risk of having fractures than women (35% of men had fractures versus 14% of women, p = 0.03). Both severity of hypercortisolism and duration of CS did not contribute to fractures rates (data not shown), but UFC was significantly higher in patients with a T‐score lower than −1.5 (Table 3).

Table 3. Biochemical Markers in Patients With Cushing’s Syndrome With a T‐Score Lower Than −1.5 and Above −1.5 Shown in Median and Ranges
Variable T‐score < −1.5 (n = 39) T‐score ≥ −1.5 (n = 42) p Values
LDDST (μg/dL) 16.6. (10.3–28.3) 11.9 (6.1–21.9) 0.12
UFC (μg/24 h) 706 (410–906) 398 (285–787) 0.03
Late‐night salivary cortisol (ng/mL) 8.3 (3.5–13.6) 5.7 (2.9–11.7) 0.39
ACTH (pg/mL) 53 (16–73) 42 (6–82) 0.88
  • LDDST = low‐dose dexamethasone suppression test; UFC = urinary free cortisol; ACTH = adrenocorticotropic hormone. Bold numbers indicate statistical significance.

One‐ and 2‐year follow‐up

Surgical tumor resection leading to biochemical remission of CS resulted in a strong increase of bone formation markers tested at 1‐year follow‐up (Table 4; Fig. 2A, B). After 2 years, the markers had decreased slightly but remained elevated. Bone resorption markers were mildly increased at time of diagnosis, increased further at 1 year post‐surgery, and returned almost to normal levels at 2 years (Table 4; Fig. 2D, E). A follow‐up bone densitometry conducted in 40 patients showed a parallel increase of the T‐score of 0.6 ± 0.8 (Fig. 2F). In particular, BMD of the spine improved (Table 5).

Table 4. Bone Turnover Markers and Bone Mass in Patients With Cushing’s Syndrome at Time of Diagnosis and During 2 Years of Follow‐Up
Time of diagnosis (n = 50) 1 year in remission (n = 45) 2 years in remission (n = 38) p (0 versus 1) p (0 versus 2) p (1 versus 2)
T‐score −1.5 (−2.0 to −0.8) – −1.1 (−1.5 to −0.4) – <0.001 –
Osteocalcin (ng/mL) 8 (5–13) 30 (14–60) 21 (13–31) <0.001 0.008 0.3
PINP (ng/mL) 35 (29–62) 117 (52–221) 69 (46–113) <0.001 0.1 0.1
BAP (μg/L) 23 (16–31) 26 (19–38) 22 (15–31) 0.2 0.4 0.1
CTX‐I (ng/mL) 0.28 (0.17–0.42) 0.51 (0.22–0.91) 0.25 (0.18–0.73) 0.01 0.1 0.04
TrAcP (U/L) 2.3 (1.7–3.4) 2.8 (1.8–4.0) 2.3 (2–3.2) 0.1 0.6 0.002
  • PINP = procollagen I‐N‐propeptide; BAP = bone alkaline phosphatase; CTX‐I = CrossLaps; TrAcP = tartrate‐resistant acid phosphatase. Bold numbers indicate statistical significance.
Table 5. Overview: T‐Scores, Z‐Scores, and BMD Values With Percent Changes (Mean and Standard Deviation)
Variable CS at time of diagnosis CS 2 years in remission p Values, percent changes (↑)
Femoral neck
T‐score femoral neck −0.81 ± 0.97 −0.59 ± 0.86 0.06
Z‐score femoral neck −0.59 ± 0.98 −0.28 ± 0.79 0.02
BMD (g/cm2) femoral neck 0.91 ± 0.12 0.95 ± 0.12 0.16; 4% ↑
Femur
T‐score femur −0.49 ± 1.11 −0.42 ± 1.04 0.67
Z‐score femur −0.40 ± 1.04 −0.37 ± 0.85 0.31
BMD (g/cm2) femur 0.95 ± 0.15 0.97 ± 0.14 0.77, 2% ↑
Spine
T‐score spine −0.96 ± 1.56 −0.55 ± 1.25 <0.001
Z‐score spine −0.85 ± 1.53 −0.58 ± 1.14 <0.001
BMD (g/cm2) spine 1.08 ± 0.22 1.13 ± 0.15 0.001, 0.6% ↑
  • BMD = bone mineral density; CS = Cushing’s syndrome. Bold numbers indicate statistical significance.

In 78% of patients, bone mineral density improved after 2 years; in 45% of patients, T‐score improved more than 0.5. No clinical fractures occurred after successful treatment of the CS. There was no significant correlation between improvement of bone mineral density and any of the bone turnover markers.

Discussion

This study investigated for the first time to our knowledge a panel of bone formation and resorption markers in a large cohort of patients with CS over the long term. The unique and comprehensive data show that initially bone metabolism is characterized by decreased bone formation and increased bone resorption, in line with the classical action of glucocorticoids. Successful treatment of endogenous Cushing’s syndrome leads to a strong activation of bone turnover, characterized by increased bone formation and bone resorption, a process that is continuous beyond year 2 after remission of CS, although at a reduced activity level. In parallel, bone mineral density increases in the majority of patients. Although 19% had low‐trauma fractures at baseline, none of the subjects experienced clinical fractures during follow‐up. In summary, these data give new insight into bone healing after remission of CS. They strongly suggest that an observational approach to the bone phenotype is justified as long as remission from CS is secured.

Reversibility of osteoporosis and bone turnover markers

Although established in osteoporosis research, bone turnover markers are not measured on a routine basis in patients with CS. However, it is a consistent result from different studies that osteocalcin is depressed in patients with CS. In fact, this finding is so reliable that it was even suggested to use osteocalcin in the diagnosis of CS.2 P1NP and procollagen carboxy‐terminal propeptide (P1CP) have also been studied in several studies, with contradictory results.23 In a retrospective study with 21 patients with CS, it was shown that osteocalcin is depressed; this applies also for PINP, whereas CTX is increased.24

Some studies already have focused on the reversibility of osteoporosis after treatment of CS. In the majority of patients, bone mineral density increased within 2 years after successful treatment8–10, 25 Hermus and colleagues showed in a study with 20 patients that bone mineral density did not change 3 or 6 months after surgery but increased thereafter in almost all patients.8 In a study with 68 patients, the patients were followed up for 4 years. Bone mineral density increased over lumbar spine and femur but decreased at the forearm.25 The authors concluded that bone minerals were redistributed from the peripheral to the axial skeleton.

In our study, bone mineral density also improved in the majority of patients but remained reduced in some. We did not find any difference in bone turnover markers between patients with improvement and without improvement.

Current treatment guidelines and treatment suggestions

As observed in our study, bone formation markers increase significantly after surgical cure, whereas bone degradation markers are mildly elevated at baseline and increase slightly at 1 year, returning within the normal range at 2 years. So far, there is no international guideline on the treatment of osteoporosis induced by endogenous CS and very few controlled interventional studies. In an opinion paper, Scillitani and colleagues recommended to treat all patients with vitamin D and calcium but not with bisphosphonates.5 In a randomized open‐label study by Di Somma and colleagues,26 39 patients (18 patients with active CS and 21 patients with CS in remission) received alendronate or no medication. Patients with active CS also received ketoconazole to control hypercortisolism. Bone mineral density improved and serum levels of osteocalcin increased in patients who received alendronate to a greater extent than those receiving no alendronate.

In a small study by the same research group,27 15 patients with CS (9 adolescent patients and 6 adults) were observed for 2 years after successful treatment, showing that osteocalcin levels and bone mineral density increased significantly.

Strengths and limitations

Although this study has several strengths, including the large prospective design and measuring a panel of bone formation and resorption markers, there are a few limitations. Some asymptomatic fractures may have been overlooked because an X‐ray was not taken systematically in each patient. Furthermore, a follow‐up bone densitometry was not available for all patients. Additionally, patients in the control group suffered from diabetes, overweight, arterial hypertension, or other diseases.

Novel aspects and outlook

This study analyzes for the first time in a comprehensive way bone turnover markers during the course of CS. The data show that cure from CS leads to increases in bone remodeling and bone mineral density, in line with spontaneous “bone healing.” Our data support a wait‐and‐watch strategy despite a high endogenous risk for additional fractures, based on the baseline assessment. This observation will influence future therapeutic strategies in patients with CS.

Our data suggest that the phase immediately after remission from CS is characterized by a high rate of bone turnover, resulting in a spontaneous net increase in bone mineral density in the majority of patients. Both bone attachment and bone degradation markers increase significantly, leading to an increase in bone mass and to a reduced risk of osteoporotic fractures. This unconstrained increase in bone formation markers after remission should be considered before specific therapy is initiated. Our data do not favor specific pharmacologic interventions with bisphosphonates or denosumab during this phase of remodeling because they may disrupt the osteoblast‐mediated bone mass increase.

Disclosures

All authors state that they have no conflicts of interest.

Acknowledgments

This work is part of the German Cushing’s Registry CUSTODES and has been supported by a grant from the Else Kröner‐Fresenius Stiftung to MR (2012_A103 and 2015_A228). Additionally, AR, FB, and MR received funding by the Deutsche Forschungsgemeinschaft (CRC/TRR 205/1 “The Adrenal Gland”). Furthermore, funds for this project were provided by the Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultät der Ludwig‐Maximilians‐Universität München eV to LB.

The data are stored on the following repository: https://figshare.com/ and will be made accessible after publication of the article.

Authors’ roles: LB served as the principal investigator in this work and was responsible for the study conception and design, the analysis and interpretation of the data, and the drafting of the manuscript. JF, SZ, AO, AR, GR and SB contributed to the collection and analysis of the data. MS, FB, MD, MB substantially contributed to the interpretation of the data and the drafting of the manuscript. RS contributed to the conceptual design of the study, the interpretation of data and the revision of the paper. MR contributed to the conceptual design of the study, the collection, analysis and interpretation of data, and the drafting and revision of the paper. All authors contributed to the critical revision of the manuscript and approved the final version for publication.

From https://asbmr.onlinelibrary.wiley.com/doi/full/10.1002/jbmr.4033

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Increased Mortality Risk in Patients With Primary and Secondary Adrenal Insufficiency

Posted on February 21, 2021 by MaryO
A retrospective cohort study was performed to compare mortality risk and causes of death in adrenal insufficiency with an individually-matched reference population. Researchers examined 6,821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) and 6,7564 individually-matched controls (primary, 20366; secondary, 39134).
It was shown that in adrenal insufficiency, mortality was elevated, particularly primary, even with individual matching, and was found early in the disease course. The data demonstrated that cardiovascular disease was the major cause but mortality from infection was also high. The adrenal crisis was a common contributor.
The outcomes suggested that early education for prompt treatment of infections and avoidance of adrenal crisis hold the potential to decrease mortality.
The Journal of Clinical Endocrinology & Metabolism, dgab096, https://doi.org/10.1210/clinem/dgab096

Abstract

Context

Mortality data in patients with adrenal insufficiency are inconsistent, possibly due to temporal and geographical differences between patients and their reference populations.

Objective

To compare mortality risk and causes of death in adrenal insufficiency with an individually-matched reference population.

Design

Retrospective cohort study.

Setting

UK general practitioner database (CPRD).

Participants

6821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) and 67564 individually-matched controls (primary, 20366; secondary, 39134).

Main outcome measures

All-cause and cause-specific mortality; hospital admission from adrenal crisis.

Results

With follow-up of 40799 and 406899 person-years for patients and controls respectively, the hazard ratio (HR; [95%CI]) for all-cause mortality was 1.68 [1.58 – 1.77]. HRs were greater in primary (1.83 [1.66 – 2.02]) than in secondary (1.52 [1.40 – 1.64]) disease; (HR; primary versus secondary disease, 1.16 [1.03 – 1.30]). The leading cause of death was cardiovascular disease (HR 1.54 [1.32-1.80]), along with malignant neoplasms and respiratory disease. Deaths from infection were also relatively high (HR 4.00 [2.15 – 7.46]). Adrenal crisis contributed to 10% of all deaths. In the first two years following diagnosis, the patients’ mortality rate and hospitalisation from adrenal crisis were higher than in later years.

Conclusion

Mortality was increased in adrenal insufficiency, especially primary, even with individual matching and was observed early in the disease course. Cardiovascular disease was the major cause but mortality from infection was also high. Adrenal crisis was a common contributor. Early education for prompt treatment of infections and avoidance of adrenal crisis hold potential to reduce mortality.

PDF available at https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgab096/6141434?redirectedFrom=fulltext

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Successful Cushing’s Surgery Leads to Better Bone Density

Posted on February 20, 2021 by MaryO

Biomarkers in a majority of Cushing’s syndrome patients with surgically induced disease remission showed a high rate of bone turnover and greater bone mineral density one and two years later, a study reports.

Before treatment, these patients were found to have greater bone degradation and poorer bone formation, as can be common to disease-related bone disorders.

Researchers believe their work is the first study of its kind, “and the data obtained will be instrumental for clinicians who care for patients with Cushing’s syndrome.”

The study, “The Effect of Biochemical Remission on Bone Metabolism in Cushing’s Syndrome: A 2‐Year Follow‐Up Study,” was published in the Journal of Bone and Mineral Research.

Two common co-conditions of Cushing’s syndrome are osteopenia, a loss of bone mass, and osteoporosis, in which the body makes too little bone, loses too much bone, or both. Studies suggest up to 80% of people with Cushing’s have evidence of reduced bone mineral density affecting the entire skeleton.

However, few risk factors to predict bone health have been identified so far, and guidelines for osteoporosis management due to Cushing’s are lacking. Uncertainty as to the natural course of osteoporosis once a diagnosis of Cushing’s syndrome has been made is also still evident.

Investigators at the University of Munich, reportedly for a first time, analyzed the natural course of bone mineral density and bone turnover (recycling) in a group of people with endogenous Cushing’s syndrome — which refers to the disease caused by excess cortisol in the bloodstream, often due to a tumor in the adrenal or pituitary glands.

They examined medical records of 89 Cushing syndrome patients with a mean age of 44, of which 74% were women. Of these, 65% had pituitary Cushing’s (Cushing’s disease), 28% had adrenal, and 7% had ectopic Cushing’s, which is caused by tumors outside the adrenal or pituitary glands. A group of 71 age- and sex-matched healthy participants were included as controls.

In all patients, blood samples were collected at the time of diagnosis (baseline) and one and two years after removing one or both adrenal glands or moving tumors affecting the pituitary gland. Blood samples were analyzed for biomarkers related to bone formation and degradation (resorption).

At the study’s beginning, the mean levels of two bone formation markers, osteocalcin and intact PINP, were significantly decreased in patients compared with controls, whereas the bone formation marker alkaline phosphatase was increased.

Both markers for bone degradation — called CTX and TrAcP — were also high, which demonstrated “increased bone resorption and decreased bone formation in [Cushing’s syndrome],” the team wrote.

While bone markers were similar in participants with a reduced bone mass relative to those with a normal bone mass, bone mineral density was lower overall. Bone mineral density was significantly lower in the neck and spine compared with the femur (thigh bone). Normal bone mineral density was reported in 28 (32%) patients, while 46 (52%) had osteopenia, and the remaining 15 (17%) lived with osteoporosis.

A history of low-trauma bone fractures due to osteoporosis occurred in 17 (19%) patients, taking place shortly before diagnosis in more than half of these (58%) people, and more than two years before a Cushing’s diagnosis in the remaining group (42%).

Compared to patients without fractures, those with fractures had a significantly lower T‐score, a bone density measure that represents how close a person is to average peak bone density. While Cushing’s subtype, age, or body mass index (BMI, body fat based on height) did not differ between groups, men had a significantly higher risk of fractures than women (35% of men vs. 14% of women).

Both disease severity and duration did not contribute to fractures rates, but urinary free cortisol (a circulating cortisol measure) was significantly higher in patients with a low T‐score.

At the one year after tumor removal, which led to Cushing’s remission based on blood tests, a significant increase in bone formation markers was reported. These biomarkers decreased slightly at two years post-surgery, but remained elevated.

At the beginning of the study, bone resorption markers were mildly increased, which rose further one year after surgery before returning almost to normal levels by two years. In parallel, bone density measures conducted in 40 patients showed a matching increase in T-score, particularly in the spine.

After two years, bone mineral density improved in 78% of patients, and T-scores improved in 45% of them. No fractures occurred after Cushing’s treatment, and there was no significant correlation between bone turnover markers and better bone mineral density.

“This study analyzes for the first time in a comprehensive way bone turnover markers during the course of [Cushing’s syndrome],” the researchers wrote. “Our data suggest that the phase immediately after remission from [Cushing’s syndrome] is characterized by a high rate of bone turnover, resulting in a spontaneous net increase in bone mineral density in the majority of patients.”

These results “will influence future therapeutic strategies in patients” with Cushing’s syndrome, they added.

 

Steve Bryson PhD
Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
From https://cushingsdiseasenews.com/2021/02/19/successful-cushings-surgery-leads-to-better-bone-density-study-finds/

Filed under: Cushing's, Rare Diseases, symptoms, Treatments | Tagged: , , | Leave a comment »

New study identifies the main genetic causes of autoimmune Addison’s disease

Posted on February 13, 2021 by MaryO

Novel genetic associations could pave the way for early interventions and personalized treatment of an incurable condition.

Scientists from the University of Bergen (Norway) and Karolinska Institutet (Sweden) have discovered the genes involved in autoimmune Addison’s disease, a condition where the body’s immune systems destroys the adrenal cortex leading to a life-threatening hormonal deficiency of cortisol and aldosterone.

Groundbreaking study

The rarity of Addison’s disease has until now made scanning of the whole genome for clues to the disease’s genetic origins difficult, as this method normally requires many thousands of study participants. However, by combining the world’s two largest Addison’s disease registries, Prof. Eystein Husebye and his team at the University of Bergen and collaborators at Karolinska Institutet in Sweden (prof. Kämpe) were able to identify strong genetic signals associated with the disease. Most of them are directly involved in the development and functioning of the human immune system including specific molecular types in the so-called HLA-region (this is what makes matching donors and recipients in organ transplants necessary) and two different types of a gene called AIRE (which stands for AutoImmune REgulator).

AIRE is a key factor in shaping the immune system by removing self-reacting immune cells. Variants of AIRE, such as the ones identified in this study, could compromise this elimination of self-reacting cells, which could lead to an autoimmune attack later in life.

Knowing what predisposes people to develop Addison’s disease opens up the possibilities of determining the molecular repercussions of the predisposing genetic variation (currently ongoing in Prof. Husebye’s lab). The fact that it is now feasible to map the genetic risk profile of an individual also means that personalised treatment aimed at stopping and even reversing the autoimmune adrenal destruction can become a feasible option in the future.

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Contact information:

Professor at the University of Bergen, Eystein Husebye – Eystein.Husebye@uib.no – cell phone +47 99 40 47 88

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

From https://www.eurekalert.org/pub_releases/2021-02/tuob-nsi021221.php

Filed under: Addison's disease, adrenal | Tagged: , , , , | Leave a comment »

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