Multiple Osteoporotic Fractures in Cushing Syndrome: A Case Report and a Review of the Literature

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript reported a case of a female patient diagnosed with Cushing syndrome many years after osteoporotic fracture, and also summarized other 19 cases of Cushing syndrome with osteoporotic fractures as the initial clinical presentation. However, this case lacks originality and novelty. It is recommended to clearly demonstrate the value of this case in the abstract and conclusion. In addition, the case report should follow the CARE guidelines for reporting, and it is suggested to add a statement at the end of the introduction stating "This case report follows the CARE guidelines."

 

Specific comments:

• Line 57: The case introduction should start with the patient's symptoms and describe whether the patient had symptoms supporting the diagnosis of Cushing syndrome.

• Line 57: Imaging of the adrenal mass should be provided.

• Line 61-62: It is necessary to add the indicators of bone metabolism at the time of the fracture, as well as whether there were typical physical characteristics of Cushing syndrome or related examinations described. It is recommended to present the entire paragraph chronologically.

• Line 73-76: Normal ranges need to be inserted and results interpreted. 1 mg Dexamethasone Suppression Test (DST) can be considered to some extent for Pseudocushings if the cortisol levels are suppressed. However, in the diagnosis of Cushing syndrome, in addition to serum cortisol, 24h urinary free cortisol (UFC), and 1 mg DST, the classical low-dose DST is also needed to qualitatively diagnose Cushing's syndrome, based on post-drug serum cortisol and 24h UFC levels. In addition to the hormonal results necessary for the qualitative diagnosis of Cushing syndrome, the hormone levels of the anterior pituitary should be added, potentially listed.

• Line 78: Bone mineral density should be provided, not just T-score. The differential diagnosis of the cause of osteoporotic fractures is missing in the text. While complications of Cushing syndrome include bone metabolism abnormalities, there is insufficient evidence to link the patient's fracture to Cushing syndrome.

• Lines 92-96: Pathology is an important basis for determining the nature of adrenal masses, which not only clarifies whether the adrenal mass is the cause of Cushing syndrome, but also provides important guidance for the patient's prognosis. It is recommended to include a detailed description of adrenal pathology.

• Lines 106-111: The discussion does not point out the unique or novel aspects of this case in relation to previous literature, limiting the significance of this case report. Additionally, the accuracy of the cited references should be verified.

• Lines 116-126, 135-139: The differences should be clearly specified between this case and other previously reported cases of Cushing syndrome with osteoporotic fractures as the primary clinical presentation. If a uniform analysis of all cases is desired, detailed statistical analysis should be conducted, rather than simply describing the similarities and differences between these cases. Such descriptive features hold little value.

 

The analysis of bone metabolism abnormalities is too scattered and does not connect well with Cushing syndrome. From the analysis of potential complications of bone metabolism in patients with Cushing syndrome, if summarizing the specific bone metabolism situation of Cushing syndrome is desired, this may become a separate topic and might lead to a lack of clarity in the discussion section. Please review and rephrase the discussion section.

 

Furthermore, details regarding how the authors differentiated Cushing syndrome from Pseudocushings should be clarified. The pathology of the adrenal mass is crucial for determining if it is responsible for Cushing syndrome and can guide prognosis and follow-up planning. The discussion should highlight the unique aspects or novelty of the case compared to previous reports and ensure the accuracy of cited literature.

 

Overall, the analysis of bone metabolism abnormalities is fragmented and not effectively linked to Cushing syndrome. To maintain focus and clarity, it is recommended that a separate topic be dedicated to summarizing the specifics of bone metabolism in Cushing syndrome. A more comprehensive analysis and restructuring of the discussion section is necessary.

Comments on the Quality of English Language

Extensive editing of English language required.

Author Response

Reviewer 1

The manuscript reported a case of a female patient diagnosed with Cushing syndrome many years after osteoporotic fracture, and also summarized other 19 cases of Cushing syndrome with osteoporotic fractures as the initial clinical presentation. However, this case lacks originality and novelty. It is recommended to clearly demonstrate the value of this case in the abstract and conclusion.

We would like to thank the reviewer for the thorough revision of our manuscript. According to his and the editors’ suggestion we pointed out the importance of our case in the abstract, introduction and conclusion of the manuscript.

Abstract

“This case report presenting a particularly long time-gap between initial osteoporosis signs and final diagnosis underlines the need for investigation for secondary osteoporosis even in low-energy fractures also in the peripheral skeleton.” (lines 21-23)

Introduction

“To the best of our knowledge, this is the first case reporting on such a large time gap between initial osteoporosis signs and final diagnosis of Cushing syndrome, with hypercortisolemic signs being attributed to other clinical conditions, leading to a relevant delay in targeted treatment. Moreover, it presents rather unusual aspects of osteoporosis, such as low-energy fractures in the ribs and the peripheral skeleton, misleading to irrelevant diagnoses. “(lines 56-61)

Conclusion

“In our case only the occurrence of vertebral fractures alerted the physician to investigate further the differential diagnosis of osteoporosis, as opposed to all previous fractures that did not raise the suspicion to investigate in this direction, resulting in a marked delay in diagnosis and treatment. These findings should be considered in everyday clinical practice in order to improve timely diagnosis and treatment of CS and to avoid further complications.” (lines 255-260)

 

In addition, the case report should follow the CARE guidelines for reporting, and it is suggested to add a statement at the end of the introduction stating "This case report follows the CARE guidelines."

The revised case report adheres to the CARE guidelines and the respective checklist can be found in the additional material. As suggested, a statement was added at the end of the introduction.

“This case report adheres to the CARE guidelines.” (lines 61-62)

 

Specific comments:

• Line 57: The case introduction should start with the patient's symptoms and describe whether the patient had symptoms supporting the diagnosis of Cushing syndrome.

We fully understand the reviewer’s comment. In the submitted version a large part of the first paragraph of the introduction was deleted, affecting significantly the understanding of the paragraph. We apologize for this. In the revised version of the manuscript all the details on the patient’s symptoms are described in detail.

“In May 2023, a 45-year-old woman was referred to our endocrinology department for further evaluation and management. The patient was already under medical treatment with olmesartan/amlodipine/hydrochlorothiazide for arterial hypertension since 2015. Additionally, she had undergone total hysterectomy with bilateral salpingo-oophorectomy due to a large benign uterine fibroid tumor (10x8 cm) in 2020 and was, subsequently, menopausal since the age of 42. She reported on regular menstruation prior to the surgical procedure. On further questioning, the patient reported on several previous fractures without relevant trauma (sternum 2015, middle phalanges of both indicators 2021, vertebral fractures involving T11 and L1 2022, sacrum 2022). She was diagnosed with osteoporosis in 2022 and has been under denosumab treatment, 60 mg every 6 months, since then. Furthermore, she was diagnosed with dyslipidemia and type 2 diabetes mellitus (T2DM) 2 months prior to her presentation in our outpatient clinic and treatment with atorvastatin/ezetimibe and metformin had been initiated, respectively.” (lines 65-77)

 

• Line 57: Imaging of the adrenal mass should be provided.

As recommended by the reviewer MRI images of the adrenal mass are now provided (now Figure 2)

 

• Line 61-62: It is necessary to add the indicators of bone metabolism at the time of the fracture, as well as whether there were typical physical characteristics of Cushing syndrome or related examinations described. It is recommended to present the entire paragraph chronologically.

Given the missing text in the initial version of the manuscript, and according to the reviewer’s recommendations this information has been revised to chronological order. Furthermore, as the first BMD was performed several years after the initial fractures of the patient, this is now clearly stated in the manuscript.

“The bone mineral density (BMD) of the lumbar spine was first defined in 2022 and with a T-score of -3.8 (Z-score -4.0, BMD 0.750 g/cm²), was indicative of osteoporosis, leading to the initiation of treatment with denosumab. (lines 84-86)

 

• Line 73-76: Normal ranges need to be inserted and results interpreted. 1 mg Dexamethasone Suppression Test (DST) can be considered to some extent for Pseudocushings if the cortisol levels are suppressed. However, in the diagnosis of Cushing syndrome, in addition to serum cortisol, 24h urinary free cortisol (UFC), and 1 mg DST, the classical low-dose DST is also needed to qualitatively diagnose Cushing's syndrome, based on post-drug serum cortisol and 24h UFC levels. In addition to the hormonal results necessary for the qualitative diagnosis of Cushing syndrome, the hormone levels of the anterior pituitary should be added, potentially listed.

According to the reviewer’s recommendation, the normal range of the results reported herein is now inserted. Among others, results on morning cortisol and ACTH, cortisol levels upon 1 mg DST, and 24h UFC are listed in the Assessment part (lines 93-107).

Furthermore, these main results excluding a pseudo-Cushing and leading to the diagnosis of an adrenal Cushing Syndrome are summarized in the revised version of the manuscript.

“In this context, the osteoporotic fractures emerging already years prior to menopause, with normal thyroid function and calcium metabolism, the worsening of the metabolic profile of the patient with dyslipidemia and T2DM, together with the described clinical signs (plethora, ecchymoses, muscle weakness) and the subsequent hormonal investigations (no cortisol suppression upon DST, elevated 24h UFC), were attributed to a florid Cushing Syndrome (CS). The presence of the adrenal mass together with the suppressed ACTH levels were confirmatory of its adrenal origin.” (lines 108-114)

 

• Line 78: Bone mineral density should be provided, not just T-score. The differential diagnosis of the cause of osteoporotic fractures is missing in the text. While complications of Cushing syndrome include bone metabolism abnormalities, there is insufficient evidence to link the patient's fracture to Cushing syndrome.

According to the reviewer’s recommendation, BMD is now presented in detail.

“The bone mineral density (BMD) of the lumbar spine was first defined in 2022 and with a T-score of -3.8 (Z-score -4.0, BMD 0.750 g/cm²), was indicative of osteoporosis, leading to the initiation of treatment with denosumab. (lines 84-86)

We understand the reviewer’s concern on the differential diagnosis of osteoporotic fractures. As the first of these emerged prior to the early menopause of the patient, estrogen depletion could not be a sufficient explanation for the fractures. Furthermore, as calcium and parathormone were within the normal range, a primary hyperparathyroidism could also be excluded. As the patient presented several clinical signs of Cushing syndrome but most importantly displayed a biochemical profile confirmatory of a florid Cushing Syndrome, with a complete lack of cortisol suppression after 1 mg dexamethasone suppression test and a 24h urinary cortisol secretion 4-fold above the normal range, osteoporosis was attributed in this context.

 

• Lines 92-96: Pathology is an important basis for determining the nature of adrenal masses, which not only clarifies whether the adrenal mass is the cause of Cushing syndrome, but also provides important guidance for the patient's prognosis. It is recommended to include a detailed description of adrenal pathology.

According to this suggestion a revision of the pathology and a detailed description of the pathology report is included in the revised version of the manuscript.

“The pathology report described a 4 cm large adrenocortical neoplasm, with a Ki-67 cell proliferation index of 2%, and 2 mitoses/50 HPFs, without atypical mitoses or capsule infiltration No necrosis was observed. Positive staining was documented for Calretinin (+), MelanA (+), and Synaptophysin (+), whereas staining for Vimentin (-), CEA (-) and HMB-45 (-) was negative. The adenoma consisted of two populations of adrenocortical cells; approximately 65% of the cells displayed lipid rich cytoplasm, and the rest dense, lipid poor cytoplasm (compact cells). Both cell populations grew together forming a trabecular pattern. The SF1 marker showed intense nuclear expression in 100% of the cells, with p53 displaying the wild type expression pattern, and β-catenin a paranuclear dot-like staining (no aberrant expression pattern). CYP11B1 showed mild to moderate cytoplasmatic expression, mainly in the lipid poor neoplastic cells, while low to no expression was documented in the lipid rich cells. CYP11B2 expression was absent in both cell populations, while diffuse and intense HSD3B2 expression was identified in all neoplastic cells. Based on the modified Weiss criteria, this tumor was classified as a benign adrenal cortical adenoma.” (lines 125-139)

 

• Lines 106-111: The discussion does not point out the unique or novel aspects of this case in relation to previous literature, limiting the significance of this case report. Additionally, the accuracy of the cited references should be verified.

We would like to thank the reviewer for his remark. We revised the cited references and discussed the unique characteristics of our case report in the revised version of our manuscript.

“Interestingly, in our case, the time lapse between the first fragility fracture and the final diagnosis of CS was particularly long, over eight years, unlike previous cases described in the literature. Additionally, as the medical history of our patient was complicated by early menopause at the age of 42, because of total hysterectomy with bilateral salpingo-oophorectomy, the accumulation of fractures could also be attributed to this later diagnosis. Still, estrogen depletion documented in our patient only began after the surgical intervention (in 2020), whereas the first osteoporotic fractures occurred several years in advance (sternum fracture 2015). Of course, an additive effect of early menopause in the already disturbed bone metabolism in our patient should be considered. Further signs such as arterial hypertension and dyslipidemia could also be recognized as menopausal consequences. However, when the diagnosis of CS was suspected, several other clinical signs, such as the plethora of the face and upper part of the chest, thin skin with several bruises, bilateral leg edema and muscle weakness were apparent and indicative of a florid CS as this was documented in the recently introduced model to estimate the pre-test probability of Cushing's syndrome according to the Cushing Score.” (lines 161-175)

 

• Lines 116-126, 135-139: The differences should be clearly specified between this case and other previously reported cases of Cushing syndrome with osteoporotic fractures as the primary clinical presentation. If a uniform analysis of all cases is desired, detailed statistical analysis should be conducted, rather than simply describing the similarities and differences between these cases. Such descriptive features hold little value.

We understand the reviewer’s concern. We fully agree that a uniform analysis would be more interesting but the data we could retrieve from other publications are not sufficiently uniform to allow such an analysis, besides from the fact that the small numbers would not ensure statistical power. Furthermore, the cases reviewed herein did not always manifest with an osteoporotic fracture, but this could be described as an incident finding (eg. The case from Al Banna et al. with the pregnant woman with dilatative cardiomyopathy, where vertebral fractures were not the leading symptom for diagnosis).

According to the reviewer’s suggestion, we performed a comparison of the different characteristics of our case with the ones already described in the literature.

“Inversely, only three cases (3/19) presented at least one peripheral fracture, including the present case.” (lines 194-195)

“Accordingly, our patient, who suffered from both vertebral and non-vertebral fractures, displayed increased 24h UFC levels and an absent cortisol suppression upon DST” (lines 197-199)

“Interestingly, though, in five of the cases, these comorbidities have only been recognized on the occasion of the fractures, as occurred in our patient” (lines 202-203)

“In line with this observation, in our case report, the patient had experienced the first fracture over 8 years prior to diagnosis” (lines 211-212)

“Our patient, who presented both vertebral and non-vertebral fractures displayed a low BMD corresponding to osteoporosis. However, as the measurement of BMD only occurred several years after the appearance of the first fragility fracture, we cannot exclude a linear evolvement from osteopenia to osteoporosis in our case.” (lines 219-223)

 

The analysis of bone metabolism abnormalities is too scattered and does not connect well with Cushing syndrome. From the analysis of potential complications of bone metabolism in patients with Cushing syndrome, if summarizing the specific bone metabolism situation of Cushing syndrome is desired, this may become a separate topic and might lead to a lack of clarity in the discussion section. Please review and rephrase the discussion section.

According to the reviewer’s suggestion in the revised version, we focused on the bone metabolism abnormalities in patients with CS, and changed the structure of this part, forming a separate paragraph.

Glucocorticoid excess mainly acts through inhibition of new bone formation, whereas during the onset of hypercortisolism also bone resorption is observed, leading in total to a rapidly increased fracture risk. Besides from the direct bone effect, hypercortisolism also leads to myopathy, growth hormone deficiency, hypogonadism and reduced calcium absorption and increased renal calcium secretion, all factors affecting bone metabolism. Furthermore, the severity of hypercortisolism, its duration and the delay to diagnosis all play a role on bone health in CS patients. Several studies acknowledged that CS patients have a higher risk of fractures than controls, despite frequently only slightly decreased BMD, and identified bone microarchitecture quantified with the trabecular bone score (TBS) as the crucial parameter particularly affected in CS. In a study TBS correlated with the levels of 24h UFC and in another with the duration of CS. Interestingly, though, even patients with mild autonomous cortisol secretion (MACS) display an altered TBS, rendering this marker a sensitive tool for the assessment of bone quality in both CS and MACS implying a continuum as in the case of cardiometabolic risk factors. It has recently been demonstrated, that, in particular post-menopausal women with MACS demonstrate a significantly higher prevalence of fragility fractures in comparison to patients with non-functioning adrenal adenomas, indicative of an altered bone metabolism in this group. Among other, it has now been suggested to screen for CS patients undergoing fragility fractures with uncom­mon features such as young age (men <50 or pre-menopausal women), or BMD values inappropriately in normal range or slightly reduced, and to additionally employ further tools such as morphometry or TBS quality assessment in these cases. 

(lines 224-245).

 

Furthermore, details regarding how the authors differentiated Cushing syndrome from Pseudocushings should be clarified. The pathology of the adrenal mass is crucial for determining if it is responsible for Cushing syndrome and can guide prognosis and follow-up planning. The discussion should highlight the unique aspects or novelty of the case compared to previous reports and ensure the accuracy of cited literature.

As previously described, in the revised version of the manuscript, the establishment of the diagnosis of Cushing Syndrome (lines 108-114 and 163-174), the detailed pathology report (lines 125-139) and the unique aspects of this case (lines 21-23, 56-61, 161-163 and 255-260) have been presented in detail.

 

Overall, the analysis of bone metabolism abnormalities is fragmented and not effectively linked to Cushing syndrome. To maintain focus and clarity, it is recommended that a separate topic be dedicated to summarizing the specifics of bone metabolism in Cushing syndrome. A more comprehensive analysis and restructuring of the discussion section is necessary.

As previously stated, this part was adequately revised (lines 224-245)

 

Comments on the Quality of English Language

Extensive editing of English language required.

English language editing was performed. 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

It is an interesting case report on multiple fractures in middle-aged woman with ACTH-independent Cushing Syndrome. In my opinion for better case  presentation lumbar spine BMD should be expressed in Z-scores (secondary osteoporosis), too. Moreover it is lacking information on the range of lumbar vertebral bodies studied, since L1 was fractured? Some more data in discussion could be found in recent review on Cushing's and bone (PMID 39008229).

Author Response

Reviewer 2

It is an interesting case report on multiple fractures in middle-aged woman with ACTH-independent Cushing Syndrome. In my opinion for better case  presentation lumbar spine BMD should be expressed in Z-scores (secondary osteoporosis), too.

We would like to thank the reviewer for his comments. According to his recommendation now BMD is also expressed in Z-score.

“The bone mineral density (BMD) of the lumbar spine was first defined in 2022 and with a T-score of -3.8 (Z-score -4.0, BMD 0.750 g/cm²), was indicative of osteoporosis, leading to the initiation of treatment with denosumab.” (lines 84-86)

Moreover it is lacking information on the range of lumbar vertebral bodies studied, since L1 was fractured?

In the submitted version a large part of the first paragraph of the introduction was deleted, affecting significantly the understanding of the paragraph. We apologize for this. In the revised version of the manuscript all the details on the patient’s symptoms are described in detail and detailed information on the vertebral and non-vertebral fractures of the patient is now available:

“In May 2023, a 45-year-old woman was referred to our endocrinology department for further evaluation and management. The patient was already under medical treatment with olmesartan/amlodipine/hydrochlorothiazide for arterial hypertension since 2015. Additionally, she had undergone total hysterectomy with bilateral salpingo-oophorectomy due to a large benign uterine fibroid tumor (10x8 cm) in 2020 and was, subsequently, menopausal since the age of 42. She reported on regular menstruation prior to the surgical procedure. On further questioning, the patient reported on several previous fractures without relevant trauma (sternum 2015, middle phalanges of both indicators 2021, vertebral fractures involving T11 and L1 2022, sacrum 2022). She was diagnosed with osteoporosis in 2022 and has been under denosumab treatment, 60 mg every 6 months, since then. Furthermore, she was diagnosed with dyslipidemia and type 2 diabetes mellitus (T2DM) 2 months prior to her presentation in our outpatient clinic and treatment with atorvastatin/ezetimibe and metformin had been initiated, respectively.” (lines 65-77)

Some more data in discussion could be found in recent review on Cushing's and bone (PMID 39008229).

We would like to thank the reviewer for his suggestion on bone metabolism in CS. Accordingly, following text was added in the revised version of the manuscript:

“Glucocorticoid excess mainly acts through inhibition of new bone formation, whereas during the onset of hypercortisolism also bone resorption is observed, leading in total to a rapidly increased fracture risk. Besides from the direct bone effect, hypercortisolism also leads to myopathy, growth hormone deficiency, hypogonadism and reduced calcium absorption and increased renal calcium secretion, all factors affecting bone metabolism (PMID 39008229). Furthermore, the severity of hypercortisolism, its duration and the delay to diagnosis all play a role on bone health in CS patients.” (lines 224-230)

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

Spyroglou et al. review the case of a 46-year-old female patient with a history of osteoporotic fractures and Cushing's syndrome. Whilst the development of secondary osteoporosis due to Cushing's syndrome is relevant, I consider that this article presents some aspects that need to be discussed.

 

The case is poorly described. The signs and symptoms of Cushing's syndrome are not properly described. Arterial hypertension, dyslipidemia and T2DM are mentioned in the abstract but not in text.  Was osteoporosis the leading symptom? Was the patient taking any medication?

 

The history of the fractures is not detailed (number? location? date? type of trauma?). All these aspects are of great importance for understanding the process.

 

The patient appears to have an oncological history - this is poorly detailed (tumour? location? systemic therapy?). A metastasic disease is mentioned in the figure, but not in the text. It is mentioned that she had a bilateral salpingo-oophorectomy - was the patient oestrogen deficient? was she treated with oestrogens? All these aspects are very poorly discussed in the text and are crucial in the assessment of osteoporosis, since they could be the cause of secondary osteoporosis.

 

The discussion includes a review of the literature, but does not address the diagnosis and origin of osteoporosis in this patient. The search criteria for the review are poorly stated, without detailed inclusion and exclusion criteria, which could lead to case selection bias. Furthermore, the literature review is poor and adds little value to previous publications.

Comments on the Quality of English Language

There are long sentences that make reading difficult.

There are interrupted sentences with latinisms that are not understood ("The patient approvaernum 2015, middle phalanges of both indicators 2021, vertebral fractures affecting T11 and L1 2022, sacrum 2022)", line 61). 

Author Response

Reviewer 3

Spyroglou et al. review the case of a 46-year-old female patient with a history of osteoporotic fractures and Cushing's syndrome. Whilst the development of secondary osteoporosis due to Cushing's syndrome is relevant, I consider that this article presents some aspects that need to be discussed.

 

The case is poorly described. The signs and symptoms of Cushing's syndrome are not properly described. Arterial hypertension, dyslipidemia and T2DM are mentioned in the abstract but not in text.  Was osteoporosis the leading symptom? Was the patient taking any medication?

The history of the fractures is not detailed (number? location? date? type of trauma?). All these aspects are of great importance for understanding the process.

We would like to thank the reviewer for the detailed revision of our manuscript.  We fully understand the reviewer’s concern. In the submitted version a large part of the first paragraph of the introduction was deleted, affecting significantly the understanding of the paragraph. We apologize for this. In the revised version of the manuscript all the details on the patient’s symptoms are described in detail.

“In May 2023, a 45-year-old woman was referred to our endocrinology department for further evaluation and management. The patient was already under medical treatment with olmesartan/amlodipine/hydrochlorothiazide for arterial hypertension since 2015. Additionally, she had undergone total hysterectomy with bilateral salpingo-oophorectomy due to a large benign uterine fibroid tumor (10x8 cm) in 2020 and was, subsequently, menopausal since the age of 42. She reported on regular menstruation prior to the surgical procedure. On further questioning, the patient reported on several previous fractures without relevant trauma (sternum 2015, middle phalanges of both indicators 2021, vertebral fractures involving T11 and L1 2022, sacrum 2022). She was diagnosed with osteoporosis in 2022 and has been under denosumab treatment, 60 mg every 6 months, since then. Furthermore, she was diagnosed with dyslipidemia and type 2 diabetes mellitus (T2DM) 2 months prior to her presentation in our outpatient clinic and treatment with atorvastatin/ezetimibe and metformin had been initiated, respectively.” (lines 65-77)

 

The patient appears to have an oncological history - this is poorly detailed (tumour? location? systemic therapy?). A metastasic disease is mentioned in the figure, but not in the text.

We understand the reviewer’s comment, particularly taking into account that the medical history was insufficiently presented due to the missing paragraph in the initially submitted manuscript. In fact, the patient never had an oncological history. A total hysterectomy had been performed due to a benign fibroid tumor of the uterus. For the adrenal mass, the suspicion of a cortisol-producing adrenal adenoma was raised and was then confirmed in the pathology report.

However, during the preoperative work-up, the chest X-ray presented several nodular opacities which were suspect for pulmonary infection (fungal, tuberculosis etc.) or for metastatic disease. To further clarify this finding, a thorax CT scan was performed. This excluded the presence of any pulmonary lesions but identified several old porotic costal fractures. Thus, all these opacities in the X-ray were old porotic costal fractures, which appeared pretty similar to metastatic disease.

To clarify this uncertainty, besides from the detailed medical history presented in the revised version of the manuscript, we added following statement.

“Thus, an infectious or a metastatic disease could be excluded.” (line 122)

 

It is mentioned that she had a bilateral salpingo-oophorectomy - was the patient oestrogen deficient? was she treated with oestrogens? All these aspects are very poorly discussed in the text and are crucial in the assessment of osteoporosis, since they could be the cause of secondary osteoporosis.

We fully understand the reviewer’s concern. In the revised version of the manuscript this issue is discussed in detail to clarify any uncertainties.

“Interestingly, in our case, the time lapse between the first fragility fracture and the final diagnosis of CS was particularly long, over eight years, unlike previous cases described in the literature. Additionally, as the medical history of our patient was complicated by early menopause at the age of 42, because of total hysterectomy with bilateral salpingo-oophorectomy, the accumulation of fractures could also be attributed to this later diagnosis. Still, estrogen depletion documented in our patient only began after the surgical intervention (in 2020), whereas the first osteoporotic fractures occurred several years in advance (sternum fracture 2015). Of course, an additive effect of early menopause in the already disturbed bone metabolism in our patient should be considered. Further signs such as arterial hypertension and dyslipidemia could also be recognized as menopausal consequences. However, when the diagnosis of CS was suspected, several other clinical signs, such as the plethora of the face and upper part of the chest, thin skin with several bruises, bilateral leg edema and muscle weakness were apparent and indicative of a florid CS as this was documented in the recently introduced model to estimate the pre-test probability of Cushing's syndrome according to the Cushing Score.” (lines 161-175)

 

The discussion includes a review of the literature, but does not address the diagnosis and origin of osteoporosis in this patient. The search criteria for the review are poorly stated, without detailed inclusion and exclusion criteria, which could lead to case selection bias. Furthermore, the literature review is poor and adds little value to previous publications.

According to the reviewer’s suggestion we added the details on the search-, inclusion- and exclusion-criteria in the revised version.

“To further elucidate common characteristics in the occurrence of osteoporotic fractures in patients with endogenous CS, we performed a literature review, using “Cushing Syndrome”, “osteoporotic”, “fractures” as search terms ((cushing disease[MeSH Terms]) OR (cushing syndrome[MeSH Terms])) AND (fracture, osteoporotic[MeSH Terms]) and included only case reports providing information on the occurrence and location of osteoporotic fractures and BMD data in patients with endogenous CS, excluding articles without biochemical information on hypercortisolism, or review articles. We further included case reports identified from the references of other articles.” (lines 176-183)

Furthermore, we performed a comparison of the different characteristics of our case with the ones already described in the literature.

“Inversely, only three cases (3/19) presented at least one peripheral fracture, including the present case.” (lines 194-195)

“Accordingly, our patient, who suffered from both vertebral and non-vertebral fractures, displayed increased 24h UFC levels and an absent cortisol suppression upon DST” (lines 197-199)

“Interestingly, though, in five of the cases, these comorbidities have only been recognized on the occasion of the fractures, as occurred in our patient” (lines 202-203)

“In line with this observation, in our case report, the patient had experienced the first fracture over 8 years prior to diagnosis” (lines 211-212)

“Our patient, who presented both vertebral and non-vertebral fractures displayed a low BMD corresponding to osteoporosis. However, as the measurement of BMD only occurred several years after the appearance of the first fragility fracture, we cannot exclude a linear evolvement from osteopenia to osteoporosis in our case.” (lines 219-223)

 

Comments on the Quality of English Language

There are long sentences that make reading difficult.

There are interrupted sentences with latinisms that are not understood ("The patient approvaernum 2015, middle phalanges of both indicators 2021, vertebral fractures affecting T11 and L1 2022, sacrum 2022)", line 61)

We apologize for this. In the submitted version a large part of the first paragraph of the introduction was deleted, affecting significantly the understanding of the paragraph. As previously described, this was adequately corrected in the revised version of the manuscript.

 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Overall, the case is much improved. I have a few suggestions. I think the analysis of abnormal bone metabolism should establish a better connection with Cushing's syndrome. Is there any difference in the relationship of bone metabolism and Cushing's syndrome between this patient and previous case reports? Adding this analysis can elevate the discussion section. In addition, evidence regarding the standardization of functional testing can be provided to enhance persuasiveness regarding the exclusion of pseudocushings.

Comments on the Quality of English Language

The manuscript has been thoroughly revised and is now much improved.

Author Response

We would like to thank the reviewer for his comments. Therefore, we added the following text in the revised version of the manuscript.

“In our case, the first described sternum fracture could timely correlate with the first phase of bone resorption occurring at the onset of hypercortisolism, while the subsequent vertebral fractures could timely coincide with both the inhibition of new bone formation due to chronic hypercortisolemia and the early estrogen deprivation after total hysterectomy. Despite the missing TBS data in our patient, the long duration of the CS appears in line with the observation about its role in CS, attributing long-term exposure to increased cortisol levels a pivotal role for the development of osteoporotic fractures. This observation could also be confirmed for several of the cases reviewed herein.” (lines 244-251)

“The patient did not smoke, drink alcohol or present major emotional lability.” (lines 78-79) “According to the diagnostic algorithm for the diagnosis of CS, the insufficient cortisol suppression upon 1 mg DST and the repeatedly elevated 24h UFC in the absence of physiological conditions associated with hypercortisolism, as in our case, are confirmatory of a CS. As no equivocal results were present at any time in our hormonal investigations, no further functional testing was indicated, and the diagnosis of CS was established.” (lines 117-121)

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

In this revised version, the authors have made significant improvements to the original manuscript, including updates in the case description, literature review, and discussion, which help clarify the case and underscore its relevance.

 

However, a few areas still require attention:

 

CASE.

-         The patient was diagnosed with arterial hypertension in 2015 and experienced a sternum fracture that same year. Did she show any other signs of hypercortisolism at that time, such as weight gain, glucose intolerance, or depression? The presence of mild symptoms of CS would help establish causality between the fractures and CS.

 

-              Since the sternum fracture occurred eight years before the diagnosis of CS, it should be better characterized (e.g., trauma, diagnosis, symptoms). Justifying this fracture as osteoporotic is essential to highlight this case's scientific interest.

 

-              Are there previous thoracic X-rays? Could the timing of the costal fractures be estimated?

 

-              In the imaging studies performed during the diagnosis and treatment of the uterine fibroid tumor, is there any evidence of adrenal gland lesions in retrospect?

 

-              I recommend major changes in the paragraph beginning on line 115 about suspected metastatic disease. Stating that multiple costal fractures were accidentally discovered in a preoperative thoracic X-ray and confirmed by CT would be more straightforward and less confusing.

 

LITERATURE REVIEW AND DISCUSSION

-   I suggest including a flowchart of the review process, detailing the number of papers reviewed, excluded, and added throw literature. Also, specify the publication dates and languages used.

 

-        The time frame from the occurrence of fractures to the diagnosis of CS should be numerically clarified (line 210).

 

Other minor comments:

 

ABSTRACT.

-              Consider removing the word "even" on line 22, as low-impact fractures are especially relevant to diagnosing osteoporosis.

 

-              The final two sentences, “In summary, fragility fractures because of osteoporosis with simultaneous altered bone architecture are a frequent finding in CS” (line 24) and “A delayed diagnosis of CS in these patients, with, sometimes, previous accumulation of such fractures before screening for the disease is a worrisome observation and should be considered in everyday clinical practice in order to improve timely diagnosis and treatment of CS, to avoid further complications” (line 26), add limited value compared to the rest of the abstract. I suggest either deleting or rephrasing them for clarity.

 

CONCLUSION

-              I recommend removing the sentence, “Interestingly, our patient displayed peculiar radiological findings raising suspicion for further clinical manifestations of CS (possibility of opportunistic fungal infections, tuberculosis or metastatic disease), complicating her management” (line 248), as it may be confusing and is not particularly relevant to this case.

Comments on the Quality of English Language

There are very long sentences that make the text difficult to read. For example, “However, when the diagnosis of CS was suspected, several other clinical signs, such as the plethora of the face and upper part of the chest, thin skin with several bruises, bilateral leg edema and muscle weakness were apparent and indicative of a florid CS as this was documented in the recently introduced model to estimate the pre-test probability of Cushing's syndrome according to the Cushing Score” (line 171). Shortening sentences like this would improve readability.

 

Author Response

In this revised version, the authors have made significant improvements to the original manuscript, including updates in the case description, literature review, and discussion, which help clarify the case and underscore its relevance.

However, a few areas still require attention:

 

CASE.

-         The patient was diagnosed with arterial hypertension in 2015 and experienced a sternum fracture that same year. Did she show any other signs of hypercortisolism at that time, such as weight gain, glucose intolerance, or depression? The presence of mild symptoms of CS would help establish causality between the fractures and CS.

 We fully understand the reviewer’s comment. One year prior to the diagnosis of arterial hypertension and sternum fracture in 2015, the patient had developed facial plethora but a rheumatological and dermatological investigation that included skin biopsy could not classify her facial redness to any condition. The patient did not smoke or consume any alcohol neither reported on major emotional lability. No glucose intolerance or weight gain was documented at the time.  Therefore, the following information was added to the revised version of the manuscript.

“The patient reported on the appearance of facial plethora since 2014 that was investigated with rheumatological and dermatological consultation and even a skin biopsy, which, however, could not classify this finding in any clinical condition.” (lines 66-68)

“The patient did not smoke, drink alcohol or present major emotional lability.” (lines 78-79)

-              Since the sternum fracture occurred eight years before the diagnosis of CS, it should be better characterized (e.g., trauma, diagnosis, symptoms). Justifying this fracture as osteoporotic is essential to highlight this case's scientific interest.

According to the patient’s information, the sternum fracture occurred upon muscular contraction, while she was pushing a door to close. Due to the thoracic pain, the patient sought medical attention, and the X-ray revealed a fresh sternum fracture.

-              Are there previous thoracic X-rays? Could the timing of the costal fractures be estimated?

Unfortunately, the patient, who lives in a remote place in the country could not provide us with older X-rays to perform such a comparison.

-              In the imaging studies performed during the diagnosis and treatment of the uterine fibroid tumor, is there any evidence of adrenal gland lesions in retrospect?

We fully agree that such a finding would be very interesting. However, imaging studies for the investigation of the uterine fibroid tumor only included an ultrasound and an MRI of the lower abdomen which, as expected, documented the large fibroid tumor but did not depict the adrenal glands.

-              I recommend major changes in the paragraph beginning on line 115 about suspected metastatic disease. Stating that multiple costal fractures were accidentally discovered in a preoperative thoracic X-ray and confirmed by CT would be more straightforward and less confusing.

According to the reviewer’s recommendation, the paragraph was amended as follows:

“As part of her preoperative assessment, she had a chest X-ray (Figure 3) where multiple round-shaped nodular opacities were accidentally discovered. The subsequent chest computerized tomography (CT) confirmed these as old porotic costal fractures (Figure 4), excluding suspicion for infection or metastasis.” (lines 125-128)

LITERATURE REVIEW AND DISCUSSION

-   I suggest including a flowchart of the review process, detailing the number of papers reviewed, excluded, and added throw literature. Also, specify the publication dates and languages used.

 As recommended by the reviewer this information have been added in the revised version of the manuscript. A PRISMA flow diagram is now also inserted to further clarify the review process. Following text was added in the revised version of the manuscript:

“To further elucidate common characteristics in the occurrence of osteoporotic fractures in patients with endogenous CS, we performed a literature review, using “Cushing Syndrome”, “osteoporotic”, “fractures” as search terms ((cushing disease[MeSH Terms]) OR (cushing syndrome[MeSH Terms])) AND (fracture, osteoporotic[MeSH Terms]) on the 30^th of April 2024. We did not define a time frame for the search but included only case reports providing information on the occurrence and location of osteoporotic fractures and BMD data in patients with endogenous CS, excluding articles on exogenous CS or other conditions related to hypercortisolism, reports without biochemical information on hypercortisolism, review articles and records in other than English language. We further included case reports identified from the references of other articles (PRISMA flow diagram - Figure 5).” (lines 182-191)

-        The time frame from the occurrence of fractures to the diagnosis of CS should be numerically clarified (line 210).

According to the reviewer’s suggestion, a timeline was added in figure 1 to clarify the occurrence of each sign and symptom.

Other minor comments:

 ABSTRACT.

-              Consider removing the word "even" on line 22, as low-impact fractures are especially relevant to diagnosing osteoporosis.

 According to the reviewer’s recommendation, the word was omitted.

-              The final two sentences, “In summary, fragility fractures because of osteoporosis with simultaneous altered bone architecture are a frequent finding in CS” (line 24) and “A delayed diagnosis of CS in these patients, with, sometimes, previous accumulation of such fractures before screening for the disease is a worrisome observation and should be considered in everyday clinical practice in order to improve timely diagnosis and treatment of CS, to avoid further complications” (line 26), add limited value compared to the rest of the abstract. I suggest either deleting or rephrasing them for clarity.

According to the reviewer’s recommendation, these sentences are now rephrased as follows:

“In summary, a delayed diagnosis of CS in patients, with previous accumulation of such fractures is a worrisome observation and should be considered in everyday clinical practice in order to improve timely diagnosis and treatment of CS.” (lines 24-27)

CONCLUSION

-              I recommend removing the sentence, “Interestingly, our patient displayed peculiar radiological findings raising suspicion for further clinical manifestations of CS (possibility of opportunistic fungal infections, tuberculosis or metastatic disease), complicating her management” (line 248), as it may be confusing and is not particularly relevant to this case.

According to the reviewer’s recommendation, the sentence was omitted.

Comments on the Quality of English Language

There are very long sentences that make the text difficult to read. For example, “However, when the diagnosis of CS was suspected, several other clinical signs, such as the plethora of the face and upper part of the chest, thin skin with several bruises, bilateral leg edema and muscle weakness were apparent and indicative of a florid CS as this was documented in the recently introduced model to estimate the pre-test probability of Cushing's syndrome according to the Cushing Score” (line 171). Shortening sentences like this would improve readability.

According to the reviewer’s suggestion, such long sentences are now rephrased in the revised version of the manuscript to ensure clarity and readability.

Author Response File: Author Response.docx