CASE REPORT
Check for updates
Multiple pathological bone fractures in a dog with adrenal-dependent Cushing’s syndrome
C. MELIÁN*1, L. PÉREZ-LÓPEZ+1, M. ENCINOSO1, F. SUÁREZ-CABRERAS, O. QUESADA-CANALESS AND J. R. JABERS
*Department of Animal Pathology, Faculty of Veterinary Medicine, University of Las Palmas de Gran Canaria, Las Palmas, Spain
*Faculty of Veterinary Medicine, Veterinary Teaching Hospital, University of Las Palmas de Gran Canaria, Las Palmas, Spain
Institute of Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria (ULPGC), Las Palmas, Spain $Department of Morphology, Faculty of Veterinary Medicine, University of Las Palmas de Gran Canaria, Las Palmas, Spain
1Corresponding author email: laura.perezlopez@ulpgc.es
Pathological bone fractures may occur secondarily to Cushing’s syndrome in people. Although low bone mineral density due to cortisol excess has been described in dogs, there is no evidence that dogs with Cushing’s disease can develop osteoporosis or secondary bone fractures. Here, we report a case of a dog with Cushing’s disease and multiple pathological bone fractures. A 14-year-old female spayed mixed-breed dog was attended due to progressive lethargy, weakness, difficulty moving, trem- bling and clinical signs of Cushing’s syndrome (polyuria, polydipsia, alopecia and abdominal disten- sion). After confirmation of the diagnosis of Cushing’s disease and 2 days after starting trilostane treatment (0.27 mg/kg every 12 hours), the dog presented to our hospital with reluctance to rise. In the computed tomography scan, decreased bone density in cervical and thoracic vertebrae, ribs scapu- lar bones and multiple rib fractures were detected. Despite 8 days of hospitalisation, reluctance to rise and walk persisted. Given the unfavourable progression of the diseases, the owner opted for euthana- sia. Post mortem evaluation confirmed a cortical carcinoma of the left adrenal gland and thin, irregular spicules and trabeculae of compact bone and reduced thickness of the cortex of the ribs.
Journal of Small Animal Practice (2025); 66, 514-520 DOI: 10.1111/jsap.13848
Accepted: 22 February 2025; Published online: 16 March 2025
INTRODUCTION
Spontaneous Cushing’s syndrome (CS) is a common endocri- nopathy in dogs, and most common clinical signs include poly- uria, polydipsia, polyphagia, weight gain and alopecia. Typically, clinical signs are initially mild and usually progressive, and the diagnosis is established after initiation of clinical manifesta- tions (Behrend et al., 2013), and sometimes the diagnosis can be a challenge since not all patients show all signs and the clini- cal presentation can be variable. Some dogs with CS may also develop clinical signs related to calcium metabolism alterations such as calcinosis cutis, soft tissue mineralization and calcium oxalate urolithiasis (Ramsey et al., 2005). In humans, osteoporo- sis and pathological bone fractures are well described in patients with CS (Lee et al., 2014). Glucocorticoid-induced osteoporo- sis due to hypercortisolism can occur in 40% to 70% of people with CS (Trementino et al., 2014), whereas bone fractures may occur in 30% to 50% of them (Braun et al., 2019). To date,
Bone fractures in a dog with Cushing’s syndrome
it is not clear whether similar metabolic alterations might occur in dogs. In fact, osteocalcin, which participates in bone forma- tion, is reduced in humans with Cushing’s syndrome, but normal concentrations have been reported in dogs with hypercortisolism (Mooney et al., 2020; Szulc, 2020). Nonetheless, in dogs with CS, low bone mineral density has been reported previously (Lee et al., 2015). The following databases (PubMed, Google Scholar and Scopus) have been searched with the following keywords, ‘bone fractures’, ‘bone mineral density’, ‘osteoporosis’, ‘Cushing’s syndrome’, ‘dogs’, ‘hypercortisolism’. No previous reports of pathological fractures in dogs with Cushing’s disease were found.
CASE HISTORY
A 14-year-old female spayed mixed-breed dog was presented at the Veterinary Teaching Hospital of the University of Las Palmas de Gran Canaria, due to progressive lethargy, weakness, diffi- culty moving, stiff gait, trembling and alopecia. The dog was fed with a balanced commercial diet. Detailed history and physical
A
B
C
D
examination revealed a 1-year duration of polyuria, polydip- sia, distended abdomen, muscle wastage, and hair thinning and alopecia in the neck, trunk and tail (Fig 1). Routine blood tests showed markedly erythrocytosis, increased liver enzymes (alkaline phosphatase, alanine aminotransferase and gamma- glutamyl transferase) and cholesterol, low normal total calcium (2.1 mmol/L), and normal phosphorus (1.8 mmol/L), creati- nine (132.6 µmol/L), albumin and total protein concentrations. Urinalysis revealed isosthenuria (SG 1.008), severe proteinuria (urine protein to creatinine ratio 30.8, reference range <0.6) and elevated urine cortisol to creatinine ratio (UCCR 9.1 x 10-5, ref- erence range from 10 × 10-6 to 30 × 10-6). In addition, Escherichia coli was isolated on the urine culture. Blood pressure was mea- sured by Doppler ultrasonography and systolic hypertension (190 mmHg) was detected. A low-dose dexamethasone sup- pression test was performed, showing lack of suppression pat- tern [cortisol concentrations at 0 hour: 190.3 nmol/L, 4 hours: 182.0 nmol/L and 8 hours: 107.6 nmol/L after administration of 0.015 mg/kg of IV dexamethasone (sodium phosphate)]. Serum cortisol was measured by chemiluminescence (Immulite 1000®, Siemens Medical Solutions, Madrid). Findings on abdominal ultrasound evaluation included increased thickness of the left adrenal gland with a maximal dorsoventral thickness of 8.9 mm, decreased thickness of the right adrenal gland with a maximal dorsoventral thickness of 3.3 mm, gallbladder mucocele and focal mineralization of spleen. The dog was initially treated with cephalexin (Cefazolina®, Normon, Spain) for the urinary tract infection (14 mg/kg/12 hours), benazepril 0.28 mg/kg/12 hours (Fortekor®, Elanco, Spain) for hypertension and proteinuria, and trilostane 0.27 mg/kg/12 hours (Vetoryl®, Dechra, Spain) for CS.
Two days after initial treatment, the dog was presented at the hospital with progressive difficulty, pain and reluctance rising. Body temperature was normal and the dog was normotensive.
A
*
B
*
A
B
*
*
Bone fractures in a dog with Cushing’s syndrome
A
B
Value: 122.000
2D Pos: X.291.540 px Y:135.721 px 3D Pos: X:15.188 mm Y :- 13.936 mm Z :- 784.318 mm
Value: 698.000
2D Pos: 405.462 px Y:187.559 p: 3D POS: X+13.625 mm Y:4.732 mm
C
D
Value: 489.000
2D Pos: X:766.519 p 3D Pos: X:11.088 ml
Point 2
Value: 107.000
20 Pos: X:244.290 px Y:245.364 3D Pos: X:9.152 mm Y:8.329 mm
A
B
C
0
*
*
*
*
*
Pathological bone fractures and other differential diagnosis such as severe muscle stiffness secondary to hypercortisolism, traumatic fractures, osteoarthrosis, polyarthritis, intervertebral disc disease or neoplasia were considered. Radiographic assessment suggested osteopenia in the ribs and the cervical, thoracic, lumbar and sacral vertebrae performing right lateral views of the cervical region, tho- rax and abdomen (Fig 2). Computed tomography (CT) scan of the cervical region revealed an increased size of external parathyroid (PT) glands with a thickness of 4.45 mm in the left PT gland and 4.5 mm in the right PT gland (Fig 3). The CT scan of the abdomi- nal region demonstrated left adrenomegaly (Fig 4) and diminished bone density in cervical and thoracic vertebrae, ribs and scapular bones (Figs 5 to 7). Bone density measurements in Hounsfield units (HU) in the affected dog were notably lower in comparison to a control female dog that was similar in age and weight to the affected dog and had no analytical abnormalities. This control dog under- went CT scan due to intervertebral disc disease. The lower bone mineral density of the dog with CS compared to the control dog was particularly observed in the vertebral bodies of the cervical (HU 122 versus 698) and thoracic (HU 107 versus 489) vertebrae (Fig 6) and ribs (HU 15 versus 494). The CT scan using bone window
settings revealed multiple rib fractures at different stages of chronic- ity (Fig 7). Chronic fractures showed osteoproliferation and recent fractures displayed fracture lines. The dog was hospitalised and analgesia (Tramadol 2 mg/kg/12 hours, Tramvetol®, Virbac, Spain) was added to the previous treatment. Despite 8 days of hospitalisa- tion, reluctance to rise and walk persisted. Given the unfavourable progression of the diseases, the owner opted for euthanasia.
The post mortem evaluation described a cortical carcinoma in the left adrenal gland, diffuse cortical atrophy of the right adrenal gland, moderate-to-severe bilateral hyperplasia of para- thyroid glands, gallbladder mucocele and pulmonary multifocal mineralization. Histopathological evaluation of the ribs demon- strated thin, irregular, heterogeneous and discontinuous spicules and trabeculae of compact bone and reduced thickness of the cortex (Fig 8).
DISCUSSION
In humans, glucocorticoid excess is a known cause of bone resorption, suppression of osteoblastogenesis and impaired bone
A
B
C
D
Bone fractures in a dog with Cushing’s syndrome
formation, which could lead to secondary osteoporosis and pathological bone fractures, with vertebrae and ribs being the most frequent site of fractures (Ebeling et al., 2022; Trementino et al., 2014). Similarly, in this case report, the dog had decreased bone density in cervical and thoracic vertebrae, ribs, and scapu- lae, and pathological rib fractures. In accordance with the obser- vations made in this dog, some studies have found lower bone mineral density and lower trabecular bones volume in dogs with spontaneous and iatrogenic CS compared to healthy dogs (Costa et al., 2010; Lee et al., 2014, 2015; Nordin et al., 1998).
In people, not all patients with bone fractures secondary to CS have low bone mineral density; there are more intricate alterations within bone microstructure that are produced by cortisol excess, and recent studies have demonstrated that assessing trabecular bone score can predict fragility fractures independent of the bone mineral density (Ferraù et al., 2023). The effects of glucocorticoid excess on bone turnover in dogs are not yet fully understood, and if there is an association between pathological bone fractures and hypercortisolism is still unknown. Severity of hypercortisolism and the duration of time of CS has been considered as possi- ble risk factors for bone fracture in people (Belaya et al., 2015; Trementino et al., 2014). The lower life expectancy of dogs may be the reason for a possible lower prevalence of bone fractures in dogs with CS compared to humans with CS. In addition, it is also unknown if dogs with CS could suffer from asymptomatic fractures as it occurs in humans (Kaltas & Makras, 2010). In fact, osteoporotic fractures can be the main presenting sign of CS in people (Cheng et al., 2023; Lee et al., 2014), and therefore, the condition of CS should be considered as a differential diagnosis for pathological fractures in dogs without clinical signs of CS.
Increased levels of PTH, increased serum phosphate, increased urinary excretion of calcium, decreased vitamin D concentration and development of calcinosis cutis and soft tissue mineraliza- tion are known to occur in dogs with CS (Ramsey et al., 2005; Corsini et al., 2021; Tebb et al., 2005). Although PTH levels were not measured in this clinical case, secondary hyperparathy- roidism was suspected since the four parathyroid glands were hyperplastic, being primary hyperparathyroidism unlikely when all parathyroid glands are hyperplastic Interestingly, primary hyperplasia of human parathyroid glands can occur in inherited problems like multiple endocrine neoplasia syndromes (Van der Walt, 2012), and the combination of CS and primary hyperpara- thyroidism has been described in humans; usually as part of a multiple endocrine neoplasia (MEN), but rarely, they can con- current together out MEN conditions (Newman et al., 2021). Based on the literature search, it is unknown if this can occur in dogs with CS, although in this clinical case, primary hyperpara- thyroidism was considered unlikely because serum total calcium concentration was not increased (Skelly, 2017): and serum phos- phorus concentration was not low or low-normal (nonetheless, ionised calcium should have been measured for a more accurate evaluation of calcium status). In addition, hyperparathyroidism secondary to impaired kidney function was also unlikely since the dog presented normal serum creatinine concentration.
In humans, the bone mineral density can reach normal levels after surgical treatment of hypercortisolism (Kristo et al., 2006;
Lee et al., 2014; Tóth & Grossman, 2013). However, com- plete recovery may require several years (Kristo et al., 2006; Lee et al., 2014). Our patient was treated with a low dose of trilostane (0.27 mg/kg/12 hours), low doses of trilostane (0.2 to 1.1 mg/kg/12 hours) have been demonstrated to be enough to achieve good clinical response, to produce less adverse effects, and longer survival time compared to higher doses of trilostane (Cho et al., 2013; Feldman, 2011; García-San José et al., 2022). Unfortunately, our patient did not have enough time to achieve clinical improvement after medical treatment since the owner elected euthanasia. However, medical treatment of canine CS is important and normalisation of PTH concentration has been demonstrated after trilostane treatment in dogs with CS (Tebb et al., 2005). Therefore, we suspect that recovery of bone mineral density can be expected in dogs with CS after long-term successful treatment. Since initial clinical signs of the dogs with CS are usually mild, and they generally show increased appetite, owners may not recognise these as an early disease. However, it is important to highlight the importance of an early recognition and treatment of dogs with confirmed CS since it may prevent for further metabolic derangements including decreased bone mineral density and bone fractures along with risks such as pulmonary thromboembolism.
In conclusion, the findings presented in this case report could suggest that glucocorticoid-induced bone fractures may occur in dogs, and these should be suspected if a dog with CS shows pain or difficulty moving. However, further investigation of the bone alterations due to cortisol excess in dogs is still needed.
Acknowledgements
The authors thank the University of Las Palmas de Gran Canaria and Spanish Ministry of Universities for the Margarita Salas postdoctoral research contract given to LPL and granted by Order UNI/501/2021, as well as financing by the European Union-Next Generation EU Funds.
Author contributions
Carlos Melián: Data acquisition, writing - original draft, review and editing. Laura Pérez-López: Writing - original draft, review and editing. Mario Encinoso: Data acquisition, review and editing; Francisco Suárez-Cabrera: Manuscript review; Oscar Quesada-Canales: Data acquisition, manuscript review; Jose Raduan Jaber: Review and editing.
Conflict of interest
No conflicts of interest have been declared.
Data availability statement
The authors confirm that the data supporting the findings of this study are available within the article, data of the study is also available from the corresponding author upon reasonable request.
References
Behrend, E.N., Kooistra, H.S., Nelson, R., Reusch, C.E. & Scott-Moncrieff, J.C. (2013) Diagnosis of spontaneous canine hyperadrenocorticism: 2012 ACVIM
consensus statement (small animal). Journal of Veterinary Internal Medicine, 27, 1292-1304.
Belaya, Z.E., Hans, D., Rozhinskaya, L.Y., Dragunova, N.V., Sasonova, N.I., Solodovnikov, A.G. et al. (2015) The risk factors for fractures and trabecular bone-score value in patients with endogenous Cushing’s syndrome. Archives of Osteoporosis, 10, 44.
Braun, L.T., Riester, A., Obwald-Kopp, A., Fazel, J., Rubinstein, G., Bidlingmaier, M. et al. (2019) Toward a diagnostic score in Cushing’s syndrome. Frontiers in Endocrinology (Lausanne), 10, 766.
Cheng, J., Songli, J. & Zhang, Z. (2023) Osteoporotic vertebral compression frac- tures caused by Cushing’s syndrome in young women: case report and litera- ture review. BMC Musculoskeletal Disorders, 24, 167.
Cho, K.D., Kang, J.H., Chang, D., Na, K.J. & Yang, M.P. (2013) Efficacy of low- and high-dose trilostane treatment in dogs (<5 kg) with pituitary-dependent hyperad- renocorticism. Journal of Veterinary Internal Medicine, 27, 91-98.
Corsini, A., Dondi, F., Serio, D.G., Zamagni, S., Golinelli, S., Fernandez, M., et al. (2021). Calcium and phosphate homeostasis in dogs with newly diagnosed naturally occur- ring hypercortisolism. Journal of Veterinary Internal Medicine, 35, 1265-1273.
Costa, L.A.V.S., Lopes, B.F., Lanis, A.B., De Oliveira, D.C., Giannotti, J.G. & Costa, F.S. (2010) Bone demineralization in the lumbar spine of dogs submitted to prednisone therapy. Journal of Veterinary Pharmacology and Therapeutics, 33, 583-586.
Ebeling, P.R., Nguyen, H.H., Aleksova, A., Vincent, A.J., Wong, P. & Milat, F. (2022) Secondary osteoporosis. Endocrine Reviews, 43, 240-313.
Feldman, E.C. (2011) Evaluation of twice-daily lower-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism. Journal of the American Veterinary Medical Association, 238, 1441-1451.
Ferraù, F., Giovinazzo, S., Alessi, Y., Catalano, A., Tessitore, A., Mormina, E. et al. (2023) Trabecular bone score, bone marrow fat and vertebral fractures in Cushing syndrome. Endocrine, 80, 441-447.
García-San José, P., Arenas Bermejo, C., Alonso-Miguel, D., González-Sanz, S., Clares-Moral, I., Portero Fuentes, M. et al. (2022) Survival of dogs with pituitary-dependent hyperadrenocorticism treated twice daily with low doses of trilostane. The Veterinary Record, 191, e1630.
Kaltas, G. & Makras, P. (2010) Skeletal diseases in Cushing’s syndrome: osteopo- rosis versus arthropathy. Neuroendocrinology, 92, 60-64.
Kristo, C., Jemtland, R., Ueland, T., Godang, K. & Bollerslev, J. (2006) Restoration of the coupling process and normalization of bone mass following successful treatment of endogenous Cushing’s syndrome: a prospective, long-term study.
European Journal of Endocrinology, 154, 109-118. Available from: https://doi. org/10.1530/eje.1.02067
Lee, D., Lee, Y., Choi, W., Chang, J., Kang, J., Na, K. et al. (2015) Quantitative CT assessment of bone mineral density in dogs with hyperadrenocorticism. Journal of Veterinary Science, 16, 531-542.
Lee, H.J., Je, J.H., Seo, J.H., Na, Y.J. & Yoo, H.J. (2014) Mutiple spontaneous rib fractures in patient with Cushing’s syndrome. Journal of Bone Metabolism, 21, 277-282.
Mooney, C.T., Shiel, R.E., Sekiya, M., Dunning, M. & Gunn, E. (2020) A preliminary study of the effect of hyperadrenocorticism on calcium and phosphate concen- trations, parathyroid hormone and markers of bone turnover in dogs. Frontiers in Veterinary Science, 7, 311.
Newman, C., Costello, M., Casey, M., Davern, R., Dinneen, K., Lowery, A. et al. (2021) A case of adrenal Cushing’s syndrome and primary hyperparathyroidism due to an atypical parathyroid adenoma. Therapeutic Advances in Endocrinology and Metabolism, 31, 20420188211030160.
Nordin, R.W., Carpenter, T.R., Hamilton, B.F. & Brewster, R.D. (1998) Trabecular bone morphometry in beagles with Hyperadrenocorticism and adrenal adeno- mas. Veterinary Pathology, 25, 256-264.
Ramsey, I.K., Tebb, A., Harris, E., Evans, H. & Herrtage, M.E. (2005) Hyperparathyroidism in dogs with hyperadrenocorticism. The Journal of Small Animal Practice, 46, 351-356.
Skelly, B.J. (2017) Primary hyperparathyroidism. In: Ettinger, S.J., Feldmann, E.C. & Cote, E. (Eds.) Textbook of veterinary internal medicine, 8th edition. St. Louis, MO: Elsevier, pp. 4169-4190.
Szulc, P. (2020) Biochemical bone turnover markers in hormonal disorders in adults: a narrative review. Journal of Endocrinological Investigation, 43, 1409-1427.
Tebb, A.J., Arteaga, A.E., & Ramsey, I.K. (2005). Canine hyperadrenocorticism: effects of trilostane on parathyroid hormone, calcium and phosphate concentra- tions. Journal of Small Animal Pratice, 46, 537-542.
Tóth, M. & Grossman, A. (2013) Glucocorticoid-induced osteoporosis: lessons from Cushing’s syndrome. Clinical Endocrinology, 79, 1-11.
Trementino, L., Appolloni, G., Ceccoli, L., Marcelli, G., Concettoni, C., Boscaro, M. et al. (2014) Bone complications in patients with Cushing’s syndrome: looking for clinical, biochemical, and genetic determinants. Osteoporosis International, 25, 913-921.
Van der Walt, J. (2012) Pathology of the parathyroid glands. Diagnostic Histopathology, 18, 221-223.