Abstract:
Osteitis fibrosa cystica or brown tumor is a rare skeletal manifestation of hyperparathyroidism. Awareness of this condition is imperative to making a correct diagnosis. We present a case with multiple pathological fractures who had undergone extensive workup for malignancy before reaching the definitive diagnosis of primary hyperparathyroidism.
KEYWORDS
brown tumor, hyperparathyroidism, osteitis fibrosa cystica
INTRODUCTION
Primary hyperparathyroidism is an endocrine disorder arising due to excessive production of parathyroid hormone, which if uncontrolled, results in deranged calcium homeostasis. Chronic exposure to parathyroid hormone leads to increased bone turnover that culminates into generalized osteopenia or multiple osteolytic bone lesions namely osteitis fibrosa cystica.1This pathological process makes bone susceptible to fracture even with minor trauma.2In most instances, the clinical diagnosis of this condition is challenging and radiographic findings can be counterproductive as they often mimic features of primary bone neoplasm or metastatic bone disease.3,4As a consequence, the duration of illness can be quite protracted before arriving at an accurate diagnosis adding to the physical, mental, and financial burden on the patient. In this instance, we present a case of 40 years male who had multiple pathological fractures initially thought to be due to multiple myeloma but later turned out to be the skeletal manifestation of primary hyperparathyroidism.
CASE REPORT
40 yrs male presented to our center, who was bedridden due to unremitting pain in the hip, arm, and buttock region for 7 months. He has had multiple hospital visits with a myriad of diagnostic investigations. He had a history of fractures sustained over the left shoulder after a fall injury from standing height 5 months back for which he was referred to the higher center for the pathological fracture. Initial review of records revealed an osteolytic lesion in the left clavicle, left humerus and femur on plain radiographs (Figure 1), and blood parameters showed calcium 11.8mg/dL (8.5 - 11.0 mg/dL), alkaline phosphatase (ALP) 2258 U/L (98 - 279 U/L), erythrocyte sedimentation rate (ESR) 40mm/hr (0-20 mm/hr ), serum creatinine 1.2 mg/dL (0.9 - 1.4 mg/dL), serum urea 30mg/dL (10 - 50mg/dL), hemoglobin 11.2gm% (12 -16), total leukocyte count 9,190 cells/cumm (4000 - 11,000) and plenty of red blood cells in urinalysis. Ultrasonography of abdomen/pelvis reported bilateral nephrolithiasis and cholelithiasis. Contrast-enhanced computed tomography (CECT) and Magnetic resonance imaging (MRI) of the pelvis and hip reported multiple expansile lytic lesions in the pelvis and bilateral femurs (Figure 2). Meanwhile, he had a history of left subtrochanteric femur fracture 3 months back followed by a right proximal third femur fracture two weeks later after sustaining a fall injury from standing height. The patient was then referred to the cancer center, where further workup with bone marrow biopsy and urine electrophoresis was inconclusive for multiple myeloma and tumor markers were within the normal limits.
The patient then visited to the Department of Endocrinology of our center one month back and further blood investigations were performed in the line of hyperparathyroidism: calcium 15.9 mg/dL (8 - 11), phosphorus 2.8 mg/dL (2.5 - 5), serum parathyroid hormone (PTH) 1959.4 pg/mL (11.1 - 79.5), vitamin D 31.88 ng/mL (30 - 80), hemoglobin 9.3 gm/dL (12 - 16), platelet 161,000 cells/cumm (150,000 - 400,000), creatinine 1.31 mg/dL (0.4 - 1.4). Iron studies showed ferritin 915.5 ng/mL (22-322), iron 50 μg/dL (50 - 175) and total iron binding capacity (TIBC) 292 μg/dL (250 -450). The patient was admitted and was managed immediately for hypercalcemia with intravenous fluid normal saline, intravenous furosemide, and intravenous Zoledronate 5 mg under close monitoring after which his calcium level reduced to 10.44 mg/dL on the next day. Serum calcium and potassium were monitored daily over the subsequent days. The patient underwent further diagnostic evaluation via Tc99m sestamibi (Figure 3), and an ultrasound of the neck suggesting the parathyroid lesion.
He underwent a partial parathyroidectomy after reviewing the case from the Department of Otorhinolaryngology. His intraoperative PTH level declined abruptly by 91% (173.8 pg/mL). Postoperatively, intravenous antibiotics and intravenous calcium gluconate 10% bolus were given. Subsequent histopathology was suggestive of parathyroid adenoma (Figure 4). On the second postoperative day, he developed an episode of hypocalcemia along with “hungry bone syndrome” as the subsequent investigation showed calcium 7.11 mg/dL (8 - 11) and PTH 5.5 pg/mL (18.5 - 88), albumin 2.57 gm/dL (3.4 - 5.5). He also complained of a tingling sensation around his mouth and in both of his hands and feet. He was then managed with an infusion of calcium gluconate at the rate of 100 mL/hr for 3 days along with a high dose of calcitriol 1 mcg/day and calcium carbonate 1500 mg/day + vitamin D3 750 IU/day. The patient’s symptoms gradually improved and were discharged with a reduced daily dose of calcitriol, calcium carbonate + vitamin D3, and once monthly dose of cholecalciferol 60,000 IU.
DISCUSSION
Osteitis fibrosa cystica or brown tumor is one of the severe manifestations of prolonged hyperparathyroidism resulting from excess osteoclast activity consisting of collections of osteoclasts intermixed with fibrous tissue and cancellous bone. The brown coloration is due to hemosiderin deposition.2,4It appears as a well-defined expansile osteolytic lesion with osteopenia on plain radiographs, and various bone erosion and cortical attenuation on CT while MRI imaging show hypointense on T1-weighted images, hypo-intense or hyperintense on T2-weighted images.4,5Brown tumor is a non-neoplastic lesion with the reported incidence in primary hyperparathyroidism of 3%.6Primary hyperparathyroidism manifests with a wide array of clinical features that includes bone fracture, kidney stones, abdominal pain, and psychiatric disturbances.7And in most cases, the brown tumor eventually regresses following normalization of the parathyroid levels.8–10
The diagnosis of the brown tumor can be challenging and misleading in various aspects. The differential diagnosis of brown tumor includes metastasis, giant cell tumor, giant cell reparative granuloma, aneurysmal bone cyst, multiple myeloma, and non-ossifying fibroma. The multiple expansile osteolytic lesions on the radiograph can be misleading to the primitive bone neoplasm and bone metastasis.5It also becomes difficult to solely make a diagnosis on basis of a histopathological point of view as a surgical bone biopsy can be inconclusive.3,4Because these conditions resemble one another on imaging and histopathology, the index case has primarily gone through extensive workup for malignancy and developed multiple pathological fractures in the meantime. In the differential diagnosis of osteolytic bone lesions, it is essential to pay attention to calcium and phosphorous homeostasis. Clinicians need to have a high suspicion of a brown tumor when their abnormal level accompanies the raised parathyroid hormone level.2The overactivity of the parathyroid gland can be triggered by hereditary factors, parathyroid carcinoma, parathyroid adenoma, or renal osteodystrophy. Of patients with primary hyperparathyroidism, 80-85% account for parathyroid adenoma.11Thus, the rise in parathyroid hormone concentration along with the ultrasonography of the neck and Tc99m sestamibi facilitate the diagnosis of parathyroid adenoma.3
The definitive management of primary hyperparathyroidism is parathyroidectomy and literature has reported intraoperative PTH decrease by 50% or more which is in accordance with the index case.12,13When parathyroidectomy is performed, partial or even total regression of the brown tumor has been reported in several studies.11,14,15Unfortunately, we could not evaluate the eventual regression pattern of the brown tumor after a successful parathyroidectomy.
This case report emphasizes brown tumors to be considered as the differential diagnosis of multiple osteolytic lesions when abnormal calcium and phosphorous accompany the high concentration of parathyroid level. Thus, awareness regarding this condition can avoid unnecessary investigations along with timely diagnosis and treatment.

AUTHOR CONTRIBUTIONS

SS, SL, SS, SK, and SD wrote the manuscript. SS and SL reviewed and edited the manuscript. All authors accepted the final version.

ACKNOWLEDGMENTS

We would like to thank Dr. Umesh Bartaula for providing us with the histology pictures.

CONFLICT OF INTEREST

None declared.

ETHICAL APPROVAL

Written informed consent was obtained from the patients. Formal approval was not necessary for a case report in our hospital setting.

CONSENT

Written informed consent was obtained from the patient in accordance with the journal’s patient consent policy.
REFERENCES
1. Grey AB. The skeletal effects of primary hyperparathyroidism. Baillieres Clin Endocrinol Metab. 1997 Apr;11(1):101–16.
2. Wasiak M, Popow M, Bogdańska M, Starzyńska-Kubicka A, Ma\ldyk P, Wasilewski P. Treatment of pathological fractures due to brown tumours in a patient with hyperparathyroidism and lack of parafibromin expression – A case report. Trauma Case Rep. 2020;30(October):100367.
3. Vaishya R, Agarwal AK, Singh H, Vijay V. Multiple ‘Brown Tumors’ Masquerading as Metastatic Bone Disease. Cureus. 2015;7(12).
4. Lee JH, Chung SM, Kim HS. Osteitis fibrosa cystica mistaken for malignant disease. Clin Exp Otorhinolaryngol. 2013;6(2):110–3.
5. Hu J, He S, Yang J, Ye C, Yang X, Xiao J. Management of brown tumor of spine with primary hyperparathyroidism : A case report and literature review. Med U S. 2019;98(14).
6. Fazaa A, Makhlouf Y, Miladi S, Sellami M, Ouenniche K, Souebni L, et al. Hyperparathyroidism: Unusual location of brown tumors. Clin Case Rep. 2022;10(2):1–5.
7. Silverberg SJ, Bilezikian JP. Chapter 66. Primary Hyperparathyroidism. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. John Wiley & Sons, Ltd; 2008 [cited 2022 Aug 14]. p. 301–6.
8. Dagang DJT, Gutierrez JB, Sandoval MAS, Lantion-Ang FL. Multiple brown tumours from parathyroid carcinoma. Case Rep. 2016 Jun 29;2016:bcr2016215961.
9. Panagopoulos A, Tatani I, Kourea HP, Kokkalis ZT, Panagopoulos K, Megas P. Osteolytic lesions (brown tumors) of primary hyperparathyroidism misdiagnosed as multifocal giant cell tumor of the distal ulna and radius: a case report. J Med Case Reports. 2018 Jun 25;12(1):176.
10. Minisola S, Gianotti L, Bhadada S, Silverberg SJ. Classical complications of primary hyperparathyroidism. Best Pract Res Clin Endocrinol Metab. 2018 Dec;32(6):791–803.
11. Mantar F, Gunduz S, Gunduz UR. A reference finding rarely seen in primary hyperparathyroidism: Brown tumor. Case Rep Med. 2012;2012:6–9.
12. Madkhali T, Alhefdhi A, Chen H, Elfenbein D. Primary hyperparathyroidism. Turk J SurgeryUlusal Cerrahi Derg. 2016 Mar 1 [cited 2022 Aug 13];32(1):58–66.
13. Jain N, Reilly RF. Hungry bone syndrome. Curr Opin Nephrol Hypertens. 2017 Jul;26(4):250–5.
14. Hadad Z, Tjelum L, Eiken P, Trolle W, Haupter I, Afzelius P. Multiple brown tumors caused by primary hyperparathyroidism as a differential diagnosis to multiple osteolytic bone metastases: A case report. J Endocrinol Metab. 2020;10(3–4):94–100.
15. De Crea C, Traini E, Oragano L, Bellantone C, Raffaelli M, Lombardi CP. Are brown tumours a forgotten disease in developed countries? Acta Otorhinolaryngol Ital. 2012;32(6):410–5.