Overt metabolic bone failure as the initial manifestation of neglected primary hyperparathyroidism: An unusual presentation and review of current practice guidelines

Abstract

Varied symptomatology exists in hyperparathyroidism. The current approaches and evaluation of altered calcium homeostasis have led to the practice of early identification and subsequent management of the adenomas. Hence, bony manifestations (deformities, lesions, and fractures) termed to be end stage of bone metabolism failure, have rarely been encountered in the last two decades. We report this infrequent presentation in a 47-year-old female, who visited the emergency department following a trivial fall. Her background history recorded left superior parathyroidectomy three months prior to fall. The clinical and radiological evaluations were suggestive of insufficiency fractures of right proximal humerus and right shaft of femur, multiple lytic lesions and other bony manifestations pathognomonic of hyperparathyroidism. Metabolic profile revealed a primary cause despite prior adenectomy, and targeted scintigraphy demonstrated a hyper-functioning right inferior parathyroid gland. The high resolution ultrasound used before the prior surgery failed to localise additional hyper-functioning glands. Post-parathyroidectomy, the hungry bone disease was adequately managed. The femur fracture required surgical stabilization. In conclusion, bony manifestations of hyperparathyroidism can be disabling and difficult to treat. Although a rare clinical presentation, the severity of bony manifestations arise from a preventable cause and that the initial evaluation of hyperparathyroidism should also include parathyroid scintigraphy, and not limited to screening of the neck with ultrasonography, for its combined additive information and improved diagnostic value.

1. Introduction

Primary hyperparathyroidism is one of the most common endocrine disorders.¹ The diagnosis is usually established in acute presentations which evolve around hypercalcemic homeostasis.¹ Indolent forms with bony involvement have rarely featured in the last two decades and the overlapping features with dystrophies, skeletal dysplasia and malignancies may obscure diagnosis.^2,3 We herein describe an usual presentation with varied manifestations of metabolic bone failure, pathognomonic of hyperparathyroidism despite previous parathyroidectomy. We also highlight the current evidence based practices in localising a hyper-functioning gland and discuss the management of various bony manifestations.

2. Case report

A 47-year-old female presented to the emergency department with pain, swelling of right thigh and painful right shoulder subsequent to a trivial fall at home. She appeared short stature, emaciated facies, cachexic, with kyphoscoliosis, deformed chest wall and lower extremities. Her background history recorded multiple hospital visits for progressive proximal muscle weakness, fatigability and loss of weight. The evaluations had revealed history of hyperparathyroidism due to a left superior parathyroid adenoma localised using ultrasonography of neck and underwent parathyroidectomy, three months prior to the fall.

The plain radiographs revealed generalised osteoporosis, multiple lytic lesions in the tibia and pelvis, along with regional changes like severe antero-lateral bowing of femur with insufficiency fracture of right shaft of femur and proximal humerus, kyphoscoliosis in spine with cod-fish and rugger jersey appearance and acro-osteolysis of hand(Fig. 1). Blood investigations suggested hypercalcaemia (3.9 mmol/L), hypophosphatemia (0.87 mmol/L), alkaline phosphatase (ALP) (1245 U/L), intact parathyroid hormone (>2000 pg/ml), hypovitaminosis D (9.5 ng/ml), creatine phosphokinase (CPK) (54 U/L). Blood urea nitrogen and urine examinations were normal. Whole body scintigraphy to evaluate tumour like lesions, however suggested features of hyperparathyroidism(Fig. 2A). Ultrasonography evaluation of neck revealed an enlarged right inferior parathyroid gland, and isolated increased uptake on parathyroid scintigraphy. (Fig. 2 B–C).

Fig. 1.

Plain radiographs depicting the variations in pathognomonic bony manifestations in hyperparathyroidism. Deformed chest wall (pectus carinatum), kyphoscoliosis with severe osteoporosis (codfish vertebra and rugger jersey spine), and right proximal humerus insufficiency facture, deformed pelvis, protrusio acetabuli, pencil thin cortical bones and brown tumours in the ischium (A and B); osteofibrous dysplasia of the tibia-well demarcated, eccentric lytic lesion without sclerotic margins (C); and acro-osteolysis of the terminal phalanges involving tuft and midshaft, radial and ulnar side sub-periosteal erosions of the middle phalanges (D).

Fig. 2.

Targeted scintigraphy images to differentiate and localise the cause for hyperparathyroidism. Whole body scintigraphy with technicium-99-methyl di phosphate for the evaluation of multiple osteolytic lesions revealed uniform increased uptake in calvaria, facial bones and vertebrae (rugger jersey like) (A); scintigraphy study at 15 minutes and 2 h respectively-showing an isolated hyper functioning gland uptake and lack of multiple gland or ectopic sites involvement (B and C). Histopathological examination suggestive of atypical parathyroid adenoma. Tumour cells in aggregates and pseudo glandular pattern showing focal pleomorphism interspersed by delicate blood vessels (20x, Hematoxylin and eosin stain) (D).

The parathyroid gland (3 x 2.5 × 2 cm in size) was surgically removed and histopathological examination showed features of atypical parathyroid adenoma(Fig. 2D). She had arrhythmic disturbances (corrected calcium levels dropped to 1.4 mmol/L) in the post-operative period and managed with calcium supplements to restore homeostasis. Open reduction and internal fixation with locking compression plate (4.5mm system) was done to stabilize the femur shaft fracture. Due to the fragile nature of the bone, bone cements were incorporated into the screw holes for stable integration of the screws with the bone. The proximal humerus fracture and the brown tumours were managed conservatively.

The rehabilitation was guarded with initial focus to recover muscle power and gait training. She was followed at monthly interval with radiographs and blood investigations. The fracture of proximal humerus united completely in two months; bony architecture of the phalanges, the osteitis fibrosa cystica or brown tumour lesions in tibia and pelvis, and the lesions in spine had resolved and obliterated within five months. Femur fracture united in seven months without implant failure (Fig. 3). At final follow-up at 18 months, she was doing well, had no recurrence or relapse and was able to ambulate independently.

Fig. 3.

Radiological outcomes, during follow-up, of the bony manifestations subsequent to restoration of calcium homeostasis in the post-parathyroidectomy period. Restoration of the bony trabecular pattern in the lytic lesions and complete resolution of the brown tumours in the pelvis and tibia (A and B) respectively; restoration of body architecture of phalanges of the hand (C); union of the surgically stabilised right femur shaft fracture without implant failures (D) and conservatively treated proximal humerus fractures (E).

3. Discussion

The symptomatology of Primary hyperparathyroidism is often non-specific and diagnosis is usually made at an early period from the altered calcium homeostasis during the acute manifestations involving the gastro-intestinal, cardiac, renal, neuropsychiatric or neuromuscular systems.¹ In the absence of acute symptoms, the diagnosis may be obscured due to overlapping clinical and radiological appearances with musculo-skeletal disorders.² However, skeletal presentations especially osteitis fibrosa cystica, acro-osteolysis and pathological fractures have been extremely rare (<2% of manifestations).⁴

Screening for ectopic sites, multiple endocrine neoplasia, malignancies featuring para-neoplastic syndrome and radiologically mimicking tumours are of paramount importance to avoid relapses.⁵ Akbaba et al. compared the investigative modalities to localise the causation on 82 patients with hyperparathyroidism and observed the sensitivity and diagnostic accuracy of single photon emission computed tomography (SPECT) and MRI to be 75.5% and 74.5%; 63.8% and 63.3% respectively, however the combined use of USG and technicium-99-sestamibi scan featured over 95% and 92% respectively.^6,7 In the case described, the initial failure to localise the additional hyperfunctioning gland using ultrasonography led to the persistence of the hyperparathyroid state and bone architecture failure. However, in the subsequent presentation, technicium-99-sestamibi scan was used in addition to localise and rule out the involvement of multiple glands, intrathyroidal and ectopic sites.

The bony manifestations of primary hyperparathyroidism may be in the form of lesions, deformities or pathological fractures.^3,4,8 The long standing generalised osteoporosis leading to deformities like kyphoscoliosis, pectus carinatum, protrusion acetabuli, and bowed lower limbs can mimic skeletal dysplasia. The pathognomonic characteristics of bony lesions had additional features in that the brown tumours were observed in the long bone (tibia) in addition to flat bones (pelvis and ribs), hand involvement showed sub-periosteal erosions in the ulnar side of middle phalanx in addition to the radial side, and that the acro-osteolysis of terminal phalanges involved both the tuft and midshaft. The recovery of the bony architecture post-parathyroidectomy has been well documented in literature with restoration of more than 70% trabecular and cortical bone in premenopausal age group.⁹ However the established deformities in the spine and long bones may require surgical correction when symptomatic.

The diagnosis of the brown tumours often involves clinical, biochemical and the radiological appearance of multicentre involvement, eccentric expansile lesion without sclerotic margins involving flat bones and long bones, and rarely require biopsy.^4,8 However, scintigraphy has been advocated, for these lesions can mimic malignancy.³ Following parathyroidectomy, the osteitis fibrosa cystica lesions and fractures healed completely with normal trabecular pattern within five months, along with the restoration of the bony architecture of spine and hand. Fracture fixation can be difficult due to the pre-existing bowing and poor quality of bone.¹ We had to incorporate bone cements for the stable integration of the screws into the bone during fixation of femur fracture and the fracture united uneventfully.¹⁰

The bony manifestations are infrequent presentations in primary hyperparathyroidism. They can be disabling and difficult to treat. Considering the severity of the morbidity arising from a preventable cause, initial evaluation of these patients should include parathyroid scintigraphy, and not limited to neck screening with USG, for its additive and improved diagnostic value.

Source of funding

None.

Declaration of competing interest

None.