Osteitis Fibrosa Cystica

Etiology

OFC may occur in any setting of PTH overproduction, including primary (both normocalcaemic and hypercalcemic), secondary, and tertiary hyperparathyroidism.[7][8][9][10] Notably, OFC is a frequent manifestation of end-stage renal disease.[11] Regarding primary hyperparathyroidism, this is most commonly due to a sporadic adenoma in up to 85% of cases and less frequently associated with parathyroid carcinoma, however, both have been associated with OFC. In the setting of carcinoma, one must distinguish OFC from osseous metastases.[12] Additionally, genetic causes of primary hyperparathyroidism, including hyperparathyroidism jaw-tumor syndrome, familial isolated hyperparathyroidism, and multiple endocrine neoplasia, have all been associated with OFC. OFC has also been demonstrated in the case of pseudohypoparathyroidism, which occurs with elevated PTH in the absence of hypercalcemia, mostly due to variable end-organ resistance.[13] As a final consideration, OFC has been demonstrated to occur in cases of elevated PTH-related peptide (where the PTH level will be suppressed), such as ectopic production by adult T-cell leukemia.[14]

Epidemiology

Following routine detection of asymptomatic hypercalcemia with a subsequent diagnosis of hyperparathyroidism through the addition of the auto analyzer in clinical practice, the prevalence of hyperparathyroidism has increased, however, concurrent ‘severe’ disease has decreased reciprocally.[2] While OFC was once a common manifestation of hyperparathyroidism with a prevalence of approximately 69%, the prevalence in the United States has significantly decreased over the last 50 years to approximately 5% with primary hyperparathyroidism and 1.5% with secondary hyperparathyroidism.[4][15] In contrast, developing nations continue to demonstrate an excessive prevalence of OFC and other late sequelae of hyperparathyroidism due to the unavailability of earlier detection.[16]

Brown tumors, the distinctive histopathological finding of localized OFC, appear to be more common in persons older than 50 years, in addition to the female gender, for which it is hypothesized that there is an element of hormonal involvement for its development.[5] Alternative theories, as to why the development of OFC, as well as the presence of parathyroid carcinoma, in which case the OFC occurs in about 90% of patients compared to a mere 5% of patients with benign disease that, may be due to the higher serum PTH associated with carcinomas.[17][18]

Pathophysiology

Sustained overproduction of PTH leads to the sequelae of hyperparathyroidism, including OFC. The most commonly involved body areas include the pelvic girdle, mandible (but not maxilla, which is an uncommon location), clavicle, ribs, and ends of long bones; however, with the progression of the disease, no bone is spared from possible involvement.[19]

Excessive PTH binds to osteoblasts, which leads to the expression of receptor activator of nuclear factor kappa-β ligand (RANKL), which itself attaches to receptor activator of nuclear factor kappa-β (RANK) on osteoclast precursors, allowing differentiation into osteoclasts and inhibition of osteoprotegerin expression. The osteoprotegerin functions to bind to RANKL and prevent interaction with RANK.[20][21] With the activation of osteoclasts, bone resorption commences through cortical destruction and fibrous cyst formation. Brown tumors are formed with the replacement of the marrow with vascularized fibrous tissue and repetitive microfractures and microhemorrhages, producing the clinical manifestations of pain, weakening, swelling, deformities, and risk for fracture.[22][23]

Histopathology

Brown tumors, also known as osteoclastomas, are the classic histological manifestation of OFC and represent localized disease.[24] Microscopically, OFC is notable foh osteoclast and osteoblast activity within the osseous tissue alongside hemosiderin-laden macrophages and cyst formation from rapid bone loss and subsequent hemorrhage, granulation, and fibrous tissue replenishment within the marrow.[25]

History and Physical

History taking should begin with assessing the disease duration, previous treatments received, and previous records to review the severity of the hyperparathyroidism. It is important to note that patients with OFC have likely had a long duration of hyperparathyroidism or have severe disease, and in addition to musculoskeletal manifestations, may demonstrate other end-organ complications, including renal (kidney stones, failure, polyuria), abdominal (pancreatitis, ulceration, nausea, vomiting, constipation), and psychiatric disturbances (fatigue, lethargy, disturbances with memory, depression).

Regarding musculoskeletal manifestations, it is essential to assess for a history of pathological fractures, review previous imaging of the skeleton (looking for osteopenia or osteoporosis), ask the patient about pain, and investigate for deformities of the bones, including bowing of the long bones. Moreover, depressed reflexes can be associated with hypercalcemia and can be reproduced upon physical examination. While any bone can be affected in OFC, most commonly, it is the mandible, clavicle, pelvic girdle, and ribs, which should prompt consideration of the presence of OFC.[19] Physical examination should also include a head and neck exam, assessing for a palpable mass over the anterior neck consistent with a parathyroid adenoma or carcinoma.

Evaluation

Due to the infrequent occurrence of OFC, routine radiological screening in the absence of clinical suspicion (such as in asymptomatic patients) is not warranted.[1][26] As discussed in the previous section, a concerning history and physical examination are justifiable for further radiological assessment. Classical radiological descriptions of OFC include a "salt-and-pepper" skull, subperiosteal bone resorption of the second and third fingers at the proximal and middle phalanges, involvement of the distal clavicle, as well as widespread brown tumors and bone cysts.[27] Generalized decreased mineral density of the bone (osteopenia) may be noted, with cortical bone being involved more commonly than cancellous bone.[6] A bone biopsy can be considered and may differentiate OFC from a bone tumor.[28] A caveat, however, is the risk of seeding of the cancerous cells in the setting of malignancy.

Laboratory findings of hyperparathyroidism include hypercalcemia (albeit occasionally may demonstrate normocalcemia), elevated, or inappropriately normal, PTH, hypophosphatemia, and elevated alkaline phosphatase (the latter correlating with the degree of overt OFC).[8] In the setting of suppressed PTH, this should lead to the consideration of hypercalcemia of malignancy, for which the underlying cancerous tissue must be identified, in addition to consultation with an oncologist. The presence of hyperparathyroidism in a young patient or a patient with a strong family history should prompt consideration of a genetic cause, with a referral to a geneticist.

In the setting of OFC, parathyroidectomy is the treatment of choice, leading to the resolution of disease; however, this requires surgical planning prior to the procedure. As a result, patients may undergo an ultrasound scan of the neck to identify the parathyroid glands, in addition to a sestamibi scan that would assist in confirming the location and potentially identifying any ectopic glandular tissue. 

Treatment / Management

Treatment of OFC involves targeting the underlying cause of hyperparathyroidism. In the setting of primary hyperparathyroidism, it will require parathyroidectomy, for which resolution of the brown tumors is expected, rendering surgery redundant. Local surgical procedures (such as incisions) may be performed at sites of OFC in the setting of functional problems, most notably persistent deformity, pathological fractures, and discomfort. Infrequent case reports have noted the usage of corticosteroids to decrease the tumor size should it persist post-parathyroidectomy.[25] Treatment of OFC has also been shown with refrigerated transplantation of osseous tissue, demonstrating resolution of the lesions on follow-up after curettage and packing of the cavity with refrigerated bone chips.[29] (B3)

It is also imperative to manage the underlying renal disease, especially in the setting of secondary hyperparathyroidism, and to treat co-existent vitamin D deficiency, which can lead to more severe musculoskeletal complications. It has also been demonstrated that oral vitamin D can lead to the regression of brown tumors and symptoms of OFC.[30](B3)

Differential Diagnosis

As OFC is rather uncommon, it is infrequently considered in the differential diagnosis, however, it is nonetheless an important differential diagnosis as its recognition would help avoid unnecessary invasive testing and procedures.[27] The presence of hypercalcemia and lytic bone lesions leads to a consideration of hypercalcemia of malignancy versus OFC from hyperparathyroidism itself. This is best differentiated by the measurement of PTH, which is depressed in hypercalcemia of malignancy but elevated (or inappropriately normal) in OFC. OFC can occasionally mimic metastatic parathyroid carcinoma, albeit this is very uncommon.[9] 

Further differential diagnoses include giant bone marrow tumors, solid aneurysmal bone cysts, and a giant cell reparative granuloma.[1][27] The distinction between the aforementioned conditions may pose challenges.[28] While bone scintigraphy can assess areas of increased uptake associated with hyperparathyroidism, this may be falsely positive for malignancy, osteomalacia, and infection. Similarly, a positron emission tomography scan cannot distinguish between benign and malignant osseous neoplasms. Furthermore, the histological assessment may demonstrate overlap between these conditions, leading to difficulty in differentiation and accurate diagnosis.[1]

Prognosis

Untreated OFC parallels the severity of hyperparathyroidism, and treatment requires resolution of the underlying hyperparathyroidism. Although OFC is a dire condition associated with suffering, the prognosis is favorable if the underlying disease driving the hyperparathyroidism can be controlled. OFC typically resolves following parathyroidectomy in the setting of primary hyperparathyroidism, rendering surgical management of the brown tumors unnecessary. It has been demonstrated that bone remineralization of the skeleton occurs, with the recovery of osteopenia and healing of the brown tumors upon radiological and histological assessment, in addition to clinical improvement expressed by both the patient and objective examination.[3]

Complications

OFC, if left untreated, may lead to perpetual pain, musculoskeletal weakness, deformities, erosions, bowing of the bones, cyst development, and fractures. Furthermore, with OFC, patients are likely to have other complications of hyperparathyroidism present, including nephrolithiasis, renal failure, fatigue, abdominal pain, psychiatric disturbances, and polyuria.[27]