Continuing Education Activity

Osteitis fibrosa cystica, often referred to as OFC, is a rare but clinically significant bone disorder characterized by profound skeletal changes resulting from excessive parathyroid hormone (PTH) activity. This condition is primarily associated with hyperparathyroidism, particularly in its severe and uncontrolled form, and is most commonly seen in patients with chronic kidney disease. As PTH plays a pivotal role in regulating calcium levels in the body, its dysregulation can lead to a cascade of skeletal and systemic complications. OFC is characterized by the resorption of bone tissue, leading to the formation of cyst-like cavities within the bones and an increased risk of fractures, deformities, and metabolic abnormalities. The incidence of this disorder has decreased significantly following earlier detection of hyperparathyroidism through routine screening of serum calcium in frequently asymptomatic patients. Understanding the pathophysiology, clinical manifestations, diagnostic criteria, and management strategies for OFC is essential for healthcare professionals in various specialties, as it plays a pivotal role in the comprehensive care of patients affected by this complex skeletal disorder. This activity reviews the evaluation and optimal management of OFC and highlights the role of the interprofessional team in detecting and treating this condition in affected individuals.

Objectives:

• Identify risk factors for the development and progression of osteitis fibrosa cystica in at-risk patient populations.

• Select appropriate laboratory studies and, if indicated, imaging modalities to evaluate patients with osteitis fibrosa cystica.

• Implement evidence-based treatment protocols for osteitis fibrosa cystica, including vitamin D supplementation, parathyroidectomy, or pharmacological interventions as indicated.

• Collaborate with an interprofessional team to develop a comprehensive care plan for patients with osteitis fibrosa cystica, addressing primary and underlying conditions.

Introduction

Osteitis fibrosa cystica (OFC), a disorder of skeletal bone, is a pathognomonic yet infrequent finding of late-stage hyperparathyroidism. OFC is also referred to by the eponym 'von Recklinghausen Disease of the Bone,' highlighting the description by Friedrich Daniel von Recklinghausen in 1891; however, it is noteworthy that the first description of this phenomenon was posed 27 years earlier in 1864 by Gerhard Engel. Moreover, it was not until 1904 that von Askanasy demonstrated the correlation between OFC and the parathyroid glands.[1]

OFC translates to 'cystic bone destruction' and occurs in the setting of chronic and sustained overactivity of the parathyroid glands with excessive release of parathyroid hormone (PTH) acting upon osseous tissues.[2] While once a common manifestation of hyperparathyroidism, OFC is now a rare occurrence in Western countries, especially in the United States, largely due to the introduction of auto analyzers in the 1970s-1980s, allowing earlier detection of even asymptomatic hyperparathyroidism and resultant prevention of late-stage osseous manifestations.[3][4] 

OFC may occur in any setting of sustained elevation of PTH, including primary, secondary, and tertiary hyperparathyroidism. Excessive osteoclast activation manifests as but is not limited to, bone swelling, pain, deformity, depleted bone mineral density, and fractures. Lesions may be either single or multiple and are characterized histologically as "brown tumors" due to repetitive microtrauma and microfractures, leading to hemosiderin deposition; however, this is a misnomer, as they do not harbor neoplastic potential.[5] While OFC may be progressive alongside continued activation of the parathyroid glands and stimulation of the osteoclasts, treatment of the underlying disorder of hyperparathyroidism, most often with a parathyroidectomy, is curative with ultimate resolution of the disease.[6]

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] 

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]

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]

Deterrence and Patient Education

In the United States, OFC is an infrequent manifestation (<5%) of hyperparathyroidism, occurring in those with longer duration and more severe disease. Hypercalcemia is routinely detected most commonly in asymptomatic patients during routine medical check-ups prior to end-organ manifestations; however, in developing countries where routine check-ups are not available, OFC and other manifestations of hyperparathyroidism are more frequently seen. It is essential to consider this uncommon complication to recognize the symptoms of bone pain, swelling, deformity, and weakness in cases of severe and untreated disease.

Enhancing Healthcare Team Outcomes

Early diagnosis of hyperparathyroidism is vital to limit end-organ damage and prevent complications such as OFC. Due to the infrequent nature of this phenomenon, however, routine radiological screening is not indicated in the absence of suspicion for OFC. Patient-centered education is a valuable tool for which the demonstration of symptoms concerning OFC (such as bone pain, weakness, deformities, and swelling) should prompt urgent evaluation to prevent untoward bone complications. Apart from the endocrinology department, other healthcare professionals are likely to be in contact with such patients, emphasizing the importance of early recognition of signs and symptoms of OFC. 

Enhancing patient-centered care and improving outcomes for individuals with OFC requires a collaborative approach involving physicians, advanced care practitioners, nurses, pharmacists, and other healthcare professionals. Clinicians must possess a deep understanding of OFC, its pathophysiology, diagnostic methods, and treatment options. This includes proficiency in interpreting bone scans, laboratory results, and monitoring bone health. Collaborative teams should develop individualized care plans based on patient-specific factors, including the severity of OFC, comorbid conditions, and patient preferences. Advocacy for patients' needs, including referrals to specialists, physical therapy, or counseling services, is a shared responsibility among the interprofessional team. By fostering strong multidisciplinary collaboration, healthcare professionals can provide patient-centered care that addresses the unique challenges OFC poses. This approach enhances patient safety, improves outcomes, and optimizes the overall care experience for individuals with this rare bone disorder.