Continuing Education Activity

Osteitis fibrosa cystica (OFC) is a skeletal disorder caused by an overproduction of parathyroid hormone from the overactive parathyroid glands. Osteitis fibrosa cystica is the late manifestation of the hyperparathyroidism. The incidence of bone lesions has decreased from 80% in the past to 15% in the present. This may be attributable to biochemical monitoring of serum calcium levels leading to earlier diagnoses in frequently asymptomatic patients. This activity reviews the evaluation and treatment of osteitis fibrosa cystica and highlights the role of the interprofessional team in early diagnosis hyperparathyroidism by performing routine blood work and prevention of skeletal complications of hyperparathyroidism.

Objectives:

• Identify the most common cause of the osteitis fibrosa cystica.
• Summarize the epidemiology of the osteitis fibrosa cystica.
• Outline the treatment and management options available for osteitis fibrosa cystica.
• Review the importance of an interprofessional team approach to the evaluation and treatment of hyperparathyroidism that will provide the best outcome.

Introduction

Osteitis fibrosa cystica (OFC) is a disorder involving the bone which is resulted from excessive production of parathyroid hormone (PTH) due to parathyroid gland hyperactivity. It was first described by Recklinghausen in 1891. Bone changes are a late presentation of hyperparathyroidism. Bone involvement in hyperparathyroidism has shown a significant decrease in incidence over the past decades (from 80% to as low as 15%). This fact might be due to the early detection of asymptomatic cases via serum calcium monitoring.[1] PTH induces osteoclast activity which results in a bone break down. Hyperparathyroidism (PHP) might be due to parathyroid adenoma (up to 85% of cases), parathyroid hyperplasia, parathyroid carcinoma, renal osteodystrophy, and hereditary factors.[2] Up to 5% of PHP cases develop OFC which can indicate a prolonged or more severe disease.

Osteitis fibrosa cystica presents as bone pain and characteristic radiologic findings including subperiosteal bone resorption in middle phalanges and distal radius, thinning of distal clavicle, bone cyst formation, “salt and pepper” pattern of the skull, brown tumor involving long bones and generalized osteopenia (up to 5% of cases). Brown tumors are caused by bone demineralization due to osteoclast activation, microfractures, and microhemorrhages. Its name comes from characteristic color resulting from hemosiderin deposition. OFC and its radiologic findings are more common in cases with parathyroid carcinoma compared to benign causes of PHP.[3][4]

Etiology

OFC results from parathyroid hormone (PTH) overproduction. PTH elevates the level of blood calcium via calcium release from the bones and calcium reabsorption in the kidney. OFC is due to increased production of PTH that can be the result of any of the following mechanisms: 

• Parathyroid adenoma

Up to 85% of hyperparathyroidism cases are due to parathyroid adenomas, which are benign lesions but metabolically active.[2]

• Hereditary factors

About 5 to 10% of hyperparathyroidism cases are from hereditary factors such as multiple endocrine neoplasia (MEN) type 1 and 2A, hyperparathyroidism-jaw tumor syndrome, and familial isolated hyperparathyroidism which can result in OFC if left undiagnosed. [11794462]  MEN Type 1 is the most common cause of hereditary hyperparathyroidism and is accounting for up to 95% of hereditary cases of OFC.[5][6][7]

• Parathyroid carcinoma                                                                                                                              

Parathyroid carcinoma is a rare cause of OFC in about <1% of hyperparathyroidism cases. Diagnosis of OFC onset due to carcinoma is challenging and difficult.[2]

• Renal complications

Renal osteodystrophy is a skeletal disorder resulting from end-stage renal disease (ESRD), which can commonly cause OFC (up to 50%). During the ESRD, kidneys are unable to make calcitriol, which promotes calcium delivery to the bones. In the shortage of calcitriol, PTH levels increase and promote calcium removal from the bones.[8]

Epidemiology

In the United States, osteitis fibrosa cystica is rare and occurs in less than 2% of patients with PHP and especially occurs in more severe disease and parathyroid carcinoma.[9] Although parathyroid carcinoma is a rare cause of PHP (<1% of cases), bone involvement such as OFC occurs more frequently in parathyroid carcinoma (up to 90% of cases) compared with benign causes of hyperparathyroidism.[10][11] Brown tumor has female predominance and occurs more frequently with aging (mainly after 50 years old) and post-menopause, which can be due to hormonal effects.[1]

Pathophysiology

Osteitis fibrosa cystica is the result of the overproduction of parathyroid hormone (PTH) in the setting of primary, secondary, and tertiary hyperparathyroidism. PTH attaches to receptors on osteoblasts, which results in the expression of RANK ligand-receptor activator. RANK ligand attaches to RANK on precursors of the osteoclasts, promoting osteoclast formation. Activated osteoclasts cause bone resorption, cortical bone destruction, and fibrous cysts formation. Osteoclast-like giant cells and vascularized fibrous tissue might replace bone marrow resulting in Brown tumors, which are non-neoplastic lesions. During the Brown tumor process, bone demineralization promotes osteoclast activation. Eventually, bone resorption can cause microfractures and microhemorrhages.[12] Overproduction of PTH can cause hyperparathyroidism via calcium release from the bone and increased reabsorption of the calcium in the kidneys.

Histopathology

On histopathologic examination, there is osteoclastic and osteoblastic activity with hemosiderin-laden macrophages and cyst formation.[9]

History and Physical

Symptoms are due to bone softening and hypercalcemia, which might include bone mass or fractures, kidney stones, peptic ulcer, weight loss, nausea, loss of appetite, psychic moans, and abdominal groans.

Evaluation

Laboratory findings include elevated serum PTH, elevated serum calcium, decreased serum phosphate, and normal or elevated alkaline phosphatase. Radiographic findings may include fractures, osteopenia, osteoporosis, bowing, and bone cysts. The skull may have a ground glass appearance or salt and pepper pattern. There are no specific radiographic findings for brown tumors. CT scan, technetium scan, and ultrasound may also be helpful to detect the disorders of the parathyroid gland.[1] It occurs mainly in the 40s and 50s and has a female predominance. Occurrence in young ages should raise the suspicion for hereditary patterns such as MEN syndrome.[13]

Treatment / Management

Treatment of osteitis fibrosa cystica starts with the management of hyperparathyroidism, which is usually parathyroidectomy and should take place after fixing the underlying metabolic issues. After parathyroidectomy, the majority of bone disorders resulting from OFC will resolve. If surgery is not the treatment option, medical treatment may be an option to manage hypercalcemia, vitamin D deficiency, and hyperphosphatemia. Serial evaluation of serum calcium, phosphate, PTH, and vitamin D determines the necessity of treatment. 

Differential Diagnosis

Giant cell tumor of the bone, solid aneurysmal bone cyst, and giant cell reparative granuloma are included in the differential diagnoses for Brown tumors.[14] OFC is a reactive and non-neoplastic lesion but sometimes may be misdiagnosed as a malignant lesion and can show histopathologic features of giant cell tumor of the bone. It can also be mistaken for a metastatic disease based on the radiologic findings, such as multiple scattered osteolytic lesions.[12][15]

Prognosis

The bone issues resulting from OFC are usually resolved after parathyroidectomy. Proper management of hyperparathyroidism results in decreased osteoclastic activity, and new bone deposition.

Complications

Osteitis fibrosa cystica might cause pain and fracture in legs, arms, spine, or any other part of the skeletal system. Hyperparathyroidism may cause renal failure and kidney stones.

Deterrence and Patient Education

In the United States, osteitis fibrosa cystica is rare and occurs in less than 2% of patients with PHP and mainly occurs in more severe disease. Hypercalcemia is usually detected as an incidental finding during routine medical check-up before any severe damage occurs.

Enhancing Healthcare Team Outcomes

Early diagnosis and management of hyperparathyroidism might limit the amount of damage from OFC. An annual medical check-up, including testing for serum calcium and phosphorus, can aid in early detection of asymptomatic hyperparathyroidism and limit its bone complications. An interprofessional team approach to the evaluation and treatment of hyperparathyroidism will provide the best outcome.