Orthopedic Surgery for Fibrous Dysplasia

As a consequence of the mutation of GNAS1 (see Etiology), there is a substitution in which cysteine or histidine (amino acids of the genomic DNA in the osteoblastic cells) is replaced by another amino acid, arginine.[11]

Osteoblastic cells expressing this mutation have a higher DNA synthesis than normal bone cells. The growth of these cells is faster, leading to an inappropriate differentiation of mesenchymal cells. At the molecular level, intracellular cyclic adenosine monophosphate (cAMP) levels are increased and osteocalcin is decreased.[15] Osteocalcin is a late marker of osteoblast differentiation. Involved bone cells are immature. They fail to produce normal amounts of collagen or to orientate appropriately to the lines of mechanical stress.

Fibrous dysplasia is caused by the sporadic mutation of the GNAS1 gene, which encodes the alpha subunit of the stimulatory G protein (G1) located on chromosome 20q13.2-13.3 of the osteoblastic cells.[10]  Although the mutation is known, the actual pathways that lead to abnormal osteoblast differentiation and function remain to be fully elucidated.

The consequence of this mutation is an inappropriate cell differentiation resulting in a disorganized fibrotic bone matrix. Cancellous bone maintenance is perturbed, and bone undergoing physiologic remodeling is replaced by an abnormal proliferation of fibrous tissue. 

The extent and pattern of disease depend on the stage of development and the location at which the mutation occurs. All the bones can be affected.

Fibrous dysplasia accounts for about 5% of all benign bone tumors.[10] The monostotic form is more common than the polyostotic form. Because many patients are asymptomatic, the true incidence of this disorder is unknown. Usually, fibrous dysplasia presents clinically in children and adolescents, with a median onset age of 8 years. Most cases manifest themselves before the age of 30 years. Males are affected more often than females, except in McCune-Albright syndrome, in which females are affected more often than males.

Monostotic fibrous dysplasia is active while it is growing but often becomes inactive after puberty. It may reactivate during pregnancy. Polyostotic disease typically remains active throughout life.

Unless malignant transformation develops, fibrous dysplasia is not a life-threatening disease. The lesions tend to stabilize as skeletal maturity is reached. Malignant transformation develops in a small minority of patients (< 0.5%).

The majority of the monostotic cases have a good evolution regardless of treatment. Polyostotic disease tends to have a poorer prognosis.[16] Polyostotic lesions are very often associated with one or more fractures.[17] A single-center study of 114 patients with craniofacial fibrous dysplasia found that those who had McCune-Albright syndrome, as compared with those who had polyostotic or monostotic fibrous dysplasia, were more likely to have aggressive disease, complications, and a greater number of operations.[18]

The recurrence rate for fibrous dysplasia has been reported to be 21% after curettage and grafting, but if patients are monitored for many years, the rate is probably closer to 100%.

Pain is a common sign of fibrous dysplasia in symptomatic patients.[17]  Most commonly, patients are asymptomatic. Patients usually seek medical care because of either painful swelling and deformity or a pathologic fracture through a weakened bone. Long bones are commonly affected. The femur is the most common location; other sites typically affected are the tibia, maxilla, and skull.

Nonskeletal manifestations include abnormal cutaneous pigmentation, precocious puberty, hyperthyroidism, Cushing disease, hyperparathyroidism, and hypophosphatemic rickets. McCune-Albright syndrome is defined as the triad of precocious puberty, polyostotic fibrous dysplasia, and cutaneous pigmentation. Typically, only females are affected by precocious puberty,[19]  but the other endocrine abnormalities occur equally in males and females. All of these abnormalities are thought to be due to the same underlying mutation.

Fracture is the most common complication of fibrous dysplasia. In polyostotic disease, fracture occurs in more than 50% of cases.

Deformity may occur in weightbearing bones.

Malignant transformation occurs in fewer than 0.5% of cases. It is more likely to occur when polyostotic disease exists or after treatment with radiation therapy. Typically, malignant transformation occurs during the third or fourth decade of life.[14]  Benign tumors have also been associated with fibrous dysplasia.[20]

Patients with McCune-Albright syndrome have a high incidence of scoliosis (probably exceeding 50%).[10]

Molecular diagnosis using the techniques of polymerase chain reaction (PCR) analysis with peptide nucleic acid (PNA) has shown that fibrous dysplasia patients have blood cells with the G protein gene (GNAS) mutation. Diagnosis of fibrous dysplasia or McCune-Albright syndrome could be helped by identification of this mutation in the peripheral blood.[21] The utility of this technique is still being evaluated.

Serum alkaline phosphatase (ALP) levels are often elevated during active phases of this disease. This test could be useful to asses the evolution of disease in patients treated with bisphosphonates.

About 25% of patients may have a vitamin D deficiency.[22] Serum calcium, phosphate, and vitamin D levels are useful to exclude rickets. Pituitary gonadotropins and gonadosteroids are assessed to assist in the workup of precocious puberty.

Patients with the polyostotic form of fibrous dysplasia, particularly McCune-Albright syndrome, must be evaluated to exclude hyperthyroidism, pituitary gigantism, or hypercortisolism (possible autonomous endocrine hyperfunction).

Plain radiography

In both monostotic and polyostotic forms of fibrous dysplasia, the most common site of involvement is the femur.[12] Lesions in the long bones are medullary and usually affect the diaphysis and extend toward the metaphysis (see the image below).

Typically, the matrix of the lesion has a ground-glass appearance. The lesion produces endosteal scalloping with a thin intact cortical shell. The contour of the bone may be expanded by the lesion. The classic deformity that results with involvement of the proximal femur is described as a shepherd's crook deformity on the basis of the deformation into varus.

Technetium-99m methylene diphosphonate bone scan

Increased uptake of the label that corresponds to osteoblastic activity is noted in the area of involvement seen on radiographs (see the image below). This study is useful in determining whether disease is monostotic or polyostotic.

Computed tomography

Computed tomography (CT) confirms a lesion confined to the interior of bone with no soft-tissue component. (See the image below.) It is helpful in distinguishing fibrous dysplasia from a malignancy.[23, 24] CT can show a homogeneous matrix. Single-photon emission CT (SPECT)/CT may be useful for the diagnosis of fibrous dysplasia.[25]

Magnetic resonance imaging

With magnetic resonance imaging (MRI),[24, 26, 27] intermediate signal intensity is present on T1-weighted images (see the first image below), and high signal intensity is present on T2-weighted images (see the second image below).

Diagnosis with imaging alone vs biopsy

Fusconi et al conducted a literary review to determine the feasibility of diagnosing fibrous dysplasia on the basis of imaging (CT and MRI with and without contrast) alone, without biopsy.[28] They concluded that it is not possible to make the diagnosis purely on the basis of imaging. A ground-glass appearance on radiography, though characteristic of fibrous dysplasia, is not pathognomonic. The authors recommended that histologic examination or follow-up imaging be conducted in cases of suspected fibrous dysplasia.

Radiographic classification

From an assessment of 227 femurs, Zhang et al suggested a radiographic classification for fibrous dysplasia of the proximal femur,[29]  which included the following five types:

• Type 1 -  Normal bone strength without angular deformity
• Type 2 - Decreased bone strength without angular deformity
• Type 3 - Isolated coxa vara with neck-shaft angle < 120°
• Type 4 - Isolated varus deformity in the proximal femoral shaft
• Type 5 - Coxa vara with varus deformity in the proximal femoral shaft

The authors found that this radiographic classification of fibrous dysplasia was reproducible and useful for evaluating fibrous dysplasia and that treatments based on it were effective. 

Needle biopsy is used to establish the diagnosis of fibrous dysplasia, especially in monostotic cases. Open biopsy should be performed only as part of a multidisciplinary team approach, with personnel experienced in the management of both benign and malignant bone and soft-tissue sarcomas.

The gross findings of fibrous dysplasia include a centrally located, tan-to-gray-white, gritty-feeling lesion. The microscopic appearance shows a fibrous/collagenous matrix with randomly oriented bone or fiber trabeculae that are formed by osseous metaplasia of spindled stromal cells (see the image below).

The spicules of immature bone that are produced are short and irregular and are not lined by osteoblasts. The appearance has been described as that of Chinese letters (see the image below). Small nodules of cartilage are found within the fibrous matrix in 10% of cases.

Surgical treatment of fibrous dysplasia is indicated in the prevention or treatment of fractures or major deformity.[30]  The most common surgical indications are fracture of a weightbearing bone and progressive disease. Asymptomatic patients do not need treatment. A needle biopsy can be performed if there is doubt about the diagnosis before the initial management. Upper-extremity lesions rarely require surgical management. Nevertheless, vascularized bone grafting has been proposed.[31]  Surgical management can be effective for both syndromic and nonsyndromic craniofacial fibrous dysplasia.[32]

There are no specific contraindications for surgical intervention in patients with fibrous dysplasia. However, care must be used in the skeletally immature patient. Internal fixation of long bones with intramedullary nails may be proposed.

In the future, effective nonsurgical treatments may be possible. Because the risk of local recurrence is high, the decision to treat must be made with informed consent to avoid inappropriate expectations. In general, the goals of surgery should be to stabilize the bone and relieve pain, rather than to excise the involved bone. The condition often is found incidentally, and the need for prophylactic treatment may be difficult to accept for an asymptomatic or minimally symptomatic patient.

Although there is no specific medical therapy for fibrous dysplasia, studies have shown decreased pain after treatment with bisphosphonates, which inhibit bone resorption by virtue of their action on osteoclasts.[33, 22, 34, 35]  

The most common drug therapy is intravenous (IV) pamidronate. An IV infusion of pamidronate (total dose of 1 mg/kg/day over 3 days, repeated every 3-6 months) has been proposed. The total dose must be administered over a 4-hour period. Vitamin D and calcium supplements must be added to the regimen. This therapy in children seems to be safe, but longer follow-up is needed to confirm the absence of collateral effects on the growth plate. An increased growth-plate thickness has been reported in children treated with bisphosphonates.[10]

The PROFIDYS study (Oral Bisphosphonate Effect on Osseous Symptoms in Fibrous Dysplasia of Bone), a double-blind study evaluating the long-term safety and results of treatment with an oral bisphosphonate (risedronate), was initiated in 2007 with the aim of evaluating bone pain and the evolution of osteolytic lesions in patients with fibrous dysplasia.

Majoor et al evaluated the biochemical (bone turnover markers [BTMs]) and clinical (pain reduction) outcome of bisphosphonate therapy in 11 patients with McCune-Albright syndrome and 30 patients with polyostotic fibrous dysplasia who were treated for a median of 6 years (range, 2-25 y).[36] ​ Their data suggested that long-term bisphosphonate therapy was beneficial and safe in the majority of patients with polyostotic fibrous dysplasia. The only prognostic factor found to influence the outcome of bisphosphonate therapy was a high skeletal burden score.

Wang et al retrospectively studied laboratory and clinical findings in 22 cases of polyostotic fibrous dysplasia associated with McCune-Albright syndrome, with the aims of (1) evaluating the efficacy and safety of bisphosphonate therapy and (2) comparing the efficacy of different bisphosphonates (ie, pamidronate and zoledronic acid) in this setting.[37] ​ They found bisphosphonate treatment to be safe and well tolerated and to cause no obvious impairment in patients' linear growth. Zoledronic acid was similar to pamidronate in terms of controlling disease activity.

Denosumab has shown potential for treatment of fibrous dysplasia.[38, 39]

If surgical treatment is required for fibrous dysplasia in long bones, intramedullary nailing is recommended.[40] This technique provides good stabilization and could prevent deformation. In younger children, nailing may have to be repeated to maintain stabilization during growth.[41]

Conservative treatment, use of plates, curettage, and bone grafting have generally been discouraged.[12, 17, 42] Deformity-correction surgery[43] is indicated in patients with mechanical axis deviation of the lower limbs.

A small study from Canada that included nine patients (10 hips) who underwent total hip arthroplasty (THA) for fibrous dysplasia found that, contrary to previous reports, low complication and revision rates were observed with cementless components and routine use of allograft material.[44]

The dysplastic bone in fibrous dysplasia can be quite difficult to ream. Fibrous dysplasia is associated with a high tendency of bone bleeding during surgery.[12]

Gui et al reported their experience with a navigation system they developed for use in conjunction with computer-aided recontouring in the surgical treatment of complex craniofacial fibrous dysplasia.[45] Surgical outcomes were assessed by superimposing postoperative computed tomography (CT) scans onto preoperative CT scans. The authors found that navigation-guided recontouring improved the accuracy and safety of the surgical treatment of complex craniofacial fibrous dysplasia.

Multiportal combined transorbital-transnasal endoscopic resection of fibrous dysplasia of the skull base and orbit has been described.[46]

The main role of follow-up is to prevent deformity as a result of the disease. The authors recommend yearly radiographs of the involved area or areas until skeletal maturity. Because fibrous dysplasia rarely undergoes remission, it is appropriate to monitor disease progression periodically, especially in the skeletally immature patient. Once skeletal maturity has been achieved, it is unusual for monostotic fibrous dysplasia to progress.

Early intervention with internal fixation of involved bones may be important in the prevention of deformity. Referral to an endocrinologist for endocrine and metabolic testing is suggested so that endocrine anomalies can be diagnosed and treated.