Polyostotic fibrous dysplasia (PFD)

Polyostotic fibrous dysplasia (PFD) is a sporadic disorder which affects multiple sites in the skeleton. The bone at these sites is rapidly resorbed and replaced by abnormal fibrous tissue and mechanically abnormal bone. PFD may occur alone or as part of the McCune-Albright Syndrome (MAS), a syndrome originally defined by the triad of PFD, cafe-au-lait pigmentation of the skin, and precocious puberty. The bony lesions are frequently disfiguring and painful, and depending on the location of the lesion, they can cause significant morbidity. Lesions in weight-bearing bones can lead to disabling fractures, while lesions in the skull can lead to compression of vital structures such as cranial nerves.

Currently there are no clearly-defined systemic therapies for this bone disease. Small, uncontrolled trials using the second generation bisphosphonate, pamidronate, suggest that bisphosphonates may be effective. This study is a phase 2, controlled, double blinded trial of the third generation oral bisphosphonate, alendronate for the treatment of fibrous dysplasia. We propose to show that treatment with alendronate will improve bone quality, decrease bone pain, decrease fractures, and, if the patient is referred to the companion bone grafting protocol, will allow for the regeneration of better quality bone.

Fibrous dysplasia (FD) is most commonly a benign bone lesion composed of disorganized fibrous connective tissue interspersed with spicules of immature woven bone and cartilagenous tissue. The majority of these patients present with single or monostotic lesions. A smaller percent present as polyostotic lesions and a subset of these are in the context of the MAS.

Polyostotic fibrous dysplasia can often be seen in a plain X-ray of the skeleton. A more sensitive method of detecting lesions is a bone scan using technetium. With this technique, lesions may be detected in a preclinical stage. Bone densitometry may be an effective technique for following changes in bone lesions and disease progression or regression at affected sites. Computed tomography (CT) is the best technique for following lesions in the skull.

The severity of bone disease in McCune-Albright syndrome is quite variable. When weight-bearing bones such as the femur are affected, limping, deformity, and fractures may occur. In many children, the arms and/or legs are of unequal length, even in the absence of actual fracture. Regions of fibrous dysplasia are also very common in the bones that form the skull and jaw. If these lesions expand, skull and facial asymmetry as well as compression of vital structures such as cranial nerves may occur. The result can be permanent disfigurement or loss of important nerve function or both.

Some children may be minimally affected, with no asymmetry, deformity or fracture, and lesions are detected only by a bone scan. In a few children, lesions are found only in the base of the skull. However, it has been shown that these lesions, evident only on bone scanning initially, can expand with time and have permanent effects upon physical appearance and function. However, it is not known what percent of patients have asymptomatic skull lesions or what percent of skull lesions detected on bone scanning are likely to progress. The skull lesions can often be the most difficult for the patient, both from the loss of function that they can cause as well as from the psychological impact of the physical disfigurement.

There is evidence that lesions in the axial skeleton are different from those in the gnathic and cranial bones. In long bones, The typical "Chinese writing" pattern of bone trabeculae is the dominant feature with the fibrous tissue predominating over the amount of abnormal bone trabeculae. In gnathic bones, the pattern is characterized by the presence of significant amounts of sclerotic bone, however, bone trabeculae are discontinuous. Furthermore, in other cranial bones, dense, sclerotic trabecular bone that forms an interconnected network is observed, similar to the pattern observed in Paget’s disease (18). The difference in the nature of these three types of lesions has implications in terms of the best imaging modality to follow the effect of treatment, as well as possible differences in response to treatment.

The Normal Bone Remodeling Cycle

One of the unique features of bone is that it is continuously renewed by the coordinated action of osteoclastic cells, which degrade bone, and osteoblastic cells, which build it. Bone contains bone remodeling units at discrete locations and at different developmental stages. The function and arrangement of these small subunits, which constantly "turn over" bone matrix constituents and mineral, create the basis for the changes in bone mass and structure observed with increasing age, and in various disease states.

Every remodeling cycle is initiated by the activation of osteoclastic precursors to form multinucleated osteoclasts and ultimately resorb bone. After resorption is terminated, the area is populated by precursor cells that differentiate into osteoblasts, which form new matrix that subsequently becomes mineralized. As the gap created by osteoclasts is filled in, these osteoblastic cells become quiescent and the surface of the newly formed bone is covered by endosteal lining cells. The area remains quiescent until another round of bone turnover is initiated at some point in time, by factors that are not yet well delineated. The rate of remodeling is standardly measured by administration of tetracycline, which binds to osteoid, at two different times prior to bone biopsy. Parameters of remodeling can then be determined by the pattern of tetracycline labeling observed.

The Remodeling Cycle in FD

In PFD/MAS, normal bone and hematopoietic marrow are replaced by an abnormal osteogenic tissue featuring abnormal bone trabeculae. Increased bone resorption has been noted in the pathophysiology of PFD/MAS, possibly through increased secretion of IL-6 which contains a cAMP response element in its promoter. The encroachment of the fibrosis tissue is associated with the resorption of pre-existing cancellous and cortical bone and resorptive changes are encountered in the new osteoid tissue that develop from the endosteal fibrosis. Clusters of osteoclasts are noted in proximity to scalloped (resorbed) bone as well as within the fibrous tissue. Analogous to bone lesions in hyperparathyroidism, mature multinucleated osteoclasts and TRAP positive mononuclear osteoclast precursors are associated with retracted cells along the edges and inside the bone trabeculae (dissecting resorption) (19). In PFD/MAS, these abnormal, retracted cells are osteoblastic based on their expression of alkaline phosphatase and other bone-related proteins, and the retraction is most likely due to excess cAMP production caused by the Gsa mutation (20). Expression of IL-6 was detected in the fibroblastic cells, in osteoblasts and in early osteocytes within the newly formed, abnormal bone with the highest levels generally found in the retracted cells, some of which were closely associated with mature osteoclasts and mononuclear precursors (19). An increased production of IL-6 by PFD/MAS cells in vitro has been reported (21). These data show that in PFD/MAS, high levels of IL-6 are found in fibroblastic cells, as well as in osteoblastic cells that deposit abnormal bone and feature morphological effects of excess cAMP (cell retraction). Thus, the abnormal patterns of bone formation and resorption which characterize PFD/MAS lesions are both related to mutation of Gsa and overproduction of cAMP.

McCune-Albright Syndrome (MAS)

The MAS is a non-inherited, genetic disorder that was first described over fifty years ago (1). The triad which has classically defined the syndrome consists of precocious puberty, café au lait skin pigmentation and polyostotic fibrous dysplasia (PFD) of bone (2). Subsequently, it was found that besides bone, skin and gonads, and a number of other tissues could be involved, predominantly endocrine tissues such as thyroid (3), adrenal (4), and various pituitary cell populations, including growth hormone-secreting somatotrophs (5-7). Besides these endocrine tissues, liver (8), heart (9), and spleen (10) have been found to be affected. Hyperfunctioning gonads resulting in precocious puberty (11), as well as other hyperfunctioning endocrine tissues together with PFD account for the majority of the associated morbidity and are the hallmarks of the presentation and disease course.

The disease presents along a spectrum both in terms of tissues involved, the severity of involvement and the age at presentation. Sometimes, children are diagnosed in early infancy with obvious bone disease and markedly increased endocrine secretions from several glands. At the opposite end of the spectrum, many children are entirely healthy, and have little or no outward evidence of bone or endocrine involvement. They may enter puberty close to the normal age, and have no unusual skin pigmentation at all.

Because of the sporadic occurrence of the disease and the pattern of skin hyperpigmentation, it was postulated that a genetic defect involving a dominant somatic mutation, occurring early in embryonic development, may be responsible for the phenotypic presentation. In 1991, activating mutations of the a subunit of the G protein (Gsa) which stimulates cAMP formation were described in affected tissues from patients with MAS (12-14). It is now generally accepted that a somatic mutation occurring early in development in the Gsa protein is responsible for MAS.

The endocrine tissues most frequently affected in MAS are the gonads (ovaries or testes), the thyroid and the growth hormone-secreting somatotrophs of the pituitary. Therapies for hyperfunctioning endocrine tissues include surgical removal of affected glands or medications directed at hormonal inhibition or blockade. The response is variable depending on the involved tissue (15-17).

While the skin hyperpigmentation can occasionally be extensive and psychologically trying for the patient, there are seldom any medical problems associated with it. Treatment of the PFD is, to date, largely ineffective and this remains the major therapeutic challenge of the disease.