Age-Related Changes and Effects of Bisphosphonates on Bone Turnover and Disease Progression in Fibrous Dysplasia of Bone

Abstract

Fibrous dysplasia (FD) is a mosaic disease in which bone is replaced with fibro‐osseous tissue. Lesions expand during childhood, reaching final burden by age 15 years. In vitro data suggest that disease activity decreases in adulthood; however, there is no clinical data to support this concept. Bone turnover markers (BTMs) have been used as markers of disease activity in FD; however, the natural history of BTM changes, the effects of antiresorptive treatment, and their association to clinical outcomes have not been described. The goals of this study are to describe 1) the natural history of FD disease activity and its association with pain; 2) the impact of bisphosphonates on the natural history of BTMs; and 3) the effect of bisphosphonates on progression of FD burden during childhood. Disease burden scores and alkaline phosphatase, osteocalcin, NTx, FGF23, and RANKL levels from 178 subjects in an FD/MAS natural history study were reviewed, including 73 subjects treated with bisphosphonates. BTMs, RANKL, and FGF23 demonstrated a sustained reduction with age. Bisphosphonate treatment did not significantly impact this age‐dependent decrease in BTMs. Pain was more prevalent and severe in adults compared with children and was not associated with BTMs. In children, the progression of disease burden was not affected by bisphosphonates. In conclusion, FD is associated with an age‐dependent decline in bone turnover and other markers of disease activity. Pain, in contrast, is more frequent and severe in adults with FD and is not related to bone turnover. Bisphosphonate treatment does not significantly impact the age‐dependent decrease in bone turnover, nor does it prevent the progression of FD disease burden in children. These findings, in association with the established adverse effects of antiresorptives, should be considered when evaluating use and response to bisphosphonates in patients being treated for FD and in any study using BTMs as surrogate endpoints. © 2019 American Society for Bone and Mineral Research.

RANKL Inhibition in Fibrous Dysplasia of Bone: A Preclinical Study in a Mouse Model of the Human Disease

“…Increased osteoclastogenesis is thought to play a role in the establishment and progression of FD lesions and currently represents the only target for a medical therapy of the disease. Indeed, multiple studies have tested the effect of bisphosphonates (BPs) in FD patients, showing some clinical benefits (reduction of bone pain), but, in the absence of significant changes in the histology and evolution of the skeletal phenotype . Potential alternative approaches rely on the identification of the specific cellular and molecular mechanism(s) leading to the enhanced osteoclast formation within FD lesions.…”

First in Mice: RANKL Neutralization in Fibrous Dysplasia

“…However, that study used an oral bisphosphonate, which may be less effective. A relatively large retrospective and a smaller prospective study showed no effect on FD lesion development or progression . Lack of efficacy of bisphosphonates on disease progression may be due to their mechanism of action.…”

“…When the mutation occurs before gastrulation, more than one germ layer can be affected, resulting in McCune‐Albright Syndrome (MAS), a complex, multisystem disorder that in addition to FD involves extraskeletal tissues, especially hyperfunctioning endocrinopathies . Although treatment exists for most endocrine diseases, options for FD are limited and have shown little to no effect on the natural history of the disease …”

Clinical Guidelines on Paget's Disease of Bone

“…An example of the limitations of expert opinion and non‐evidence‐based treatment in another focal bone disease was recently provided by the study of Florenzano and colleagues, which coincidentally appeared in the same issue of JBMR as the new Paget's disease guideline. These authors reported that the commonly used practice of giving bisphosphonate therapy to children with fibrous dysplasia in an attempt to modify natural history of the disease had no demonstrable effect on disease progression or disease burden, contrary to what one might expect from knowledge of bone physiology and pharmacology.…”