Zoledronic Acid in a Mouse Model of Human Fibrous Dysplasia: Ineffectiveness on Tissue Pathology, Formation of \u201cGiant Osteoclasts\u201d and Pathogenetic Implications

Alessandro Corsi,Rossella Labella,Annamaria Di Filippo,Michele Dello Spedale Venti,Biagio Palmisano,Samantha Donsante,Marta Serafini,Francesca Fabretti,Cristina Remoli,Emanuela Spica,Mara Riminucci,Ilenia Coletta

doi:10.1007/s00223-020-00752-w

Abstract

We compared the effects of a nitrogen-containing bisphosphonate (N-BP), zoledronic acid (ZA), and an anti-mouse RANKL antibody (anti-mRANKL Ab) on the bone tissue pathology of a transgenic mouse model of human fibrous dysplasia (FD). For comparison, we also reviewed the histological samples of a child with McCune–Albright syndrome (MAS) treated with Pamidronate for 3 years. EF1α-GsαR201C mice with FD-like lesions in the tail vertebrae were treated with either 0.2 mg/kg of ZA at day 0, 7, and 14 or with 300 μg/mouse of anti-mRANKL Ab at day 0 and 21. All mice were monitored by Faxitron and histological analysis was performed at day 42. ZA did not affect the progression of the radiographic phenotype in EF1α-GsαR201C mice. FD-like lesions in the ZA group showed the persistence of osteoclasts, easily detectable osteoclast apoptotic activity and numerous “giant osteoclasts”. In contrast, in the anti-mRANKL Ab-treated mice, osteoclasts were markedly reduced/absent, the radiographic phenotype reverted and the FD-like lesions were extensively replaced by newly formed bone. Numerous “giant osteoclasts” were also detected in the samples of the child with MAS. This study supports the hypothesis that osteoclasts per se, independently of their resorptive activity, are essential for development and expansion of FD lesions.

Highlights

Nitrogen-containing bisphosphonates (N-BPs) constitute the major class of drugs used to treat various bone diseases including osteoporosis, hypercalcemia of malignancy, Paget bone disease and pediatric disorders with low bone density and increased bone fragility as osteogenesis imperfecta [1, 2]
Using the transgenic EF1α- GsαR201C mouse model of fibrous dysplasia (FD) [16] and a murine analog of denosumab anti-mouse RANKL antibody, we recently demonstrated that the beneficial effect of RANKL inhibition in FD is underlaid by critical changes in the histopathology of the disease [17]
As expected from our previous study [17] and consistent with the results of the radiographic analysis, histology of the tail vertebrae of mice treated with anti-mRANKL Ab (Fig. 1h, i) revealed the deposition of new bone within the affected vertebrae, the amount of which varied according to the radiographic phenotype at the beginning of treatment and was significantly higher compared to zoledronic acid (ZA)-treated mice (Fig. 2a)

Summary

Introduction

Nitrogen-containing bisphosphonates (N-BPs) constitute the major class of drugs used to treat various bone diseases including osteoporosis, hypercalcemia of malignancy, Paget bone disease and pediatric disorders with low bone density and increased bone fragility as osteogenesis imperfecta [1, 2]. N-BPs treatment may associate with the appearance of “giant osteoclasts”, large polykaryons with even more than 40 nuclear profiles, compared to 2–8 nuclear profiles found in normal osteoclasts, that are often detached from the bone surface and up to 30% apoptotic [3, 4]. N-BPs are currently used to treat fibrous dysplasia of bone [Polyostotic FD/McCune–Albright syndrome (MAS); OMIM#174800]. FD is a potentially crippling skeletal disease caused by post-zygotic activating mutations of the alpha subunit of the stimulatory G protein encoded by the GNAS gene (GNAS complex locus; GNAS, OMIM *139320) that can occur either isolated or in association with non-skeletal disorders (mainly hyper-functional endocrinopathies and skin hyperpigmented lesions) in the MAS (for review see [5]). FD lesions are characterized by marrow fibrosis, abnormal bone trabeculae with defective mineralization and increased

Methods

Results

Conclusion