High- and low-dose OPG–Fc cause osteopetrosis-like changes in infant mice

Bargman, Renee; Posham, R.; Boskey, Adele L.; Carter, Erin; DiCarlo, Edward F.; Verdelis, Kostas; Raggio, Cathleen; Pleshko, Nancy

doi:10.1038/pr.2012.118

Cited by 21 publications

(16 citation statements)

References 39 publications

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“…Similar to most of the conditions mentioned in this review, these abnormalities result in altered bone quality and increased fracture risk. The condition may be caused by genetic abnormalities in regulators of osteoclast activity or by excessive suppression of bone turnover . Bone quality in osteopetrosis was characterized in the toothless rat and the osteopetrotic mouse by X‐ray diffraction and FTIRI; the latter showing microhardness was increased in osteopetrotic bone, the former demonstrated the persistence of small crystals.…”

Section: Bone Quality Changes In Diseasementioning

confidence: 99%

Bone quality changes associated with aging and disease: a review

Boskey

Imbert

2017

Annals of the New York Academy of Sciences

118

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Bone quality encompasses all the characteristics of bone that, in addition to density, contribute to its resistance to fracture. In this review, we consider changes in architecture, porosity and composition, including collagen structure, mineral composition and crystal size. These factors all are known to vary with tissue and animal ages, and health status. Bone morphology and presence of micro-cracks which also contribute to bone quality, will not be discussed in this review. Correlations with mechanical performance for collagen cross-linking, crystallinity and carbonate content are contrasted with mineral content. Age dependent changes in humans and rodents are discussed in terms of using rodent models of disease. Examples are osteoporosis, osteomalacia, osteogenesis imperfecta, and osteopetrosis, in both humans and animal models. Each of these conditions, along with aging, are associated with increased fracture risk for distinct reasons.

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Section: Bone Quality Changes In Diseasementioning

confidence: 99%

Bone quality changes associated with aging and disease: a review

Boskey

Imbert

2017

Annals of the New York Academy of Sciences

118

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“…Denosumab recognizes human and monkey, but not mouse or rat RANKL, so other recombinant RANKL inhibitors such as RANK‐Fc and OPG‐Fc have been used to inhibit RANKL in animal models . In this study, RANKL was inhibited by RANK‐Fc or OPG‐Fc, using dosing regimens intended to maximally inhibit osteoclasts throughout the 12‐week treatment period.…”

Section: Discussionmentioning

confidence: 99%

RANKL Inhibitors Induce Osteonecrosis of the Jaw in Mice With Periapical Disease

Aghaloo

Cheong

Bezouglaia

et al. 2013

Journal of Bone and Mineral Research

112

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Antiresorptive medications are essential in treating diseases of pathologic osteoclastic bone resorption, including bone cancer and osteoporosis. Bisphosphonates (BPs) are the most commonly used antiresorptives in clinical practice. Although inhibition of bone resorption is important in regulating unwanted malignant and metabolic osteolysis, BP treatment is associated with potential side effects, including osteonecrosis of the jaws (ONJ). Recently, non-BP antiresorptive medications targeting osteoclastic function and differentiation, such as denosumab, have entered the clinical arena. Denosumab treatment results in a similar rate of ONJ as BPs. Animal models of ONJ, using high-dose BP treatment in combination with tooth extraction or dental disease, provide valuable tools and insight in exploring ONJ pathophysiology. However, the ability of other antiresorptives to induce ONJ-like lesions in animal models has not been explored. Such studies would be beneficial in providing support for the role of osteoclast inhibition in ONJ pathogenesis versus a direct BP effect on oral tissues. Here, we tested the ability of the receptor activator of NF-kB ligand (RANKL) inhibitors RANK-Fc (composed of the extracellular domain of RANK fused to the fragment crystallizable [Fc] portion of immunoglobulin G [IgG]) and OPG-Fc (composed of the RANKL-binding domains of osteoprotegerin [OPG] linked to the Fc portion of IgG) to induce ONJ in mice in the presence of periapical disease, but in the absence of dental extractions. We demonstrate radiographic evidence of ONJ in RANK-Fc–treated and OPG-Fc–treated mice, including inhibition of bone loss, increased bone density, lamina dura thickening, and periosteal bone deposition. These findings closely resembled the radiographic appearance of an ONJ patient on denosumab treatment. Histologic examination revealed that RANK-Fc treatment and OPG-Fc treatment resulted in absence of osteoclasts, periosteal bone formation, empty osteocytic lacunae, osteonecrosis, and bone exposure. In conclusion, we have successfully induced ONJ in mice with periapical disease, using potent osteoclast inhibitors other than BPs. Our findings, coupled with ONJ animal models using high-dose BPs, suggest that osteoclast inhibition is pivotal to the pathogenesis of ONJ.

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“…Treatment ended 12 weeks after the transition time point. Doses of RANK-Fc and ALN were based on results of previous studies that showed increased bone mineral density without side effects using the same dose [1][2][3]. Weaning was carried out between 3 and 4 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…The oim/oim mice, as a result of an inappropriate stop codon in the collagen I alpha 2 chain's gene, have a aI(I) 3 triple helix instead of the expected aI(1) 2 aI(2) helix [11] and provide a reproducible model with a moderate-to-severe (Type III) form of OI [34], including the presence of spontaneous fractures. Both alendronate (a bisphosphonate) and RANKFc, an inhibitory antibody to RANKL (receptor activator of nuclear factor-jB ligand), tested in short-term (8-week) studies showed a comparable reduction in the number of fractures relative to saline-treated oim/oim mice [2]. The bone composition assessed by Fourier transform infrared (FTIR) imaging after short-term alendronate treatment of the oim/oim mouse, however, was unchanged relative to saline-treated mice [8].…”

Section: Introductionmentioning

confidence: 99%

“…The bone composition assessed by Fourier transform infrared (FTIR) imaging after short-term alendronate treatment of the oim/oim mouse, however, was unchanged relative to saline-treated mice [8]. RANK-Fc blocks the formation, activation, and survival of osteoclasts [2,3,13]. Because RANKL inhibitors have a shorter half-life in bone than do bisphosphonates, they are being investigated as an alternative therapy.…”

Section: Introductionmentioning

confidence: 99%

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Are Changes in Composition in Response to Treatment of a Mouse Model of Osteogenesis Imperfecta Sex-dependent?

Boskey

Marino

Spevak

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Osteogenesis imperfecta (OI) is a genetic disease characterized by skeletal fragility and deformity. There is extensive debate regarding treatment options in adults with OI. Antiresorptive treatment reduces the number of fractures in growing oim/oim mice, an animal model that reproducibly mimics the moderate-to-severe form of OI in humans. Effects of long-term treatments with antiresorptive agents, considered for treatment of older patients with OI with similar presentation (moderate-tosevere OI) are, to date, unknown. Questions/purposes Fourier transform infrared (FTIR) imaging, which produces a map of the spatial variation in chemical composition in thin sections of bone, was used to address the following questions: (1) do oim/oim mice show a sex dependence in compositional properties at 6.5 months of age; (2) is there a sex-dependent response to treatment with antiresorptive agents used in the treatment of OI in humans; and (3) are any compositional parameters in oim/oim mice corrected to wild-type (WT) values after treatment? Methods FTIR imaging data were collected from femurs from four to five mice per sex per genotype per treatment. Treatments were 24 weeks of saline, alendronate, or RANKFc; and 12 weeks of saline + 12 weeks RANK-Fc and 12 weeks of alendronate + RANK-Fc. FTIR imaging compositional parameters measured in cortical and cancellous bones were mineral-to-matrix ratio, carbonate-to-mineral ratio, crystal size/perfection, acid phosphate substitution, collagen maturity, and their respective distributions (heterogeneities). Because of the small sample size, nonparametric statistics (Mann-Whitney U-and Kruskal-Wallis tests with Bonferroni correction) were used to compare saline-treated male and female mice of different genotypes and treatment effects by sex and genotype, respectively. Statistical significance was defined as p \ 0.05.One or more of the authors (CLR) has received research funding from Amgen (Thousand Oaks, CA, USA) in partial support of this study in an amount less than USD 10,000. One or more of the authors (ALB) owns stock in Amgen (Thousand Oaks, CA) in an amount less than USD 10,000 and in Merck (Kenilworth, NJ, USA) in an amount less than USD 10,000. Results At 6.5 months, saline-treated male cortical oim/ oim bone had increased mineral-to-matrix ratio (p = 0.016), increased acid phosphate substitution (p = 0.032), and decreased carbonate-to-mineral ratio (p = 0.016) relative to WT. Cancellous bone in male oim/oim also had increased mineral-to-matrix ratio (p = 0.016) relative to male WT. Female oim/oim mouse bone composition for all cortical and cancellous bone parameters was comparable to WT (p [ 0.05). Only the female WT mice showed a response of mean compositional properties to treatment, increasing mineral-to-matrix after RANK-Fc treatment in cancellous bone (p = 0.036) compared with saline-treated mice. Male oim/oim increased mineral-to-matrix cortical and cancellous bone heterogeneity in response to all long-term treatments except for saline + RANK-Fc (p...

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High- and low-dose OPG–Fc cause osteopetrosis-like changes in infant mice

Cited by 21 publications

References 39 publications

Bone quality changes associated with aging and disease: a review

Bone quality changes associated with aging and disease: a review

RANKL Inhibitors Induce Osteonecrosis of the Jaw in Mice With Periapical Disease

Are Changes in Composition in Response to Treatment of a Mouse Model of Osteogenesis Imperfecta Sex-dependent?

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