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Bone. 2018 Nov;116:172-180. doi: 10.1016/j.bone.2018.07.026. Epub 2018 Aug 2.

Siglec-15-targeting therapy increases bone mass in rats without impairing skeletal growth.

Author information

1
Department of Orthopaedic Surgery, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
2
Department of Orthopaedic Surgery, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan. Electronic address: takamasa@med.hokudai.ac.jp.
3
Rare Disease Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
4
Pharmacovigilance Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
5
Hokkaido University, Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Sapporo, Japan.

Abstract

The treatment of juvenile osteoporosis has not been established due to a lack of data regarding the efficacy and adverse effects of therapeutic agents. The possible adverse effects of the long-term use of antiresorptive therapies on skeletal growth in children is of particular concern. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption, and its deficiency suppresses bone remodeling in the secondary spongiosa, but not in the primary spongiosa, due to a compensatory mechanism of osteoclastogenesis. This prompted us to develop an anti-Siglec-15 therapy for juvenile osteoporosis because most anti-resorptive drugs have potential adverse effects on skeletal growth. Using growing rats, we investigated the effects of an anti-Siglec-15 neutralizing antibody (Ab) on systemic bone metabolism and skeletal growth, comparing this drug to bisphosphonate, a first-line treatment for osteoporosis. Male 6-week-old F344/Jcl rats were randomized into six groups: control (PBS twice per week), anti-Siglec-15 Ab (0.25, 1, or 4 mg/kg every 3 weeks), and alendronate (ALN) (0.028 or 0.14 mg/kg twice per week). Treatment commenced at 6 weeks of age and continued for the next 6 weeks. Changes in bone mass, bone metabolism, bone strength, and skeletal growth during treatment were analyzed. Both anti-Siglec-15 therapy and ALN increased bone mass and the mechanical strength of both the femora and lumbar spines in a dose-dependent manner. Anti-Siglec-15 therapy did not have a significant effect on skeletal growth as evidenced by micro-CT-based measurements of femoral length and histology, whereas high-dose ALN resulted in growth retardation with histological abnormalities in the growth plates of femurs. This unique property of the anti-Siglec-15 Ab can probably be attributed to compensatory signaling for Siglec-15 inhibition in the primary spongiosa, but not in the secondary spongiosa. Thus, anti-Siglec-15 therapy could be a safe and effective for juvenile osteoporosis.

KEYWORDS:

Anti-Siglec-15 Ab; Growth plate; Juvenile osteoporosis; Osteoclasts; Siglec-15

PMID:
30076992
DOI:
10.1016/j.bone.2018.07.026

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