Minodronate treatment improves low bone mass and reduces progressive thoracic scoliosis in a mouse model of adolescent idiopathic scoliosis

Abstract

Recent studies have shown an association between osteopenia and adolescent idiopathic scoliosis (AIS) and implied that osteopenia plays a causative role in AIS development. This study aimed to determine if minodronate (MIN) treatment could prevent curve progression by increasing bone mass in a thoracic restraint (TR) mouse model, which develops causes the development of thoracic scoliosis similar to human AIS. A total of 100 young female C57BL6J mice were divided into four groups: (1) control with vehicle (CON/VEH; n = 20), (2) control with MIN (CON/MIN; n = 20), (3) TR with vehicle (TR/VEH; n = 30), or (4) TR with MIN (TR/MIN; n = 30). MIN (0.01 mg/kg/week) and vehicle were administered intraperitoneally to their respective groups. TR was performed at age 4 weeks, and the mice were sacrificed at age 9 weeks. Body weights, spine radiographs, femoral bone mineral density (BMD), serum bone marker levels, and histomorphometry of the cancellous bone of the thoracic vertebrae were analyzed. TR significantly reduced weight gain in the TR/VEH group relative to the CON/VEH group. TR also induced osteoporosis with accelerated bone resorption, as indicated by decreases in femoral BMDs and thoracic cancellous bone volume and increases in serum bone resorption marker levels and histomorphometric resorption parameters in the TR/VEH group. MIN partially improved body weight gain and improved poor bone structure relative to the TR/VEH group by suppressing high bone resorption in the TR/MIN mice. MIN significantly reduced the curve magnitudes, as indicated by a 43% lower curve magnitude in the TR/MIN mice than in the TR/VEH mice (17.9 ± 8.9° vs. 31.5 ± 13.1°; p< 0.001). The administration of MIN increased bone mass and reduced the severity of scoliosis in the TR mice. MIN was suggested as a possible inhibitor of scoliosis development.

Abnormal lacuno‐canalicular network and negative correlation between serum osteocalcin and Cobb angle indicate abnormal osteocyte function in adolescent idiopathic scoliosis

“…Despite the unclear pathomechanism on how the abnormal bone qualities could contribute to the initiation or progression, or both, of AIS, the observed close clinical association and prognostic value of low bone mass have been supported by our initial pilot studies on the effect of improving bone quality in reducing curve progression (ClinicalTrials.gov: NCT01103115). A recent proof‐of‐concept study demonstrated the beneficial effect of minodronate (a third‐generation bisphosphonate) on reducing curve progression in a scoliosis mouse model, suggesting a novel therapeutic option for AIS (60). However, because of the unclear long‐term effect of anti‐osteoporotic drugs on growing adolescents, our group have also explored the clinical effect of vibration therapy on bone mass in AIS (61).…”

Analysis of sagittal curvature and its influencing factors in adolescent idiopathic scoliosis

“…It is a three-dimensional deformity of the coronal, sagittal, and horizontal surfaces of the spine. Patients with thoracic scoliosis have a higher incidence of neck pain, back pain and low back pain due to the presence of coronal plane deformity and reduced thoracic kyphosis [2] and abnormal spine biomechanics [3,4] . The loss of physiological curvature leads to pathological changes in the spine and accelerated disc degeneration, affecting the health-related quality of life of patients [5] .…”

Characteristics of Scoliosis in Mice Induced by Chondrocyte-specific Inactivation of L-type Amino Acid Transporter 1

“…Previous studies have reported that parathyroid hormone and bisphosphonate treatments exhibit preventive effects in mouse models of scoliosis and that decreased BMD is a factor in scoliosis formation. 28,29 However, in the Sko mice, BMD loss appeared after the onset and progression of scoliosis (scoliosis was observed from 1 or 2 weeks and rapidly progressed by 6 weeks, whereas BMD loss developed from 6 weeks), and no significant differences were observed in the bone microstructure between the right and left sides of the bone trabeculae. Therefore, reduced BMD and bone quality may not be the causes of the onset and progression of scoliosis in the Sko mice.…”