OBJECTIVES: Rheumatoid arthritis (RA) is characterized by chronic inflammation of the synovium, progressive erosion of the articular cartilage, and joint destruction. RA also causes secondary osteoporosis and muscle wasting. We investigated the effects of ibandronate (IBN), a bisphosphonate; eldecalcitol (ELD), an active vitamin D3 derivative; and combination treatment with both agents on secondary osteoporosis and muscle wasting using adjuvant-induced arthritis rats. METHODS: Arthritis was induced in 8-week-old male Lewis rats. Rats were randomized into 4 treatment groups and an untreated normal control group: IBN (subcutaneously, once every 2 weeks, 10 µg/kg), ELD (orally, once daily, 30 ng/kg/day), IBN + ELD, vehicle, and control. Paw thickness measurements were performed for evaluation of arthritis. The femur was scanned using dual-energy X-ray absorptiometry. Cross-sectional areas of left tibialis and anterior muscle fibers and the expression of MuRF1, atrogin-1, MyoD, and myogenin in the gastrocnemius muscle were measured to evaluate muscle wasting. RESULTS: IBN and/or ELD increased bone mineral density (BMD) in the femur. In addition, there was an additive effect of combination treatment compared with single treatments for BMD. However, IBN and/or ELD did not inhibit muscle wasting in adjuvant-induced arthritis rats. CONCLUSIONS: Combination treatment with IBN and ELD may be effective for secondary osteoporosis associated with RA. Other treatments are necessary for muscle wasting associated with RA. Studies in humans are needed to confirm these findings.
Absorptiometry, Photon ; Animals ; Arthritis ; Arthritis, Rheumatoid ; Bone Density ; Cartilage, Articular ; Cholecalciferol ; Femur ; Humans ; Inflammation ; Joints ; Male ; Muscle, Skeletal ; Myogenin ; Osteoporosis ; Rats ; Synovial Membrane ; Vitamin D

OBJECTIVES: While it has been pointed out that an anteroposterior (AP) view of the lumbar spine may lead to overestimation of the bone mineral density (BMD), a lateral view is expected lead to the early detection of BMD loss on scanning cancellous bone. Vertebral fracture is often seen in aged osteoporotic patients, and it is important to prevent this fracture. Therefore, we aimed to identify the optimal site for BMD measurement to assess the risk of vertebral fracture. METHODS: Forty-seven female patients with fresh osteoporotic vertebral fracture and BMD measurements were included in this study (Fracture group). As a non-fractured control group, 218 female patients with BMD measurements were enrolled (Control group). We compared BMD values based on AP and lateral views of the lumbar spine from L2 to L4 and the femoral neck. With a lateral view of the lumbar spine, we measured both the total vertebral body and vertebral body center, mainly composed of cancellous bone. RESULTS: BMD of the AP lumbar spine in the Fracture group was significantly lower than in the Control group (P < 0.05). In the subanalyses for comparisons between age-matched fracture and control groups, BMD of only the AP lumbar spine in the Fracture group was significantly lower than in the Control group (P < 0.01). CONCLUSIONS: AP lumbar spine BMD is optimal for assessing vertebral fracture occurrence.
Bone Density* ; Female ; Femur Neck ; Humans ; Spine

OBJECTIVES: Reduced bone quality caused by vitamin C deficiency in older persons may lead to incidental fragility fractures during bisphosphonate treatment, although bisphosphonate increases bone mineral density (BMD). This study aimed to evaluate the effects of minodronate and ascorbic acid (Aa) on BMD, bone quality, and bone strength in Aa(-)deficient osteogenic disorder Shionogi (ODS) rats. METHODS: Six-month-old ODS rats were divided into four groups (n = 20 per group): (1) Aa supplementation (Aa(+)); (2) Aa(-)deficient (Aa(-)); (3) Aa supplementation and minodronate administration (Aa(+) + Mino); and (4) Aa(-)deficient and minodronate administration (Aa(-) + Mino). BMD, bone strength, bone histomorphometry, and bone quality determined using Fourier transform infrared spectroscopy imaging (FTIRI) were evaluated after 4 and 8 weeks. RESULTS: BMD was significantly higher in the Aa(+) + Mino group than in the Aa(-) group (p < 0.05). Bone strength was significantly higher in the Aa(+) and Aa(+) + Mino groups than in the Aa(-) group (p < 0.05). Furthermore, bone strength was significantly higher in the Aa(+) + Mino group than in the Aa(-) + Mino group (p < 0.05). Minodronate treatment irrespective of Aa supplementation significantly decreased bone resorption compared with the Aa(+) and Aa(-) groups (p < 0.05). No significant differences in the parameters evaluated by FTIRI were observed between the groups. CONCLUSIONS: Aa supplementation improved bone strength in ODS rats. Combined treatment with minodronate and Aa, but not minodronate alone, improved bone strength and increased BMD. Aa is required for bone health because it is essential for osteoblast differentiation.
Animals ; Ascorbic Acid Deficiency ; Ascorbic Acid* ; Bone Density* ; Bone Resorption ; Humans ; Osteoblasts ; Rats* ; Spectroscopy, Fourier Transform Infrared ; Vitamins*

OBJECTIVES: Glucocorticoid (GC) treatment inhibits activation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation from stem cells. As a result, GC treatment results in bone loss, GC-induced osteoporosis (GIO), elevated fracture risk, and delayed bone healing. Bisphosphonates such as alendronate (ALN) are recommended for treating or preventing GIO, and lowintensity pulsed ultrasound (LIPUS) facilitates fracture healing and maturation of regenerated bone. Combined therapy with ALN and LIPUS may stimulate cancellous bone healing in GIO rats. Here, we examined the effect of ALN and LIPUS on cancellous bone osteotomy repair in the proximal tibia of GIO rats. METHODS: Prednisolone (10 mg/kg body weight/day) was administered for 4 weeks to induce GIO in 6-month-old female Sprague-Dawley rats. Tibial osteotomy was then performed and daily subcutaneous injection of ALN (1-µg/kg body weight) was subsequently administered alone or in combination with LIPUS (20 min/day) for 2 or 4 weeks. RESULTS: ALN significantly increased bone mineral density (BMD) at 2 and 4 weeks, and ALN + LIPUS significantly increased BMD at 4 weeks. Bone union rates were significantly increased after 2 and 4 weeks ALN and ALN + LIPUS treatment. Lastly, ALN and ALN + LIPUS significantly increased the proportion of Runx2 positive cells at 4 weeks. CONCLUSIONS: ALN monotherapy and combined ALN and LUPUS treatment augmented BMD and stimulated cancellous bone repair with increased Runx2 expression at the osteotomy site in GIO rats. However, the combined treatment had no additional effect on cancellous bone healing compared to ALN monotherapy.
Alendronate* ; Animals ; Bone Density ; Bone Diseases, Metabolic* ; Diphosphonates ; Female ; Fracture Healing ; Humans ; Infant ; Injections, Subcutaneous ; Osteoblasts ; Osteoporosis ; Osteotomy* ; Prednisolone ; Rats* ; Rats, Sprague-Dawley ; Stem Cells ; Tibia* ; Transcription Factors ; Ultrasonic Waves*

Objectives: The purpose of this study is to investigate the stage of chronic kidney disease (CKD) in adenine-induced CKD model rats by serum analyses, and to examine bone mineral density (BMD), bone strength, and microstructure of trabecular and cortical bone in these rats. Methods: Eight-week-old, male Wistar rats (n = 42) were divided into 2 groups: those fed a 0.75% adenine diet for 4 weeks until 12 weeks of age to generate CKD model rats (CKD group); and sham rats. The CKD and sham groups were sacrificed at 12, 16, and 20 weeks of age (n = 7 in each group and at 12, 16, and 20 weeks), and various parameters were evaluated, including body weight, renal wet weight, muscle wet weight, renal histology, biochemical tests, BMD, biomechanical testing, and micro-computed tomography (CT). The parameters were compared between the 2 groups at the various time points. Results: In the CKD model rats, at 20 weeks of age, serum creatinine, phosphorus, and intact-PTH levels were elevated, and serum calcium levels were normal, indicating that the CKD was stage IV and associated with secondary hyperparathyroidism. Decreased BMDs of the whole body and the femur were observed as bone changes, and micro-CT analysis showed deterioration of bone microstructure of the cortical bone that resulted in decreased bone strength in the cortical and trabecular bone. Conclusions These CKD model rats showed stage IV CKD and appear appropriate for evaluating the effects of several treatments for CKD-related osteoporosis and mineral bone disorder.

Objectives: Chronic kidney disease (CKD) complicated by secondary hyperparathyroidism (SHPT) is associated with an increased risk of fragility fractures. Etelcalcetide (EC) is a treatment for SHPT that reduces serum parathyroid hormone (PTH) levels. However, the effects of combined treatment with osteoporosis drugs such as teriparatide (TPTD) remain unclear. This study investigates the combined effects of EC and TPTD on bone in CKD model rats. Methods: The CKD model was established in 8-week-old male Wistar rats by feeding them a 0.75% adenine diet for 4 weeks. At 20 weeks of age, the rats were divided into 4 groups (n = 9–10 in each group): CKD group (vehicle administration), TPTD group (30 μg/kg, 3 times/week), EC group (0.6 mg/kg, daily), and Comb group (TPTD and EC combined). EC was injected for 12 weeks starting at 20 weeks of age, and TPTD was injected for 8 weeks starting at 24 weeks of age. After treatment, the followings were evaluated: bone mineral density, bone strength, biochemical tests, bone and fat histomorphometry, and micro-computed tomography. Results: In CKD model rats, the combination of EC and TPTD was more effective in increasing cortical bone thickness and bone strength and inhibiting porosity. In addition, the combined treatment decreased bone marrow adiposity and fibrosis, and it increased bone mass and improved bone microstructure in trabecular bone. Conclusions With the observed benefits such as improved bone mass, bone strength, structural properties, and bone marrow adiposity, combination therapy may be a potential way to improve bone fragility in CKD.