A novel therapeutic strategy for adolescent idiopathic scoliosis based on osteoporotic concept

Adolescent idiopathic scoliosis (AIS) is a complex three dimensional spinal deformity which occurs mostly in prepubertal and pubertal girls. Although bracing and surgery have been the mainstays of treatment for AIS, because of the complications and poor compliance, many patients with this disorder continue to experience significant residual symptoms. The etiology and pathogenesis of AIS is unclear, but recent studies show the association between osteopenia and AIS and imply that osteopenia play a causative role in the development of AIS. Anti-osteoporosis treatment can improve bone strength, prevent osteoporosis and rebalance the OPG–RANK–RANKL system, which may help to prevent curve progression in AIS. This report proposes that anti-osteoporosis treatment may be an effective treatment for AIS.     

Zoledronate reverses mandibular bone loss in osteoprotegerin-deficient mice

Summary  To characterize the changes in osteoprotegerin-deficient (OPG−/−) mice mandibles and the possible mandibular bone loss prevention by zoledronate. This preventive effect in the mandible differed from that in the proximal tibia and was independent of the OPG pathway. Introduction  The study aimed to characterize both the changes in the mandible in osteoprotegerin-deficient (OPG^−/−) mice and possible mandibular bone loss prevention by zoledronate. Methods  Twenty-eight 6-week-old female mice (C57BL/6J), including OPG^−/− (n = 21) and wild-type (WT) (n = 7) mice, were assigned to four groups after 2 weeks of acclimatization to local vivarium conditions: wild mice with vehicle (WT group); OPG^−/− mice with vehicle (OPG^−/− group); and OPG^−/− mice that were subcutaneously injected with either 50 or 150 μg/kg zoledronate (Zol-50 and Zol-150 groups, respectively). Mice were sacrificed at 4 weeks after these treatments and after fasting for 12 h. Sera were harvested for biochemical analyses. The right mandible and tibia of each mouse were selected for microCT analysis. Student’s t-test was performed for comparisons of bone parameters at different sites in the WT group. Analysis of variance (ANOVA) was used to compare the biomarkers and bone parameters in the different treatment groups. Results  Serum bone-specific alkaline phosphatase (B-ALP) and tartrate-resistant acid phosphatase 5b (TRACP-5b) were significantly decreased in WT mice as compared to the levels in the OPG^−/− mice (P < 0.05). Zoledronate treatment decreased the high serum B-ALP activity observed in OPG^−/− mice to the levels seen in WT mice, while serum TRACP-5b concentrations were decreased to levels even lower than those in WT mice. There were substantial variations in BMD and microstructure of the mandibular and proximal tibial trabeculae. Mandibular bone loss was less affected by OPG gene deprivation than the proximal tibia was. Both zoledronate groups showed greater BMD, trabecular BV/TV, Tb.Th, Tb.N, and Conn.D and a significant decrease in Tb.Sp and SMI as compared to the findings in OPG^−/− mice (P < 0.05). However, higher apparent BMD and more compact plate-like trabeculae were observed in the mandible after treatment with zoledronate as compared to the findings in the proximal tibia. No significant differences were found in any parameter in both zoledronate groups. Conclusions  The present study showed that zoledronate could reverse the significant bone loss in mice mandibles that was induced by OPG gene deficiency. This preventive effect, which was accompanied with considerable inhibition of bone turnover, differed in the mandible and in the proximal tibia and was independent of the OPG pathway. Drs. Sheng and Xu contributed equally to this work.     

Effects of zoledronic acid on bone fusion in osteoporotic patients after lumbar fusion

Summary

Treatment with zoledronic acid in osteoporotic patients with spinal fusion shortens the duration of time to fusion, improves the fusion rate, prevents the subsequent adjacent vertebral compression fractures, improves the clinical outcomes, and prevents immobilization-induced bone loss in the hip.

Introduction

The objective of the study was to explore the effects of zoledronic acid on the healing process in osteoporotic patients following spinal fusion in a randomized, placebo-controlled, and triple-blinded study.

Methods

Seventy-nine osteoporotic patients with single-level degenerative spondylolisthesis were randomly assigned to receive either zoledronic acid infusion (zoledronic acid group) or saline infusion (controls) after spinal fusion. Functional radiography and CT scans were used to evaluate fusion status. Bone formation was graded into three categories: Grade A (bridging bone bonding with adjacent vertebral bodies), Grade B (bridging bone bonding with either superior or inferior vertebral body), or Grade C (incomplete bony bridging). A solid fusion was defined as less than 5° of angular motion with Grade A or B bone formation. Adjacent vertebral compression fractures (VCF) were assessed on MRI at 12 months after surgery. Serum level of carboxy terminal cross-linked telopeptide of type I collagen (β-CTX) and amino-terminal propeptide of type I procollagen (PINP) was measured. Bone mineral density (BMD) was measured by DXA. Oswestry Disability Index (ODI) was used to assess the clinical outcomes.

Results

Grade A or B bridging bone was more frequently observed in zoledronic acid group at 3, 6, and 9 months post-operation compared to the control group (p?<?0.05). At 12?-months post-operation, bridging bone and solid fusion were not significantly different between groups. No patients in zoledronic acid group showed aVCF, whereas six patients (17 %) in the control group did (p?<?0.05). Both β-CTX and PINP were suppressed in zoledronic acid group. BMD at the femoral neck decreased rapidly and did not return to the preoperative level in the controls at 3 (?1.4 %), 6 (?2.5 %), and 12 (?0.8 %) months after surgery. Zoledronic acid prevented this immobilization-induced bone loss and increased BMD. ODI showed the improved clinical outcomes compared with controls at 9 and 12 months post-surgery.

Conclusion

Treatment with zoledronic acid in osteoporotic patients with spinal fusion shortens the time to fusion, improves the fusion rate, prevents subsequent aVCFs, and improves clinical outcomes.

     

Imaging assessment of bone quality in osteoporosis

Noninvasive and/or nondestructive techniques can provide structural information about bone beyond simple bone densitometry. Although bone densitometry provides important information about osteoporotic fracture risk, many studies indicate that bone mineral density only partly explains bone strength. Quantitative assessment of macrostructural characteristics, such as geometry, and microstructural features, such as relative trabecular volume, trabecular spacing, and connectivity, may improve the ability to estimate bone strength. Methods for quantitatively assessing macrostructure include (besides conventional radiographs) dualenergy x-ray absorptiometry (DXA) and computed tomography (CT), particularly volumetric quantitative computed tomography (vQCT). Methods for assessing microstructure of trabecular bone noninvasively and/or nondestructively include high-resolution computed tomography (hrCT), microcomputed tomography (μCT), high-resolution magnetic resonance (hrMR), and micromagnetic resonance μMR. Volumetric QCT, hrCT, and hrMR are generally applicable in vivo; μCT and μMR are principally applicable in vitro. Despite progress, problems remain. The important balances between spatial resolution and sampling size, or between signal-to-noise and radiation dose or acquisition time, need further consideration, as do the complexity and expense of the methods vs their availability and accessibility. Clinically, the challenges for bone imaging include balancing the advantages of simple bone densitometry vs the more complex architectural features of bone or the deeper research requirements vs the broader clinical needs. The biological differences between the peripheral appendicular skeleton and the central axial skeleton must be further addressed. Finally, the relative merits of these sophisticated imaging techniques must be weighed with respect to their applications as diagnostic procedures, requiring high accuracy or reliability, vs their monitoring applications requiring high precision or reproducibility.     

Actions of osteoporosis treatments on bone histomorphometric remodeling: a two-fold principal component analysis

Summary

This was the first study to apply principal component analysis method to bone histomorphometric parameters. The results corroborated teriparatide’s distinct, yet different, mechanisms of action, which stimulate both bone formation and resorption.

Introduction

This study consolidated bone histomorphometric parameters and compared the effects of two osteoporosis treatments on bone remodeling by using a principal component analysis (PCA).

Methods

Included in this analysis were postmenopausal women with osteoporosis who were treated with either teriparatide or alendronate and who completed transiliac bone biopsy at either 6 or 18 months in the randomized, double-blind Forteo Alendronate Comparator Trial. Eighteen histomorphometric parameters were grouped into formation and resorption categories. The first principal component of each category was estimated through the PCA. The summation of principal formation component (PFC) and principal resorption component (PRC) was calculated to represent the overall level of bone turnover. The difference between PFC and PRC was computed to determine the balance between formation and resorption.

Results

The PFC was significantly higher in the teriparatide group than in the alendronate group (P?<?0.0001), while the PRC was numerically lower in the alendronate group (P?=?0.18). The mean difference between the PFC and PRC was positive in the teriparatide group and negative in the alendronate group.

Conclusions

Our approach of consolidating bone histomorphometric remodeling parameters corroborated the idea that the distinct, yet different, mechanisms of action of teriparatide treatment stimulate both bone formation and resorption, and alendronate treatment suppresses both bone formation and resorption.     

The Influence of Center of Rotation on the Assessment of Trabecular Bone Densitometric and Structural Properties

The center of rotation is a physical location in the microCT scanner, defined by the axis of rotation of the sample stage. This physical location is always well defined during calibration of the instrument and fitted by an appropriate algorithm. However, in real images of limited contrast and with X-ray photon noise, this algorithm exhibits poorer precision and the optimum center of rotation cannot be always acquired. Thus, adjustment by operator is necessary to determine whether the center of rotation was correct, in order that the structural information of the sample can be correctly interpreted. In this paper, the effect of center of rotation on the assessment of densitometric and structural properties of trabecular bone was firstly evaluated. Twenty female Sprague–Dawley rats of 7-month-old were randomly assigned to ovariectomized (OVX) and SHAM-operated (SHAM) groups. The left tibiae were harvested at 3 weeks postoperatively. High resolution microCT was used to identify the densitometric and microstructural properties of trabeculae in the proximal ends of tibia. After CT scanning, the best artificial center of rotation for each scan was obtained. Bone parameters analyses were performed on the centers at different places away from the best artificial center of ±0.2, ±0.5, ±1.0, ±1.5, and ±2.0 pixels, respectively. The general linear model (GLM) repeated measures procedure was used to investigate the difference in the parameters between the two groups (OVX vs. SHAM) and the possible effects of center displacements. A significant difference between OVX and SHAM groups was found in all parameters (p < 0.05) except Tb.Th, DA, and BS/BV. TBMD, DA, BS/BV, and Conn.D were decreased while BV/TV and Tb.Th were increased with the center deflection. Variations of these parameters were acceptable when the displacements were limited within ±1.5 pixels for tBMD, BV/TV, DA, and Conn.D, and ±1.0 pixels for Tb.Th and BS/BV. These changes were similar in both OVX and SHAM groups. The changing curves of bone parameters vs. centers could be well fitted by quadric regression models, by which the real center could be acquired, and thus the precision of microCT analysis would be improved. There were some inevitable differences between the best artificial and real centers.     

Inflammatory myofibroblastic tumor of bone: two cases occurring in long bone

Inflammatory myofibroblastic tumor (IMT) is an unusual tumor composed of differentiated myofibroblastic spindle cells usually accompanied by numerous plasma cells and lymphocytes. IMT was originally described in the lung; occurrence in a long bone is rare. We present two examples of IMT arising in a long bone: one in the humerus and one in the femur. In both cases, imaging shows a poorly delineated osteolytic lesion with cortical bone destruction that aggressively extends into surrounding soft tissue. Histologically, the lesion is dominated by differentiated spindle cells with aprominent collagenous stroma and an inflammatory component including plasma cells and lymphocytes, and with positive immunoreactivity for anaplastic lymphoma kinase. The absence of cytologic atypia helps differentiate this lesion from malignant spindle cell tumors.     

Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104)

The benefits of exercise are well established but one major barrier for many is time. It has been proposed that short period resistance training (RT) could play a role in weight control by increasing resting energy expenditure (REE) but the effects of different kinds of RT has not been widely reported. We tested the acute effects of high-intensity interval resistance training (HIRT) vs. traditional resistance training (TT) on REE and respiratory ratio (RR) at 22 hours post-exercise. In two separate sessions, seventeen trained males carried out HIRT and TT protocols. The HIRT technique consists of: 6 repetitions, 20 seconds rest, 2/3 repetitions, 20 secs rest, 2/3 repetitions with 2′30″ rest between sets, three exercises for a total of 7 sets. TT consisted of eight exercises of 4 sets of 8–12 repetitions with one/two minutes rest with a total amount of 32 sets. We measured basal REE and RR (TT0 and HIRT0) and 22 hours after the training session (TT22 and HIRT22). HIRT showed a greater significant increase (p < 0.001) in REE at 22 hours compared to TT (HIRT22 2362 ± 118 Kcal/d vs TT22 1999 ± 88 Kcal/d). RR at HIRT22 was significantly lower (0.798 ± 0.010) compared to both HIRT0 (0.827 ± 0.006) and TT22 (0.822 ± 0.008). Our data suggest that shorter HIRT sessions may increase REE after exercise to a greater extent than TT and may reduce RR hence improving fat oxidation. The shorter exercise time commitment may help to reduce one major barrier to exercise.     

Osteocyte Estrogen Receptor β (Ot-ERβ) Regulates Bone Turnover and Skeletal Adaptive Response to Mechanical Loading Differently in Male and Female Growing and Adult Mice

Age-related bone loss is a failure of balanced bone turnover and diminished skeletal mechanoadaptation. Estrogen receptors, ERα and ERβ, play critical roles in osteoprotective regulation activated by estrogen and mechanical signals. Previous studies mainly focused on ERα and showed that osteocyte-ERα (Ot-ERα) regulated trabecular, but not cortical bone, and played a minor role in load-induced cortical adaptation. However, the role of Ot-ERβ in bone mass regulation remains unrevealed. To address this issue, we characterized bone (re)modeling and gene expression in male and female mice with Ot-ERβ deletion (ERβ-dOT) and littermate control (LC) at 10 weeks (young) or 28 weeks (adult) of age, as well as their responses to in vivo tibial compressive loading. Increased cancellous bone mass appeared in the L₄ vertebral body of young male ERβ-dOT mice. At the same time, femoral cortical bone gene expression showed signs consistent with elevated osteoblast and osteoclast activities (type-I collagen, Cat K, RANKL). Upregulated androgen receptor (AR) expression was observed in young male ERβ-dOT mice relative to LC, suggesting a compensatory effect of testosterone on male bone protection. In contrast, bone mass in L₄ decreased in adult male ERβ-dOT mice, attributed to potentially increased bone resorption activity (Cat K) with no change in bone formation. There was no effect of ERβ-dOT on bone mass or gene expression in female mice. Sex-dependent regulation of Ot-ERβ also appeared in load-induced cortical responsiveness. Young female ERβ-dOT mice showed an enhanced tibial cortical anabolic adaptation compared with LC. In contrast, an attenuated cortical anabolic response presented at the proximal tibia in male ERβ-dOT mice at both ages. For the first time, our findings suggest that Ot-ERβ regulates bone (re)modeling and the response to mechanical signals through different mechanisms in males and females. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).