Current Aspects on the Pathophysiology of Bone Metabolic Defects during Progression of Scoliosis in Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1), which is the most common phacomatoses, is an autosomal dominant disorder characterized by clinical presentations in various tissues and organs, such as the skin, eyes and nervous and skeletal systems. The musculoskeletal implications of NF1 include a variety of deformities, including scoliosis, kyphoscoliosis, spondylolistheses, congenital bony bowing, pseudarthrosis and bone dysplasia. Scoliosis is the most common skeletal problem, affecting 10–30% of NF1 patients. Although the pathophysiology of spinal deformities has not been elucidated yet, defects in bone metabolism have been implicated in the progression of scoliotic curves. Measurements of Bone Mineral Density (BMD) in the lumbar spine by using dual energy absorptiometry (DXA) and quantitative computer tomography (QCT) have demonstrated a marked reduction in Z-score and osteoporosis. Additionally, serum bone metabolic markers, such as vitamin D, calcium, phosphorus, osteocalcin and alkaline phosphatase, have been found to be abnormal. Intraoperative and histological vertebral analysis confirmed that alterations of the trabecular microarchitecture are associated with inadequate bone turnover, indicating generalized bone metabolic defects. At the molecular level, loss of function of neurofibromin dysregulates Ras and Transforming Growth factor-β1 (TGF-β1) signaling and leads to altered osteoclastic proliferation, osteoblastic activity and collagen production. Correlation between clinical characteristics and molecular pathways may provide targets for novel therapeutic approaches in NF1.

Moderate Exercise Protects Against Joint Disease in a Murine Model of Osteoarthritis

Exercise is recommended as a non-pharmacological therapy for osteoarthritis (OA). Clinical studies investigating the impact of exercise on OA have primarily focussed on the assessment of joint pain and mobilisation, where positive outcomes have been demonstrated. Clinical imaging studies provide limited information on the impact of exercise (positive or negative) on the actual bone and soft tissue pathology. Various exercise regimes, with differing intensities and duration, have been used in a range of OA models, with disparate results. The present study provides definitive insight into the effect of moderate exercise on early joint pathology in the destabilisation of the medial meniscus (DMM) mouse model of OA. Exercise was induced by forced treadmill walking for 3 or 7 weeks. Joints were analysed by microcomputed tomography and histology. Exercise offered protection against cartilage damage and joint inflammation, and a temporary protection against osteosclerosis. Furthermore, exercise modified the metaphyseal trabecular microarchitecture of the osteoarthritic leg. Collectively, our findings provide scientific support for the clinical recommendation of moderate exercise as a physical therapy in OA. In addition to indirect benefit via positive physiological effects of weight loss, our data suggest direct short-term benefits in ameliorating pathology of cartilage, synovitis and bone.

Osteoporosis: From Molecular Mechanisms to Therapies 3.0

Osteoporosis is a common skeletal disorder that occurs as a result of an imbalance between bone resorption and bone formation, with bone breakdown exceeding bone building. Bone resorption inhibitors, e.g., bisphosphonates, have been designed to treat osteoporosis. Teriparatide, an anabolic agent, stimulates bone formation and corrects the characteristic changes in the trabecular microarchitecture. However, these drugs are associated with significant side effects. It is therefore crucial that we continue to research the pathogenesis of osteoporosis and seek novel modes of therapy. This editorial summarizes and discusses the themes of the six articles published in our Special Issue “Osteoporosis: From Molecular Mechanisms to Therapies 3.0”, a continuation of our 2020 Special Issue "Osteoporosis: From Molecular Mechanisms to Therapies". These Special Issues detail important global scientific findings that contribute to our current understanding of osteoporosis.

Poor bone quality in patients with rheumatoid arthritis receiving long-term bisphosphonate therapy for glucocorticoid-induced osteoporosis: an iliac bone biopsy study

Background Bisphosphonates (BPs) have been shown to reduce the incidence of vertebral fractures during the first year or two of glucocorticoid (GC) treatments and are therefore recommended as a first-line treatment for the prevention and treatment of GC-induced osteoporosis (GIO). However, there are theoretical concerns about the long-term use of BPs in low-turnover osteoporosis caused by chronic GC therapy. Methods We analyzed the trabecular microarchitecture, bone metabolism, and material strength of bone biopsy samples from the iliac crest of female patients with rheumatoid arthritis (RA) receiving an average of 6.7 years of BP therapy for GIO (GIOBP group, n = 10), compared with those of age- and bone mineral density (BMD)-matched non-RA postmenopausal women with no history of anti-osteoporosis medication use (reference group, n=10). Results Patients in the GIOBP group had a significantly greater fracture severity index, as calculated by the sum of the Genant visual semiquantitative grading scores of vertebral fractures (T4-L5) compared with the reference patients. Micro-computed tomography analysis showed that the degree of mineralization and trabecular microarchitecture were significantly lower in the GIOBP group than in the BMD-matched reference patients. Patients in the GIOBP group exhibited lower bone contact stiffness, determined by micro-indentation testing, than in the reference group. The contact stiffness of the bone was negatively correlated with the fracture severity index and the daily prednisolone dosage. Immunohistochemistry and serum bone turnover markers showed decreased osteoclastic activity, impaired mineralization, and an increased fraction of empty lacunae in the GIOBP group. Conclusions Our findings indicate that patients with RA receiving long-term BP for GIO are still at high risk for fragility fractures because of poor bone quality.

Age-Specific Normative Values of Lumbar Spine Trabecular Bone Score (TBS) in Taiwanese Men and Women

Trabecular bone score (TBS) is a novel method for assessing trabecular microarchitecture. Normative values of TBS are available for various populations of the world but are not yet available for Taiwanese adults. Therefore, the purpose of this study was to estimate age-specific, normative TBS curves for Taiwanese men and women. Medical records of general health examinations from a regional hospital in Southern Taiwan were reviewed. Individuals aged 30–90 years with data on lumbar spine bone mineral density (BMD) were included. TBS was retrospectively calculated from dual-energy X-ray absorptiometry scans using TBS iNsight software. Of the 12,028 patients included, 4533 (37.7%) were male and the mean age was 55.8 years. The mean TBS was 1.392 (standard deviation (SD) 0.089) for men and 1.344 (SD 0.107) for women. In women, TBS declined at a rate of 0.0004/year among those aged 30.0–45.9 years, 0.0106/year among those 46.0–60.7 years, and 0.0028/year among those 60.8–90.0 years. In men, TBS declined at a constant rate of 0.0023/year over the entire age range. In conclusion, age-adjusted, normative curves of TBS for Taiwanese men and women are presented, which could be used to facilitate the use of TBS in assessing bone status in clinical practice.

7,8-dihydroxyflavone Modulates Bone Formation and Resorption and Ameliorates Ovariectomy-Induced Osteoporosis

Imbalances in bone formation and resorption cause osteoporosis. Mounting evidence supports that brain-derived neurotrophic factor (BDNF) implicates in this process. 7,8-dihydroxyflavone (7,8-DHF), a plant-derived small molecular TrkB agonist, mimics the functions of BDNF. We show that both BDNF and 7,8-DHF promoted the proliferation, osteogenic differentiation and mineralization of MC3T3-E1 cells. These effects might be attributed to the activation of the Wnt/β-catenin signaling pathway as the expression of cyclin D1, phosphorylated-glycogen synthase kinase-3β (p-GSK3β), β-catenin, Runx2, Osterix and osteoprotegerin (OPG) were all significantly up-regulated. Knockdown of β-catenin restrained the up-regulation of Runx2 and Osterix stimulated by 7,8-DHF. In particular, blocking TrkB by its specific inhibitor K252a suppressed 7,8-DHF-induced osteoblastic proliferation, differentiation and expression of osteoblastogenic genes. Moreover, BDNF and 7,8-DHF repressed osteoclastic differentiation of RAW264.7 cells. The transcription factor c-fos and osteoclastic genes such as tartrate-resistant acid phosphatase (TRAP), matrix metalloprotein-9 (MMP-9), Adamts5 were inhibited by 7,8-DHF. More importantly, 7,8-DHF attenuated bone loss, improved trabecular microarchitecture, tibial biomechanical properties and bone biochemical indexes in an ovariectomy (OVX) rat model. The current work highlights the dual regulatory effects that 7,8-DHF exerts on bone remodeling.

Microarchitecture of titanium cylinders obtained by additive manufacturing does not influence osseointegration in the sheep

Large bone defects are a challenge for orthopedic surgery. Natural (bone grafts) and synthetic biomaterials have been proposed but several problems arise such as biomechanical resistance or viral/bacterial safety. The use of metallic foams could be a solution to improve mechanical resistance and promote osseointegration of large porous metal devices. Titanium cylinders have been prepared by additive manufacturing (3D printing/rapid prototyping) with a geometric or trabecular microarchitecture. They were implanted in the femoral condyles of aged ewes; the animals were left in stabling for 90 and 270 days. A double calcein labeling was done before sacrifice; bones were analyzed by histomorphometry. Neither bone volume, bone/titanium interface nor mineralization rate were influenced by the cylinder’s microarchitecture; the morphometric parameters did not significantly increase over time. Bone anchoring occurred on the margins of the cylinders and some trabeculae extended in the core of the cylinders but the amount of bone inside the cylinders remained low. The rigid titanium cylinders preserved bone cells from strains in the core of the cylinders. Additive manufacturing is an interesting tool to prepare 3D metallic scaffolds, but microarchitecture does not seem as crucial as expected and anchoring seems limited to the first millimeters of the graft.

Short-term glucocorticoid excess blunts abaloparatide-induced increase in femoral bone mass and strength in mice

Glucocorticoids (GCs), such as prednisolone, are widely used to treat inflammatory diseases. Continuously long-term or high dose treatment with GCs is one of the most common causes of secondary osteoporosis and is associated with sarcopenia and increased risk of debilitating osteoporotic fragility fractures. Abaloparatide (ABL) is a potent parathyroid hormone-related peptide analog, which can increase bone mineral density (aBMD), improve trabecular microarchitecture, and increase bone strength. The present study aimed to investigate whether GC excess blunts the osteoanabolic effect of ABL. Sixty 12–13-week-old female RjOrl:SWISS mice were allocated to the following groups: Baseline, Control, ABL, GC, and GC + ABL. ABL was administered as subcutaneous injections (100 μg/kg), while GC was delivered by subcutaneous implantation of a 60-days slow-release prednisolone-pellet (10 mg). The study lasted four weeks. GC induced a substantial reduction in muscle mass, trabecular mineral apposition rate (MAR) and bone formation rate (BFR/BS), and endocortical MAR compared with Control, but did not alter the trabecular microarchitecture or bone strength. In mice not receiving GC, ABL increased aBMD, bone mineral content (BMC), cortical and trabecular microarchitecture, mineralizing surface (MS/BS), MAR, BFR/BS, and bone strength compared with Control. However, when administered concomitantly with GC, the osteoanabolic effect of ABL on BMC, cortical morphology, and cortical bone strength was blunted. In conclusion, at cortical bone sites, the osteoanabolic effect of ABL is generally blunted by short-term GC excess.