Identification of ENPP1 Haploinsufficiency in Patients With Diffuse Idiopathic Skeletal Hyperostosis and Early-Onset Osteoporosis

Homozygous ENPP1 mutations are associated with autosomal recessive hypophosphatemic rickets type 2 (ARHR2), severe ossification of the spinal ligaments, and generalized arterial calcification of infancy type 1. There are a limited number of reports on phenotypes associated with heterozygous ENPP1 mutations. Here, we report a series of three probands and their families with heterozygous and compound heterozygous ENPP1 mutations. The first case (case 1) was a 47-year-old male, diagnosed with early-onset osteoporosis and low-normal serum phosphate levels, which invoked suspicion for hypophosphatemic rickets. The second and third cases were 77- and 54-year-old females who both presented with severe spinal ligament ossification and the presumptive diagnosis of diffuse idiopathic skeletal hyperostosis (DISH). Upon workup, fibroblast growth factor 23 (FGF23) was noted to be relatively high in case 2 and serum phosphorous was low-normal in case 3, and the diagnoses of X-linked hypophosphatemic rickets (XLH) and ARHR2 were considered. Genetic testing for genes related to congenital hypophosphatemic rickets was therefore performed, revealing heterozygous ENPP1 variants in cases 1 and 2 (case 1, c.536A>G, p.Asn179Ser; case 2, c.1352A>G, p.Tyr451Cys) and compound heterozygous ENPP1 variants in case 3 constituting the same variants present in cases 1 and 2 (c.536A>G, p.Asn179Ser and c.1352A>G, p.Tyr451Cys). Several in silico tools predicted the two variants to be pathogeneic, a finding confirmed by in vitro biochemical analysis demonstrating that the p.Asn179Ser and p.Tyr451Cys ENPP1 variants possessed a catalytic velocity of 45% and 30% compared with that of wild-type ENPP1, respectively. Both variants were therefore categorized as pathogenic loss-of-function mutations. Our findings suggest that ENPP1 mutational status should be evaluated in patients presenting with the diagnosis of idiopathic DISH, ossification of the posterior longitudinal ligament (OPLL), and early-onset osteoporosis. © 2022 American Society for Bone and Mineral Research (ASBMR).     

CT-Based Evaluation of Diffuse Idiopathic Skeletal Hyperostosis in Adult Population; Prevalence,Associations and Interobserver Agreement

Diffuse idiopathic skeletal hyperostosis (DISH), being an asymptomatic condition, is generally discovered incidentally on imaging and it has not received much attention for research on clinical grounds. We assessed the prevalence of DISH, its associated factors, and interobserver agreement for computed tomography (CT)-based diagnosis of DISH. CT scans of chest, abdomen, and pelvis performed for various clinical indications were retrospectively reviewed. Resnick criteria were used for the diagnosis of DISH. Moreover, enthesopathy along with comorbidities was assessed. CT scans were observed by 3 observers having different experience levels. Out of total 416 patients, the prevalence of DISH was 30.8%. Strong positive agreement was observed between observer 1 and 2 (k = 0.89), observer 1 and 3 (k = 0.91), and observer 2 and 3 (k = 0.94). Reporting rate of DISH was 59.3%. Regression analyses showed that enthesopathy was 2.45 times (adjusted odds ratio [AOR]: 2.45, 95% confidence intervals [CI]: 1.48–4.05), diabetic patients were 4.74 times (AOR: 4.74, 95% CI: 2.89–7.78) while hypertensive patients were 2.17 times (AOR: 2.17, 95% CI: 1.30–3.62) more likely to have DISH in comparison to those who do not have DISH. A high prevalence of DISH was observed in our cohort. Enthesopathy and comorbidities like diabetes and hypertension were significant factors associated with DISH. Moreover, excellent agreement was observed in defining DISH on CT according to Resnick criteria.     

Calcitonin Simultaneously Regulates Both Periosteal Hyperostosis and Trabecular Osteopenia in the Spinal Hyperostotic Mouse (twy/twy) In Vivo

The twy (tiptoe-walking-Yoshimura) mouse, established in Japan in 1978 by brother-sister mating of ICR strain mice, is a valuable mutant as a model of ossification of the posterior longitudinal ligament (OPLL). OPLL causes severe myelopathy and has been thought to be very similar to ankylosing spinal hyperostosis (ASH) and diffuse idiopathic skeletal hyperostosis (DISH). In the twy mouse, both an increase in vertebral cortical membranous bone formation and a decrease in trabecular bone mass due to accelerated bone resorption occur simultaneously. This process is attributed to an inherited autosomal recessive single gene (twy). Calcitonin's suppression of bone resorption has been well established in the past, whereas the effects of this hormone on bone formation remain to be defined. Of particular interest is the simultaneous action of calcitonin on the abnormally accelerated bone formation and resorption. Thirty twy mice and 14 ICR mice were divided into seven groups, and changes induced by calcitonin on vertebral cortical appositional rate and on trabecular bone mass were investigated histomorphometrically. Results were (1) osteoclastic activity on trabecular surface was clearly suppressed by chicken calcitonin injected subcutaneously for 4 weeks; (2) no significant difference between the lumbar vertebral periosteal bone formation of calcitonin (CA) and vehicle-administrated twy mice groups. However, on the periosteal surface of the cervical vertebrae of the 6-week-old twy mice, the abnormally accelerated bone formation was suppressed by CA administration. This was also true for the elderly twy mice, although the effect was less pronounced. In conclusion, CA suppressed the abnormally hyperactivated periosteal bone formation. Results also suggested a possible therapeutic value of CA for OPLL. Received: 22 January 1998 / Accepted: 12 May 1998     

Vaccination with DKK1-derived Peptides Promotes Bone Formation and Bone Mass in an Aged Mouse Osteoporosis Model

The investigation of agents for the treatment of osteoporosis has been a long-standing effort. The Wnt pathway plays an important role in bone formation and regeneration, and expression of Wnt pathway inhibitors, Dickkopf-1 (DKK1), appears to be associated with changes in bone mass. Inactivation of DKK1 leads to substantially increased bone mass in genetically manipulated animals. DKK1-derived peptides (DDPs) were added to BMP2-stimulated MC3T3-E1 preosteoblastic cells in vitro to evaluate inhibitory activity of DDPs in MC3T3-E1 cell differentiation. Study was extended in vivo on old female mice to show whether or not inhibition of endogenous DKK1 biological activity using DDPs vaccination approach leads to increase of bone formation, bone density, and improvement of bone microstructure. We reported that synthetic DDPs were able to reduce alkaline phosphatase activity, prevent mineralization and inhibit the differentiation of MC3T3-E1 cells in vitro. Furthermore, vaccination with these DDPs in aged female mice 4 times for a total period of 22 weeks promoted bone mass and bone microstructure. 3D microCT and histomorphometric analysis showed that there were significant increase in bone mineral densities, improvement of bone microstructure and promotion of bone formation in the vaccinated mice, especially in the mice vaccinated with DDP-A and DDP-C. Histological and scanning electron microscopy image analysis also indicated that vaccination increased trabecular bone mass and significantly decreased fragmentation of bone fibers. Taken together, these preclinical results suggest that vaccination with DDPs represents a promising new therapeutic approach for the treatment of bone-related disorders, such as osteoporosis.     

Longitudinal Changes of Circulating miRNAs During Bisphosphonate and Teriparatide Treatment in an Animal Model of Postmenopausal Osteoporosis

MicroRNAs regulate bone homeostasis, and circulating microRNAs have been proposed as novel bone biomarkers. The effect of anti-osteoporotic treatment on circulating microRNAs has not been described in detail. Therefore, we performed a comprehensive analysis of microRNA serum levels in ovariectomized (OVX) and sham-operated (SHAM) rats over 12 weeks of antiresorptive or osteoanabolic treatment. Forty-two Sprague Dawley rats underwent SHAM surgery (n = 10) or ovariectomy (n = 32). After 8 weeks, OVX rats were randomized to antiresorptive treatment with zoledronate (n = 11), osteoanabolic treatment with teriparatide (n = 11), or vehicle treatment (n = 10). Serum samples were collected at weeks 8, 12, 16, and 20 after surgery. A total of 91 microRNAs were analyzed by RT-qPCR in serum samples collected at week 20. Based on the results, 29 microRNAs were selected for longitudinal analysis at all four study time points. Changes in bone mineral density and microstructure were followed up by in vivo micro-CT and ex vivo nano-CT. Ovariectomy resulted in the loss of trabecular bone, which was reversed by osteoanabolic and antiresorptive treatment. Differential expression analysis identified 11 circulating miRNAs that were significantly regulated after treatment. For example, miR-107 and miR-31-5p increased in vehicle-treated OVX animals, whereas they decreased during teriparatide treatment. Additional miRNAs were identified that showed significant correlations to bone microstructure or bone miRNA expression, including miR-203a-3p, which exhibited a significant negative correlation to vertebral and tibial trabecular bone volume fraction (%). Longitudinal analysis confirmed eight microRNAs with significant changes in serum over time that were prevented by teriparatide and zoledronate treatment (miR-34a-5p, miR-31-5p, miR-30d-3p, miR-378a-5p) or teriparatide treatment only (miR-375-3p, miR-183-5p, miR-203a-3p, miR-203b-3p). Gene target network analysis identified WNT and Notch signaling as the main signaling pathways controlled by these miRNAs. Thus, ovariectomy results in time-dependent deregulation of circulating miRNAs compared with SHAM animals. Anti-osteoporotic treatments can rescue this effect, showing that bone-related miRNAs might act as novel biomarkers for treatment monitoring. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Restriction of Dietary Phosphate Ameliorates Skeletal Abnormalities in a Mouse Model for Craniometaphyseal Dysplasia

Craniometaphyseal dysplasia (CMD), a rare genetic bone disorder, is characterized by lifelong progressive thickening of craniofacial bones and metaphyseal flaring of long bones. The autosomal dominant form of CMD is caused by mutations in the progressive ankylosis gene ANKH (mouse ortholog Ank), encoding a pyrophosphate (PPi) transporter. We previously reported reduced formation and function of osteoblasts and osteoclasts in a knockin (KI) mouse model for CMD (Ank^KI/KI) and in CMD patients. We also showed rapid protein degradation of mutant ANK/ANKH. Mutant ANK protein displays reduced PPi transport, which may alter the inorganic phosphate (Pi) and PPi ratio, an important regulatory mechanism for bone mineralization. Here we investigate whether reducing dietary Pi intake can ameliorate the CMD-like skeletal phenotype by comparing male and female Ank^+/+ and Ank^KI/KI mice exposed to a low (0.3%) and normal (0.7%) Pi diet for 13 weeks from birth. Serum Pi and calcium (Ca) levels were not significantly changed by diet, whereas PTH and 25-hydroxy vitamin D (25-OHD) were decreased by low Pi diet but only in male Ank^+/+ mice. Importantly, the 0.3% Pi diet significantly ameliorated mandibular hyperostosis in both sexes of Ank^KI/KI mice. A tendency of decreased femoral trabeculation was observed in male and female Ank^+/+ mice as well as in male Ank^KI/KI mice fed with the 0.3% Pi diet. In contrast, in female Ank^KI/KI mice the 0.3% Pi diet resulted in increased metaphyseal trabeculation. This was also the only group that showed increased bone formation rate. Low Pi diet led to increased osteoclast numbers and increased bone resorption in all mice. We conclude that lowering but not depleting dietary Pi delays the development of craniofacial hyperostosis in CMD mice without severely compromising serum levels of Pi, Ca, PTH, and 25-OHD. These findings may have implications for better clinical care of patients with CMD. © 2020 American Society for Bone and Mineral Research.     

Targeting the LRP5 Pathway Improves Bone Properties in a Mouse Model of Osteogenesis Imperfecta

The cell surface receptor low‐density lipoprotein receptor‐related protein 5 (LRP5) is a key regulator of bone mass and bone strength. Heterozygous missense mutations in LRP5 cause autosomal dominant high bone mass (HBM) in humans by reducing binding to LRP5 by endogenous inhibitors, such as sclerostin (SOST). Mice heterozygous for a knockin allele (Lrp5^p.A214V) that is orthologous to a human HBM‐causing mutation have increased bone mass and strength. Osteogenesis imperfecta (OI) is a skeletal fragility disorder predominantly caused by mutations that affect type I collagen. We tested whether the LRP5 pathway can be used to improve bone properties in animal models of OI. First, we mated Lrp5^+/p.A214V mice to Col1a2^+/p.G610C mice, which model human type IV OI. We found that Col1a2^+/p.G610C;Lrp5^+/p.A214V offspring had significantly increased bone mass and strength compared to Col1a2^+/p.G610C;Lrp5^+/+ littermates. The improved bone properties were not a result of altered mRNA expression of type I collagen or its chaperones, nor were they due to changes in mutant type I collagen secretion. Second, we treated Col1a2^+/p.G610C mice with a monoclonal antibody that inhibits sclerostin activity (Scl‐Ab). We found that antibody‐treated mice had significantly increased bone mass and strength compared to vehicle‐treated littermates. These findings indicate increasing bone formation, even without altering bone collagen composition, may benefit patients with OI. © 2014 American Society for Bone and Mineral Research.     

Soy Affects Trabecular Microarchitecture and Favorably Alters Select Bone-Specific Gene Expressions in a Male Rat Model of Osteoporosis

We have recently reported that soy isoflavones particularly when provided in the context of soy protein are capable of preventing loss of bone mineral density due to orchidectomy in F344 rats. We hypothesize, that soy isoflavones also exert beneficial effects on bone microstructural properties, in part, by enhancing bone formation. Therefore, in the present study, we examined the dose-dependent effects of soy isoflavones on femoral bone microarchitectural properties and select bone-specific gene expressions in the same rat model. Seventy-two, 13-month old rats were either orchidectomized (ORX; 5 groups) or sham-operated (Sham; 1 group) and immediately placed on dietary treatments for 180 days. Four of the ORX groups were fed either casein- or soy protein-based diets each with one of two doses of isoflavones either 600 or 1200 mg/kg diet. Rats in the remaining ORX control and Sham groups were fed a control casein-based diet. Soy protein at the high isoflavone dose, and to a lesser extent with the lower dose, reduced the magnitude of the ORX-induced decreases in trabecular bone volume (BV/TV) and trabecular number (Th.N) and increase in trabecular separation (Tb.Sp) at the femoral neck site. These modulations of trabecular microstructural properties by isoflavones may be due to increased mRNA levels of alkaline phosphatase (ALP), collagen type I (COL), and osteocalcin (OC), which are associated with enhanced bone formation. These findings confirm our earlier observations that the modest bone protective effects of soy isoflavones are due to increased rate of bone formation.     

VEGF Improves Skeletal Muscle Regeneration After Acute Trauma and Reconstruction of the Limb in a Rabbit Model

Background

Complicated tibial fractures with severe soft tissue trauma are challenging to treat. Frequently associated acute compartment syndrome can result in scarring of muscles with impaired function. Several studies have shown a relationship between angiogenesis and more effective muscle regeneration. Vascular endothelial growth factor (VEGF) is associated with angiogenesis but it is not clear whether it would restore muscle force, reduce scarring, and aid in muscle regeneration after acute musculoskeletal trauma.

Questions/purposes

Therefore, we asked whether local application of VEGF (1) restores muscle force, (2) reduces scar tissue formation, and (3) regenerates muscle tissue.

Methods

We generated acute soft tissue trauma with increased compartment pressure in 22 rabbits and shortened the limbs to simulate fracture débridement. In the test group (n = 11), a VEGF-coated collagen matrix was applied locally around the osteotomy site. After 10 days of limb shortening, gradual distraction of 0.5 mm per 12 hours was performed to restore the original length. Muscle force was measured before trauma and on every fifth day after trauma. Forty days after shortening we euthanized the animals and histologically determined the percentage of connective and muscle tissue.

Results

Recovery of preinjury muscle strength was greater in the VEGF group (2.4 N; 73%) when compared with the control (1.8 N; 53%) with less connective and more muscle tissue in the VEGF group. The recovery of force was related to the percentage of connective tissue versus muscle fibers.

Conclusions

Local application of VEGF may improve restoration of muscle force by reducing connective tissue and increasing the relative amount of muscle fibers.

Clinical Relevance

VEGF may be useful to improve skeletal muscle repair by modulating muscle tissue regeneration and fibrosis reduction after acute trauma.     

Caloric Restriction Decreases Cortical Bone Mass but Spares Trabecular Bone in the Mouse Skeleton: Implications for the Regulation of Bone Mass by Body Weight

Introduction: Body weight is positively correlated with bone mass and density, and both muscle mass and body fat are thought to play a role in regulating bone metabolism. We examined bone metabolism in calorically restricted mice to determine how alterations in soft tissue mass affect bone mass, density, and strength. Materials and Methods: Caloric restriction (CR) was initiated in male mice at 14 wk of age at 10% restriction, increased to 25% restriction at 15 wk, and then increased to 40% restriction at 16 wk, where it was maintained until 24 wk of age when the study was terminated. Control mice were fed ad libitum (AL). Body composition, BMD, and BMC were measured by DXA, BMD and BMC in the femoral metaphysis were measured by pQCT, femora were tested in three‐point bending, serum leptin and IGF‐1 were measured using immunoassay, and osteoblast and osteoclast numbers were determined using histomorphometry. Results: Body weight, lean mass, fat mass, percent body fat, serum leptin, and serum IGF‐1 were all significantly lower in CR mice than AL mice. Whole body BMC and BMD did not differ significantly between the two groups. Femur BMC, BMD, cortical thickness, and fracture strength decreased significantly in CR mice, but trabecular bone volume fraction in the femur did not change with food restriction. Vertebral cortical thickness also decreased with caloric restriction, whereas spine BMC, BMD, and trabecular bone volume fraction were significantly increased with caloric restriction. Conclusions: Caloric restriction and its related weight reduction are associated with marked decreases in lean mass, fat mass, serum leptin and IGF‐1, and cortical bone mass. Consistent with the opposite effects of leptin on cortical and cancellous bone, trabecular bone mass is spared during food restriction.     

A Longitudinal Study of Skeletal Histomorphometry at 6 and 24 Months Across Four Bone Envelopes in Postmenopausal Women With Osteoporosis Receiving Teriparatide or Zoledronic Acid in the SHOTZ Trial

Previously, we reported the effects of teriparatide (TPTD) and zoledronic acid (ZOL) on bone formation based on biochemical markers and bone histomorphometry of the cancellous envelope at month 6 in postmenopausal women with osteoporosis who participated in the 12‐month primary Skeletal Histomorphometry in Subjects on Teriparatide or Zoledronic Acid Therapy (SHOTZ) study. Patients were eligible to enter a 12‐month extension on their original treatment regimen: TPTD 20 μg/day (s.c. injection) or ZOL 5 mg/year (i.v. infusion). A second biopsy was performed at month 24. Here we report longitudinal changes between and within each treatment group in the cancellous, endocortical, intracortical, and periosteal bone envelopes in patients with evaluable biopsies at months 6 and 24 (paired data set: TPTD, n = 10; ZOL, n = 9). Between‐group differences are also reported in the larger set of patients with evaluable biopsies at month 6 (TPTD, n = 28; ZOL, n = 30). Data from the cancellous envelope at month 6 or month 24 provided a reference to compare differences across envelopes within each treatment group. The 24‐month results extend our earlier report that TPTD and ZOL possess different tissue‐level mechanisms of action. Moreover, these differences persisted for at least 2 years in all four bone envelopes. Few longitudinal differences were observed within or across bone envelopes in ZOL‐treated patients, suggesting that the low bone formation indices at month 6 persisted to month 24. Conversely, the magnitude of the effect of TPTD on bone formation varied across individual envelopes: median values for mineralizing surface (MS/BS) and bone formation rate (BFR/BS) at month 6 were approximately 3‐fold to 5‐fold higher in the endocortical and intracortical envelopes compared to the cancellous envelope. Although MS/BS and BFR/BS declined in these envelopes at month 24, median values continued to exceed, or were not significantly different from, those in the cancellous envelope. This study demonstrates for the first time that bone formation indices are higher with TPTD treatment than with ZOL in all four bone envelopes and the difference persists for at least 2 years. Moreover, the magnitude of the effect of TPTD in cortical bone remains robust at 24 months. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).     

Reference Value of Dual X-Ray Absorptiometry-Derived Lumbar Spine Trabecular Bone Score in the Thai Population

Introduction: Little is known about the normative values of trabecular bone score (TBS) in Thailand. We aimed to provide reference values of dual-energy x-ray absorptiometry (DXA)-derived lumbar spine TBS in Thai community-dwelling adults of varying ages. Methodology: Bone density studies of participants aged 20–90 years who underwent bone mineral density (BMD) testing at Srinagarind Hospital, Kohn Kaen, Thailand were reviewed. DXA studies were performed using a narrow fan-beam bone densitometer. Lumbar spine TBS for each of the L1–L4 vertebra was obtained using the iNsight software. Mean TBS (L1–L4 TBS) was calculated. This study was approved by the institutional research ethics committee (HE581241). Results: A total of 1372 participants were included. The mean ± SD age was 57.25 ± 17.35 years and 799 (58.2%) were female. There were 476 (34.7%) and 243 (17.7%) participants with osteopenia (T-score -1.0 to -2.5) and osteoporosis (T-score ≤-2.5) of the lumbar spine. Age and sex stratified analysis of L1–L4 TBS revealed peak TBS among females aged 30–49 years (mean ± SD: 1.42 ± 0.08) and males aged 30–59 years (mean ± SD: 1.42 ± 0.09). The rate of L1–L4 TBS reduction from ages 30 to 90 year is 13.4% (0.27%/year) for females and 5.6% (0.11%/year) for males. Conclusion: This is the first study reporting a normative database for DXA derived TBS in Thai community-dwelling population. We found that TBS decreased with age at the rate of approximately 0.27%/year for females and 0.11%/year for males.     

Longitudinal Assessment of In Vivo Bone Dynamics in a Mouse Tail Model of Postmenopausal Osteoporosis

Recently, it has been shown that transient bone biology can be observed in vivo using time-lapse micro-computed tomography (μCT) in the mouse tail bone. Nevertheless, in order for the mouse tail bone to be a model for human disease, the hallmarks of any disease must be mimicked. The aim of this study was to investigate whether postmenopausal osteoporosis could be modeled in caudal vertebrae of C57Bl/6 mice, considering static and dynamic bone morphometry as well as mechanical properties, and to describe temporal changes in bone remodeling rates. Twenty C57Bl/6 mice were ovariectomized (OVX, n = 11) or sham-operated (SHM, n = 9) and monitored with in vivo μCT on the day of surgery and every 2 weeks after, up to 12 weeks. There was a significant decrease in bone volume fraction for OVX (−35%) compared to SHM (+16%) in trabecular bone (P < 0.001). For OVX, high-turnover bone loss was observed, with the bone resorption rate exceeding the bone formation rate (P < 0.001). Furthermore there was a significant decrease in whole-bone stiffness for OVX (−16%) compared to SHM (+11%, P < 0.001). From these results we conclude that the mouse tail vertebra mimics postmenopausal bone loss with respect to these parameters and therefore might be a suitable model for postmenopausal osteoporosis. When evaluating temporal changes in remodeling rates, we found that OVX caused an immediate increase in bone resorption rate (P < 0.001) and a delayed increase in bone formation rate (P < 0.001). Monitoring transient bone biology is a promising method for future research.     

重度骨质疏松条件下椎弓根螺钉内固定的可靠性研究

目的评价重度骨质疏松条件下椎弓根螺钉的稳定性,为椎弓根内固定在合并有重度骨质疏松症的患者中的选用提供力学理论基础。方法采用新鲜尸体脊柱标本,检测骨密度后,根据诊断标准,选用正常骨质的2具尸体标本、重度骨质疏松的4具尸体标本,分离T12~L5节段成单个椎体以备后用;然后在骨质正常椎体置入椎弓根螺钉12枚作对照组;在重度骨质疏松水平,分单纯置入椎弓根螺钉(pedicle screw,PS)、经磷酸钙骨水泥(calcium phosphate cement,CPC)强化钉道后置入椎弓根螺钉、经聚甲基丙烯酸甲酯(polymethylmethacrylate,PMMA)强化钉道后置入椎弓根螺钉三种方法置钉,依次为PS组、CPC/PS组和PMMA/PS组,进行螺钉轴向拔出实验,测最大拔出力、刚度和能量吸收值,对所测指标进行组间对比分析。结果重度疏松条件下,PS组、CPC/PS组和PMMA/PS各组最大拔出力、刚度、能量吸收值均显著低于对照组(P0.005);但是,PMMA/PS组三项指标均显著高于PS组、CPC/PS组(P0.001);PS组、CPC/PS组之间比较仅最大拔出力存在显著性差异(P0.05),刚度与能量吸收值差异无统计学意义(P0.05)。结论重度骨质疏松条件下,椎弓根螺钉固定强度明显下降,不宜单纯应用普通椎弓根螺钉行脊柱内固定治疗,采用普通骨水泥强化钉道后置钉可以提高椎弓根螺钉稳定性。     

The Length and Proportions of the Thoracolumbar Spine in Children with Idiopathic Scoliosis

The length of the thoracolumbar spine was measured on standardized X-ray films from 274 children (61/2-181/2 years) with idiopathic scoliosis and 212 controls. Where possible, the height and width (transverse diameter) of two vertebral bodies (T-6 and L-4) were also measured.

Although a tendency towards longer spines in the scoliotics could be found, there was no significant difference between children with idiopathic scoliosis and controls in this respect. In girls the pubertal growth-spurt of the spine was found to start about 1 year earlier than in the controls and the growth of the spine seemed to cease later in the scoliotics.

The height and width of T-6 was significantly greater in the scoliotics than in the controls for girls under 13 years of age. In the older girls and in the boys no significant difference could be demonstrated. The height of L-4 tended to be greater in the scoliotic boys and younger girls, though the differences were not statistically significant. The index height/width was calculated for T-6 and L-4 in all groups of patients and higher values could be demonstrated in the scoliotics for all test groups.

The greater height of T-6 in scoliotics might indicate a longer thoracic spine in these children. The higher values of the height/width indices suggest that the thoracolumbar spine in children with idiopathic scoliosis has an increased slenderness compared with the spine in non-scoliotic children.     

An Inverse Agonist Ligand of the PTH Receptor Partially Rescues Skeletal Defects in a Mouse Model of Jansen's Metaphyseal Chondrodysplasia

Jansen's metaphyseal chondrodysplasia (JMC) is a rare disease of bone and mineral ion physiology that is caused by activating mutations in PTHR1. Ligand-independent signaling by the mutant receptors in cells of bone and kidney results in abnormal skeletal growth, excessive bone turnover, and chronic hypercalcemia and hyperphosphaturia. Clinical features further include short stature, limb deformities, nephrocalcinosis, and progressive losses in kidney function. There is no effective treatment option available for JMC. In previous cell-based assays, we found that certain N-terminally truncated PTH and PTHrP antagonist peptides function as inverse agonists and thus can reduce the high rates of basal cAMP signaling exhibited by the mutant PTHR1s of JMC in vitro. Here we explored whether one such inverse agonist ligand, [Leu¹¹,dTrp¹²,Trp²³,Tyr³⁶]-PTHrP(7-36)NH₂ (IA), can be effective in vivo and thus ameliorate the skeletal abnormalities that occur in transgenic mice expressing the PTHR1-H223R allele of JMC in osteoblastic cells via the collagen-1α1 promoter (C1HR mice). We observed that after 2 weeks of twice-daily injection and relative to vehicle controls, the IA analog resulted in significant improvements in key skeletal parameters that characterize the C1HR mice, because it reduced the excess trabecular bone mass, bone marrow fibrosis, and levels of bone turnover markers in blood and urine. The overall findings provide proof-of-concept support for the notion that inverse agonist ligands targeted to the mutant PTHR1 variants of JMC can have efficacy in vivo. Further studies of such PTHR1 ligand analogs could help open paths toward the first treatment option for this debilitating skeletal disorder. © 2019 American Society for Bone and Mineral Research.     

Combinatorial Inhibition of Myostatin and Activin A Improves Femoral Bone Properties in the G610C Mouse Model of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a collagen-related bone disorder characterized by fragile osteopenic bone and muscle weakness. We have previously shown that the soluble activin receptor type IIB decoy (sActRIIB) molecule increases muscle mass and improves bone strength in the mild to moderate G610C mouse model of OI. The sActRIIB molecule binds multiple transforming growth factor-β (TGF-β) ligands, including myostatin and activin A. Here, we investigate the musculoskeletal effects of inhibiting activin A alone, myostatin alone, or both myostatin and activin A in wild-type (Wt) and heterozygous G610C (+/G610C) mice using specific monoclonal antibodies. Male and female Wt and +/G610C mice were treated twice weekly with intraperitoneal injections of monoclonal control antibody (Ctrl-Ab, Regn1945), anti-activin A antibody (ActA-Ab, Regn2476), anti-myostatin antibody (Mstn-Ab, Regn647), or both ActA-Ab and Mstn-Ab (Combo, Regn2476, and Regn647) from 5 to 16 weeks of age. Prior to euthanasia, whole body composition, metabolism and muscle force generation assessments were performed. Post euthanasia, hindlimb muscles were evaluated for mass, and femurs were evaluated for changes in microarchitecture and biomechanical strength using micro–computed tomography (μCT) and three-point bend analyses. ActA-Ab treatment minimally impacted the +/G610C musculoskeleton, and was detrimental to bone strength in male +/G610C mice. Mstn-Ab treatment, as previously reported, resulted in substantial increases in hindlimb muscle weights and overall body weights in Wt and male +/G610C mice, but had minimal skeletal impact in +/G610C mice. Conversely, the Combo treatment outperformed ActA-Ab alone or Mstn-Ab alone, consistently increasing hindlimb muscle and body weights regardless of sex or genotype and improving bone microarchitecture and strength in both male and female +/G610C and Wt mice. Combinatorial inhibition of activin A and myostatin more potently increased muscle mass and bone microarchitecture and strength than either antibody alone, recapturing most of the observed benefits of sActRIIB treatment in +/G610C mice. © 2022 American Society for Bone and Mineral Research (ASBMR).