Signaling Pathways Affecting Skeletal Health

Skeletal health is dependent on the balance between bone resorption and formation during bone remodeling. Multiple signaling pathways play essential roles in the maintenance of skeletal integrity by positively or negatively regulating bone cells. During the last years, significant advances have been made in our understanding of the essential signaling pathways that regulate bone cell commitment, differentiation and survival. New signaling anabolic pathways triggered by parathyroid hormone, local growth factors, Wnt signaling, and calcium sensing receptor have been identified. Novel signals induced by interactions between bone cells-matrix (integrins), osteoblasts/osteocytes (cadherins, connexins), and osteoblasts/osteoclast (ephrins, Wnt-RhoA, semaphorins) have been discovered. Recent studies revealed the key pathways (MAPK, PI3K/Akt) that critically control bone cells and skeletal mass. This review summarizes the most recent knowledge on the major signaling pathways that control bone cells, and their potential impact on the development of therapeutic strategies to improve human bone health.     

Bone Marrow Adipose Tissue and Skeletal Health

Purpose of Review

To summarize and discuss recent progress and novel signaling mechanisms relevant to bone marrow adipocyte formation and its physiological/pathophysiological implications for bone remodeling.

Recent Findings

Skeletal remodeling is a coordinated process entailing removal of old bone and formation of new bone. Several bone loss disorders such as osteoporosis are commonly associated with increased bone marrow adipose tissue. Experimental and clinical evidence supports that a reduction in osteoblastogenesis from mesenchymal stem cells at the expense of adipogenesis, as well as the deleterious effects of adipocyte-derived signaling, contributes to the etiology of osteoporosis as well as bone loss associated with aging, diabetes mellitus, post-menopause, and chronic drug therapy. However, this view is challenged by findings indicating that, in some contexts, bone marrow adipose tissue may have a beneficial impact on skeletal health.

Summary

Further research is needed to better define the role of marrow adipocytes in bone physiology/pathophysiology and to determine the therapeutic potential of manipulating mesenchymal stem cell differentiation.

     

Emerging Impact of Skeletal Muscle in Health and Disease

Calcified Tissue International -     

Epidemiology of Skeletal Health in Type 1 Diabetes

The skeleton is adversely affected by type 1 diabetes (T1D). Patients with T1D of both sexes have an increased risk of fracture that begins in childhood and extends across the entire lifespan. T1D is characterized by mild to modest deficits in bone density, structure, and microarchitecture. Current evidence suggests that the observed bone deficits in T1D are the result of impaired bone formation rather than increased bone resorption. There is emerging data that bone quality is impaired in T1D, which may explain the findings that fracture risk is elevated out of proportion to the degree of bone mineral deficit. In this review, we summarize the current knowledge regarding the epidemiology of skeletal health in T1D. Given the high individual and societal burden of osteoporotic fracture, there is an urgent need to better understand the etiology of T1D-related bone disease so that clinical strategies to prevent fracture can be developed.     

Imaging Technologies for Assessment of Skeletal Health in Men

Conventional radiography can detect most fractures, evaluate their healing, and visualize characteristic skeletal abnormalities for some metabolic bone diseases. Dual-energy X-ray absorptiometry (DXA) is used to measure areal bone mineral density (BMD) in order to diagnose osteoporosis, estimate fracture risk, and monitor changes in BMD over time. Vertebral fracture assessment by DXA can diagnose vertebral fractures with less ionizing radiation, greater patient convenience, and lower cost than conventional radiography. Quantitative computed tomography (QCT) measures volumetric BMD separately in cortical and trabecular bone compartments. High resolution peripheral QCT and high resolution magnetic resonance imaging are noninvasive research tools that assess the microarchitecture of bone. The use of these technologies and others has been associated with special challenges in men compared with women, provided insights into differences in the pathogenesis of osteoporosis in men and women, and enhanced understanding of the mechanisms of action of osteoporosis treatments.     

Effects of Incretin-Based Therapies and SGLT2 Inhibitors on Skeletal Health

Anti-diabetic drugs are widely used and are essential for adequate glycemic control in patients with type 2 diabetes. Recently, marketed anti-diabetic drugs include incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2) inhibitors. In contrast to well-known detrimental effects of thiazolidinediones on bone metabolism and fracture risk, clinical data on the safety of incretin-based therapies is limited. Based on meta-analyses of trials investigating the glycemic-lowering effect of GLP-1 receptor agonists and DPP4 inhibitors, it seems that incretin-based therapies are not associated with an increase in fracture risk. Sodium-glucose co-transporter 2 inhibitors may alter calcium and phosphate homeostasis as a result of secondary hyperparathyroidism induced by increased phosphate reabsorption. Although these changes may suggest detrimental effects of SGLT-2 inhibitors on skeletal integrity, treatment-related direct effects on bone metabolism seem unlikely. Observed changes in BMD, however, seem to result from increased bone turnover in the early phase of drug-induced weight loss. Fracture risk, which is observed in older patients with impaired renal function and elevated cardiovascular disease risk treated with SGLT2 inhibitors, seems to be independent of direct effects on bone but more likely to be associated with falls and changes in hydration status secondary to osmotic diuresis.     

Management of Skeletal Health in Patients With Asymptomatic Primary Hyperparathyroidism

Asymptomatic primary hyperparathyroidism (PHPT) may cause adverse skeletal effects that include high bone remodeling, reduced bone mineral density (BMD), and increased fracture risk. Parathyroid surgery, the definitive treatment for PHPT, has been shown to increase BMD and appears to reduce fracture risk. Current guidelines recommend parathyroid surgery for patients with symptomatic PHPT or asymptomatic PHPT with serum calcium >1 mg/dL above the upper limit of normal, calculated creatinine clearance <60 mL/min, osteoporosis, previous fracture, or age <50 yr. The type of operation performed (parathyroid exploration or minimally invasive procedure) and localizing studies to identify the abnormal parathyroid glands preoperatively should be individualized according to the skills of the surgeon and the resources of the institution. In patients who choose not to be treated surgically or who have contraindications for surgery, medical therapy should include a daily calcium intake of at least 1200 mg and maintenance of serum 25-hydroxyvitamin D levels of at least 20 ng/mL (50 nmol/L). Bisphosphonates and estrogens have been shown to provide skeletal benefits that appear to be similar to parathyroid surgery. Cinacalcet reduces serum calcium in PHPT patients with intractable hypercalcemia but has not been shown to improve BMD. It is not known whether any medical intervention reduces fracture risk in patients with PHPT. There are insufficient data on the natural history and treatment of normocalcemic PHPT to make recommendations for management of this disorder.     

航天员中长期飞行骨骼健康管理研究现状

骨质疏松是航天员太空飞行后面临的主要健康威胁之一。中长期飞行会对航天员骨骼健康带来明显影响。1个月的太空飞行骨丢失量相当于绝经后妇女1年的丢失量。目前对失重后骨质疏松的研究和评估方法主要是骨密度、定量CT、有限元分析和生物力学测定。骨丢失的对抗性措施和治疗老年性骨质疏松症类似,主要包括运动锻炼、营养补充和药物治疗等。本文概述了国内外这一领域的研究现状、骨骼健康评估方法、常用对抗骨丢失应对措施,尝试提出对我国航天员中长期飞行骨骼健康管理的初步建议。     

Aneuploidy and DNA fragmentation in morphologically abnormal sperm

In light of the relative success of ICSI in the treatment of male infertility, much importance has been made to the selection of morphologically viable sperm. However, correlation between specific sperm morphology and chromosomal abnormalities is still relatively limited and less is known about the connection between sperm morphology and DNA integrity. Sperm obtained from isolated teratozoospermic men ( n  = 10) and control men ( n  = 9) were analysed using FISH (for chromosomes 13, 18, 21, X and Y) and TUNEL assays to determine the level of aneuploidy and DNA fragmentation. Sperm morphology was evaluated on its ability to identify the level of chromosomal abnormalities or fragmented DNA in sperm. Sperm from teratozoospermic men, compared with fertile men, had higher rates of total chromosomal abnormality ( p  < 0.05), total aneuploidy ( p  < 0.01) and chromosome 13 disomy ( p  < 0.01). Associations between particular types of sperm morphology and chromosomal abnormalities were observed in both control (tapered heads) and teratozoospermic (amorphous heads and tail abnormalities) samples. Levels of DNA fragmented sperm were higher in teratozoospermic men than in the control men (60.28 ± 21.40% vs. 32.40 ± 17.20%, p  < 0.05) and positively correlated to sperm with bent necks in control samples and round heads in teratozoospermic samples ( p  < 0.05). Sperm of isolated teratozoospermic men have higher rates of chromosomal abnormalities and DNA fragmentation than that of the fertile controls. Specific abnormal sperm morphology can be correlated to chromosomal abnormalities and level of DNA fragmentation in sperm.     

Loss of Heterozygosity and DNA Aneuploidy in Colorectal Adenocarcinoma

Background: This study evaluated the relationship between DNA aneuploidy and loss of heterozygosity (LOH) at different genetic loci in colorectal adenocarcinoma.Methods: A total of 112 patients with surgically removed colorectal adenocarcinoma in Taipei Veterans General Hospital from January 1999 to July 2001 were included in this study. The pattern of DNA ploidy was determined with DNA flow cytometry, and the LOH of various genetic loci was determined with fluorescence polymerase chain reaction and denaturing gradient gel electrophoresis. The relationship between DNA ploidy, LOH of various genetic loci, and clinicopathologic variables was analyzed with the ² test with Yates correction as well as by multivariate binary logistic regression analysis.Results: Seventy-one (63.4%) of the 112 carcinomas had DNA aneuploidy. The DNA aneuploidy was not associated with any clinicopathologic variable. Ninety-one tumors (81.3%) exhibited LOH in at least one genetic locus. In the univariate analysis, the DNA aneuploidy was associated with LOH of Tp53-penta, D8S254, D5S346, and high-frequency LOH (P = .001, P = .016, P = .041, and P < .001, respectively). In the multivariate analysis, the most significant factor influencing DNA aneuploidy was D8S254, followed by Tp53-penta, high-frequency LOH, and D5S346.Conclusions: DNA aneuploidy is strongly associated with LOH at specific genetic loci.     

The Women's Health Initiative: A Landmark Resource for Skeletal Research Since 1992

The Women's Health Initiative (WHI) is a large longitudinal study designed to investigate strategies for the prevention and control of common chronic diseases in postmenopausal women, including cardiovascular disease, cancer, and osteoporotic fractures. The WHI consisted of three overlapping clinical trials of hormone therapy, diet modification to reduce total dietary fat, and calcium/vitamin D supplementation. Women who were ineligible for the hormone therapy or diet modification trials or not interested were invited to participate in the observational study. Women were recruited into WHI from 1993 to 1998 at 40 US clinical centers. WHI enrolled 26,046 underrepresented minority women and 135,762 white women. Women could participate in each trial if eligible. The final enrollment included 27,347 women in the hormone trial; 48,835 women in the diet modification trial; 36,282 women in the calcium/vitamin D trial, and 93,676 in the observational study. After the main study ended in 2005, women were invited to continue follow-up for exposures and outcomes through two extensions to 2020. Proposals were recently submitted to continue follow-up through 2027. Information was collected on an extensive number of risk factors for fractures at baseline and over the follow-up, including fall and fracture history, weight patterns, comorbidities, diet, reproductive history, medications, anthropometry, and biomarkers. Bone mineral density was measured at three WHI clinical centers (n = 11,020) chosen to maximize race/ethnic diversity. WHI encourages outside investigators to make use of the publicly available WHI data and to access the biobank of specimens ( www.whi.org ). © 2020 American Society for Bone and Mineral Research.     

Aneuploidy in spermatozoa of infertile men with teratozoospermia

Recent studies have shown that aneuploidy in spermatozoa of infertile men with poor semen quality is increased. The purpose of this study was to determine whether poor sperm morphology is associated with the incidence of spermatozoa with numerical chromosome abnormalities. Semen samples from 20 infertile teratozoospermic men were studied using multicolour fluorescence in situ hybridization (FISH). Men were divided into four groups according to the proportion of normal sperm morphology: infertile men with <10% (group A, n=7), 10-19% (group B, n=6), and 20-29% (group C, n=7) of morphologically normal spermatozoa, and controls (group D, n=5) with > or =30% normal forms. Two hybridizations were performed. All the samples were analysed using probes for chromosomes 1 and 7 and, in addition, in group A and in controls with normal semen parameters probes for chromosomes X, Y and 18 were also used. Ten thousand spermatozoa were scored per hybridization. Severely teratozoospermic men (<10% normal forms) had significantly higher frequency of disomy 7, 18, YY, XY and diploidy in their spermatozoa when compared with controls. The results suggest that poor sperm morphology is associated with numerical chromosome abnormalities of spermatozoa. Severely teratozoospermic men may be at an increased risk of producing aneuploid offspring.     

Uncoupling of Bone Turnover may Compromise Skeletal Health of Young Patients With Haemophilia A

There is evidence that bone mass is decreased and bone metabolism is dysregulated in children with haemophilia (CWH). The objective of this study was to investigate the impact of haemophilia on skeletal health in children, with regards to bone mineral density (BMD) and metabolic bone profile. This study included 51 male CWH A. Dual-energy X-ray absorptiometry (DXA) was performed to assess BMD in lumbar spine (LS) and total body less head (TBLH) and Z-scores were calculated (low BMD Z-score<-2, low-normal BMD Z-score between -1 and -2). Serum levels of osteocalcin (OC), procollagen type I C-terminal propeptide (PICP), bone alkaline phosphatase (bALP), bone tartrate-resistant acid phosphatase 5b (TRAP5b), vitamin D, parathormone (PTH), urinary calcium/creatinine (uCa/uCr) and urine deoxypyridinoline/creatinine (uDPD/uCr) were measured. Mean BMD Z-scores were lower than predicted at both sites of measurement. More specifically, 10% of CWH A had low and 20% low-normal BMD Z-scores in LS, whereas 9.1% had low-normal TBLH BMD Z-scores and there were no patients with low BMD Z-scores at this site of measurement. 36.7% of CWH had low vitamin D levels and 19.6% had a history of fracture. Also, patients with haemophilia had lower OC and higher uDPD/uCr levels while OC positively correlated to BMD Z-scores and uDPD/uCr negatively correlated to BMD Z-scores at both sites. No statistically significant differences were observed with regards to mode of treatment, number of haemorrhages and the presence of target-joints. CWH A had decreased BMD Z-scores at both sites with an uncoupling of bone turnover LS BMD seemed to be more affected than TBLH BMD.     

Skeletal dysplasia

Skeletal dysplasias are genetic conditions causing a structural abnormality in the bone and cartilage leading to growth disturbance. There are many different types of dysplasias most of which are rare. Although the incidence of the each individual types of skeletal dysplasia is low, skeletal dysplasia as a group should be recognized early for appropriate management. The aim of this article is to present a brief overview of skeletal dysplasia and the management of the more common among these presenting to the orthopaedic surgeon.