Genetic Risk Scores Implicated in Adult Bone Fragility Associate With Pediatric Bone Density

Using adult identified bone mineral density (BMD) loci, we calculated genetic risk scores (GRS) to determine if they were associated with changes in BMD during childhood. Longitudinal data from the Bone Mineral Density in Childhood Study were analyzed (N = 798, 54% female, all European ancestry). Participants had up to 6 annual dual energy X‐ray scans, from which areal BMD (aBMD) Z‐scores for the spine, total hip, and femoral neck were estimated, as well as total body less head bone mineral content (TBLH‐BMC) Z‐scores. Sixty‐three single‐nucleotide polymorphisms (SNPs) were genotyped, and the percentage of BMD‐lowering alleles carried was calculated (overall adult GRS). Subtype GRS that include SNPs associated with fracture risk, pediatric BMD, WNT signaling, RANK‐RANKL‐OPG, and mesenchymal stem cell differentiation were also calculated. Linear mixed effects models were used to test associations between each GRS and bone Z‐scores, and if any association differed by sex and/or chronological age. The overall adult, fracture, and WNT signaling GRS were associated with lower Z‐scores (eg, spine aBMD Z‐score: β_adult = –0.04, p = 3.4 × 10^?7; β_fracture = –0.02, p = 8.9 × 10^?6; β_WNT = –0.01, p = 3.9 × 10^?4). The overall adult GRS was more strongly associated with lower Z‐scores in females (p‐interaction ≤ 0.05 for all sites). The fracture GRS was more strongly associated with lower Z‐scores with increasing age (p‐interaction ≤ 0.05 for all sites). The WNT GRS associations remained consistent for both sexes and all ages (p‐interaction > 0.05 for all sites). The RANK‐RANKL‐OPG GRS was more strongly associated in females with increasing age (p‐interaction < 0.05 for all sites). The mesenchymal stem cell GRS was associated with lower total hip and femoral neck Z‐scores, in both boys and girls, across all ages. No associations were observed between the pediatric GRS and bone Z‐scores. In conclusion, adult identified BMD loci associated with BMD and BMC in the pediatric setting, especially in females and in loci involved in fracture risk and WNT signaling. © 2015 American Society for Bone and Mineral Research.     

Biomechanics of Bone: Determinants of Skeletal Fragility and Bone Quality

Bone fragility can be defined by biomechanical parameters, including ultimate force (a measure of strength), ultimate displacement (reciprocal of brittleness) and work to failure (energy absorption). Bone fragility is influenced by bone size, shape, architecture and tissue ‘quality’. Many osteoporosis treatments build bone mass but also change tissue quality. Antiresorptive therapies, such as bisphosphonates, substantially reduce bone turnover, impairing microdamage repair and causing increased bone mineralization, which can increase the brittleness of bone. Anabolic therapies, such as parathyroid hormone (PTH-(1–84)) or teriparatide (PTH-(1–34)), increase bone turnover and porosity, which offset some of the positive effects on bone strength. Osteoporosis therapies may also affect bone architecture by causing the redistribution of bone structure. Restructuring of bone during treatment may change bone fragility, even in the absence of drug effects on bone mineral density (BMD). This effect may explain why some drugs can affect fracture incidence disproportionately to changes in BMD. For instance, in a recent clinical trial, PTH-(1–34) therapy caused a dose-related increase in spinal BMD without any dose-dependent effect on the observed decrease in spinal fracture incidence. This apparent disassociation between spinal BMD and bone fragility is probably due to effects of PTH-(1–34) on bone architecture within vertebral bodies. While it has been shown that BMD is highly heritable, bone mineral distribution and architecture are also under strong genetic influence. Recent findings suggest that different genes regulate trabecular and cortical structures within lumbar vertebrae, producing a wide range of bone architectural designs. These findings suggest that there is no single optimal bone architecture; instead many different architectural solutions produce adequate bone strength. Received: 14 June 2001 / Accepted: 3 September 2001     

Bone Mineral Density and Body Composition in Underweight and Normal Elderly Subjects

The importance of malnutrition as a risk factor in osteoporosis is emphasized by the evidence that patients with fractures of the proximal femur are often undernourished. In this study, nutritional status, bone mineral mass and its association with body composition were investigated in underweight and normal weight elderly subjects. Moreover the hypothesis that malnutrition in elderly is associated with a higher risk of osteoporosis was tested. The participants were 111 elderly subjects divided into two groups according to body mass index (BMI): 51 patients were underweight (BMI < 22 kg/m²) while in 60 subjects BMI ranged from 22 to 30 kg/m². In all patients anthropometric parameters and blood indices of malnutrition and of bone turnover were measured. Fat-free soft mass (FFSM), fat mass (FM), bone mineral content (BMC) and bone mineral density (BMD) ‘total body’ and at the hip were obtained by dual-energy X-ray densitometry. Dietary intake was evaluated with the diet history method, while resting energy expenditure (REE) was measured by indirect calorimetry. Underweight subjects had other signs of malnutrition, such as low visceral proteins, sarcopenia, and an inadequate energy intake. Moreover they showed a significant reduction of BMC and BMD compared with normal subjects. In men with BMI <22 kg/m², T-score was below −2.5 (−3 at femoral neck and −2.7 at total hip) while men in the control group had normal bone mineral parameters. T-score at different sites was lower in underweight women than in underweight men, always showing values under −3.5, with clear osteoporosis and a high fracture risk. In healthy women the T-score values indicated the presence of mild osteoporosis. In underweight subjects, low levels of albumin (< 35 g/l) were associated with higher femoral bone loss. Using a partial correlation model, BMC, adjusted for age, bone area, knee height and albumin showed a significant association with FM in women (r= 0.48; p < 0.01) and with FFSM in men (r= 0.48; p < 0.05). Albumin, when adjusted for other variables, was significantly correlated (r= 0.52; p < 0.05) with femoral neck BMC only in women. In conclusion, the underweight state in the elderly is associated with malnutrition and osteoporosis; other factors occurring in malnutrition, besides body composition changes, such as protein deficiency, could be involved in the association between underweight and osteoporosis. Moreover bone mineral status seems to be related to fat-free soft mass tissue in men while in women it is much more closely associated with total body fat. Received: 3 January 2000 / Accepted: 3 July 2000     

Bone Structure and Volumetric BMD in Overweight Children: A Longitudinal Study

The effect of excess body fat on bone strength accrual is not well understood. Therefore, we assessed bone measures in healthy weight (HW) and overweight (OW) children. Children (9–11 yr) were classified as HW (n = 302) or OW (n = 143) based on body mass index. We assessed total (ToD) and cortical (CoD) volumetric BMD and bone area, estimates of bone strength (bone strength index [BSI]; stress‐strain index [SSIp]), and muscle cross‐sectional area (CSA) at the distal (8%), midshaft (50%), and proximal (66%) tibia by pQCT. We used analysis of covariance to compare bone outcomes at baseline and change over 16 mo. At baseline, all bone measures were significantly greater in OW compared with HW children (+4–15%; p ≤ 0.001), with the exception of CoD at the 50% and 66% sites. Over 16 mo, ToA increased more in the OW children, whereas there was no difference for change in BSI or ToD between groups at the distal tibia. At the tibial midshaft, SSIp was similar between groups at baseline when adjusted for muscle CSA, but low when adjusted for body fat in the OW group. At both sites, bone strength increased more in OW because of a greater increase in bone area. Changes in SSIp were associated with changes in lean mass (r = 0.70, p < 0.001) but not fat mass. In conclusion, although OW children seem to be at an advantage in terms of absolute bone strength, bone strength did not adapt to excess body fat. Rather, bone strength was adapted to the greater muscle area in OW children.     

New Markers of Bone Fragility in Hemodialysis Patients: A Monocentric Study

Introduction: Mechanisms underlying bone fragility in patients under dialysis are various. The assessment of bone disorder is not yet codified in these patients. Our study aimed to determine the relationship between the serum fibroblast growth factor 23 (FGF23) level and bone fragility. We also aimed to assess the bone alkaline phosphatase (bAP) to the C-terminal telopeptide of type I (CTX) ratio and the FGF23*bAP product to CTX ratio in patients under hemodialysis. Methodology: We conducted a cross-sectional study, including 76 patients under hemodialysis. To assess bone fragility, we measured bAP, CTX, and FGF 23. We calculated the bAP to the CTX ratio (bAP/CTX) and the FGF23*bAP product to the CTX ratio (FGF23*bAP/CTX). We defined bone fragility as the existence of osteoporosis or fragility fractures. Receiver operating characteristic (ROC) curves were evaluated for each biological using the existence of osteoporosis or fragility fracture as the gold standard for bone fragility. Results: There were 51 men. The mean age was 53.36 ± 14.27 years. Bone fragility was noted in 25 cases. Patients with osteoporosis had higher FGF*bAP/CTX and bAP/CTX ratios. The ability of the ratio (bAP/CTX) to distinguish patients with osteoporosis from those without osteoporosis was good, with a ROC AUC of 0.707. The optimal ratio cut-off value with the highest accuracy was 9.72. The ability of the ratio (FGF23*bAP/CTX) to distinguish patients with bone fragility was good, with a ROC AUC of 0.701. The optimal ratio cut-off value with the highest accuracy was 1621.89 (sensitivity 60%, specificity 78.4%). Conclusion: Our study showed FGF23, FGF23*bAP product to CTX ratio, and the bAP to CTX ratio can be used as markers of bone fragility in hemodialysis patients. Therefore, these noninvasive and relatively inexpensive methods may serve to diagnose bone fragility in patients under hemodialysis.     

Geometric Indices of Hip Bone Strength in Obese,Overweight, and Normal-Weight Adolescent Girls

The aim of this study was to compare hip bone strength indices in obese, overweight, and normal-weight adolescent girls using hip structure analysis (HSA). This study included 64 postmenarcheal adolescent girls (14 obese, 21 overweight, and 29 normal weight). The 3 groups (obese, overweight, and normal weight) were matched for maturity (years since menarche). Body composition and bone mineral density (BMD) of whole body, lumbar spine, and proximal femur were assessed by dual-energy X-ray absorptiometry (DXA). To evaluate hip bone strength, DXA scans were analyzed at the femoral neck (FN) at its narrow neck (NN) region, the intertrochanteric (IT), and the femoral shaft (FS) by the HSA program. Cross-sectional area and section modulus were measured from hip BMD profiles. Total hip BMD and FN BMD were significantly higher in obese and overweight girls in comparison with normal-weight girls (p < 0.05). However, after adjusting for weight, using a one-way analysis of covariance, there were no significant differences among the 3 groups regarding HSA variables. This study suggests that in obese and overweight adolescent girls, axial strength and bending strength indices of the NN, IT, and FS are adapted to the increased body weight.     

Effects of Bone Matrix Proteins on Fracture and Fragility in Osteoporosis

Bone mineral density alone cannot reliably predict fracture risk in humans and laboratory animals. Therefore, other factors including the quality of organic bone matrix components and their interactions may be of crucial importance to understanding of fragility fractures. Emerging research evidence shows, that in addition to collagen, certain noncollagenous proteins (NCPs) play a significant role in the structural organization of bone and influence its mechanical properties. However, their contribution to bone strength still remains largely undefined. Collagen and NCPs undergo different post-translational modifications, which alter the quality of the extracellular matrix and the response of bone to mechanical load. The primary focus of this overview is on NCPs that, together with collagen, contribute to structural and mechanical properties of bone. Current information on several mechanisms through which some NCPs influence bone's resistance to fracture, including the role of nonenzymatic glycation, is also presented.     

Infection by CagA-Positive Helicobacter pylori Strains and Bone Fragility: A Prospective Cohort Study

Helicobacter pylori (HP) infection is a common and persistent disorder acting as a major cofactor for the development of upper gastrointestinal diseases and several extraintestinal disorders including osteoporosis. However, no prospective study assessed the effects of HP on bone health and fracture risk. We performed a HP screening in a population-based cohort of 1149 adults followed prospectively for up to 11 years. The presence of HP infection was assessed by serologic testing for serum antibodies to HP and the cytotoxin associated gene-A (CagA). The prevalence of HP infection did not differ among individuals with normal bone mineral density (BMD), osteoporosis, and osteopenia. However, HP infection by CagA-positive strains was significantly increased in osteoporotic (30%) and osteopenic (26%) patients respect to subjects with normal BMD (21%). Moreover, anti-CagA antibody levels were significantly and negatively associated with lumbar and femoral BMD. Consistent with these associations, patients affected by CagA-positive strains had a more than fivefold increased risk to sustain a clinical vertebral fracture (HR 5.27; 95% CI, 2.23–12.63; p < .0001) and a double risk to sustain a nonvertebral incident fracture (HR 2.09; 95% CI, 1.27–2.46; p < .005). Reduced estrogen and ghrelin levels, together with an impaired bone turnover balance after the meal were also observed in carriers of CagA-positive HP infection. HP infection by strains expressing CagA may be considered a risk factor for osteoporosis and fractures. Further studies are required to clarify in more detail the underlying pathogenetic mechanisms of this association. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Prediction of Bone Mineral Density and Fragility Fracture by Genetic Profiling

Although the susceptibility to fracture is partly determined by genetic factors, the contribution of newly discovered genetic variants to fracture prediction is still unclear. This study sought to define the predictive value of a genetic profiling for fracture prediction. Sixty‐two bone mineral density (BMD)‐associated single‐nucleotide polymorphisms (SNPs) were genotyped in 557 men and 902 women who had participated in the Dubbo Osteoporosis Epidemiology Study. The incidence of fragility fracture was ascertained from X‐ray reports between 1990 and 2015. Femoral neck BMD was measured by dual‐energy X‐ray absorptiometry. A weighted polygenic risk score (genetic risk score [GRS]) was created as a function of the number of risk alleles and their BMD‐associated regression coefficients for each SNP. The association between GRS and fracture risk was assessed by the Cox proportional hazards model. Individuals with greater GRS had lower femoral neck BMD (p < 0.01), but the variation in GRS accounted for less than 2% of total variance in BMD. Each unit increase in GRS was associated with a hazard ratio of 1.20 (95% CI, 1.04 to 1.38) for fracture, and this association was independent of age, prior fracture, fall, and in a subset of 33 SNPs, independent of femoral neck BMD. The significant association between GRS and fracture was observed for the vertebral and wrist fractures, but not for hip fracture. The area under the receiver‐operating characteristic (ROC) curve (AUC) for the model with GRS and clinical risk factors was 0.71 (95% CI, 0.68 to 0.74). With GRS, the correct reclassification of fracture versus nonfracture ranged from 12% for hip fracture to 23% for wrist fracture. A genetic profiling of BMD‐ associated genetic variants could improve the accuracy of fracture prediction over and above that of clinical risk factors alone, and help stratify individuals by fracture status. © 2016 American Society for Bone and Mineral Research.     

Paget's Disease of Bone: Pathophysiology, Diagnosis, and Management

Paget's disease of bone is a common geriatric disorder of skeletal remodeling, which may have a viral etiology. Safe and effective treatments are now available for associated complications of symptomatic involvement. The orthopaedic surgeon should have a fundamental understanding of the complications of Paget's disease and should be familiar with the indications for treatment, as well as available medical and surgical therapies.     

Low Bone Mineral Density and Fragility Fractures in Permanent Vegetative State Patients

Disuse of the musculoskeletal system causes bone loss. Whether patients in vegetative state, a dramatic example of immobilization after severe brain injury, suffer from bone loss and fractures is currently unknown. Serum markers of bone turnover, bone mineral density (BMD) measurements, and clinical data were cross‐sectionally analyzed in 30 consecutive vegetative state patients of a dedicated apallic care unit between 2003 and 2007 and compared with age‐ and sex‐matched healthy individuals. Vegetative state patients showed low calcium levels and vitamin D deficiency compared with healthy controls. Serum bone turnover markers revealed high turnover as evidenced by markedly elevated carboxy‐terminal telopeptide of type I collagen (β‐crosslaps) and increased levels of alkaline phosphatase. BMD measured by dual‐energy X‐ray absorptiometry (DXA) scanning showed strongly decreased T‐ and Z‐scores for hip and spine. Over a period of 5 years, 8 fragility fractures occurred at peripheral sites in 6 of 30 patients (n = 3 femur, n = 2 tibia, n = 2 fibula, n = 1 humerus). In conclusion, high bone turnover and low BMD is highly prevalent in vegetative state patients, translating into a clinically relevant problem as shown by fragility fractures in 20% of patients over a time period of 5 years. © 2014 American Society for Bone and Mineral Research.     

Osteomyelitis of the Temporal Bone: Terminology,Diagnosis, and Management

Objectives To review the terminology, clinical features, and management of temporal bone osteomyelitis. Design and Setting Prospective study in a tertiary care center from 2001 to 2008. Participants Twenty patients visiting the outpatient department diagnosed with osteomyelitis of the temporal bone. Main Outcome Measures The age, sex, clinical features, cultured organisms, surgical interventions, and classification were analyzed. Results Of the 20 cases, 2 (10%) were diagnosed as acute otitis media. Eighteen (90%) had chronic otitis media. Nineteen (95%) were classified as medial temporal bone osteomyelitis and one (5%) as lateral temporal osteomyelitis. The most common clinical features were ear discharge (100%), pain (83%), and granulations (100%). Facial nerve palsy was seen in seven cases (35%) and parotid involvement in one case. Ten patients (56%) had diabetes mellitus. The organisms isolated were Pseudomonas aeruginosa (80%) and Staphylococcus aureus (13.33%). Histopathology revealed chronic inflammation in 20 patients (100%) and osteomyelitic bony changes in 14 (70%). Surgical debridement was the most preferred modality of treatment (87%). Conclusion A new classification of temporal bone osteomyelitis has been proposed. Bacterial cultures must be performed in all patients. Antibiotic therapy is the treatment of choice. Surgical intervention is necessary in the presence of severe pain, complications, refractory cases, or the presence of bony sequestra on radiology.