Spine BMD Z-score Research Articles

LONG-TERM SPORT OR EXERCISE COMMENCED BEFORE 16 YEARS OF AGE REDUCES ADVERSE BODY COMPOSITION OUTCOMES IN CEREBRAL PALSY

INTRODUCTION & AIMS Bone mineral density (BMD) and appendicular lean mass (ALM) deficits are common in people with cerebral palsy (CP), increasing sarcopenia and osteoporosis risk, while sport/exercise participation before age 16 improves adult peak bone mass accretion. This study investigated the effects of high-level sport/exercise participation commenced before 16 years of age on body composition in ambulatory adults with CP. METHODS Body composition was measured via dual-energy X-ray absorptiometry in a cross-sectional observational pilot study of 26 adults (m=19; f=7; GMFCS I-III) grouped via self-reported activity level into Low (<150 minutes moderate-vigorous activity weekly; n=10), Post-16 (active but commenced participation after 16; n=6), and Pre-16 (active and commenced participation before 16; n=10). Between-group Z-score differences were assessed via Kruskal-Wallis one-way ANOVA, with post-hoc comparisons via Mann-Whitney U-test. RESULTS Whole body, spine and hip BMD Z-scores were significantly higher in Pre-16 (1.020 (0.639), 1.210 (1.102), and 0.450 (1.325), respectively) versus Low (-0.500 (0.715), -0.840 (0.957), and -1.020 (1.059), respectively) (p<0.001-0.008). Thirteen participants, including four competitive athletes, had low BMD, and 15, including eight athletes, had moderate-significant ALM deficits, versus age- and sex-specific reference populations. CONCLUSION Ambulatory adults with CP who exceed physical activity guidelines and commenced participation before 16 years of age have higher BMD than those who are sedentary or commenced participation after 16 years. Sport and exercise across the lifespan are critical to ameliorate adverse body composition outcomes common in CP, however, some athletes remain at-risk and require targeted combined resistance training and dietary interventions in addition to sport training to address low ALM and BMD.

Reductions in Bone Mineral Density Are Apparent Early in Children With Prevalent Osteonecrosis Lesions Following Leukemia Therapy.

Osteonecrosis (ON) is a serious complication of childhood acute lymphoblastic leukemia. We determined the prevalence of osteonecrotic lesions in our patient population by a one-time multisite magnetic resonance imaging (MRI) more than 1 year following leukemia therapy. MRI findings were evaluated in relationship to clinical factors (including longitudinal changes in bone mineral density [BMD]). Eighty-six children enrolled in the Steroid Associated Osteoporosis in the Pediatric Population (STOPP) study were evaluated for ON at 3.1 ± 1.3 years following therapy. Thirty children had a total of 150 confirmed ON lesions (35%). Lumbar spine (LS) BMD Z-scores (mean ± SD) were low at diagnosis and similar between patients with and without ON (-1.09 ± 1.53 versus -1.27 ± 1.25, p = 0.549). LS BMD Z-scores declined from baseline to 12 months in children with ON (-0.31 ± 1.02) but not in those without (0.13 ± 0.82, p = 0.035); the hip BMD Z-scores from baseline to 24 months declined in both groups, but to a greater extent in those with ON (-1.77 ± 1.22) compared to those without (-1.03 ± 1.07, p = 0.045). At the time of the MRI, mean total hip and total body (TB) BMD Z-scores were lower in children with ON (hip -0.98 ± 0.95 versus -0.28 ± 1.06, p = 0.010; TB -1.36 ± 1.10 versus -0.48 ± 1.50, p = 0.018). Pain occurred in 11/30 (37%) with ON versus 20/56 (36%) without, p = 0.841. In multivariable models, older age at diagnosis (odds ratio [OR] 1.57; 95% confidence interval [CI], 1.15-2.13; p = 0.004), and hip BMD Z-score at MRI (OR 2.23; 95% CI, 1.02-4.87; p = 0.046) were independently associated with ON. Overall, one-third of children demonstrated ON after leukemia therapy. Those with ON had greater reductions in spine and hip BMD Z-scores in the first 1 and 2 years of therapy, respectively. Older age and lower hip BMD Z-scores at MRI were significantly associated with prevalent, off-therapy ON. These data assist in identifying children at risk of ON. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Relationships among Physical Activity, Pain, and Bone Health in Youth and Adults with Thalassemia: An Observational Study.

Patients with thalassemia (Thal) engage in less physical activity than non-Thal populations, which may contribute to pain and osteoporosis. The purpose of this study was to assess relationships between physical activity, pain, and low bone mass in a contemporary sample of patients with Thal. Seventy-one patients with Thal (50 adults ≥18 years, 61% male, 82% transfusion-dependent) completed the Brief Pain Inventory Short Form and validated physical activity questionnaires for youth and adults. Nearly half of the patients reported daily somatic pain. Using multiple regression, after controlling for age and gender, sedentary behavior was positively associated with pain severity (p = 0.017, r 2 = 0.28). Only 37% of adult participants met CDC recommendations for physical activity. Spine BMD Z-score was higher (-2.1 ± 0.7) in those who met activity guidelines compared to those who did not (-2.8 ± 1.2, p = 0.048). A positive relationship was observed between self-reported physical activity (hours/week) and hip BMD Z-score in adults with Thal after controlling for transfusion status and sedentary activity time (p = 0.009, r 2 = 0.25). These results suggest that decreased physical activity and increased sedentary behavior contribute to low bone mass, which may be related to pain severity in some patients with Thal. Studies focused on increasing physical activity may contribute to improved bone health and reduced pain in patients with Thal.

Prevalence and risk factors of fractures in transfusion dependent thalassemia - A Hong Kong Chinese population cohort.

ObjectiveTo delineate the prevalence and associated risk factors of low BMD, osteoporosis/bone fragility and fracture in transfusion‐dependent thalassemia (TDT) in the Chinese population in Hong Kong.Design, Patients and MeasurementsA retrospective cohort study design was employed. Patients of TDT who had serial Hologic dual‐energy X‐ray absorptiometry (DXA) from 2010 to 2016 and received regular transfusion for at least 5 years were recruited. Clinical and biochemical data, from 5 years before the first DXA scan, were retrieved from the electronic record system of the Hospital Authority, till 30 June 2020. Low bone mineral density and osteoporosis/bone fragility are defined by the ISCD 2019 position guidelines.ResultsSeventy‐seven patients were included in the analysis. The fracture prevalence of TDT among the Chinese population in Hong Kong was 15.58%. Up to 55.84% of patients had low bone mineral density, and 5.19% patients had osteoporosis/bone fragility state. The median age at first fracture was 31.73 years (range 24.06–44.18 years). In the regression analysis, a higher log(10) transformation of average ferritin levels over 5 years before the first DXA scan was significantly associated with fracture occurrence regardless of bisphosphonate treatment (OR 310.73, 95% CI 3.99–24183.89, p = .010). Mean average ferritin level over 5 years was 6695.5 ± 2365.7 pmol/L (fracture group) versus 4350.7 ± 3103.2 pmol/L (non‐fracture group), p = .016. Hip and spine BMD Z‐score did not have statistically significant association with fracture occurrence.ConclusionIron overloading plays an important role in adverse bone health in TDT. Dual X‐ray densitometry is insufficient in predicting fracture risk.

SAT-080 SLC29A3 Pathogenic Variant as a Causal for Dysosteosclerosis, a Poor Osteoclast Form of Osteopetrosis

Background: Dysosteosclerosis (DSS) is a rare autosomal recessive form of osteopetrosis characterized by metaphyseal osteosclerosis and platyspondyly. At the histopathological level, a paucity of osteoclasts has been described when the disease presents genetic heterogeneity. SLC29A3 encodes a nucleoside transporter, that colocalizes intracellularly on the lysosomal membrane, is essential for lysosomal function and which is expressed in osteoclasts. Clinical case: We present a female patient from a nonconsanguineous camerunense family with DSS. Her first fracture at the age of 1 year occurred in the proximal right humerus following a very mild trauma. Subsequently she was referred to our clinic at the age of 1.8 months. At the last evaluation in our clinic at the age of 5.6 years she had suffered 5 femur fractures, 2 humerus fractures and a tibia/fibula fracture. XRays shown cortical thickening and widening of the diaphysis of the long bones, cranial base sclerosis, broad ribs with sclerosis and platyspondyly. Bone marrow biopsies and bone biopsy were not performed. The subject did not have any neurological symptoms, dental anomalies or present any dermatological issues. Dual-energy X-ray absorptiometry of the individual showed a lumbar spine BMD Z-score of +8 at 20 months of age, +7.1 at 3 years 5 months, +6.4 at 4 years 6 months and +5.1 at 5 years 6 months of age. TRACP 5 B 4.7 U/L is low in concordance with an osteoclast poor osteopetrosis, and the RANKL>>2.1 ipMol/L is high. On the other hand, CTX 1.298 ng/mL is normal. We identified and confirmed the homozygous pathogenic variant p.Arg386Gln in SLC29A3 using whole exome sequencing and sanger capillary electrophoresis.Conclusion: In summary, we show that a homozygous change in exon 6 of SCL29A3 (NM_00074; c.1157G>A; pArg386Gln) results in a phenotype of Dysosteosclerosis, adding a case to the small group of patients were pathogenic variants in this gene have been described causing sclerosing bone dysplasias with hallmarks of dysosteosclerosis. Interestingly, the other DSS cases and H syndrome cases confirms the clinical heterogeneity of disorders caused by mutations in SLC29A3 and the lack of a clear genotype-phenotype correlation. Phenotypically is also interesting to show that in our patient the bone mineral density has been decreasing over the time, with the concording increasing of TRAB5b. More mutations and functional investigations are needed to get a clearer picture for SCLC29A3 and how is involve in the process of osteoclast differentiation and activity.

LRP5, Bone Density, and Mechanical Stress: A Case Report and Literature Review

The Wnt-β-catenin pathway receptor, low-density lipoprotein receptor-related protein 5 (LRP5), is a known regulator of bone mineral density. It has been hypothesized that specific human polymorphisms in LRP5 impact bone density, in part, by altering the anabolic response of bone to mechanical loading. Although experiments in animal models support this hypothesis, there is limited evidence that LRP5 polymorphisms can alter the anabolic response of bone to mechanical loading in humans. Herein, we report a young male who harbors a rare LRP5 missense mutation (A745V) and who provides potential proof of principle for this mechanotransduction hypothesis for low bone density. The subject had no history of fractures until age 18, a year into a career in competitive distance running. As he continued to run over the following 2 years, his mileage threshold to fracture steadily and rapidly decreased until he was diagnosed with severe osteoporosis (lumbar spine BMD Z-score of −3.2). By contextualizing this case within the existing LRP5 and mechanical stress literature, we speculate that this represents the first documented case of an individual in whom a genetic mutation altered the anabolic response of bone to mechanical stress in a manner sufficient to contribute to osteoporosis.

Genome-wide association study of extreme high bone mass: Contribution of common genetic variation to extreme BMD phenotypes and potential novel BMD-associated genes.

BackgroundGeneralised high bone mass (HBM), associated with features of a mild skeletal dysplasia, has a prevalence of 0.18% in a UK DXA-scanned adult population. We hypothesized that the genetic component of extreme HBM includes contributions from common variants of small effect and rarer variants of large effect, both enriched in an extreme phenotype cohort.MethodsWe performed a genome-wide association study (GWAS) of adults with either extreme high or low BMD. Adults included individuals with unexplained extreme HBM (n = 240) from the UK with BMD Z-scores ≥+3.2, high BMD females from the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) (n = 1055) with Z-scores +1.5 to +4.0 and low BMD females also part of AOGC (n = 900), with Z-scores −1.5 to −4.0. Following imputation, we tested association between 6,379,332 SNPs and total hip and lumbar spine BMD Z-scores. For potential target genes, we assessed expression in human osteoblasts and murine osteocytes.ResultsWe observed significant enrichment for associations with established BMD-associated loci, particularly those known to regulate endochondral ossification and Wnt signalling, suggesting that part of the genetic contribution to unexplained HBM is polygenic. Further, we identified associations exceeding genome-wide significance between BMD and four loci: two established BMD-associated loci (5q14.3 containing MEF2C and 1p36.12 containing WNT4) and two novel loci: 5p13.3 containing NPR3 (rs9292469; minor allele frequency [MAF] = 0.33%) associated with lumbar spine BMD and 11p15.2 containing SPON1 (rs2697825; MAF = 0.17%) associated with total hip BMD. Mouse models with mutations in either Npr3 or Spon1 have been reported, both have altered skeletal phenotypes, providing in vivo validation that these genes are physiologically important in bone. NRP3 regulates endochondral ossification and skeletal growth, whilst SPON1 modulates TGF-β regulated BMP-driven osteoblast differentiation. Rs9292469 (downstream of NPR3) also showed some evidence for association with forearm BMD in the independent GEFOS sample (n = 32,965). We found Spon1 was highly expressed in murine osteocytes from the tibiae, femora, humeri and calvaria, whereas Npr3 expression was more variable.ConclusionWe report the most extreme-truncate GWAS of BMD performed to date. Our findings, suggest potentially new anabolic bone regulatory pathways that warrant further study.

Alteration in serum klotho levels in anorexia nervosa patients

Klotho is a trans-membrane protein which can be shed to act as a hormone; its blood levels may be regulated by the GH/IGF-1 axis. Klotho deficient mice exhibit short lifespan and characteristics of aging and malnutrition, including decreased fat and muscle mass, osteopenia, and impaired fertility. As anorexia nervosa (AN) is characterized by malnutrition and GH resistance, we hypothesized klotho levels would be altered in AN, and aimed to assess klotho levels in undernourished AN patients and changes in klotho following weight rehabilitation. 19 adolescent female AN inpatients (aged 16.1±1.8 years) admitted to an inpatient service for eating disorders in a tertiary center were recruited. Blood samples were obtained on admission and after weight restoration (interval 4.0±2.3 months) and analyzed for klotho, IGF-1, calcium, phosphorus, and alkaline phosphatase. Klotho levels on admission were lower than expected for age, and correlated with lumbar spine BMD Z-score (r=-0.81, p<0.001) and alkaline phosphatase levels (r=0.66, p=0.003) but not with age, height-SDS, weight-SDS, BMI-SDS, or serum calcium, phosphorus and IGF-1 levels. Both IGF-1 and klotho levels increased significantly during hospitalization (IGF-1: 44±17nmol/l to 53±11nmol/l, p=0.008; klotho: 1061±421pg/ml to 1519±781pg/ml, p=0.008). Klotho levels are low in the acute stage of AN and increase with nutritional rehabilitation. Low klotho on admission may be secondary to low IGF-1 levels and may contribute to the clinical manifestations of AN. The role of klotho in the pathophysiology of AN and as a novel marker of disease severity should be further explored.

Osteoporosis in children with chronic illness: lessons from natural history studies that guide clinical practice

Children with serious chronic illnesses have the potential for significant bone morbidity, particularly in the context of disorders with impaired muscle function and the need for glucocorticoid (GC) treatment. Recently, studies have shown that vertebral fractures are often the first sign of osteoporosis in this context. Longitudinal studies have taught us that vertebral fractures are most frequent in the first year of GC therapy among children with GC-treated diseases, that vertebral fractures are often asymptomatic and thereby go undetected in the absence of routine monitoring, and that even asymptomatic vertebral fractures predict an increased risk of future fractures. Other discrete clinical predictors of incident vertebral fractures are evident early in the course of GC therapy, including decreases in spine BMD Z-scores and increases in body mass index Z-scores in the first 6 months of GC therapy. Taken together, these observations highlight that the first year of GC therapy is a critical period for monitoring in order to identify bone morbidity in a timely fashion. Children with risk factors for bone morbidity other than GC therapy (such as neuromuscular disorders and immobilization) are also at increased risk for vertebral and non-vertebral fractures fractures. As such, routine surveillance for vertebral fractures (for example, with a lateral spine radiograph) is now considered a key facet of the bone health evaluation in children with chronic immobilization or GC-treated diseases. While some risk factors for osteoporosis will be permanent (such as immobilization arising from disorders such as cerebral palsy), other children will experience transient threats to bone health. This is an important distinction, since children with transient threats have the potential for vertebral body reshaping, either spontaneously or with bone-targeted treatment such as bisphosphonate therapy. Recovery from fracture-induced deformity is growth-dependent, underscoring the importance of timely diagnosis and intervention during childhood in those with limited potential for spontaneous vertebral body reshaping. Prevention begins with optimization of conservative measures, including physical activity, nutrition, treatment of co-morbid endocrinopathies and aggressive treatment of the underlying disease using the lowest effective GC dose. These measures may be insufficient to prevent first-time fractures in some, raising the need for bone-specific therapy in line with a secondary prevention approach. Secondary prevention is predicated upon identification of early signs of osteoporosis and intervention to prevent disease progression. Since bone-targeted treatment is typically reserved for children with overt fragility, careful monitoring to avoid advanced osteoporosis presentations is paramount. Bisphosphonates are the most commonly prescribed agents in children; however, interest in the use of novel osteo-anabolic therapy is mounting given bone histomorphometric observations that osteoporosis in children with serious chronic illnesses is typically characterized by significant reductions in bone turnover.

Evidence of energy deficiency, using doubly‐labeled water, among adolescent endurance runners (LB316)

Background: Inadequate energy intake has been hypothesized to partially contribute to runners’ low BMD levels.Purpose: To assess the nutritional adequacy of adolescent runners’ diets and identify relationships between runners’ energy status, menstrual function, relevant hormones, biomarkers of bone metabolism, and bone mass.Methods: Twelve adolescent runners (age 16.0 ± 0.3y) completed a 7‐d food log, daily 24‐hr recalls, and assessments of serum hormones, biomarkers of bone turnover, anthropometrics, menstrual function, sports participation, and training volume. Additionally, they underwent a doubly‐labeled water protocol. Runners provided a baseline urine sample and consumed body weight‐specific cocktails 0.12g·kg‐1 of 2H2O and 0.25g·kg‐1 of H218O. Follow‐up first‐void urine samples were collected on days 1, 3, 5, and 7.Results: Among the adolescent runners (BMI= 19.7 kg/m2), who ran 31.2 (±11.1) miles/wk, mean (SD) 7‐day energy intake and expenditure values were 2,213.3 (±374.1) kcal and 3,131.6 (±403.3) kcal, respectively. Thus, runners consumed 918.3 (±449.9) kcal less than expended. Current weekly running mileage was inversely related to body weight (r= ‐0.78, p= 0.003), BMI (r= ‐0.66, p=0.02), gynecological age (r= ‐0.58, p= 0.05),serum estradiol (r= ‐0.64, p= 0.02), spine BMD (r= ‐0.77, p= 0.004), spine BMC (r= ‐0.79, p= 0.002), and spine BMD Z‐score (r= ‐0.63, p= 0.03), but positively related to CTX (r= 0.62, p= 0.03),.Conclusion: Among the runners, energy expended was significantly higher than energy consumed. This energy deficit may have contributed to low BMD, as miles of running per week, a proxy of exercise energy expenditure, correlated with a marker of bone resorption, and was inversely related to body mass, menstrual variables, and bone mass.

Pediatric solid organ transplantation and osteoporosis: a descriptive study on bone histomorphometric findings

Organ transplantation may lead to secondary osteoporosis in children. This study characterized bone histomorphometric findings in pediatric solid organ transplant recipients who were assessed for suspected secondary osteoporosis. Iliac crest biopsies were obtained from 19 children (7.6-18.8 years, 11 male) who had undergone kidney (n = 6), liver (n = 9), or heart (n = 4) transplantation a median 4.6 years (range 0.6-16.3 years) earlier. All patients had received oral glucocorticoids at the time of the biopsy. Of the 19 patients, 21 % had sustained peripheral fractures and 58 % vertebral compression fractures. Nine children (47 %) had a lumbar spine BMD Z-score below -2.0. Histomorphometric analyses showed low trabecular bone volume (< -1.0 SD) in 6 children (32 %) and decreased trabecular thickness in 14 children (74 %). Seven children (37 %) had high bone turnover at biopsy, and low turnover was found in 6 children (32 %), 1 of whom had adynamic bone disease. There was a great heterogeneity in the histological findings in different transplant groups, and the results were unpredictable using non-invasive methods. The observed changes in bone quality (i.e. abnormal turnover rate, thin trabeculae) rather than the actual loss of trabecular bone, might explain the increased fracture risk in pediatric solid organ transplant recipients.

Changes in DXA and Quantitative CT Measures of Musculoskeletal Outcomes Following Pediatric Renal Transplantation

This prospective study evaluated changes in dual energy X-ray absorptiometry (DXA) whole body bone mineral content (WB-BMC) and spine areal bone mineral density (spine-BMD), and tibia quantitative computed tomography (QCT) trabecular and cortical volumetric BMD and cortical area in 56 children over 12 months following renal transplantation. At transplant, spine-BMD Z-scores were greater in younger recipients (<13 years), versus 898 reference participants (p < 0.001). In multivariate models, greater decreases in spine-BMD Z-scores were associated with greater glucocorticoid dose (p < 0.001) and declines in parathyroid hormone levels (p = 0.008). Changes in DXA spine-BMD and QCT trabecular BMD were correlated (r = 0.47, p < 0.01). At 12 months, spine-BMD Z-scores remained elevated in younger recipients, but did not differ in older recipients (≥ 13) and reference participants. Baseline WB-BMC Z-scores were significantly lower than reference participants (p = 0.02). Greater glucocorticoid doses were associated with declines in WB-BMC Z-scores (p < 0.001) while greater linear growth was associated with gains in WB-BMC Z-scores (p = 0.01). Changes in WB-BMC Z-scores were associated with changes in tibia cortical area Z-scores (r = 0.52, p < 0.001), but not changes in cortical BMD Z-scores. Despite resolution of muscle deficits, WB-BMC Z-scores at 12 months remained significantly reduced. These data suggest that spine and WB DXA provides insight into trabecular and cortical outcomes following pediatric renal transplantation.

The development of bone mineral lateralization in the arms

Bone mineral content (BMC) is known to be greater in the dominant arm after the age of 8 years. We studied a group of children and found that BMC sidedness gradually increased up to the age of 6 years and then remained stable into late adolescence. Bone mineral content (BMC) exhibits sidedness in the arms after the age of 8 years, but it is not known whether BMC is greater in the dominant arm from birth or whether lateralization develops in early childhood. To address this, we examined bone mineral status in relation to handedness and age. Subjects (N = 158) were children recently initiating glucocorticoids for underlying disease (leukemia 43 %, rheumatic conditions 39 %, nephrotic syndrome 18 %). Handedness was determined by questionnaire and BMC by dual-energy X-ray absorptiometry. Median age was 7.2 years (range, 1.5 to 17.0 years), 49 % was male, and the spine BMD Z-score was -0.9 (SD, 1.3). By linear regression, BMC sidedness in the arms was significantly related to age (r = 0.294, p = 0.0005). Breakpoint analysis revealed two lines with a knot at 6.0 years (95 % CI, 4.5-7.5 years). The formula for the first line was: dominant:nondominant arm BMC ratio = 0.029 × age [in years] + 0.850 (r = 0.323, p = 0.017). The slope of the second line was not different from 0 (p = 0.332), while the slopes for the two lines were significantly different (p = 0.027). These results show that arm BMC sidedness in this patient group develops up to age 6 years and then remains stable into late adolescence. This temporal profile is consistent with mechanical stimulation of the skeleton in response to asymmetrical muscle use as handedness becomes manifest.

Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa

Anorexia nervosa (AN) is prevalent in adolescents and is associated with decreased bone mineral accrual at a time critical for optimizing bone mass. Low BMD in AN is a consequence of nutritional and hormonal alterations, including hypogonadism and low estradiol levels. Effective therapeutic strategies to improve BMD in adolescents with AN have not been identified. Specifically, high estrogen doses given as an oral contraceptive do not improve BMD. The impact of physiologic estrogen doses that mimic puberty on BMD has not been examined. We enrolled 110 girls with AN and 40 normal-weight controls 12 to 18 years of age of similar maturity. Subjects were studied for 18 months. Mature girls with AN (bone age [BA] ≥15 years, n = 96) were randomized to 100 µg of 17β-estradiol (with cyclic progesterone) or placebo transdermally for 18 months. Immature girls with AN (BA < 15 years, n = 14) were randomized to incremental low-dose oral ethinyl-estradiol (3.75 µg daily from 0 to 6 months, 7.5 µg from 6 to 12 months, 11.25 µg from 12 to 18 months) to mimic pubertal estrogen increases or placebo for 18 months. All BMD measures assessed by dual-energy X-ray absorptiometry (DXA) were lower in girls with AN than in control girls. At baseline, girls with AN randomized to estrogen (AN E + ) did not differ from those randomized to placebo (AN E-) for age, maturity, height, BMI, amenorrhea duration, and BMD parameters. Spine and hip BMD Z-scores increased over time in the AN E+ compared with the AN E- group, even after controlling for baseline age and weight. It is concluded that physiologic estradiol replacement increases spine and hip BMD in girls with AN.

Bone biopsy findings and correlation with clinical, radiological, and biochemical parameters in children with fractures

In children the diagnosis of osteoporosis is based on fracture history and DXA-derived BMD. Bone biopsy is an invasive but accurate method for studying bone characteristics. In this study we evaluated bone biopsy findings and their correlation with noninvasive measures of bone health. Transiliac bone biopsy was performed on 24 consecutive children (17 boys, median age 12 years, range 6 to 16 years) evaluated for suspected primary osteoporosis. Biopsy findings were compared with normative data and correlated with clinical, radiological, biochemical, and densitometric findings. The patients had sustained altogether 64 nonvertebral fractures (median 2.5) from low- or moderate-energy traumas, and 14 patients (58%) had vertebral fractures. The median lumbar spine BMD Z-score was -1.2 (range -3.1 to +1.0). Hypovitaminosis D was present in 58%. Histomorphometry showed low bone volume in 7 patients and normal bone volume in 17. Bone turnover was high in 7, low in 7, and normal in 10 patients. Histomorphometric findings correlated poorly with fracture history, serum bone turnover markers, and DXA findings. Vitamin D deficiency and low lumbar BMD were associated with high bone turnover in the biopsy. These findings underscore the difficulties in diagnosing pediatric osteoporosis. Bone histomorphometry gives additional information and may be useful when considering bisphosphonate treatment in children with suspected primary osteoporosis.

Assessment of bone remodelling in childhood-onset systemic lupus erythematosus

To identify predictors of bone remodelling in children and young adults with SLE. Ninety subjects with SLE aged 8-22 years underwent yearly measurements of height, bone age, bone turnover markers, serum Type I IFNs, SLEDAI and BMD. Predictors of bone turnover were examined using serum osteocalcin as a marker of bone formation and both serum tartrate-resistant acid phosphatase (TRAP) and urine N-telopeptide (NTx) as markers of bone resorption. Subjects demonstrated short stature, high BMI and bone age delay. A spine BMD Z-score of less than -2.0 was seen in 16.1% of subject visits. Serum osteocalcin was negatively correlated with glucocorticoid dose (Spearman rank correlation coefficient R = -0.34, P < 0.0001) but was not associated with SLEDAI after adjustment for confounders. Serum TRAP was negatively associated with SLEDAI, even after controlling for confounders (P = 0.04). Similar results were obtained for urine NTx. There was a negative association between TRAP and serum IFN-β (P = 0.03). In this population of children and young adults with moderate lupus disease activity, glucocorticoid dose was a negative predictor of bone formation, whereas lupus disease activity was not. Interestingly, lupus disease activity was a negative predictor of bone resorption, suggesting that lupus disease activity is not the primary factor contributing to the bone deficits of childhood-onset SLE. The potential protective role of IFN-β and the effects of SLE treatment on bone loss require further study.

Camurati-engelmann disease: Unique variant featuring a novel mutation in TGFβ1 encoding transforming growth factor beta 1 and a missense change in TNFSF11 encoding RANK ligand

We report a 32-year-old man and his 59-year-old mother with a unique and extensive variant of Camurati-Engelmann disease (CED) featuring histopathological changes of osteomalacia and alterations within TGFβ1 and TNFSF11 encoding TGFβ1 and RANKL, respectively. He suffered leg pain and weakness since childhood and reportedly grew until his late 20s, reaching 7 feet in height. He had deafness, perforated nasal septum, torus palatinus, disproportionately long limbs with knock-knees, low muscle mass, and pseudoclubbing. Radiographs revealed generalized skeletal abnormalities, including wide bones and cortical and trabecular bone thickening in keeping with CED, except that long bone ends were also affected. Lumbar spine and hip BMD Z-scores were + 7.7 and + 4.4, respectively. Biochemical markers of bone turnover were elevated. Hypocalciuria accompanied low serum 25-hydroxyvitamin D (25[OH]D) levels. Pituitary hypogonadism and low serum insulin-like growth factor (IGF)-1 were present. Karyotype was normal. Despite vitamin D repletion, iliac crest histology revealed severe osteomalacia. Exon 1 of TNFRSF11A (RANK), exons 2, 3, and 4 of LRP5, and all coding exons and adjacent mRNA splice junctions of TNFRSF11B (OPG), SQSTM1 (sequestosome 1), and TNSALP (tissue nonspecific alkaline phosphatase) were intact. His asymptomatic and less dysmorphic 5′11″ mother, also with low serum 25(OH)D, had milder clinical, radiological, biochemical, and histopathological findings. Both individuals were heterozygous for a novel 12-bp duplication (c.27_38dup, p.L10_L13dup) in exon 1 of TGFβ1, predicting four additional leucine residues in the latency-associated-peptide segment of TGFβ1, consistent with CED. The son was also homozygous for a single base transversion in TNFSF11, predicting a nonconservative amino acid change (c.107C > G, p.Pro36Arg) in the intracellular domain of RANKL that was heterozygous in his nonconsanguineous parents. This TNFSF11 variant was not found in the SNP Database, nor in published TNFSF11 association studies, but it occurred in four of the 134 TNFSF11 alleles (3.0%) we tested randomly among individuals without CED. Perhaps the unique phenotype of this CED family is conditioned by altered RANKL activity. © 2011 American Society for Bone and Mineral Research.

Insufficient Energy Intake, Menstrual Disturbances, And Reduced Bone Mass Among Adolescent Runners With Dietary Restraint

Previously, we found a negative association between elevated dietary restraint and bone mass in female adolescent endurance runners, however diet and energy expenditure were not assessed. PURPOSE: Evaluate energy intake and expenditure, menstrual function, bone mass, and hormones relevant to bone metabolism in a sample of 41 female adolescent runners (age 15.7 ± 0.2y) with normal (N= 28) and elevated (N= 13) levels of cognitive dietary restraint. METHODS: For 7d, runners recorded dietary intake, underwent daily 24hr recalls, and wore a combined accelerometer and heart rate monitor to determine energy expenditure. On the 8th day, runners provided a morning saliva sample, had a fasted blood draw, underwent a dual-energy x-ray absorptiometry scan to measure bone mass and body composition, had height and weight measured, and completed a questionnaire regarding training volume, menstrual function, sports participation history and the Three Factor Eating Inventory to determine cognitive dietary restraint. RESULTS: Girls with elevated restraint were heavier (57.6 ± 2.1kg vs. 52.5 ± 1.4kg, P< 0.05) and trended toward having a higher body fat (%) (24.8 ± 1.7 vs. 21.2 ± 1.2, P= 0.09). However, those with restraint also had a lower relative intake (kcal/kg/d) (37.9 ± 2.6 vs. 44.0 ± 1.8, P= 0.06) and higher total (2218.0 ± 61.2 vs. 2066.5 ± 40.8, P< 0.05) and activity (777.8 ± 46.3 vs. 679.8 ± 30.9, P= 0.09) energy expenditures (kcal/d). Energy availability (kcal/kgFFM/d) was lower, but not significant, in those with elevated restraint (32.5 ± 3.1 vs. 38.9 ± 2.1, P= 0.11). Salivary cortisol (nmol/L) (18.8 ± 2.2 vs. 13.5 ± 1.4, P< 0.05) and leptin (ng/ml) (7.9 ± 0.9 vs. 5.0 ± 0.6, P< 0.05) levels were higher in those with restraint, while estradiol, IGF-1, T3 were not significantly different. Further, runners with elevated restraint exhibited a lower adjusted (BMI, fat free mass) lumbar spine BMD Z-score (-0.84 ± 0.17 vs. -0.18 ± 0.11, P< 0.005) and a higher prevalence of amenorrhea (38.5% vs. 13.0%, P= 0.08). CONCLUSIONS: The lower bone mass and menstrual disturbances currently and previously observed in runners with self-reported elevated cognitive dietary restraint may be due to the development of a chronic energy deficit. Further, evaluating cognitive restraint may serve as a means of assessing runners at risk of developing low bone mass.

Bone Health in Children and Adolescents After Renal Transplantation

The basis for lifelong bone health is established in childhood and adolescence. Whereas pediatric renal transplant (RTx) patients are at risk for impaired bone mass gain and fractures, scarce data on this subject are available. We performed a cross-sectional and longitudinal study of bone health in a national cohort of 106 pediatric RTx patients (median age, 12.6 yr; median follow-up, 5.1 yr after RTx). The patients underwent clinical evaluation, DXA for BMD, and spinal imaging for vertebral fractures. In longitudinal analysis, the median lumbar spine BMD Z-score was lowest (median, -1.0) at 1 yr postoperatively but increased to a peak value of -0.2 at 5 yr. In boys, the lumbar spine BMD Z-score increased also during puberty but decreased in girls. In cross-sectional analysis, the lumbar spine, hip, and whole body BMD Z-scores were < -2 SD in 4%, 6%, and 6% of the patients, respectively. Sixteen percent had sustained peripheral fractures, and 8% had vertebral fractures. Female sex and age >15 yr (OR, 56.26; 95% CI, 5.17-611.82; p = 0.0007) as well as high plasma PTH levels (OR, 4.03; 95% CI, 1.37-11.85; p = 0.009) were significant predictors for low BMD. Three-year cumulative glucocorticoid dose, outside the immediate post-RTx years, was not associated with BMD parameters. The observed BMD results were satisfactory. However, the high (8%) prevalence of vertebral fractures warrants careful evaluation of bone health in these patients.

Higher Milk Requirements for Bone Mineral Accrual in Adolescent Girls Bearing Specific Caucasian Genotypes in the VDR Promoter

Low milk intakes hamper bone mineral acquisition during adolescence, especially in European girls. We hypothesized that ethnic-specific polymorphisms of the vitamin D receptor gene promoter (VDRp) influence this milk/bone association. We evaluated lumbar spine BMC and BMD, milk/dairy products and calcium intakes, markers of P-Ca metabolism, and VDRp polymorphisms at the Cdx-2 binding (rs11568820) and -1012 (rs4516035) loci in 117 healthy European peri- and postmenarcheal girls (14.9 +/- 1.6 yr) during a 4-yr follow-up. Calcium intakes from milk, nonmilk dairy products, and nondairy products averaged 199, 243, and 443 mg/d at the initiation of the study. Results show no association between milk intakes and bone mass accrual in girls bearing an A/A genotype at the -1012 VDRp locus (30% of the cohort). In contrast, A/G or G/G girls had lower spine BMC (-13%, p = 0.031), BMD (-10%, p = 0.004), and BMD Z-score (-0.84 SD, p = 0.0003) when their milk intakes were <260 ml/d compared with genotype-matched girls with higher milk intakes and with girls with an A/A genotype. The negative impact of low milk intake persisted up to 19.0 +/- 1.7 yr. These findings suggest that European girls bearing a -1012 A/G or G/G VDRp genotype should have higher milk/calcium intakes for optimal vertebral mass accrual during adolescence than girls bearing an A/A genotype, a genotype found in 30% of European and 98% of Asian and Sub-Saharan African populations. VDRp genotype diversity may contribute to the ethnic differences observed in milk requirements for bone health during adolescence.