Familial resemblance and diversity in bone mass and strength in the population are established during the first year of postnatal life

Familial resemblance and diversity in bone structure and strength in adulthood are determined in part during growth. Whether these characteristics are established during gestation or shortly after birth is not known. Total‐body, lumbar spine, and femoral neck size and mass and indices of tibial bending strength and distal radial compressive strength were measured using bone densitometry and quantitative computed tomography in 236 girls at 18.5 years of age. Among them, 219, 141, and 105 girls had crown‐heel length (CHL) and weight recorded at birth and at 6 and 12 months of age, and then height and weight were recorded at 3, 5, 10, 13, and 15 years of age in 181, 176, 127, 111, and 228 girls, respectively. Of these girls, 101 and 93 girls also had bone structure assessed at 11 and 13 years of age, respectively. Similar bone measurements were made once in 78 mother‐father pairs. CHL and weight at birth did not correlate or did so weakly with bone traits in girls at 18 years of age. By contrast, CHL at 6 months correlated with the height, bone traits, and strength at puberty and at 18 years of age (r = 0.24–0.56, p < .001) in girls and with their parents' height and bone traits (r = 0.15–0.37, p < .05). When the girls' CHL at 6 months was stratified into quartiles, the absolute and relative differences in bone traits observed at puberty (～11.5 years) were maintained as these traits tracked during the ensuing 7 years. Similarly, weight at 6 months correlated with the girls' bone traits at puberty and 18 years of age (r = 0.22–0.55, p < .05). During puberty and at 18 years of age, the girls' bone traits correlated with the corresponding traits in their parents (r = 0.32–0.43, p < .01). It is concluded that familial resemblance in bone structural strength and the position of an individual's bone traits relative to others in adulthood are likely to be established during the first year of life. Thus susceptibility to bone fragility late in life has its antecedents established early in life. © 2010 American Society for Bone and Mineral Research     

Physical Activity Benefits the Skeleton of Children Genetically Predisposed to Lower Bone Density in Adulthood

Both genetics and physical activity (PA) contribute to bone mineral density (BMD), but it is unknown if the benefits of physical activity on childhood bone accretion depend on genetic risk. We, therefore, aimed to determine if PA influenced the effect of bone fragility genetic variants on BMD in childhood. Our sample comprised US children of European ancestry enrolled in the Bone Mineral Density in Childhood Study (N = 918, aged 5 to 19 years, and 52.4% female). We used a questionnaire to estimate hours per day spent in total, high‐, and low‐impact PA. We calculated a BMD genetic score (% BMD lowering alleles) using adult genome‐wide association study (GWAS)‐implicated BMD variants. We used dual‐energy X‐ray absorptiometry to estimate femoral neck, total hip, and spine areal‐BMD and total body less head (TBLH) bone mineral content (BMC) Z‐scores. The BMD genetic score was negatively associated with each bone Z‐score (eg, TBLH‐BMC: estimate = –0.03, p = 1.3 × 10^?6). Total PA was positively associated with bone Z‐scores; these associations were driven by time spent in high‐impact PA (eg, TBLH‐BMC: estimate = 0.05, p = 4.0 × 10^?10) and were observed even for children with lower than average bone Z‐scores. We found no evidence of PA‐adult genetic score interactions (p interaction > 0.05) at any skeletal site, and there was no evidence of PA‐genetic score–Tanner stage interactions at any skeletal site (p interaction > 0.05). However, exploratory analyses at the individual variant level revealed that PA statistically interacted with rs2887571 (ERC1/WNT5B) to influence TBLH‐BMC in males (p interaction = 7.1 × 10^?5), where PA was associated with higher TBLH‐BMC Z‐score among the BMD‐lowering allele carriers (rs2887571 AA homozygotes: estimate = 0.08 [95% CI 0.06, 0.11], p = 2.7 × 10^?9). In conclusion, the beneficial effect of PA on bone, especially high‐impact PA, applies to the average child and those genetically predisposed to lower adult BMD (based on GWAS‐implicated BMD variants). Independent replication of our exploratory individual variant findings is warranted. © 2016 American Society for Bone and Mineral Research.     

Plasma phosphatidylcholine concentrations of polyunsaturated fatty acids are differentially associated with hip bone mineral density and hip fracture in older adults: the Framingham Osteoporosis Study

Polyunsaturated fatty acids (PUFAs) may influence bone health. The objective of this work was to examine associations between plasma phosphatidylcholine (PC) PUFA concentrations and hip measures: (1) femoral neck bone mineral density (FN‐BMD) (n = 765); (2) 4‐year change in FN‐BMD (n = 556); and (3) hip fracture risk (n = 765) over 17‐year follow‐up among older adults in the Framingham Osteoporosis Study. BMD measures were regressed on quintile of plasma PC PUFAs (docosahexaenoic acid [DHA], linoleic acid [LA], and arachidonic acid [AA]), adjusted for covariates. Hazard ratios (HR) and 95% confidence interval (CI) for hip fracture were estimated by quintile of plasma PC PUFAs, adjusted for covariates. Higher concentrations of PC DHA were associated with loss of FN‐BMD over 4 years in women (p‐trend = 0.04), but was protective in men in the uppermost quintile compared to men grouped in the lower four quintiles, in post hoc analysis (p = 0.01). PC LA concentrations were inversely associated with baseline FN‐BMD in women (p‐trend = 0.02), and increased hip fracture risk in women and men (p‐trend = 0.05), but body mass index (BMI) adjustment attenuated these associations (p‐trend = 0.12 and p‐trend = 0.14, respectively). A trend toward a protective association was observed between PC AA and baseline FN‐BMD in men (p‐trend = 0.06). Women and men with the highest PC AA concentrations had 51% lower hip fracture risk than those with the lowest (HR = 0.49, 95% CI = 0.24–1.00). Opposing effects of PC DHA on FN‐BMD loss observed in women and men need further clarification. Bone loss associated with PC LA may be confounded by BMI. High PC AA concentrations may be associated with reduced hip fracture risk. © 2012 American Society for Bone and Mineral Research.     

Influence of a 3‐year exercise intervention program on fracture risk,bone mass,and bone size in prepubertal children

Published prospective pediatric exercise intervention studies are short term and use skeletal traits as surrogate endpoints for fractures, whereas other reports infer exercise to be associated with more trauma and fractures. This prospective, controlled exercise intervention study therefore followed both skeletal traits and fracture risk for 36 months. Fractures were registered in children aged 7 to 9 years; there were 446 boys and 362 girls in the intervention group (2129 person‐years) and 807 boys and 780 girls in the control group (4430 person‐years). The intervention included school physical education of 40 minutes per day for 3 years. The control children achieved the Swedish standard of 60 minutes per week. In a subsample of 76 boys and 48 girls in the intervention group and 55 boys and 44 girls in the control group, bone mineral content (BMC, g) and bone width (cm) were followed in the lumbar spine and hip by dual‐energy X‐ray absorptiometry (DXA). The rate ratio (RR) for fractures was 1.08 (0.71, 1.62) [mean (95% confidence interval)]. In the DXA‐measured children, there were no group differences at baseline in age, anthropometrics, or bone traits. The mean annual gain in the intervention group in lumbar spine BMC was 0.9 SD higher in girls and 0.8 SD higher in boys (both p < .001) and in third lumbar vertebra width 0.4 SD higher in girls and 0.3 SD higher in boys (both p < .05) than in control children. It is concluded that a moderately intense 3‐year exercise program in 7‐ to 9‐year‐old children increases bone mass and possibly also bone size without increasing fracture risk. © 2011 American Society for Bone and Mineral Research     

Vertebral morphology in aromatase inhibitor–treated males with idiopathic short stature or constitutional delay of puberty

Aromatase inhibitors (AIs), blockers of estrogen biosynthesis, delay bone maturation and therefore are used increasingly to promote growth in children and adolescents with growth disorders. The effects of treatment on skeletal health are largely unknown. Since estrogen deficiency is associated with various detrimental skeletal effects, we evaluated in this cross‐sectional posttreatment study vertebral body morphology, dimensions and endplates, and intervertebral disks by the use of magnetic resonance imaging (MRI) in two cohorts of males previously treated with the AI letrozole or placebo. Males with idiopathic short stature received treatment with letrozole or placebo for 2 years during prepuberty or early puberty; males with constitutional delay of puberty received letrozole or placebo in combination with low‐dose testosterone for 1 year during early or midpuberty. In males with idiopathic short stature, mild vertebral body deformities were found in 5 of 11 (45%) letrozole‐treated subjects, whereas in the placebo group no deformities were detected (p = .01). In the cohort of males with constitutional delay of puberty, a high prevalence of endplate and intervertebral disk abnormalities was observed in both the letrozole‐ and the placebo‐treated groups. We conclude that AI therapy during prepuberty or early puberty may predispose to vertebral deformities, which probably reflect impaired vertebral body growth rather than impaired bone quality and compression fractures. If AIs are used in growth indications, follow‐up of vertebral morphology is indicated. © 2010 American Society for Bone and Mineral Research     

Pubertal maturation characteristics and the rate of bone mass development longitudinally toward menarche.

To assess risks for osteoporosis and to compare bone mass in different groups of healthy children or children with diseases, it is important to have knowledge of their sexual maturation status during puberty. The aim of our study was to evaluate bone mass formation longitudinally in relation to pubertal maturation characteristics in healthy white girls. We investigated the bone mineral content (BMC) and the bone mineral density (BMD) at different skeletal sites in 151 girls with increasing pubertal stages in relation with their chronological age and with an early or late onset of puberty or menarche and with a slow or fast maturation. Bone mass was measured at the onset of puberty, during puberty, and at menarche. We conclude the following: (1) from midpuberty to menarche, the increase in bone mass formation is highest at all skeletal sites in white girls; (2) early mature girls at the onset of puberty have slightly but definitely lower bone masses at all skeletal sites and at all pubertal stages than late mature girls, whereas the average bone mass formation from the onset of puberty to menarche is similar in both groups; (3) girls with a slow rate of pubertal maturation have lower bone mass values 2 years after the onset of puberty, but at menarche bone mass is similar compared with fast maturers; and (4) it cannot be confirmed that there is an effect of menarcheal age on bone mass values at menarche.     

Effects of repetitive loading on the growth‐induced changes in bone mass and cortical bone geometry: A 12‐month study in pre/peri‐ and postmenarcheal tennis players

Pre‐ and early puberty may be the most opportune time to strengthen the female skeleton, but there are few longitudinal data to support this claim. Competitive female premenarcheal (pre/peri, n = 13) and postmenarcheal (post, n = 32) tennis players aged 10 to 17 years were followed over 12 months. The osteogenic response to loading was studied by comparing the playing and nonplaying humeri for dual‐energy X‐ray absorptiometry (DXA) bone mineral content (BMC) and magnetic resonance imaging (MRI) total bone area (ToA), medullary area (MedA), cortical area (CoA), and muscle area (MCSA) at the humerus. Over 12 months, growth‐induced gains (nonplaying arm) in BMC, ToA, and CoA were greater in pre/peri (10% to 19%, p < .001) than in post (3% to 5%, p < .05 to .001) players. At baseline, BMC, ToA, CoA, and MCSA were 8% to 18% greater in the playing versus nonplaying arms in pre/peri and post players (all p < .001); MedA was smaller in the playing versus nonplaying arms in post only players (p < .05). When comparing the annual gains in the playing arm relative to changes in the nonplaying arm, the increases in ToA and CoA were greater in pre/peri than post players (all p < .05). The smaller the side‐to‐side differences in BMC and CoA at baseline, the larger the exercise benefits at 12 months (r = ?0.39 to ?0.48, p < .01). The exercise‐induced change in MCSA was predictive of the exercise benefits in BMC in pre/peri players only (p < .05). In conclusion, both pre/peri‐ and postmenarcheal tennis players showed significant exercise‐induced skeletal benefits within a year, with greater benefits in cortical bone geometry in pre/perimenarcheal girls. © 2011 American Society for Bone and Mineral Research.     

Racial/Ethnic and Socioeconomic Differences in Bone Loss Among Men

As men age, they lose bone and are susceptible to fracture. Despite having lower fracture rates than women, men have worse fractures than women do. Racial/ethnic and socioeconomic status (SES) disparities in fracture rates exist, yet data on rates of bone loss by race/ethnicity and SES among men are limited. We examined annualized percentage change in bone mineral density (%ΔBMD) at the hip (N = 681), spine (N = 663), and forearm (N = 636) during 7 years of follow‐up among men aged 30–79 years at baseline. Multivariable models tested whether race/ethnicity, income, or genetic ancestry predicted annualized %ΔBMD after controlling for an extensive set of covariates. Annualized %ΔBMD ranged from ?0.65(0.04)% (femoral neck) to +0.26(0.03)% (1/3 distal radius), and changes were consistent across age groups with the exception of the ultradistal radius, where annualized declines increased with age. Neither self‐identified race/ethnicity nor genetic ancestry were associated with annualized %ΔBMD. In contrast, income was strongly associated (dose‐response) with annualized %ΔBMD at total hip (independent of confounders, self‐identified race/ethnicity, and genetic ancestry). Fully adjusted least‐square mean change in annualized %ΔBMD at the total hip were ?0.24(0.12)% and ?0.16(0.06)% steeper among men with low and moderate incomes, respectively, than among men with higher incomes (overall p = 0.0293). Results show a linear decline in bone that begins relatively early in life among men, that rates of bone loss do not vary with race/ethnicity (self‐identified or “objectively” measured), and that income plays an important role in relation to bone loss at the hip. These data suggest that fracture risk in men may be driven in part by income‐related differences in bone loss, but also, that the known higher fracture risk among white men is not the result of racial/ethnic differences in bone loss, but rather, early life exposures that lead to attainment of higher peak bone mass among minorities. © 2014 American Society for Bone and Mineral Research.     

Insulin Resistance and the IGF‐I‐Cortical Bone Relationship in Children Ages 9 to 13 Years

IGF‐I is a pivotal hormone in pediatric musculoskeletal development. Although recent data suggest that the role of IGF‐I in total body lean mass and total body bone mass accrual may be compromised in children with insulin resistance, cortical bone geometric outcomes have not been studied in this context. Therefore, we explored the influence of insulin resistance on the relationship between IGF‐I and cortical bone in children. A secondary aim was to examine the influence of insulin resistance on the lean mass‐dependent relationship between IGF‐I and cortical bone. Children were otherwise healthy, early adolescent black and white boys and girls (ages 9 to 13 years) and were classified as having high (n = 147) or normal (n = 168) insulin resistance based on the homeostasis model assessment of insulin resistance (HOMA‐IR). Cortical bone at the tibia diaphysis (66% site) and total body fat‐free soft tissue mass (FFST) were measured by peripheral quantitative computed tomography (pQCT) and dual‐energy X‐ray absorptiometry (DXA), respectively. IGF‐I, insulin, and glucose were measured in fasting sera and HOMA‐IR was calculated. Children with high HOMA‐IR had greater unadjusted IGF‐I (p < 0.001). HOMA‐IR was a negative predictor of cortical bone mineral content, cortical bone area (Ct.Ar), and polar strength strain index (pSSI; all p ≤ 0.01) after adjusting for race, sex, age, maturation, fat mass, and FFST. IGF‐I was a positive predictor of most musculoskeletal endpoints (all p < 0.05) after adjusting for race, sex, age, and maturation. However, these relationships were moderated by HOMA‐IR (p_Interaction < 0.05). FFST positively correlated with most cortical bone outcomes (all p < 0.05). Path analyses demonstrated a positive relationship between IGF‐I and Ct.Ar via FFST in the total cohort (β_{Indirect Effect} = 0.321, p < 0.001). However, this relationship was moderated in the children with high (β_{Indirect Effect} = 0.200, p < 0.001) versus normal (β_{Indirect Effect} = 0.408, p < 0.001) HOMA‐IR. These data implicate insulin resistance as a potential suppressor of IGF‐I‐dependent cortical bone development, though prospective studies are needed. © 2017 American Society for Bone and Mineral Research.     

The Relationship Between Greater Prepubertal Adiposity,Subsequent Age of Maturation,and Bone Strength During Adolescence

This longitudinal study investigated whether greater prepubertal adiposity was associated with subsequent timing of maturation and bone strength during adolescence in 135 girls and 123 boys participating in the Iowa Bone Development Study. Greater adiposity was defined using body mass index (BMI) data at age 8 years to classify participants as overweight (OW, ≥85th percentile for age and sex) or healthy weight (HW). Maturation was defined as the estimated age of peak height velocity (PHV) based on a series of cross‐sectional estimates. Measurements were taken at ages 11, 13, 15, and 17 years for estimates of body composition by dual‐energy X‐ray absorptiometry (DXA), bone compression (bone strength index), and torsion strength (polar strength‐strain index) at the radius and tibia by pQCT, and femoral neck bending strength (section modulus) by hip structural analysis. Bone strength in OW versus HW were evaluated by fitting sex‐specific linear mixed models that included centered age (visit age – grand mean age of cohort) as the time variable and adjusted for change in fat mass, and limb length in model 1. Analyses were repeated using biological age (visit age – age PHV) as the time variable for model 1 with additional adjustment for lean mass in model 2. BMI was negatively associated with age of maturation (p < 0.05). OW versus HW girls had significantly greater bone strength (p < 0.001) in model 1, whereas OW versus HW boys had significantly greater bone strength (p < 0.001) at the tibia and femoral neck but not radius (p > 0.05). Analyses were repeated using biological age, which yielded reduced parameter estimates for girls but similar results for boys (model 1.) Differences were no longer present after adjustment for lean mass (model 2) in girls (p > 0.05) whereas differences at the tibia were sustained in boys (p < 0.05). These findings demonstrate sex‐ and site‐specific differences in the associations between adiposity, maturation, and bone strength. © 2016 American Society for Bone and Mineral Research.     

Bone Strength and Structural Deficits in Children and Adolescents With a Distal Forearm Fracture Resulting From Mild Trauma

Although distal forearm fractures (DFFs) are common during childhood and adolescence, it is unclear whether they reflect underlying skeletal deficits or are simply a consequence of the usual physical activities, and associated trauma, during growth. Therefore, we examined whether a recent DFF, resulting from mild or moderate trauma, is related to deficits in bone strength and cortical and trabecular bone macro‐ and microstructure compared with nonfracture controls. High‐resolution peripheral quantitative computed tomography was used to assess micro‐finite element‐derived bone strength (ie, failure load) and to measure cortical and trabecular bone parameters at the distal radius and tibia in 115 boys and girls with a recent (<1 year) DFF and 108 nonfracture controls aged 8 to 15 years. Trauma levels (mild versus moderate) were assigned based on a validated classification scheme. Compared with sex‐matched controls, boys and girls with a mild‐trauma DFF (eg, fall from standing height) showed significant deficits at the distal radius in failure load (–13% and –11%, respectively; p < 0.05) and had higher (“worse”) fall load‐to‐strength ratios (both +10%; p < 0.05 for boys and p = 0.06 for girls). In addition, boys and girls with a mild‐trauma DFF had significant reductions in cortical area (–26% and –23%, respectively; p < 0.01) and cortical thickness (–14% and –13%, respectively; p < 0.01) compared with controls. The skeletal deficits in the mild‐trauma DFF patients were generalized, as similar changes were present at the distal tibia. By contrast, both boys and girls with a moderate‐trauma DFF (eg, fall from a bicycle) had virtually identical values for all of the measured bone parameters compared with controls. In conclusion, DFFs during growth have two distinct etiologies: those owing to underlying skeletal deficits leading to fractures with mild trauma versus those owing to more significant trauma in the setting of normal bone strength. © 2014 American Society for Bone and Mineral Research.     

Placental Size Is Associated Differentially With Postnatal Bone Size and Density

We investigated relationships between placental size and offspring adolescent bone indices using a population‐based, mother–offspring cohort. The Avon Longitudinal Study of Parents and Children (ALSPAC) recruited pregnant women from the southwest of England between 1991 and 1993. There were 12,942 singleton babies born at term who survived at least the first 12 months. From these, 8933 placentas were preserved in formaldehyde, with maternal permission for their use in research studies. At the approximate age of 15.5 years, the children underwent a dual‐energy X‐ray absorptiometry (DXA) scan (measurements taken of the whole body minus head bone area [BA], bone mineral content [BMC], and areal bone mineral density [aBMD]). A peripheral quantitative computed tomography (pQCT) scan (Stratec XCT2000L; Stratec, Pforzheim, Germany) at the 50% tibial site was performed at this visit and at approximately age 17.7 years. In 2010 a sample of 1680 placentas were measured and photographed. To enable comparison of effect size across different variables, predictor and outcome variables were standardized to Z‐scores and therefore results may be interpreted as partial correlation coefficients. Complete placental, DXA, and pQCT data were available for 518 children at age 15.5 years. After adjustment for gender, gestational age at birth, and age at time of pQCT, the placental area was positively associated with endosteal circumference (β [95% CI]: 0.21 [0.13, 0.30], p < 0.001), periosteal circumference (β [95% CI]: 0.19 [0.10, 0.27], p < 0.001), and cortical area (β [95% CI]: 0.10 [0.01, 0.18], p = 0.03), and was negatively associated with cortical density (β [95% CI]: –0.11 [–0.20, –0.03], p = 0.01) at age 15.5 years. Similar relationships were observed for placental volume, and after adjustment for additional maternal and offspring covariates. These results suggest that previously observed associations between placental size and offspring bone development persist into older childhood, even during puberty, and that placental size is differentially related to bone size and volumetric density. © 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).     

Rapid growth produces transient cortical weakness: A risk factor for metaphyseal fractures during puberty

Fractures of the distal radius in children have a similar incidence to that found in postmenopausal women but occur more commonly in boys than in girls. Fractures of the distal tibia are uncommon in children and show no sex specificity. About 90% of lengthening of the radius but only 30% of lengthening of the tibia during puberty occur at the distal growth plate. We speculated that more rapid modeling at the distal radial metaphysis results in a greater dissociation between growth and mineral accrual than observed at the distal tibia. We measured the macro‐ and microarchitecture of the distal radial and tibial metaphysis using high‐resolution peripheral quantitative computed tomography in a cross‐sectional study of 69 healthy boys and 60 healthy girls aged from 5 to 18 years. Bone diameters were larger but total volumetric bone mineral density (vBMD) was lower at the distal radius (not at the distal tibia) by 20% in boys and by 15% in girls at Tanner stage III than in children of the same sex at Tanner stage I (both p < .05). In boys at Tanner stage III, total vBMD was lower because the larger radial total cross‐sectional area (CSA) had a thinner cortex with lower vBMD than in boys at Tanner stage I. In girls at Tanner stage III, the larger total radial CSA was not associated with a difference in cortical thickness or cortical vBMD relative to girls in Tanner stage I. Cortical thickness and density at both sites in both sexes after Tanner stage III were greater than in younger children. Trabecular bone volume fraction (BV/TV) was higher in boys than in girls at both sites and more so after puberty because trabeculae were thicker in more mature boys but not in girls. There was no sex‐ or age‐related differences in trabecular number at either site. We infer that longitudinal growth outpaces mineral accrual in both sexes at the distal radius, where bone grows rapidly. The dissociation produces transitory low cortical thickness and vBMD in boys but not in girls. These structural features in part may account for the site and sex specificity of metaphyseal fractures during growth. © 2010 American Society for Bone and Mineral Research     

Skeletal muscle fat content is inversely associated with bone strength in young girls

Childhood obesity is an established risk factor for metabolic disease. The influence of obesity on bone development, however, remains controversial and may depend on the pattern of regional fat deposition. Therefore, we examined the associations of regional fat compartments of the calf and thigh with weight‐bearing bone parameters in girls. Data from 444 girls aged 9 to 12 years from the Jump‐In: Building Better Bones study were analyzed. Peripheral quantitative computed tomography (pQCT) was used to assess bone parameters at metaphyseal and diaphyseal sites of the femur and tibia along with subcutaneous adipose tissue (SAT, mm²) and muscle density (mg/cm³), an index of skeletal muscle fat content. As expected, SAT was positively correlated with total‐body fat mass (r = 0.87–0.89, p < .001), and muscle density was inversely correlated with total‐body fat mass (r = ?0.24 to ?0.28, p < .001). Multiple linear regression analyses with SAT, muscle density, muscle cross‐sectional area, bone length, maturity, and ethnicity as independent variables showed significant associations between muscle density and indices of bone strength at metaphyseal (β = 0.13–0.19, p < .001) and diaphyseal (β = 0.06–0.09, p < .01) regions of the femur and tibia. Associations between SAT and indices of bone strength were nonsignificant at all skeletal sites (β = 0.03–0.05, p > .05), except the distal tibia (β = 0.09, p = .03). In conclusion, skeletal muscle fat content of the calf and thigh is inversely associated with weight‐bearing bone strength in young girls. © 2011 American Society for Bone and Mineral Research     

Outcome of Long‐Term Bisphosphonate Therapy in McCune‐Albright Syndrome and Polyostotic Fibrous Dysplasia

McCune‐Albright syndrome (MAS) is a rare bone disorder characterized by fibrous dysplasia (FD), endocrinopathies, and café‐au‐lait patches. FD patients have been shown to respond favorably to treatment with bisphosphonates, but data are scarce in the more severe polyostotic form (PFD), including MAS, and factors determining treatment outcome are not known, particularly in the long‐term. We evaluated the biochemical (bone turnover markers [BTMs]) and clinical (pain reduction) outcome of bisphosphonate therapy in 11 patients with MAS and 30 patients with PFD: median duration of treatment 6 years (range, 2 to 25 years). Prognostic factors for treatment outcome were identified in both groups. Patients with MAS were younger at diagnosis (p = 0.001), all had precocious puberty, and four (36%) had additional growth hormone (GH) excess associated with severe craniofacial FD. Extent of skeletal disease was more severe in MAS compared to PFD. MAS patients had higher serum alkaline phosphatase (ALP) concentrations (p = 0.005), higher skeletal burden scores (p < 0.001), and more fractures (p = 0.021). MAS patients had also higher levels of FGF‐23 (p = 0.008) and higher prevalence of hypophosphatemia (p = 0.013). Twenty‐four of 30 PFD patients (80%) demonstrated a complete clinical and biochemical response within a year of starting treatment (p = 0.015), compared to only four of 11 MAS patients (36%). There were no nonresponders. In the whole group, FGF‐23, total ALP, P1NP, and CTX positively correlated with skeletal burden scores (all p ≤ 0.001), which was the only significant risk factor for an incomplete response to bisphosphonate therapy (p < 0.01). Our data suggest a beneficial and safe outcome of long‐term bisphosphonate therapy in the majority of patients with PFD, although response to therapy was limited by the higher skeletal disease burden in MAS patients. In the PFD/MAS population studied, the only identified prognostic factor that influenced the outcome of bisphosphonate therapy was a high skeletal burden score. © 2016 American Society for Bone and Mineral Research.     

Fat mass accumulation compromises bone adaptation to load in finnish women: A cross‐sectional study spanning three generations

Body weight and lean mass correlate with bone mass, but the relationship between fat mass and bone remains elusive. The study population consisted of 396 girls and 138 premenopausal mothers and 114 postmenopausal grandmothers of these girls. Body composition and tibial length were assessed using dual‐energy X‐ray absorptiometry (DXA), and bone traits were determined at the tibia using peripheral quantitative computed tomography (pQCT) in the girls at the ages of 11.2 ± 0.8, 13.2 ± 0.9, and 18.3 ± 1.0 years and in the mothers (44.7 ± 4.1 years) and grandmothers (70.7 ± 6.3 years). The values of relative bone strength index (RBSI), an index reflecting the ratio of bone strength to the load applied on the tibia, were correlated among family members (all p < .05). The mean values of RBSI were similar among 11‐ and 18‐year‐old girls and premenopausal women but significantly lower in 13‐year‐old girls and postmenopausal women. However, in each age group, subjects in the highest BMI tertiles had the lowest RBSI values (all p < .01). RBSI was inversely associated with body weight (all p < .01), indicating a deficit in bone strength relative to the applied load from greater body weight. RBSI was inversely associated with fat mass (all p < .001) across age groups and generations but remained relatively constant with increasing lean mass in girls and premenopausal women (all p > .05), indicating that the bone‐strength deficit was attributable to increased fat mass, not lean mass. Moreover, the adverse effect of fat mass was age‐dependent, with every unit increase in fat mass associated with a greater decrease in RBSI in pre‐ and postmenopausal women than in girls (all p < .001). This is largely due to the different capacity of young and adult bones to increase diaphyseal width by periosteal apposition in response to increased load. In summary, increasing body weight with fat accumulation is accompanied by an age‐dependent relative bone‐strength deficit in women because the beneficial effects of increased fat mass on bone, if any, do not compensate for the mechanical burden that it imposes. © 2010 American Society for Bone and Mineral Research.     

The role of estrogen receptor α in growth plate cartilage for longitudinal bone growth

Estrogens enhance skeletal growth during early sexual maturation, whereas high estradiol levels during late puberty result in growth plate fusion in humans. Although the growth plates do not fuse directly after sexual maturation in rodents, a reduction in growth plate height is seen by treatment with a high dose of estradiol. It is unknown whether the effects of estrogens on skeletal growth are mediated directly via estrogen receptors (ERs) in growth plate cartilage and/or indirectly via other mechanisms such as the growth hormone/insulin‐like growth factor 1 (GH/IGF‐1) axis. To determine the role of ERα in growth plate cartilage for skeletal growth, we developed a mouse model with cartilage‐specific inactivation of ERα. Although mice with total ERα inactivation displayed affected longitudinal bone growth associated with alterations in the GH/IGF‐1 axis, the skeletal growth was normal during sexual maturation in mice with cartilage‐specific ERα inactivation. High‐dose estradiol treatment of adult mice reduced the growth plate height as a consequence of attenuated proliferation of growth plate chondrocytes in control mice but not in cartilage‐specific ERα^?/? mice. Adult cartilage‐specific ERα^?/? mice continued to grow after 4 months of age, whereas growth was limited in control mice, resulting in increased femur length in 1‐year‐old cartilage‐specific ERα^?/? mice compared with control mice. We conclude that during early sexual maturation, ERα in growth plate cartilage is not important for skeletal growth. In contrast, it is essential for high‐dose estradiol to reduce the growth plate height in adult mice and for reduction of longitudinal bone growth in elderly mice. © 2010 American Society for Bone and Mineral Research.     

A High Amount of Local Adipose Tissue Is Associated With High Cortical Porosity and Low Bone Material Strength in Older Women

Obesity is associated with increased risk of fractures, especially at skeletal sites with a large proportion of cortical bone, such as the humerus and ankle. Obesity increases fracture risk independently of BMD, indicating that increased adipose tissue could have negative effects on bone quality. Microindentation assesses bone material strength index (BMSi) in vivo in humans. The aim of this study was to investigate if different depots of adipose tissue were associated with BMSi and cortical bone microstructure in a population based group of 202 women, 78.2 ± 1.1 (mean ± SD) years old. Bone parameters and subcutaneous (s.c.) fat were measured at the tibia with an XtremeCT device. BMSi was assessed using the OsteoProbe device, and based on at least 11 valid reference point indentations at the mid‐tibia. Body composition was measured with dual X‐ray absorptiometry. BMSi was inversely correlated to body mass index (BMI) (r = –0.17, p = 0.01), whole body fat mass (r = –0.16,p = 0.02), and, in particular, to tibia s.c. fat (r = –0.33, p < 0.001). Tibia s.c. fat was also correlated to cortical porosity (Ct.Po; r = 0.19, p = 0.01) and cortical volumetric BMD (Ct.vBMD; r = –0.23, p = 0.001). Using linear regression analyses, tibia s.c. fat was found to be independent of covariates (age, height, log weight, bisphosphonates or glucocorticoid use, smoking, calcium intake, walking speed, and BMSi operator) and associated with BMSi (β = –0.34,p < 0.001), Ct.Po (β = 0.18, p = 0.01), and Ct.vBMD (β = –0.32, p < 0.001). BMSi was independent of covariates associated with cortical porosity (β = –0.14, p = 0.04) and cortical volumetric BMD (β = 0.21, p = 0.02) at the distal tibia, but these bone parameters could only explain 3.3% and 5.1% of the variation in BMSi, respectively. In conclusion, fat mass was independently and inversely associated with BMSi and Ct.vBMD, but positively associated with Ct.Po, indicating a possible adverse effect of adipose tissue on bone quality and bone microstructure. Local s.c. fat in tibia was most strongly associated with these bone traits, suggesting a local or paracrine, rather than systemic, negative effect of fat on bone. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).     

Impaired bone health and asymptomatic vertebral compressions in fracture-prone children: a case-control study

Frequent fractures in children may be a sign of impaired bone health, but it remains unestablished when and how fracture‐prone children should be assessed. This prospective study elucidated skeletal characteristics and predisposing factors in children with recurrent fractures. Findings were used to establish guidelines for screening. During a 12‐month period we recorded fracture history for all children (n = 1412) treated for an acute fracture at a large university hospital. All apparently healthy children over 4 years of age, who had sustained: (1) at least one vertebral fracture; (2) two long‐bone fractures before age 10 years; or (3) three long‐bone fractures before age 16 years, were recruited. They underwent dual‐energy X‐ray absorptiometry (DXA), laboratory tests, and spinal radiography. Information regarding family history and lifestyle factors were collected. Findings were compared with healthy controls. Sixty‐six fracture‐prone children (44 males, mean age 10.7 years; 5% of all children with fractures) were identified. Altogether, they had sustained 183 long‐bone fractures (median 3, range 0–7); 11 children had sustained vertebral fracture(s). Patients had significantly lower bone mineral density (BMD) at lumbar spine (p < 0.001), hip (p = 0.007), and whole body (p < 0.001) than the controls; only 5 children (8%) had a BMD Z‐score < ?2.0. Asymptomatic vertebral compressions were prevalent, especially in those under 10 years of age. Hypercalciuria (11%) and hyperphosphaturia (22%) were significantly more prevalent than in controls. Serum concentration of 25‐hydroxyvitamin D (S‐25OHD) was below 50 nmol/L in 55%; low levels were associated with low BMD and vertebral compressions. The fracture‐prone children had lower calcium intake, less physical activity, and more often had siblings with fractures than the controls. The findings suggest that a thorough pediatric evaluation, including DXA and spinal radiography, is often indicated already after a second significant low‐energy fracture in children, in order to detect potentially preventable adverse lifestyle factors and nutritional deficits and to identify those with compromised overall bone health. © 2012 American Society for Bone and Mineral Research.     

Current Physical Activity Is Independently Associated With Cortical Bone Size and Bone Strength in Elderly Swedish Women

Physical activity is believed to have the greatest effect on the skeleton if exerted early in life, but whether or not possible benefits of physical activity on bone microstructure or geometry remain at old age has not been investigated in women. The aim of this study was to investigate if physical activity during skeletal growth and young adulthood or at old age was associated with cortical geometry and trabecular microarchitecture in weight‐bearing and non–weight‐bearing bone, and areal bone mineral density (aBMD) in elderly women. In this population‐based cross‐sectional study 1013 women, 78.2 ± 1.6 (mean ± SD) years old, were included. Using high‐resolution 3D pQCT (XtremeCT), cortical cross‐sectional area (Ct.CSA), cortical thickness (Ct.Th), cortical periosteal perimeter (Ct.Pm), volumetric cortical bone density (D.Ct), trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular separation (Tb.Sp) were measured at the distal (14% level) and ultra‐distal tibia and radius, respectively. aBMD was assessed using DXA (Hologic Discovery A) of the spine and hip. A standardized questionnaire was used to collect information about previous exercise and the Physical Activity Scale for the Elderly (PASE) was used for current physical activity. A linear regression model (including levels of exercise during skeletal growth and young adulthood [10 to 30 years of age], PASE score, and covariates) revealed that level of current physical activity was independently associated with Ct.CSA (β = 0.18, p < 0.001) and Ct.Th (β = 0.15, p < 0.001) at the distal tibia, Tb.Th (β = 0.11, p < 0.001) and BV/TV (β = 0.10, p = 0.001) at the ultra‐distal tibia, and total hip aBMD (β = 0.10, p < 0.001). Current physical activity was independently associated with cortical bone size, in terms of thicker cortex but not larger periosteal circumference, and higher bone strength at the distal tibia on elderly women, indicating that physical activity at old age may decrease cortical bone loss in weight‐bearing bone in elderly women. © 2016 American Society for Bone and Mineral Research.