Jennifer Walsh

Obesity is a risk factor for fracture in children but is protective against fracture in adults: A paradox

With the rise in obesity worldwide, an important debate has developed as to whether excess fat has a detrimental or protective effect on skeletal health in children and adults. Obese children appear to be over represented in fracture groups and recent evidence suggests that fat may be detrimental to bone accrual in children, although this effect may be confined to adolescence during rapid skeletal growth. Fat induced alterations in hormonal factors and cytokines during growth may play a pivotal role in disturbing bone accrual. In contrast, the widely accepted opinion is that fat appears to be protective of bone in adults and minimises bone loss in postmenopausal women. Recent evidence suggests that in adults, site specific fat depots may exert differing effects on bone (with visceral fat acting as a pathogenic fat depot and subcutaneous fat exerting protective effects), and that the effects of fat mass on bone and fracture risk may vary by skeletal site; obesity protects against hip and vertebral fractures but is a risk factor for fractures of the humerus and ankle. The incidence of fracture during adolescence is rising and osteoporosis remains a considerable health burden in older adults. Understanding the effects of fat mass on bone during growth and early adulthood is vital in informing future health strategies and pharmacotherapies to optimise peak bone mass and prevent fracture.

Bisphosphonates for postmenopausal osteoporosis

Bisphosphonates are effective in reducing bone turnover, increasing BMD and reducing fracture risk in postmenopausal women with osteoporosis. The licensed bisphosphonates exhibit some differences in potency and speed of onset and offset of action. These differences mean that different agents may be more advantageous in different situations. Uncertainties still exist around the optimum duration of treatment and treatment holidays, how best to use bisphosphonates with anabolic treatments, and the benefits of treatment in patients who do not have a BMD T-score below -2.5.

Bone Density, Microstructure and Strength in Obese and Normal Weight Men and Women in Younger and Older Adulthood

Obesity is associated with greater areal BMD (aBMD) and is considered protective against hip and vertebral fracture. Despite this, there is a higher prevalence of lower leg and proximal humerus fracture in obesity. We aimed to determine if there are site‐specific differences in BMD, bone structure, or bone strength between obese and normal‐weight adults. We studied 100 individually‐matched pairs of normal (body mass index [BMI] 18.5 to 24.9 kg/m2) and obese (BMI >30 kg/m2) men and women, aged 25 to 40 years or 55 to 75 years. We assessed aBMD at the whole body (WB), hip (TH), and lumbar spine (LS) with dual‐energy X‐ray absorptiometry (DXA), LS trabecular volumetric BMD (Tb.vBMD) by quantitative computed tomography (QCT), and vBMD and microarchitecture and strength at the distal radius and tibia with high‐resolution peripheral QCT (HR‐pQCT) and micro–finite element analysis. Serum type 1 procollagen N‐terminal peptide (P1NP) and collagen type 1 C‐telopeptide (CTX) were measured by automated electrochemiluminescent immunoassay (ECLIA). Obese adults had greater WB, LS, and TH aBMD than normal adults. The effect of obesity on LS and WB aBMD was greater in older than younger adults (p < 0.01). Obese adults had greater vBMD than normal adults at the tibia (p < 0.001 both ages) and radius (p < 0.001 older group), thicker cortices, higher cortical BMD and tissue mineral density, lower cortical porosity, higher trabecular BMD, and higher trabecular number than normal adults. There was no difference in bone size between obese and normal adults. Obese adults had greater estimated failure load at the radius (p < 0.05) and tibia (p < 0.01). Differences in HR‐pQCT measurements between obese and normal adults were seen more consistently in the older than the younger group. Bone turnover markers were lower in obese than in normal adults. Greater BMD in obesity is not an artifact of DXA measurement. Obese adults have higher BMD, thicker and denser cortices, and higher trabecular number than normal adults. Greater differences between obese and normal adults in the older group suggest that obesity may protect against age‐related bone loss and may increase peak bone mass.

Lumbar spine peak bone mass and bone turnover in men and women: a longitudinal study

SummaryPeak bone mass is an important determinant of bone mass in later life, but the age of peak bone mass is still unclear. We found that bone size and density increase and bone turnover decreases until age 25. It may be possible to influence bone accrual into the third decade.IntroductionPeak bone mass is a major determinant of bone mass in later life. Bone growth and maturation is site-specific, and the age of peak bone mass is still unclear. It is important to know the age to which bone accrual continues so strategies to maximise bone mass can be targeted appropriately. This study aims to ascertain the age of lumbar spine peak bone mass.MethodsWe measured lumbar spine BMC, estimated volume and BMAD by DXA and biochemical markers of bone turnover in 116 healthy males and females ages 11 to 40, followed up at an interval of five to nine years.ResultsThe majority of peak bone mass was attained by the mid-twenties. Increases in BMC in adolescents and young adults were mostly due to increases in bone size. Bone turnover markers decreased through adolescence and the third decade and the decreasing rate of change in bone turnover corresponded with the decreasing rate of change in lumbar spine measurements.ConclusionsSkeletal maturation and bone mineral accrual at the lumbar spine continues into the third decade.

Feeding and bone.

Diurnal variation in bone turnover is responsive to feeding and fasting, and feeding results in an acute decrease in bone resorption. These responses may be governed by multiple intermediary systems, and investigation of these systems has led to new potential therapeutic agents for osteoporosis. Here we review the current understanding of the mediators of bone turnover response to feeding, including calcitropic hormones, cortisol, gut peptides and pancreatic peptides. We also discuss the results of clinical trials of analogues of ghrelin, amylin and GLP-2 in the treatment of low bone density, and the potential bone effects of GLP-1 mimetics that are used in the treatment of type 2 diabetes.

Effects of Depot medroxyprogesterone acetate on bone density and bone metabolism before and after peak bone mass: a case-control study.

INTRODUCTION Depot medroxyprogesterone acetate (DMPA; Depo-Provera, Tadworth, UK) contraception is used by more than 9 million women worldwide and has a high usage among teenagers in the United Kingdom and the United States. Previous studies have found that DMPA use is associated with a bone density deficit. OBJECTIVES This case-control matched study aims to eliminate potential confounding factors, identify whether the effect of DMPA on the skeleton is age specific, and determine the effects of DMPA on hormones and bone turnover. DESIGN/PARTICIPANTS We measured bone density, bone turnover, and hormones in individually matched case-control pairs of women: 50 pairs aged 18-25 yr and 50 pairs aged 35-45 yr. RESULTS DMPA use was associated with a 5% bone density deficit at the lumbar spine and hip in women who started DMPA use before age 20 yr but not after age 34 yr. Bone turnover was increased in DMPA users in both age groups. DMPA users had lower estradiol and higher IGF-I than controls, and younger DMPA users had higher dehydroepiandrosterone sulfate than controls. In a multiple regression model, estradiol and IGF-I were associated with bone turnover, but addition of DMPA to the model made the association with estradiol nonsignificant. CONCLUSIONS DMPA use is associated with a bone density deficit at the spine and hip when used before peak bone mass. DMPA acts on the skeleton mainly through estrogen deficiency.

Leptin May Play a Role in Bone Microstructural Alterations in Obese Children

CONTEXT Bone mass is low and fracture risk is higher in obese children. Hormonal changes in relation to skeletal microstructure and biomechanics have not been studied in obese children. OBJECTIVE The objective of the study was to ascertain the relationships of obesity-related changes in hormones with skeletal microstructure and biomechanics. DESIGN High resolution peripheral quantitative computed tomography (HR-pQCT) was used to compare three-dimensional cortical and trabecular microstructure and biomechanics at load-bearing and nonload bearing sites in obese and lean children. The relationship between leptin, adiponectin, testosterone, estrogen, osteocalcin and sclerostin and skeletal microstructure was also determined. SETTING The study was conducted at a tertiary pediatric endocrine unit in the United Kingdom. PARTICIPANTS Obese and lean children were matched by gender and pubertal stage. RESULTS Radial cortical porosity (mean difference -0.01 [95% CI: -0.02, -0.004], P = .003) and cortical pore diameter (mean difference -0.005 mm [95% CI: -0.009, -0.001], P = .011) were lower in obese children. Tibial trabecular thickness was lower (mean difference -0.009 mm [95% CI: -0.014, -0.004], P = .003), and trabecular number was higher (mean difference 0.23 mm(-1) [95% CI: 0.08, 0.38], P = .004) in obese children. At the radius, fat mass percentage negatively correlated with cortical porosity (r = -0.57, P < .001) and pore diameter (r = -0.38, P = .02) and negatively correlated with trabecular thickness (r = -0.62, P < .001) and trabecular von Mises stress (r = -0.39, P = .019) at the tibia. No difference was observed in the other biomechanical parameters of the radius and tibia. Leptin was higher in obese children (805.3 ± 440.6 pg/ml vs 98.1 ± 75.4 pg/ml, P < .001) and was inversely related to radial cortical porosity (r = 0.60, 95% CI: [-0.80, -0.30], P < .001), radial cortical pore diameter (r = 0.51, 95% CI [-0.75, -0.16], P = .002), tibial trabecular thickness (r = 0.55, 95% CI: [-0.78, -0.21], P = .001) and tibial trabecular von Mises stress (r = -0.39, 95% CI: -0.65, 0.04, P = .02). CONCLUSION Childhood obesity alters radial and tibial microstructure. Leptin may direct these changes. Despite this, the biomechanical properties of the radius and tibia do not adapt sufficiently in obese children to withstand the increased loading potential from a fall. This may explain the higher incidence of fracture in obese children.

Free 25-hydroxyvitamin D is low in obesity, but there are no adverse associations with bone health

BACKGROUND The mechanism and clinical significance of low circulating 25-hydroxyvitamin D [25(OH)D] in obese people are unknown. Low total 25(OH)D may be due to low vitamin D-binding proteins (DBPs) or faster metabolic clearance. However, obese people have a higher bone mineral density (BMD), which suggests that low 25(OH)D may not be associated with adverse consequences for bone. OBJECTIVE We sought to determine whether 1) vitamin D metabolism and 2) its association with bone health differ by body weight. DESIGN We conducted a cross-sectional observational study of 223 normal-weight, overweight, and obese men and women aged 25-75 y in South Yorkshire, United Kingdom, in the fall and spring. A subgroup of 106 subjects was also assessed in the winter. We used novel techniques, including an immunoassay for free 25(OH)D, a stable isotope for the 25(OH)D3 half-life, and high-resolution quantitative tomography, to make a detailed assessment of vitamin D physiology and bone health. RESULTS Serum total 25(OH)D was lower in obese and overweight subjects than in normal-weight subjects in the fall and spring (geometric means: 45.0 and 40.8 compared with 58.6 nmol/L, respectively; P < 0.001) but not in the winter. Serum 25(OH)D was inversely correlated with body mass index (BMI) in the fall and spring and in the winter. Free 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)2D] were lower in obese subjects. DBP, the DBP genotype, and the 25(OH)D3 half-life did not differ between BMI groups. Bone turnover was lower, and bone density was higher, in obese people. CONCLUSIONS Total and free 25(OH)D and 1,25(OH)2D are lower at higher BMI, which cannot be explained by lower DBP or the shorter half-life of 25(OH)D3 We speculate that low 25(OH)D in obesity is due to a greater pool of distribution. Lower 25(OH)D may not reflect at-risk skeletal health in obese people, and BMI should be considered when interpreting serum 25(OH)D as a marker of vitamin D status.

Very low birth weight survivors have reduced peak bone mass and reduced insulin sensitivity

Context  Increasing numbers of very low birth weight (VLBW) infants are surviving into adulthood because of improvements in neonatal intensive care. Adverse events in early life can have long‐term effects through reprogramming of metabolic systems.

Cortical Consolidation of the Radius and Tibia in Young Men and Women

CONTEXT Bone size, geometry, density, and microarchitecture are important determinants of bone strength. By understanding how these properties change during skeletal development, we can better understand bone fragility. OBJECTIVES The aim of the study was to compare the geometry, microarchitecture, and strength of the radius and tibia in men and women at the end of adolescence and in young adulthood and to relate these properties to biochemical bone turnover markers and bone regulatory hormones. DESIGN We conducted a cross-sectional study of 116 healthy men and women ages 16-18 (n = 56) and 30-32 (n = 60) yr. OUTCOME MEASURES We used high-resolution peripheral quantitative computed tomography to measure bone size, geometry, and microarchitecture at the distal radius and tibia and micro-finite element modeling to estimate bone strength. We measured bone turnover markers (β C-terminal telopeptide of type I collagen and amino-terminal propeptide of type I procollagen) and hormones known to affect bone metabolism (estradiol, testosterone, IGF-I, and PTH). RESULTS Bone strength was greater in men than in women, and at the radius it was greater in men ages 30-32 yr than ages 16-18 yr. The gender difference was due to greater cortical perimeter, trabecular area, and trabecular density in men. The age difference was due to greater cortical thickness and cortical tissue mineral density and lower cortical porosity. IGF-I was related to two of these five key properties at the radius (cortical perimeter and cortical thickness). None of the hormones were predictors of density or structure at the tibia. CONCLUSIONS Cortical modeling of long bones continues beyond the end of adolescence. IGF-I may be a determinant of this process at the radius.