Factors influencing peak bone mass gain

Abstract

Bone mass is a key determinant of osteoporosis and fragility fractures. Epidemiologic studies have shown that a 10% increase in peak bone mass (PBM) at the population level reduces the risk of fracture later in life by 50%. Low PBM is possibly due to the bone loss caused by various conditions or processes that occur during adolescence and young adulthood. Race, gender, and family history (genetics) are responsible for the majority of PBM, but other factors, such as physical activity, calcium and vitamin D intake, weight, smoking and alcohol consumption, socioeconomic status, age at menarche, and other secondary causes (diseases and medications), play important roles in PBM gain during childhood and adolescence. Hence, the optimization of lifestyle factors that affect PBM and bone strength is an important strategy to maximize PBM among adolescents and young people, and thus to reduce the low bone mass or osteoporosis risk in later life. This review aims to summarize the available evidence for the common but important factors that influence bone mass gain during growth and development and discuss the advances of developing high PBM.

Keywords

peak bone mass / children / adolescents / genetic / risk factors

Introduction

Osteoporosis is a systemic osteopathy characterized by a decrease in bone density and quality, the destruction of bone microstructure, and an increase in bone brittleness caused by genetic and environmental factors [¹]. Bone mineral density (BMD) is recognized as the most important predictor of osteoporosis, and fracture is the ultimate manifestation. Currently, approximately 200 million people worldwide suffer from osteoporosis [²], and 83.9 million of which are in China [³]. As reported, the burden of treatment for osteoporosis and osteoporotic fractures has been rising rapidly. Approximately 2.33 million osteoporotic fractures are estimated in 2010 in China, which cost $9.45 billion [⁴].

BMD is the bone mineral content (BMC) in the bone tissue and a measurable indicator related to bone mass, reflecting bone strength [⁵]. Various factors can affect the accumulation and loss of BMD in bone tissue, and the perniciousness of bone loss are well recognized in adults, especially among the elderly. However, the attention to bone health during childhood and adolescence is not sufficient as a 10% increase in peak bone mass (PBM) gain can delay the onset of osteoporosis by 13 years [⁶], and a 6.4% decrease in bone mass in children period has been associated with a twofold risk of fracture in adulthood [⁷].

The process of gaining PBM is influenced by a number of factors, including genetics and ethnicity, nutrition (calcium and vitamin D), physical activity, exposure to risk factors (such as smoking and alcohol intake), and some diseases and medications. Osteoporosis is the most common cause of low BMD, but other diseases, such as osteogenesis imperfecta (OI), can be characterized by low BMD. Besides osteoporosis, other diseases, such as OI and osteomalacia, are common causes of low BMD.

OI is a rare connective tissue disorder characterized by the increased frequency of fractures [⁸]. About 85% of patients with OI have an autosomal dominant mutation in the type 1 collagen coding genes (COL1A1 and COL1A2), and patients with mild OI may remain undiagnosed until adulthood and present early-onset or accelerated osteoporosis [⁹]. In addition, osteomalacia, a disorder in which a newly formed osteoid at the site of bone turnover is not properly mineralized, can be characterized by reduced BMD [⁹]. Therefore, understanding the determinants of bone acquisition from adolescence to young adulthood and the strategies to optimize PBM are critical. The main purpose of this paper is to summarize the available factors, such as genetic factors, dietary factors, chronic diseases and medications, and other environmental factors (including weight, smoking and alcohol consumption, vitamin D, calcium, and physical activity), that influence bone mass gain in children, adolescents, and young adults.

Peak bone mass

BMD measurement

According to the World Health Organization (WHO), the dual energy X-ray absorptiometry (DXA) screening can be applied to diagnose osteoporosis among postmenopausal women and men (age>50 years). The individuals with T-score at lumbar spine (LS) or hip below −2.5 can be diagnosed with osteoporosis, and individuals with T-score of -1 to -2.5 can be diagnosed with osteopenia or low bone mass [¹⁰]. For children and young adults, the International Society for Clinical Densitometry has advocated the use of Z-score, which describes standard deviations from healthy age- and sex-matched individuals’ BMD, rather than T-score, and the wording “low bone mass” is for Z-scores less than or equal to −2.0 standard deviation [¹¹]. Although radiographic examination is more frequently applied in the clinical diagnosis of vertebral fractures, DXA scan can be used to do this assessment. A study of vertebral fracture assessment (VFA) has used the DXA scan in 20 children and adolescents and reported a sensitivity of 83% and specificity of 100% for VFA compared with the VFA of subjects with lateral spine radiographs as the gold standard [¹²]. A more recent study by Adiotomre et al. reported that the mean sensitivity values of radiographs and DXA in diagnosing vertebral fracture are 74% and 70%, respectively, with specificity of up to 96% and 97%, respectively, in 250 children aged 5–15 years [¹³].

Quantitative computed tomography (QCT) can also assess bone mass but is not as widely utilized as DXA. QCT can measure cortical and trabecular BMD separately. The volumetric BMD (as opposed to “areal” DXA-BMD) and geometric/structural parameters, which contribute to bone strength, can also be obtained [¹⁴]. A limitation is that the WHO definition of osteoporosis in terms of bone densitometry (T-score of −2.5 or below using DXA) is not applicable. An alternative method of estimating BMD is derived from quantitative ultrasound (QUS), which usually consists of two different ultrasound measurement techniques, namely, the broadband ultrasound attenuation and the velocity of sound, typically at the heel calcaneus [¹⁵]. QUS is safe, rapid, and relatively cheap. Thus, QUS may be used in very large samples, such as approximately 500 000 samples in the UK Biobank.

Timing of PBM accumulation

PBM, the largest amount of bone accumulated at the end of growth, is a very important predictor of osteoporosis and fracture risk in the future. Generally, bone mass is believed to considerably increase during the first 20 years and reaches a plateau in the late adolescence or young adulthood in males and females [¹⁶,¹⁷] (Fig. 1). A longitudinal data have shown that in women and men, more than 94% of BMD is acquired at the age of 16 [¹⁸]. Puberty is an important period for bone acquisition and contributes largely to the PBM value [¹⁹]. However, the timing of PBM is still disputed. Other data have suggested that the bone mineral is still being accumulated until the third decade of life [²⁰,²¹].

PBM and fracture risk

Population-based studies have shown that roughly half of the boys and one-third of the girls would undergo a fracture by age of 18 and 1/5 would have two or more fractures [²²,²³]. Epidemiologic studies have shown that a 10% increase in PBM at the population level reduces the risk of fracture later in life by 50% [²⁴]. A large cohort study including 6213 children with mean age of 9.9 years followed for two years has shown that the risk of fracture is related to BMD and BMC. Moreover, a weak inverse relationship exists between BMD and subsequent fracture risk (odds ratio (OR) per standard deviation (SD) decrease= 1.12; 95% CI: 1.02–1.25), and fracture risk is inversely related to BMC adjusted for bone area, height, and weight (OR= 1.89; 95% CI: 1.18–3.04) [²⁵]. Additional studies using DXA and pQCT have also suggested a significant association between the forearm fracture in children and the lower areal and among vBMD, cortical area, and bone strength [²⁶]. A low PBM may lead to higher risk of osteoporosis and fracture, whereas a high PBM may reduce or delay the onset of osteoporosis, which provides great reserves for adults and elderly. Therefore, achieving a high bone density and bone strength accrual during childhood and adolescence is more conducive for the prevention of fractures. In addition, understanding the factors that influence bone mass and bone microarchitecture early in life is important because poor bone health is associated with fracture risk in later life.

Factors influencing PBM gain

Bone health in adulthood is largely dependent on bone density acquired during childhood and adolescence. The bone mass gain during childhood and adolescence is influenced by multiple factors, including gender, genetic factors, ethnicity, and other environmental factors, such as physical activity, diet (calcium and protein intake), endocrine status (sex hormones, growth hormone, insulin-like growth factor 1, and vitamin D), and other risk factors, such as alcohol intake and cigarette smoking (including passive smoking) [⁵,²⁴,²⁷–²⁹]. As environmental and behavioral factors account for 20% to 40% of adult PBM [³⁰,³¹], the early identification of the factors associated with poor bone health and the provision of reliable counseling may help children and teenagers take action to maximize BMD before their PBM is completed.

Genetics of PBM

Family and twin studies suggest that BMD has a high heritability, and the estimates range from 50% to 85% [³²,³³]. Before the genome-wide association study (GWAS) is widely carried out, the LRP5 [³⁴] and ESR1 [³⁵] genes have been identified to be associated with BMD in children and adolescents. Although the GWAS for osteoporosis and related traits are mostly conducted in the adult population, some have also been performed among younger individuals, including children [³⁶–³⁸], teenagers [³⁹], and premenopausal women [⁴⁰,⁴¹]. The Avon Longitudinal Study of Parents and Children (ALSPAC) study has confirmed that the SP7 (Sp7 transcription factor) [³⁶], nuclear factor kB receptor activating factor (RANK) [⁴²], and osteoporogeterin (OPG) [⁴²] are associated with BMD in children. In 2012, a large-scale GWAS has been conducted in a children cohort (Generation R) in the Netherlands [³⁷] and determined that WNT16 rs917727_T is associated with systemic and head BMD in 2660 children. This site is also associated with BMD in adults. The study by Kemp et al. [⁴³] determined that a subset of the loci associated with adult BMD are also associated with BMD in children. The rare variants near EN1, which are first identified in adults [⁴⁴], are confirmed to be associated with high bone mass in children [⁴⁵]. Recently, Chesi et al. [³⁸] reported two loci associated with BMD achieving a genome-wide significant level. These loci are rs7797976 within CPED1 in girls and rs7035284 on 9p21.3 in boys. The association between CPED1–WNT16–FAM3C and BMD has been previously reported for other skeletal sites (skull and total body aBMD) in children of European ancestry [³⁷]. Importantly, this locus is also associated with wrist BMD, bone strength, cortical bone thickness, and fracture risk of forearm in adults [⁴⁶], PBM in premenopausal women [⁴¹], and bone mass and fracture risk of European elderly [⁴⁷,⁴⁸]. The loci associated with BMD in childhood are sometimes associated with BMD in adults (some with sex- and puberty-specific effects) [³⁸,⁴⁹], suggesting that the effect of genetic variants on BMD may act over the whole lifetime. Until now, several GWAS have successfully identified many variants and genes in children and young adults (Table 1 and Fig. 2).

Obesity/overweight and bone health

To date, little agreement exists on the effect of overweight and adiposity on the skeletal development and the mechanisms underpinning these changes [⁵²]. Understanding how the body composition influences the bone health and development of children and young adults is critical because childhood and adolescence are important stages for bone growth. Recently, a systematic review and meta-analysis of 27 studies, including 5958 subjects aged 2–18 years, have shown that overweight and obese children have significantly higher BMD compared with normal-weight children (P<0.05) [⁵³]. These studies in children have suggested a positive relationship between adiposity and BMD, which started to weaken in later childhood, reversed during adolescence [⁵⁴,⁵⁵], and potentially maintained until early adulthood [⁵⁶].

A longitudinal study [⁵⁷] has followed 71 young females (aged 17–22 years) for six years and found that weight gainers have higher BMD and greater cortical thickness at the proximal femur shaft than individuals with stable weight. Wetzsteon and colleagues [⁵⁸] followed up 445 children (aged 9–11 years) for 16 months and identified that absolute bone strength is greater in overweight children, but the increase in bone strength is because of the lean mass change and not fat mass. Another study [⁵⁹] has also suggested that overweight males have higher bone quality (total BMD, total area, trabecular bone volume fraction (BV/TV), and trabecular number at the radius) compared with normal-weight young males, but the bone quality of overweight adolescents seems to have adapted to lean mass and not fat mass. More recent studies have also supported that lean mass is more important for optimizing bone strength during growth, whereas fat mass may negatively affect bone strength in weight-bearing sites in children and adolescents [⁶⁰,⁶¹].

Leptin, as a multifunctional important cytokine derived from fat tissue, has an important role in bone metabolism and development [⁶²]. First, leptin can promote the differentiation of bone marrow stromal cells (BMSC) into osteoblastic lineage and inhibit differentiation into fat [⁶³]. Second, leptin can directly act on osteoblasts, enhance differentiation and maturation of osteoblasts, and finally improve bone formation [⁶⁴]. Third, leptin can also inhibit osteoclast development, which may be through the immune system to affect the secretion of cytokines, stimulate the expression of OPG in peripheral blood monocytes, reducing the expression level of RANK ligand (RANKL) via the RANKL/RANK/OPG system to inhibit the generation of osteoclasts and bone absorption [⁶³]. Alternatively, leptin can act on the central hypothalamic pathway and the sympathetic nervous system to inhibit osteoblast proliferation. In this central pathway, leptin binds to hypothalamic receptors, inducing an increase in the sympathetic activity that signals to osteoblasts via the b2 adrenergic receptors (Adrb2) [⁶²]. Subsequently, two different downstream pathways, namely, the c-myc and the PKA-ATF4 pathways, are activated. In the c-myc pathway, the expression of c-myc is inhibited, thereby regulating the expression of cyclin D1, which finally leads to the suppression of osteoblast proliferation [⁶²]. The RANKL expression is upregulated via the PKA–ATF4 pathway, which consequently enhances the bone resorption of osteoclasts [⁶²]. By contrast, in the arcuate nuclei, leptin signal transduction upregulates CART expression, which suppresses the synthesis of RANKL in osteoblasts via an unknown mechanism.

The effect of physical activity in optimizing PBM

Throughout life, the bone is a living tissue that can respond to strains produced by muscular activity and mechanical load [⁵]. Adolescence is generally considered the best time to strengthen bones. During this period, the rate of bone modeling and remodeling is high, and the periosteal surface is growing rapidly. Physical activity during puberty increases the bone mass on the bone surface and enhances bone strength. The effects of physical activity on bone mass mainly come from the mechanical load from the direct stimulation of femur and muscle contraction. A high-magnitude, rapidly applied, and novel loading is most effective, and the duration is less important when the threshold number of cycles is reached [⁶⁵]. In addition, physical activity can increase the absorption of nutrients, such as vitamin D and calcium [⁶⁶]. Most studies have shown that physical activity is one of the main nonpharmacological methods to increase and maintain BMD and geometry [⁶⁵]. Conversely, skeletal unloading due to cast immobilization or prolonged bedrest leads to bone loss [⁶⁷].

A longitudinal study has shown that physically active adolescents (aged 8–15 years) have 8%–10% greater hip BMC at age 23–30 years than less active individuals [⁶⁸]. A 4-year exercise program in children determined that girls and boys who added various intensities of physical activity (40 min/day and 5 days/week) have gained higher lumbar spine BMC by 7.0% and 3.3%, respectively, and higher femoral neck width by 1.7% and 0.6%, respectively, than the control subjects who only have normal physical education curriculum and duration within normal limits [⁶⁹]. Another longitudinal trial study has shown that children who engaged in school-based exercise interventions for nine months have higher whole body (6.2%), total hip (7.7%), and femoral neck (8.1%) BMC compared with the controls [⁷⁰]. After three years of discontinuation of the intervention, these benefits persisted with a sustained 7%–8% increment of BMC in the total hip and femoral neck of conditioned individuals [⁷⁰]. A controlled cross-sectional study conducted among professional baseball players has shown that the effect of physical activity during youth on bone strength and bone size is kept throughout life [⁷¹]. Janz et al. [⁷²] conducted a 10-year prospective study on 530 participants starting at age 5, with five measurements at ages 8, 11, 13, 15, and 17 years, and tried to address how moderate-and-vigorous intensity physical activity (MVPA) affects bone mass and geometric properties. This study determined that individuals who experienced the most MVPA have higher bone mass and better geometry at age 17 years.

The effect of physical activity on BMD or BMC has also been proven in randomized controlled trials (RCTs) [⁷³–⁷⁶]. Fuchs et al. [⁷³] investigated the effect of high-intensity jumping on the lumbar spine and the hip bone mass in prepubertal 5.9–9.8 year-old children. The jumping and control groups have participated in exercise intervention three times per week during school days. After seven months, the BMC at lumbar spine (P<0.05) and the femoral neck (P<0.001) and the BMD at the lumbar spine (P<0.01) and bone area at femoral neck (P<0.001) have significantly increased in the jumping group [⁷³]. In another RCT [⁷⁶], a 10 min jumping activity twice a week for eight months during adolescence seems to improve bone accrual in a sex-specific manner. The bone mass of the whole body has increased in boys, whereas the bone mass at the lumbar spine and hip has improved in girls.

The effect of socioeconomic status on BMD

Bone mass depends on the acquisition in childhood and decline in adulthood and can be influenced by socioeconomic conditions throughout life [⁷⁷]. Socioeconomic status (SES) is suggested to be associated with a variety of acute and chronic diseases, including osteoporosis [⁷⁸,⁷⁹]. However, the currently available literature has remained controversial [⁸⁰–⁸²]. Low SES has a strong and well-documented association with various adverse health outcomes and increases the risk of hip fracture in the elderly [⁸³,⁸⁴]. However, the association between low SES and femoral neck BMD, which is the main indicator of hip fracture risk, is not observed [⁸⁵,⁸⁶].

Overall, the findings are more consistent among Indian, Korean, and Australian women, in which women who have lower education and/or income usually have lower BMD [⁸¹,⁸²,⁸⁷]. For men, the results are relatively inconsistent [⁸¹,⁸²,⁸⁸]. An early study reported that osteoporosis is a disease of men with higher SES in New Zealand [⁸⁸], whereas another study in Australia has suggested no association between SES and BMD in men [⁸²]. In Korean men, an association between low education and household income and low BMD is observed [⁸¹]. In 2013, Karlamangla et al. reported that socioeconomic advantage in childhood, which is independent of adult SES, is associated with great bone strength at the femoral neck [⁸⁹]. Crandall et al. also reported that socioeconomic advantage in childhood, not current financial advantage, and higher adult education level are associated with higher adult lumbar spine BMD in 729 midlife adults in the United States [⁷⁷].

The influence of age at menarche on bone mass

Menarche refers to the first menstrual period of women, which is the beginning of the female sexual cycle. Menarche is an important indicator of female puberty and a sensitive indicator for evaluating female growth and maturity. The early and delayed age of menarche may affect the health of adult women. For example, the early onset of menarche may increase the risk of type 2 diabetes [⁹⁰] and breast [⁹¹] and endometrial [⁹²] cancers. Studies have reported that menarche is an important sign of the rapid increase in BMD [⁹³]. Early adolescence is an important period of female BMD growth, and women with early menarche have higher bone mass [⁹³]. However, another study has shown that late menarche may be beneficial for adult bone strength when controlling prepubertal bone strength [⁹⁴]. Therefore, from a clinical perspective, the relationship between menarche age and PBM should be studied.

Late menarche is regarded as a risk factor for osteoporosis as it possibly alters PBM achievement. Most studies have reported that late menarche is associated with lower BMD at several skeletal sites [⁹⁴–⁹⁶] and higher fracture risk for different skeletal sites [⁹⁷–⁹⁹]. Also, epidemiological studies have indicated that for the same reduced lifetime exposure to estrogen, individuals with late menarche have higher risk of fracture at spine, proximal femur, and forearm than individuals with early menopause [⁹⁷–⁹⁹]. Chevalley et al. [⁹⁵] reported that subjects with later menarche age (14.0 years (0.7 sd)) has lower aBMD than those with earlier menarche age (12.1 years (0.7 sd)) in total radius, diaphysis, and metaphysis in 124 healthy women aged 20.4 years (0.6 sd), and LATER vs. EARLIER has shown lower total and cortical volumetric BMD and cortical thickness (CTh). Interestingly, Šešelj et al. [⁹⁴] analyzed the data derived from serial hand-wrist radiographs of female participants and indicated that late menarche may lead to great bone diameter and strong bone strength, which may even result in lower BMC or BMD. The age of menarche also affects the occurrence of osteoporosis in postmenopausal women. A study including 243 postmenopausal women has found that 18% of the participants have osteoporosis, and individuals with menarche greater than 13 years tended to have osteoporosis (OR= 4.46; P = 0.035) [¹⁰⁰].

The effect of calcium and vitamin D on bone growth

Calcium accounts for 1%–2% of adult human body weight, and more than 99% of the total body calcium can be found in bones and teeth [¹⁰¹]. The transepithelial calcium absorption is initiated with calcium entry into the epithelial cells from the intestinal luminal through the calcium-permeable channels, and this process is strongly supported by vitamin D action [¹⁰²]. The vitamin D endocrine system plays an important role in maintaining the extracellular fluid calcium concentration and bone homeostasis [¹⁰³]. Usually, the vitamin D status is assessed by measuring the serum 25-hydroxyvitamin D (25-OHD) concentration, and vitamin D deficiency is diagnosed by measuring the serum 25-OHD [¹⁰⁴]. Calcium and vitamin D are the main nutritional interventions to prevent and treat osteoporosis [¹⁰⁵]. However, vitamin D deficiency is a global health problem and considered as common in elderly, children, and adults [¹⁰⁶]. For example, severe vitamin D deficiency (serum level of 25-OHD below 15 nmol/L or 6 ng/mL) leads to rickets in children and osteomalacia in adults.

In a 12-month randomized double-blind study, Dibba et al. assessed the effect of calcium supplementation on forearm BMC in 80 girls and 80 boys (aged 8.3–11.9 years) who are adjusted for height, weight, and bone width and determined that the group with calcium supplementation has higher BMC and BMD at the distal radius and midshaft compared with the control group [¹⁰⁷]. Another randomized study lasting 13 months identified that the intervention in boys aged 16–18 years with calcium carbonate supplementation (1000 mg calcium/day) has resulted in greater BMC in different sites, including the whole body, lumbar spine, hip, and intertrochanter, compared with the control group with placebo [¹⁰⁸]. Ho et al. undertook a 1-year follow-up study among 104 Chinese girls receiving 600 mg calcium/day in 375 mL soymilk and 95 girls aged 14–16 years as control and found a percentage increase (45%–113%) in intertrochanter BMD, trochanter BMD, total hip BMD, and total hip BMC in the supplementation group compared with the control group [¹⁰⁹]. However, another trial in 96 girls, with mean age of 12 years supplied with 792 mg calcium/day for 18 months, is observed with gains in BMD and BMC in total body, lumbar spine, and total hip, but gains in BMC and BMD do not exist after 42 months, suggesting a short-term effect [¹¹⁰]. In a 2-year trial of milk intervention with and without 5 or 8 mg vitamin D₃ (cholecalciferol) among 757 Chinese girls, Du et al. reported that individuals receiving additional vitamin D₃ has greater increase in the change in total body BMD and BMC compared with those only receiving milk [¹¹¹].

In a meta-analysis [¹¹²] including six studies with 541 individuals receiving vitamin D and 343 receiving placebo aged 1 month to 20 years, Winzenberg et al. reported that vitamin D supplementation affects the BMD increase at the lumbar spine, but not at the total hip and the forearm. Individuals with vitamin D deficiency can benefit from vitamin D supplementation, particularly in lumbar spine BMD and total body BMC, but the benefit no longer exists in children and adolescents with normal vitamin D levels [¹¹²]. In a 1-year trial, 179 girls (aged 10–17 years) are randomly assigned into three groups (oral vitamin D doses of 200 IU/day or 2000 IU/day and oral placebo). Results show that hip BMC and bone area have increased in the high-dose group, and the BMD and/or the BMC at several skeletal sites have increased significantly in both supplementation groups in premenarcheal girls (P<0.05), but no significant change in BMD or BMC in postmenarcheal girls is observed [¹¹³]. Another study performed among 50 Indian underprivileged adolescent girls (aged 14–15 years) has shown that vitamin D supplementation (7.5 mg ergocalciferol, 4 times/year) can increase the total BMD and bone area in individuals who are within 2 years of menarche, but not in those who are≥2 years postmenarche [¹¹⁴]. Al-Shaar et al. [¹¹⁵] investigated the effect of weekly vitamin D₃ supplementation (1400 and 14 000 IU) on the hip geometric dimensions in 338 boys and girls (mean age at approximately 13 years) for over one year and found that vitamin D supplementation increases aBMD (7.9% for low doses, 6.8% for high doses, and 4.2% for placebo) and reduces the buckling ratio of the narrow neck (6.1% for low doses, 2.4% for high doses, and 1.9% for placebo). Conversely, no significant change in any parameter of interest in boys has been observed [¹¹⁵].

The effect of smoking and alcohol on BMD

Tobacco contains a variety of compounds. Most of these compounds are harmful to humans, and nicotine is the most abundant and most toxic substance. Nicotine changes the permeability of the blood vessel wall, hinders the exchange of substances inside and outside the blood vessels, leading to ineffective absorption and utilization of nutrients, such as protein and calcium. Other toxic substances in tobacco also increase the acidity of the blood and promote the dissolution of bones [¹¹⁶]. The pathogenesis of alcohol-induced osteoporosis is not completely clear, and the effect of alcohol on the bone is believed to be through direct and indirect actions [¹¹⁷]. The direct effect of alcohol on the activity of bone cells is the inhibition of the growth of marrow mesenchymal stem cells and its transformation into osteoblasts [¹¹⁸]. Nevertheless, elucidating the mechanism of the influence of alcohol on bone metabolism is complicated because the effects of alcohol on different organs (including bone) depend on the time profile and the extent of alcohol exposure.

In a study with 1068 young men (mean age=18.9 years), Lorentzon et al. [¹¹⁹] reported that smoking for an average of four years is significantly associated with lower aBMD (between −1.8% and −5.0%) and lower cortical thickness (-2.9% to -4.0%) depending on skeletal sites. In another prospective study of females aged 11–19 years, Dorn et al. reported that individuals who smoke frequently have lower rate of BMD accrual at the lumbar spine and the total hip [¹²⁰]. A 5-year longitudinal study including 833 young men aged 18–20 years has shown that the individuals who started to smoke since baseline have substantially smaller increases in aBMD at the total body (P<0.01) and lumbar spine (P = 0.04) and considerably greater decreases in aBMD at the total hip (P<0.01) and femoral neck (P<0.01) than individuals who did not smoke at baseline and follow-up stage [¹²¹]. Some studies have investigated the relationship between alcohol intake and PBM in the late adolescence and young adulthood stages, and the results are inconsistent. Some studies suggest that alcohol intake has a significant negative association with BMD [¹²¹,¹²²], whereas others suggested that alcohol intake has a significant positive association with BMD [¹²³]. Some studies found no association between alcohol intake and bone outcomes [¹²⁰,¹²⁴]. Lucas et al. observed a significant association between low BMD (Z-score<−1) in late adolescence and having ever smoking and drinking by age of 13 years (OR= 2.33) after adjusting for menarche age and sports practice [¹²⁵]. However, a study among 723 healthy young male soldiers has shown that soldiers who had moderate alcohol consumption have high BMD (P≤0.015) [¹²⁶].

Secondary causes of bone loss

Many clinical conditions affecting young people (Table 2) can be associated with the loss of bone mass and quality, leading to an increased risk of fracture throughout life. In this review, some common conditions that can lead to bone loss and their underlying mechanisms are summarized.

Endocrine states

Endocrine states, such as glucocorticoid osteoporosis, growth hormone deficiency, diabetes, and primary hyperparathyroidism, are common secondary causes of osteoporosis and low BMD. The main feature in the pathogenesis of glucocorticoids on bone loss is that glucocorticoids decrease the number and function of osteoblasts, leading to the suppression of bone formation and enhancement of the activity of osteoclasts [¹²⁷]. During the period of initial exposure to glucocorticoids, glucocorticoids can enhance the expression of RANKL and the macrophage colony stimulating factor, which are the necessary factors for osteoclast formation, leading to an increase in bone resorption [¹²⁷]. In addition, other indirect actions mediating the increase in bone resorption and decrease in bone formation are reported. For example, glucocorticoids decrease the expression of insulin-like growth factor 1 (IGF-1) and sex steroids, leading to suppression of bone formation and enhancement of bone resorption, respectively. Meanwhile, glucocorticoids reduce calcium absorption from the intestines by inhibiting vitamin D actions and inhibit renal tubular calcium reabsorption to enhance bone resorption [¹²⁷].

The optimal levels of growth hormone, IGF-1, thyroid hormone, and gonadal sex steroids are essential for the completion of normal skeletal growth, puberty, and bone mineral accrual. Growth hormone deficiency is associated with delayed skeletal maturation and low BMD mainly through reduced bone formation [¹²⁸]. Another example of the endocrine causes of low BMD on the young individuals is type 1 diabetes mellitus, which is one of the common endocrine pediatric diseases. The pathogenesis of diabetes-related osteoporosis is complicated and mainly includes calcium, vitamin D metabolism, and insulin abnormalities, resulting in low blood calcium and low blood phosphorus, which cause the loss of basic materials for bone formation. At the same time, hyperglycemia may stimulate the formation of excessive cytokines, such as IL-1 and IL-6, reduce the OPG/RANKL ratio, further promote the formation and activity of osteoclasts, and inhibit the differentiation and mineralization of osteoblasts [¹²⁹]. Primary hyperparathyroidism is associated with an increase in the expression of RANKL by cells of the osteoblast lineage and an increase in osteoclast-mediated bone resorption [¹³⁰].

Gastrointestinal and nutritional conditions

Multiple nutrients are needed in bone growth, development, and maintenance. Disorders resulting from nutrient deficiency, especially malnutrition calcium deficiency during childhood and adolescence, may affect the attainment of normal PBM. Celiac disease, in children, is associated with bone loss because of nutritional deficiency and malabsorption [¹³¹,¹³²]. Decreased calcium absorption and an increase in the levels of inflammatory cytokines, including IL-1, IL-6, and TNF-a, may be responsible for the increase in bone resorption [¹³³]. Inflammatory bowel diseases (IBDs), consisting of ulcerative colitis and Crohn’s disease, are associated with bone loss. The mechanisms responsible for the bone loss in IBD include disease-related inflammatory activity and treatment-related side effects, including glucocorticoid therapy and nutritional deficiencies, leading to low body mass index and contributing to hypogonadism [¹³⁴]. Anorexia nervosa is associated with weight loss, low BMD, and risk of fracture [¹³⁵]. Also, the serum markers of bone formation are suppressed and the markers of bone resorption are increased, suggesting that bone formation is uncoupled from bone resorption [¹³⁰].

Autoimmune disorders

The immune system and immune factors play an important role in the development of osteoporosis. For example, rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and multiple sclerosis (MS) can lead to bone loss. RA is a common rheumatic disease, and the underlying disease activity and ongoing use of glucocorticoids can contribute to bone loss and risk for fractures. Cytokines, such as TNF-a and IL-1, can promote osteoclastic activity. Increased RANKL/OPG ratio and elevated bone turnover markers and sedimentation rate are predictors of rapid and persistent bone loss in patients with RA [¹³⁶]. The mechanism of bone loss in AS is multifactorial. One factor is systemic inflammation, which increases the expression of RANKL. RANKL combines with the RANK receptor on the surface of osteoclast precursor cells, promoting osteoclast differentiation and maturation [¹³⁷]. Mature osteoclasts secrete proteolytic enzymes and hydrochloric acid, which play a role in bone absorption that eventually leads to bone resorption and bone mass reduction, even osteoporosis [¹³⁷]. Osteoclast-inducing inflammatory cytokines, such as IL-1, IL-6, soluble IL-6 receptor, and TNF-a, are elevated in patients with SLE and contribute to bone loss [¹³⁰]. MS is a chronic inflammatory-demyelinating central nervous system disease that usually affects young adults [¹³⁰,¹³⁸] and reduces the physical inactivity and the mechanical load on the bones, which may be the major contributing factors for bone loss or osteoporosis [¹³⁹].

Renal diseases

Hypercalciuria is related to low bone density and increased incidence of fracture and characterized by increased bone absorption, increased intestinal calcium absorption, and decreased renal tubular calcium reabsorption, which results in net calcium loss [¹⁴⁰]. Individuals with chronic kidney disease (CKD) have a high prevalence of Klotho deficiency and low expression of Klotho, resulting in increased fibroblast growth factor (FGF23) levels [¹⁴¹]. Klotho deficiency enhances osteoblast activity while increasing the expression of FGF23 that suppresses osteoblast differentiation. Thus, the role of Klotho on the bone at different stages of CKD is still unknown [¹⁴¹]. Renal tubular acidosis is characterized by normal anion gap and hyperchloremic metabolic acidosis [¹⁴²]. When the hydrogen ion load is greater than the normal daily acid load, the bone buffers the hydrogen ions, which may result in a spectrum of metabolic bone disorders ranging from osteomalacia to osteoporosis and fractures [¹⁴²]. Defective renal acidification may lead to an osteoblast-mediated activation of osteoclasts and a compensatory mobilization of alkali and calcium from the bone, resulting in bone loss [¹³⁰]. In the cortical collecting tubule, calcium reabsorption is also reduced, resulting in renal calcium unbalance and bone loss [¹³⁰].

Drug-induced bone loss

Drug-induced osteoporosis is a common type of secondary osteoporosis. Glucocorticoids are the most common cause of drug-induced osteoporosis (See the section of “Endocrine states”), and other drugs, such as proton pump inhibitors (PPIs), heparin, and anticonvulsants, also affect bone metabolism. PPIs are used for the disorders of the upper gastrointestinal tract. By increasing gastric pH, PPIs may decrease calcium absorption and induce negative effects on skeletal homeostasis [¹³⁰]. As an effective drug for the treatment of thromboembolic disorders, heparin bound to OPG, the decoy receptor for RANKL, allows RANKL to induce osteoclastogenesis, which leads to enhanced bone resorption [¹³⁰]. Anticonvulsants may cause bone loss, but the mechanisms are not clear. Anticonvulsants may accelerate vitamin D metabolism and can lead to low 25-OHD levels, high bone turnover, and secondary hyperparathyroidism, increasing the risk of bone loss [¹⁴³].

Perspectives

PBM is obtained in early adulthood and affected by puberty developmental status. Genetics has a huge effect on BMD (especially PBM), but other factors also play very important roles. Factors, such as heredity, race, gender, age, and puberty development, are difficult to modify at present, but other factors, such as weight, nutrition, lifestyle (such as smoking and drinking), and physical activity, can be intervened. As environmental and behavioral factors account for 20%–40% of adult PBM, optimizing the factors associated with PBM and bone structure is a very important strategy for improving the bone accrual and strengthening the bone structure to decrease the risk of osteoporosis/fracture in later life. As the primary modifiable factors, diet and nutrition (e.g., calcium and vitamin D), physical activity, and exercise should be given more attention. More studies should be conducted to investigate the intensity, frequency, duration, and mode of physical activity in the future. Approximately 11 000 Chinese young individuals aged 15–25 years have been collected for follow-up to investigate the association of lifestyle and nutritional intake with bone mass gain.

References

[1] Ferrari SL, Rizzoli R. Gene variants for osteoporosis and their pleiotropic effects in aging. Mol Aspects Med 2005; 26(3): 145–167

[2] Pisani P, Renna MD, Conversano F, Casciaro E, Di Paola M, Quarta E, Muratore M, Casciaro S. Major osteoporotic fragility fractures: risk factor updates and societal impact. World J Orthop 2016; 7(3): 171–181

[3] Liu ZH, Zhao YL, Ding GZ, Zhou Y. Epidemiology of primary osteoporosis in China. Osteoporos Int 1997; 7(Suppl 3): 84–87

[4] Si L, Winzenberg TM, Jiang Q, Chen M, Palmer AJ. Projection of osteoporosis-related fractures and costs in China: 2010–2050. Osteoporos Int 2015; 26(7): 1929–1937

[5] Rizzoli R, Bianchi ML, Garabédian M, McKay HA, Moreno LA. Maximizing bone mineral mass gain during growth for the prevention of fractures in the adolescents and the elderly. Bone 2010; 46(2): 294–305

[6] Hernandez CJ, Beaupré GS, Carter DR. A theoretical analysis of the relative influences of peak BMD, age-related bone loss and menopause on the development of osteoporosis. Osteoporos Int 2003; 14(10): 843–847

[7] Boreham CA, McKay HA. Physical activity in childhood and bone health. Br J Sports Med 2011; 45(11): 877–879

[8] Forlino A, Marini JC. Osteogenesis imperfecta. Lancet 2016; 387(10028): 1657–1671

[9] Jha S, Chapman M, Roszko K. When low bone mineral density and fractures is not osteoporosis. Curr Osteoporos Rep 2019; 17(5): 324–332

[10] Writing Group for the ISCD Position Development Conference. Indications and reporting for dual-energy X-ray absorptiometry. J Clin Densitom 2004; 7(1): 37–44

[11] Gordon CM, Bachrach LK, Carpenter TO, Crabtree N, El-Hajj Fuleihan G, Kutilek S, Lorenc RS, Tosi LL, Ward KA, Ward LM, Kalkwarf HJ. Dual energy X-ray absorptiometry interpretation and reporting in children and adolescents: the 2007 ISCD Pediatric Official Positions. J Clin Densitom 2008; 11(1): 43–58

[12] Kyriakou A, Shepherd S, Mason A, Faisal Ahmed S. A critical appraisal of vertebral fracture assessment in paediatrics. Bone 2015; 81: 255–259

[13] Adiotomre E, Summers L, Allison A, Walters SJ, Digby M, Broadley P, Lang I, Morrison G, Bishop N, Arundel P, Offiah AC. Diagnostic accuracy of DXA compared to conventional spine radiographs for the detection of vertebral fractures in children. Eur Radiol 2017; 27(5): 2188–2199

[14] Adams JE. Quantitative computed tomography. Eur J Radiol 2009; 71(3): 415–424

[15] Hunter DJ, de Lange M, Andrew T, Snieder H, MacGregor AJ, Spector TD. Genetic variation in bone mineral density and calcaneal ultrasound: a study of the influence of menopause using female twins. Osteoporos Int 2001; 12(5): 406–411

[16] Faulkner RA, Bailey DA. Osteoporosis: a pediatric concern? Med Sport Sci 2007; 51: 1–12

[17] Bachrach LK, Hastie T, Wang MC, Narasimhan B, Marcus R. Bone mineral acquisition in healthy Asian, Hispanic, black, and Caucasian youth: a longitudinal study. J Clin Endocrinol Metab 1999; 84(12): 4702–4712

[18] Berger C, Goltzman D, Langsetmo L, Joseph L, Jackson S, Kreiger N, Tenenhouse A, Davison KS, Josse RG, Prior JC, Hanley DA; CaMos Research Group. Peak bone mass from longitudinal data: implications for the prevalence, pathophysiology, and diagnosis of osteoporosis. J Bone Miner Res 2010; 25(9): 1948–1957

[19] Bonjour JP, Chevalley T. Pubertal timing, bone acquisition, and risk of fracture throughout life. Endocr Rev 2014; 35(5): 820–847

[20] Recker RR, Davies KM, Hinders SM, Heaney RP, Stegman MR, Kimmel DB. Bone gain in young adult women. JAMA 1992; 268(17): 2403–2408

[21] Teegarden D, Proulx WR, Martin BR, Zhao J, McCabe GP, Lyle RM, Peacock M, Slemenda C, Johnston CC, Weaver CM. Peak bone mass in young women. J Bone Miner Res 1995; 10(5): 711–715

[22] Bishop N, Arundel P, Clark E, Dimitri P, Farr J, Jones G, Makitie O, Munns CF, Shaw N; International Society of Clinical Densitometry. Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2013 Pediatric Official Positions. J Clin Densitom 2014; 17(2): 275–280

[23] Mäyränpää MK, Mäkitie O, Kallio PE. Decreasing incidence and changing pattern of childhood fractures: a population-based study. J Bone Miner Res 2010; 25(12): 2752–2759

[24] Gordon CM, Zemel BS, Wren TA, Leonard MB, Bachrach LK, Rauch F, Gilsanz V, Rosen CJ, Winer KK. The determinants of peak bone mass. J Pediatr 2017; 180: 261–269

[25] Clark EM, Ness AR, Bishop NJ, Tobias JH. Association between bone mass and fractures in children: a prospective cohort study. J Bone Miner Res 2006; 21(9): 1489–1495

[26] Kalkwarf HJ, Laor T, Bean JA. Fracture risk in children with a forearm injury is associated with volumetric bone density and cortical area (by peripheral QCT) and areal bone density (by DXA). Osteoporos Int 2011; 22(2): 607–616

[27] Cooper C, Westlake S, Harvey N, Javaid K, Dennison E, Hanson M. Review: developmental origins of osteoporotic fracture. Osteoporos Int 2006; 17(3): 337–347

[28] Nilsson M, Ohlsson C, Mellström D, Lorentzon M. Previous sport activity during childhood and adolescence is associated with increased cortical bone size in young adult men. J Bone Miner Res 2009; 24(1): 125–133

[29] Rudäng R, Darelid A, Nilsson M, Nilsson S, Mellström D, Ohlsson C, Lorentzon M. Smoking is associated with impaired bone mass development in young adult men: a 5-year longitudinal study. J Bone Miner Res 2012; 27(10): 2189–2197

[30] Bachrach LK. Acquisition of optimal bone mass in childhood and adolescence. Trends Endocrinol Metab 2001; 12(1): 22–28

[31] Heaney RP, Abrams S, Dawson-Hughes B, Looker A, Marcus R, Matkovic V, Weaver C. Peak bone mass. Osteoporos Int 2000; 11(12): 985–1009

[32] Ralston SH. Genetic determinants of osteoporosis. Curr Opin Rheumatol 2005; 17(4): 475–479

[33] Zhai G, Andrew T, Kato BS, Blake GM, Spector TD. Genetic and environmental determinants on bone loss in postmenopausal Caucasian women: a 14-year longitudinal twin study. Osteoporos Int 2009; 20(6): 949–953

[34] Koay MA, Tobias JH, Leary SD, Steer CD, Vilariño-Güell C, Brown MA. The effect of LRP5 polymorphisms on bone mineral density is apparent in childhood. Calcif Tissue Int 2007; 81(1): 1–9

[35] Tobias JH, Steer CD, Vilarino-Güell C, Brown MA. Estrogen receptor alpha regulates area-adjusted bone mineral content in late pubertal girls. J Clin Endocrinol Metab 2007; 92(2): 641–647

[36] Timpson NJ, Tobias JH, Richards JB, Soranzo N, Duncan EL, Sims AM, Whittaker P, Kumanduri V, Zhai G, Glaser B, Eisman J, Jones G, Nicholson G, Prince R, Seeman E, Spector TD, Brown MA, Peltonen L, Smith GD, Deloukas P, Evans DM. Common variants in the region around Osterix are associated with bone mineral density and growth in childhood. Hum Mol Genet 2009; 18(8): 1510–1517

[37] Medina-Gomez C, Kemp JP, Estrada K, Eriksson J, Liu J, Reppe S, Evans DM, Heppe D, van den Put L, Herrera L, Ring SM, Kruithof C, Timpson NJ, Zillikens MC, Olstad OK, St Pourcain B, Hofman A, Jaddoe VW, Smith GD, Lorentzon M, Gautvik KM, Uitterlinden AG, Brommage R, Ohlsson C, Tobias JH, Rivadeneira F. Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity, pleiotropy and age-specific effects at the WNT16 locus. Bone 2012; 50: S33

[38] Chesi A, Mitchell JA, Kalkwarf HJ, Bradfield JP, Lappe JM, McCormack SE, Gilsanz V, Oberfield SE, Hakonarson H, Shepherd JA, Kelly A, Zemel BS, Grant SFA. A trans-ethnic genome-wide association study identifies gender-specific loci influencing pediatric aBMD and BMC at the distal radius. Hum Mol Genet 2015; 24(17): 5053–5059

[39] Paternoster L, Lorentzon M, Vandenput L, Karlsson MK, Ljunggren Ö, Kindmark A, Mellstrom D, Kemp JP, Jarett CE, Holly JMP, Sayers A, St Pourcain B, Timpson NJ, Deloukas P, Davey Smith G, Ring SM, Evans DM, Tobias JH, Ohlsson C. Genome-wide association meta-analysis of cortical bone mineral density unravels allelic heterogeneity at the RANKL locus and potential pleiotropic effects on bone. PLoS Genet 2010; 6(11): e1001217

[40] Koller DL, Ichikawa S, Lai D, Padgett LR, Doheny KF, Pugh E, Paschall J, Hui SL, Edenberg HJ, Xuei X, Peacock M, Econs MJ, Foroud T. Genome-wide association study of bone mineral density in premenopausal European-American women and replication in African-American women. J Clin Endocrinol Metab 2010; 95(4): 1802–1809

[41] Koller DL, Zheng HF, Karasik D, Yerges-Armstrong L, Liu CT, McGuigan F, Kemp JP, Giroux S, Lai D, Edenberg HJ, Peacock M, Czerwinski SA, Choh AC, McMahon G, St Pourcain B, Timpson NJ, Lawlor DA, Evans DM, Towne B, Blangero J, Carless MA, Kammerer C, Goltzman D, Kovacs CS, Prior JC, Spector TD, Rousseau F, Tobias JH, Akesson K, Econs MJ, Mitchell BD, Richards JB, Kiel DP, Foroud T. Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women. J Bone Miner Res 2013; 28(3): 547–558

[42] Paternoster L, Ohlsson C, Sayers A, Vandenput L, Lorentzon M, Evans DM, Tobias JH. OPG and RANK polymorphisms are both associated with cortical bone mineral density: findings from a metaanalysis of the Avon longitudinal study of parents and children and gothenburg osteoporosis and obesity determinants cohorts. J Clin Endocrinol Metab 2010; 95(8): 3940–3948

[43] Kemp JP, Medina-Gomez C, Estrada K, St Pourcain B, Heppe DHM, Warrington NM, Oei L, Ring SM, Kruithof CJ, Timpson NJ, Wolber LE, Reppe S, Gautvik K, Grundberg E, Ge B, van der Eerden B, van de Peppel J, Hibbs MA, Ackert-Bicknell CL, Choi K, Koller DL, Econs MJ, Williams FMK, Foroud T, Zillikens MC, Ohlsson C, Hofman A, Uitterlinden AG, Davey Smith G, Jaddoe VWV, Tobias JH, Rivadeneira F, Evans DM. Phenotypic dissection of bone mineral density reveals skeletal site specificity and facilitates the identification of novel loci in the genetic regulation of bone mass attainment. PLoS Genet 2014; 10(6): e1004423

[44] Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ, Dahia CL, Park-Min KH, Tobias JH, Kooperberg C, Kleinman A, Styrkarsdottir U, Liu CT, Uggla C, Evans DS, Nielson CM, Walter K, Pettersson-Kymmer U, McCarthy S, Eriksson J, Kwan T, Jhamai M, Trajanoska K, Memari Y, Min J, Huang J, Danecek P, Wilmot B, Li R, Chou WC, Mokry LE, Moayyeri A, Claussnitzer M, Cheng CH, Cheung W, Medina-Gómez C, Ge B, Chen SH, Choi K, Oei L, Fraser J, Kraaij R, Hibbs MA, Gregson CL, Paquette D, Hofman A, Wibom C, Tranah GJ, Marshall M, Gardiner BB, Cremin K, Auer P, Hsu L, Ring S, Tung JY, Thorleifsson G, Enneman AW, van Schoor NM, de Groot LCPGM, van der Velde N, Melin B, Kemp JP, Christiansen C, Sayers A, Zhou Y, Calderari S, van Rooij J, Carlson C, Peters U, Berlivet S, Dostie J, Uitterlinden AG, Williams SR, Farber C, Grinberg D, LaCroix AZ, Haessler J, Chasman DI, Giulianini F, Rose LM, Ridker PM, Eisman JA, Nguyen TV, Center JR, Nogues X, Garcia-Giralt N, Launer LL, Gudnason V, Mellström D, Vandenput L, Amin N, van Duijn CM, Karlsson MK, Ljunggren Ö, Svensson O, Hallmans G, Rousseau F, Giroux S, Bussière J, Arp PP, Koromani F, Prince RL, Lewis JR, Langdahl BL, Hermann AP, Jensen JEB, Kaptoge S, Khaw KT, Reeve J, Formosa MM, Xuereb-Anastasi A, Åkesson K, McGuigan FE, Garg G, Olmos JM, Zarrabeitia MT, Riancho JA, Ralston SH, Alonso N, Jiang X, Goltzman D, Pastinen T, Grundberg E, Gauguier D, Orwoll ES, Karasik D, Davey-Smith G; AOGC Consortium, Smith AV, Siggeirsdottir K, Harris TB, Zillikens MC, van Meurs JBJ, Thorsteinsdottir U, Maurano MT, Timpson NJ, Soranzo N, Durbin R, Wilson SG, Ntzani EE, Brown MA, Stefansson K, Hinds DA, Spector T, Cupples LA, Ohlsson C, Greenwood CMT; UK10K Consortium, Jackson RD, Rowe DW, Loomis CA, Evans DM, Ackert-Bicknell CL, Joyner AL, Duncan EL, Kiel DP, Rivadeneira F, Richards JB. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature 2015; 526(7571): 112–117

[45] Mitchell JA, Chesi A, McCormack SE, Roy SM, Cousminer DL, Kalkwarf HJ, Lappe JM, Gilsanz V, Oberfield SE, Shepherd JA, Kelly A, Zemel BS, Grant SFA. Rare EN1 variants and pediatric bone mass. J Bone Miner Res 2016; 31(8): 1513–1517

[46] Zheng HF, Tobias JH, Duncan E, Evans DM, Eriksson J, Paternoster L, Yerges-Armstrong LM, Lehtimäki T, Bergström U, Kähönen M, Leo PJ, Raitakari O, Laaksonen M, Nicholson GC, Viikari J, Ladouceur M, Lyytikäinen LP, Medina-Gomez C, Rivadeneira F, Prince RL, Sievanen H, Leslie WD, Mellström D, Eisman JA, Movérare-Skrtic S, Goltzman D, Hanley DA, Jones G, St Pourcain B, Xiao Y, Timpson NJ, Smith GD, Reid IR, Ring SM, Sambrook PN, Karlsson M, Dennison EM, Kemp JP, Danoy P, Sayers A, Wilson SG, Nethander M, McCloskey E, Vandenput L, Eastell R, Liu J, Spector T, Mitchell BD, Streeten EA, Brommage R, Pettersson-Kymmer U, Brown MA, Ohlsson C, Richards JB, Lorentzon M. WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk. PLoS Genet 2012; 8(7): e1002745

[47] Estrada K, Styrkarsdottir U, Evangelou E, Hsu YH, Duncan EL, Ntzani EE, Oei L, Albagha OM, Amin N, Kemp JP, Koller DL, Li G, Liu CT, Minster RL, Moayyeri A, Vandenput L, Willner D, Xiao SM, Yerges-Armstrong LM, Zheng HF, Alonso N, Eriksson J, Kammerer CM, Kaptoge SK, Leo PJ, Thorleifsson G, Wilson SG, Wilson JF, Aalto V, Alen M, Aragaki AK, Aspelund T, Center JR, Dailiana Z, Duggan DJ, Garcia M, Garcia-Giralt N, Giroux S, Hallmans G, Hocking LJ, Husted LB, Jameson KA, Khusainova R, Kim GS, Kooperberg C, Koromila T, Kruk M, Laaksonen M, Lacroix AZ, Lee SH, Leung PC, Lewis JR, Masi L, Mencej-Bedrac S, Nguyen TV, Nogues X, Patel MS, Prezelj J, Rose LM, Scollen S, Siggeirsdottir K, Smith AV, Svensson O, Trompet S, Trummer O, van Schoor NM, Woo J, Zhu K, Balcells S, Brandi ML, Buckley BM, Cheng S, Christiansen C, Cooper C, Dedoussis G, Ford I, Frost M, Goltzman D, González-Macías J, Kähönen M, Karlsson M, Khusnutdinova E, Koh JM, Kollia P, Langdahl BL, Leslie WD, Lips P, Ljunggren Ö, Lorenc RS, Marc J, Mellström D, Obermayer-Pietsch B, Olmos JM, Pettersson-Kymmer U, Reid DM, Riancho JA, Ridker PM, Rousseau F, Slagboom PE, Tang NL, Urreizti R, Van Hul W, Viikari J, Zarrabeitia MT, Aulchenko YS, Castano-Betancourt M, Grundberg E, Herrera L, Ingvarsson T, Johannsdottir H, Kwan T, Li R, Luben R, Medina-Gómez C, Palsson ST, Reppe S, Rotter JI, Sigurdsson G, van Meurs JB, Verlaan D, Williams FM, Wood AR, Zhou Y, Gautvik KM, Pastinen T, Raychaudhuri S, Cauley JA, Chasman DI, Clark GR, Cummings SR, Danoy P, Dennison EM, Eastell R, Eisman JA, Gudnason V, Hofman A, Jackson RD, Jones G, Jukema JW, Khaw KT, Lehtimäki T, Liu Y, Lorentzon M, McCloskey E, Mitchell BD, Nandakumar K, Nicholson GC, Oostra BA, Peacock M, Pols HA, Prince RL, Raitakari O, Reid IR, Robbins J, Sambrook PN, Sham PC, Shuldiner AR, Tylavsky FA, van Duijn CM, Wareham NJ, Cupples LA, Econs MJ, Evans DM, Harris TB, Kung AW, Psaty BM, Reeve J, Spector TD, Streeten EA, Zillikens MC, Thorsteinsdottir U, Ohlsson C, Karasik D, Richards JB, Brown MA, Stefansson K, Uitterlinden AG, Ralston SH, Ioannidis JP, Kiel DP, Rivadeneira F. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 2012; 44(5): 491–501

[48] Rivadeneira F, Styrkársdottir U, Estrada K, Halldórsson BV, Hsu YH, Richards JB, Zillikens MC, Kavvoura FK, Amin N, Aulchenko YS, Cupples LA, Deloukas P, Demissie S, Grundberg E, Hofman A, Kong A, Karasik D, van Meurs JB, Oostra B, Pastinen T, Pols HA, Sigurdsson G, Soranzo N, Thorleifsson G, Thorsteinsdottir U, Williams FM, Wilson SG, Zhou Y, Ralston SH, van Duijn CM, Spector T, Kiel DP, Stefansson K, Ioannidis JP, Uitterlinden AG; Genetic Factors for Osteoporosis (GEFOS) Consortium. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 2009; 41(11): 1199–1206

[49] Mitchell JA, Chesi A, Elci O, McCormack SE, Kalkwarf HJ, Lappe JM, Gilsanz V, Oberfield SE, Shepherd JA, Kelly A, Zemel BS, Grant SF. Genetics of bone mass in childhood and adolescence: effects of sex and maturation interactions. J Bone Miner Res 2015; 30(9): 1676–1683

[50] Chesi A, Mitchell JA, Kalkwarf HJ, Bradfield JP, Lappe JM, Cousminer DL, Roy SM, McCormack SE, Gilsanz V, Oberfield SE, Hakonarson H, Shepherd JA, Kelly A, Zemel BS, Grant SFA. A genomewide association study identifies two sex-specific loci, at SPTB and IZUMO3, influencing pediatric bone mineral density at multiple skeletal sites. J Bone Miner Res 2017; 32(6): 1274–1281

[51] Paternoster L, Lorentzon M, Lehtimäki T, Eriksson J, Kähönen M, Raitakari O, Laaksonen M, Sievänen H, Viikari J, Lyytikäinen LP, Mellström D, Karlsson M, Ljunggren O, Grundberg E, Kemp JP, Sayers A, Nethander M, Evans DM, Vandenput L, Tobias JH, Ohlsson C. Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure. PLoS Genet 2013; 9(2): e1003247

[52] Dimitri P. The impact of childhood obesity on skeletal health and development. J Obes Metab Syndr 2019; 28(1): 4–17

[53] van Leeuwen J, Koes BW, Paulis WD, van Middelkoop M. Differences in bone mineral density between normal-weight children and children with overweight and obesity: a systematic review and meta-analysis. Obes Rev 2017; 18(5): 526–546

[54] Clark EM, Ness AR, Tobias JH. Adipose tissue stimulates bone growth in prepubertal children. J Clin Endocrinol Metab 2006; 91(7): 2534–2541

[55] Wey HE, Binkley TL, Beare TM, Wey CL, Specker BL. Cross-sectional versus longitudinal associations of lean and fat mass with pQCT bone outcomes in children. J Clin Endocrinol Metab 2011; 96(1): 106–114

[56] Burrows M, Baxter-Jones A, Mirwald R, Macdonald H, McKay H. Bone mineral accrual across growth in a mixed-ethnic group of children: are Asian children disadvantaged from an early age? Calcif Tissue Int 2009; 84(5): 366–378

[57] Petit MA, Beck TJ, Hughes JM, Lin HM, Bentley C, Lloyd T. Proximal femur mechanical adaptation to weight gain in late adolescence: a six-year longitudinal study. J Bone Miner Res 2008; 23(2): 180–188

[58] Wetzsteon RJ, Petit MA, Macdonald HM, Hughes JM, Beck TJ, McKay HA. Bone structure and volumetric BMD in overweight children: a longitudinal study. J Bone Miner Res 2008; 23(12): 1946–1953

[59] Hoy CL, Macdonald HM, McKay HA. How does bone quality differ between healthy-weight and overweight adolescents and young adults? Clin Orthop Relat Res 2013; 471(4): 1214–1225

[60] Dimitri P, Jacques RM, Paggiosi M, King D, Walsh J, Taylor ZA, Frangi AF, Bishop N, Eastell R. Leptin may play a role in bone microstructural alterations in obese children. J Clin Endocrinol Metab 2015; 100(2): 594–602

[61] Farr JN, Amin S, LeBrasseur NK, Atkinson EJ, Achenbach SJ, McCready LK, Joseph Melton L 3rd, Khosla S. Body composition during childhood and adolescence: relations to bone strength and microstructure. J Clin Endocrinol Metab 2014; 99(12): 4641–4648

[62] Chen XX, Yang T. Roles of leptin in bone metabolism and bone diseases. J Bone Miner Metab 2015; 33(5): 474–485

[63] Thomas T, Burguera B. Is leptin the link between fat and bone mass? J Bone Miner Res 2002; 17(9): 1563–1569

[64] Upadhyay J, Farr OM, Mantzoros CS. The role of leptin in regulating bone metabolism. Metabolism 2015; 64(1): 105–113

[65] Bailey CA, Brooke-Wavell K. Exercise for optimising peak bone mass in women. Proc Nutr Soc 2008; 67(1): 9–18

[66] Wanner M, Richard A, Martin B, Linseisen J, Rohrmann S. Associations between objective and self-reported physical activity and vitamin D serum levels in the US population. Cancer Causes Control 2015; 26(6): 881–891

[67] Zhang P, Hamamura K, Yokota H. A brief review of bone adaptation to unloading. Genomics Proteomics Bioinformatics 2008; 6(1): 4–7

[68] Baxter-Jones AD, Kontulainen SA, Faulkner RA, Bailey DA. A longitudinal study of the relationship of physical activity to bone mineral accrual from adolescence to young adulthood. Bone 2008; 43(6): 1101–1107

[69] Löfgren B, Dencker M, Nilsson JA, Karlsson MK. A 4-year exercise program in children increases bone mass without increasing fracture risk. Pediatrics 2012; 129(6): e1468–e1476

[70] Meyer U, Ernst D, Zahner L, Schindler C, Puder JJ, Kraenzlin M, Rizzoli R, Kriemler S. 3-Year follow-up results of bone mineral content and density after a school-based physical activity randomized intervention trial. Bone 2013; 55(1): 16–22

[71] Warden SJ, Mantila Roosa SM, Kersh ME, Hurd AL, Fleisig GS, Pandy MG, Fuchs RK. Physical activity when young provides lifelong benefits to cortical bone size and strength in men. Proc Natl Acad Sci USA 2014; 111(14): 5337–5342

[72] Janz KF, Letuchy EM, Burns TL, Eichenberger Gilmore JM, Torner JC, Levy SM. Objectively measured physical activity trajectories predict adolescent bone strength: Iowa Bone Development Study. Br J Sports Med 2014; 48(13): 1032–1036

[73] Fuchs RK, Bauer JJ, Snow CM. Jumping improves hip and lumbar spine bone mass in prepubescent children: a randomized controlled trial. J Bone Miner Res 2001; 16(1): 148–156

[74] Hind K, Burrows M. Weight-bearing exercise and bone mineral accrual in children and adolescents: a review of controlled trials. Bone 2007; 40(1): 14–27

[75] Gunter K, Baxter-Jones AD, Mirwald RL, Almstedt H, Fuchs RK, Durski S, Snow C. Impact exercise increases BMC during growth: an 8-year longitudinal study. J Bone Miner Res 2008; 23(7): 986–993

[76] Weeks BK, Young CM, Beck BR. Eight months of regular in-school jumping improves indices of bone strength in adolescent boys and girls: the POWER PE study. J Bone Miner Res 2008; 23(7): 1002–1011

[77] Crandall CJ, Merkin SS, Seeman TE, Greendale GA, Binkley N, Karlamangla AS. Socioeconomic status over the life-course and adult bone mineral density: the Midlife in the U.S. Study. Bone 2012; 51(1): 107–113

[78] Navarro MC, Saavedra P, Jódar E, Gómez de Tejada MJ, Mirallave A, Sosa M. Osteoporosis and metabolic syndrome according to socio-economic status, contribution of PTH, vitamin D and body weight: the Canarian Osteoporosis Poverty Study (COPS). Clin Endocrinol (Oxf) 2013; 78(5): 681–686

[79] Du Y, Zhao LJ, Xu Q, Wu KH, Deng HW. Socioeconomic status and bone mineral density in adults by race/ethnicity and gender: the Louisiana osteoporosis study. Osteoporos Int 2017; 28(5): 1699–1709

[80] Brennan SL, Henry MJ, Wluka AE, Nicholson GC, Kotowicz MA, Williams JW, Pasco JA. BMD in population-based adult women is associated with socioeconomic status. J Bone Miner Res 2009; 24(5): 809–815

[81] Myong JP, Kim HR, Choi SE, Koo JW. The effect of socioeconomic position on bone health among Koreans by gender and menopausal status. Calcif Tissue Int 2012; 90(6): 488–495

[82] Brennan SL, Winzenberg TM, Pasco JA, Wluka AE, Dobbins AG, Jones G. Social disadvantage, bone mineral density and vertebral wedge deformities in the Tasmanian Older Adult Cohort. Osteoporos Int 2013; 24(6): 1909–1916

[83] Brennan SL, Henry MJ, Kotowicz MA, Nicholson GC, Zhang Y, Pasco JA. Incident hip fracture and social disadvantage in an Australian population aged 50 years or greater. Bone 2011; 48(3): 607–610

[84] Quah C, Boulton C, Moran C. The influence of socioeconomic status on the incidence, outcome and mortality of fractures of the hip. J Bone Joint Surg Br 2011; 93 (6): 801–805

[85] Brennan SL, Henry MJ, Wluka AE, Nicholson GC, Kotowicz MA, Pasco JA. Socioeconomic status and bone mineral density in a population-based sample of men. Bone 2010; 46(4): 993–999

[86] Aggarwal N, Raveendran A, Khandelwal N, Sen RK, Thakur JS, Dhaliwal LK, Singla V, Manoharan SR. Prevalence and related risk factors of osteoporosis in peri- and postmenopausal Indian women. J Midlife Health 2011; 2(2): 81–85

[87] Vaidya SV, Ekbote VH, Khadilkar AV, Chiplonkar SA, Pillay D, Divate U. Bone status of women over 40 years of age from two socioeconomic strata. Endocr Res 2012; 37(1): 25–34

[88] Elliot JR, Gilchrist NL, Wells JE. The effect of socioeconomic status on bone density in a male Caucasian population. Bone 1996; 18(4): 371–373

[89] Karlamangla AS, Mori T, Merkin SS, Seeman TE, Greendale GA, Binkley N, Crandall CJ. Childhood socioeconomic status and adult femoral neck bone strength: findings from the Midlife in the United States Study. Bone 2013; 56(2): 320–326

[90] Lim JS, Lee HS, Kim EY, Yi KH, Hwang JS. Early menarche increases the risk of type 2 diabetes in young and middle-aged Korean women. Diabet Med 2015; 32(4): 521–525

[91] Ritte R, Lukanova A, Tjønneland A, Olsen A, Overvad K, Mesrine S, Fagherazzi G, Dossus L, Teucher B, Steindorf K, Boeing H, Aleksandrova K, Trichopoulou A, Lagiou P, Trichopoulos D, Palli D, Grioni S, Mattiello A, Tumino R, Sacerdote C, Quirós JR, Buckland G, Molina-Montes E, Chirlaque MD, Ardanaz E, Amiano P, Bueno-de-Mesquita B, van Duijnhoven F, van Gils CH, Peeters PHM, Wareham N, Khaw KT, Key TJ, Travis RC, Krum-Hansen S, Gram IT, Lund E, Sund M, Andersson A, Romieu I, Rinaldi S, McCormack V, Riboli E, Kaaks R. Height, age at menarche and risk of hormone receptor-positive and-negative breast cancer: a cohort study. Int J Cancer 2013; 132(11): 2619–2629

[92] Gong TT, Wang YL, Ma XX. Age at menarche and endometrial cancer risk: a dose-response meta-analysis of prospective studies. Sci Rep 2015; 5(1): 14051

[93] Ito M, Yamada M, Hayashi K, Ohki M, Uetani M, Nakamura T. Relation of early menarche to high bone mineral density. Calcif Tissue Int 1995; 57(1): 11–14

[94] Šešelj M, Nahhas RW, Sherwood RJ, Chumlea WC, Towne B, Duren DL. The influence of age at menarche on cross-sectional geometry of bone in young adulthood. Bone 2012; 51(1): 38–45

[95] Chevalley T, Bonjour JP, Ferrari S, Rizzoli R. Influence of age at menarche on forearm bone microstructure in healthy young women. J Clin Endocrinol Metab 2008; 93(7): 2594–2601

[96] Gilsanz V, Chalfant J, Kalkwarf H, Zemel B, Lappe J, Oberfield S, Shepherd J, Wren T, Winer K. Age at onset of puberty predicts bone mass in young adulthood. J Pediatr 2011; 158(1): 100––105.e2

[97] Yoshida S, Ikari K, Furuya T, Toyama Y, Taniguchi A, Yamanaka H, Momohara S. A GC polymorphism associated with serum 25-hydroxyvitamin D level is a risk factor for hip fracture in Japanese patients with rheumatoid arthritis: 10-year follow-up of the Institute of Rheumatology, Rheumatoid Arthritis cohort study. Arthritis Res Ther 2014; 16(2): R75

[98] Roy DK, O’Neill TW, Finn JD, Lunt M, Silman AJ, Felsenberg D, Armbrecht G, Banzer D, Benevolenskaya LI, Bhalla A, Bruges Armas J, Cannata JB, Cooper C, Dequeker J, Diaz MN, Eastell R, Yershova OB, Felsch B, Gowin W, Havelka S, Hoszowski K, Ismail AA, Jajic I, Janott I, Johnell O, Kanis JA, Kragl G, Lopez Vaz A, Lorenc R, Lyritis G, Masaryk P, Matthis C, Miazgowski T, Gennari C, Pols HAP, Poor G, Raspe HH, Reid DM, Reisinger W, Scheidt-Nave C, Stepan JJ, Todd CJ, Weber K, Woolf AD, Reeve J; European Prospective Osteoporosis Study (EPOS). Determinants of incident vertebral fracture in men and women: results from the European Prospective Osteoporosis Study (EPOS). Osteoporos Int 2003; 14(1): 19–26

[99] Silman AJ. Risk factors for Colles’ fracture in men and women: results from the European Prospective Osteoporosis Study. Osteoporos Int 2003; 14(3): 213–218

[100] Mendoza-Romo MA, Ramírez-Arriola MC, Velasco-Chávez JF, Rivera-Martínez JG, de Jesús RN, Valdez-Jiménez LA. Parity and menarche as risk factors for osteoporosis in postmenopausal women. Ginecol Obstet Mex 2014; 82(2): 75–82 (in Spanish)

[101] Cashman KD. Calcium intake, calcium bioavailability and bone health. Br J Nutr 2002; 87(Suppl 2): S169–S177

[102] Masuyama R. Bone and Nutrition. Vitamin D independent calcium absorption. Clin Calcium 2015; 25(7): 1023–1028 (in Japanese)

[103] Sahota O. Understanding vitamin D deficiency. Age Ageing 2014; 43(5): 589–591

[104] Munns C, Zacharin MR, Rodda CP, Batch JA, Morley R, Cranswick NE, Craig ME, Cutfield WS, Hofman PL, Taylor BJ, Grover SR, Pasco JA, Burgner D, Cowell CT; Paediatric Endocrine Group; Paediatric Bone Australasia. Prevention and treatment of infant and childhood vitamin D deficiency in Australia and New Zealand: a consensus statement. Med J Aust 2006; 185(5): 268–272

[105] Kitchin B, Morgan SL. Not just calcium and vitamin D: other nutritional considerations in osteoporosis. Curr Rheumatol Rep 2007; 9(1): 85–92

[106] Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357(3): 266–281

[107] Dibba B, Prentice A, Ceesay M, Stirling DM, Cole TJ, Poskitt EM. Effect of calcium supplementation on bone mineral accretion in gambian children accustomed to a low-calcium diet. Am J Clin Nutr 2000; 71(2): 544–549

[108] Prentice A, Ginty F, Stear SJ, Jones SC, Laskey MA, Cole TJ. Calcium supplementation increases stature and bone mineral mass of 16- to 18-year-old boys. J Clin Endocrinol Metab 2005; 90(6): 3153–3161

[109] Ho SC, Guldan GS, Woo J, Yu R, Tse MM, Sham A, Cheng J. A prospective study of the effects of 1-year calcium-fortified soy milk supplementation on dietary calcium intake and bone health in Chinese adolescent girls aged 14 to 16. Osteoporos Int 2005; 16(12): 1907–1916

[110] Lambert HL, Eastell R, Karnik K, Russell JM, Barker ME. Calcium supplementation and bone mineral accretion in adolescent girls: an 18-mo randomized controlled trial with 2-y follow-up. Am J Clin Nutr 2008; 87(2): 455–462

[111] Du X, Zhu K, Trube A, Zhang Q, Ma G, Hu X, Fraser DR, Greenfield H. School-milk intervention trial enhances growth and bone mineral accretion in Chinese girls aged 10–12 years in Beijing. Br J Nutr 2004; 92(1): 159–168

[112] Winzenberg T, Powell S, Shaw KA, Jones G. Effects of vitamin D supplementation on bone density in healthy children: systematic review and meta-analysis. BMJ 2011; 342: c7254

[113] El-Hajj Fuleihan G, Nabulsi M, Tamim H, Maalouf J, Salamoun M, Khalife H, Choucair M, Arabi A, Vieth R. Effect of vitamin D replacement on musculoskeletal parameters in school children: a randomized controlled trial. J Clin Endocrinol Metab 2006; 91(2): 405–412

[114] Khadilkar AV, Sayyad MG, Sanwalka NJ, Bhandari DR, Naik S, Khadilkar VV, Mughal MZ. Vitamin D supplementation and bone mass accrual in underprivileged adolescent Indian girls. Asia Pac J Clin Nutr 2010; 19(4): 465–472

[115] Al-Shaar L, Nabulsi M, Maalouf J, El-Rassi R, Vieth R, Beck TJ, El-Hajj Fuleihan G. Effect of vitamin D replacement on hip structural geometry in adolescents: a randomized controlled trial. Bone 2013; 56(2): 296–303

[116] Li T.Research progress on pathogenesis of smoking-induced osteoporosis. Chin J Osteoporos (Zhongguo Gu Zhi Shu Song Za Zhi) 2010; 16(5): 381–386 (in Chinese)

[117] Mikosch P. Alcohol and bone. Wien Med Wochenschr 2014; 164(1-2): 15–24

[118] Suh KT, Kim SW, Roh HL, Youn MS, Jung JS. Decreased osteogenic differentiation of mesenchymal stem cells in alcohol-induced osteonecrosis. Clin Orthop Relat Res 2005; (431): 220–225

[119] Lorentzon M, Mellström D, Haug E, Ohlsson C. Smoking is associated with lower bone mineral density and reduced cortical thickness in young men. J Clin Endocrinol Metab 2007; 92(2): 497–503

[120] Dorn LD, Beal SJ, Kalkwarf HJ, Pabst S, Noll JG, Susman EJ. Longitudinal impact of substance use and depressive symptoms on bone accrual among girls aged 11–19 years. J Adolesc Health 2013; 52(4): 393–399

[121] Rudäng R, Darelid A, Nilsson M, Nilsson S, Mellström D, Ohlsson C, Lorentzon M. Smoking is associated with impaired bone mass development in young adult men: a 5-year longitudinal study. J Bone Miner Res 2012; 27(10): 2189–2197

[122] Lucas R, Fraga S, Ramos E, Barros H. Early initiation of smoking and alcohol drinking as a predictor of lower forearm bone mineral density in late adolescence: a cohort study in girls. PLoS One 2012; 7(10): e46940

[123] Winther A, Dennison E, Ahmed LA, Furberg AS, Grimnes G, Jorde R, Gjesdal CG, Emaus N. The Tromsø Study: Fit Futures: a study of Norwegian adolescents’ lifestyle and bone health. Arch Osteoporos 2014; 9(1): 185

[124] Dorn LD, Pabst S, Sontag LM, Kalkwarf HJ, Hillman JB, Susman EJ. Bone mass, depressive, and anxiety symptoms in adolescent girls: variation by smoking and alcohol use. J Adolesc Health 2011; 49(5): 498–504

[125] Lucas R, Fraga S, Ramos E, Barros H. Early initiation of smoking and alcohol drinking as a predictor of lower forearm bone mineral density in late adolescence: a cohort study in girls. PLoS One 2012; 7(10): e46940

[126] Eleftheriou KI, Rawal JS, James LE, Payne JR, Loosemore M, Pennell DJ, World M, Drenos F, Haddad FS, Humphries SE, Sanders J, Montgomery HE. Bone structure and geometry in young men: the influence of smoking, alcohol intake and physical activity. Bone 2013; 52(1): 17–26

[127] Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 2007; 18(10): 1319–1328

[128] Aimaretti G, Corneli G, Rovere S, Croce CG, Ghigo E, Procopio M. Is GH therapy useful to preserve bone mass in transition-phase patients with GH deficiency? J Endocrinol Invest 2005; 28(10 Suppl): 28–32

[129] Antonopoulou M, Bahtiyar G, Banerji MA, Sacerdote AS. Diabetes and bone health. Maturitas 2013; 76(3): 253–259

[130] Mirza F, Canalis E. Management of endocrine disease: secondary osteoporosis: pathophysiology and management. Eur J Endocrinol 2015; 173(3): R131–R151

[131] Duerksen DR, Leslie WD. Positive celiac disease serology and reduced bone mineral density in adult women. Can J Gastroenterol 2010; 24(2): 103–107

[132] Heikkilä K, Pearce J, Mäki M, Kaukinen K. Celiac disease and bone fractures: a systematic review and meta-analysis. J Clin Endocrinol Metab 2015; 100(1): 25–34

[133] Di Stefano M, Mengoli C, Bergonzi M, Corazza GR. Bone mass and mineral metabolism alterations in adult celiac disease: pathophysiology and clinical approach. Nutrients 2013; 5(11): 4786–4799

[134] Laakso S, Valta H, Verkasalo M, Toiviainen-Salo S, Makitie O. Compromised peak bone mass in patients with inflammatory bowel disease—a prospective study. J Pediatr 2014; 164(6): 1436–1443.e1

[135] Faje AT, Karim L, Taylor A, Lee H, Miller KK, Mendes N, Meenaghan E, Goldstein MA, Bouxsein ML, Misra M, Klibanski A. Adolescent girls with anorexia nervosa have impaired cortical and trabecular microarchitecture and lower estimated bone strength at the distal radius. J Clin Endocrinol Metab 2013; 98(5): 1923–1929

[136] Geusens PP, Landewé RB, Garnero P, Chen D, Dunstan CR, Lems WF, Stinissen P, van der Heijde DM, van der Linden S, Boers M. The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destruction. Arthritis Rheum 2006; 54(6): 1772–1777

[137] Magrey MN, Khan MA. The paradox of bone formation and bone loss in ankylosing spondylitis: evolving new concepts of bone formation and future trends in management. Curr Rheumatol Rep 2017; 19(4): 17

[138] Gupta S, Ahsan I, Mahfooz N, Abdelhamid N, Ramanathan M, Weinstock-Guttman B. Osteoporosis and multiple sclerosis: risk factors, pathophysiology, and therapeutic interventions. CNS Drugs 2014; 28(8): 731–742

[139] Ye S, Wu R, Wu J. Multiple sclerosis and fracture. Int J Neurosci 2013; 123(9): 609–616

[140] Coe FL, Worcester EM, Evan AP. Idiopathic hypercalciuria and formation of calcium renal stones. Nat Rev Nephrol 2016; 12(9): 519–533

[141] Khairallah P, Nickolas TL. Updates in CKD-associated osteoporosis. Curr Osteoporos Rep 2018; 16(6): 712–723

[142] Sharma S, Gupta A, Saxena S. Comprehensive clinical approach to renal tubular acidosis. Clin Exp Nephrol 2015; 19(4): 556–561

[143] Fitzpatrick LA. Pathophysiology of bone loss in patients receiving anticonvulsant therapy. Epilepsy Behav 2004; 5(Suppl 2): 3–15

RIGHTS & PERMISSIONS

Higher Education Press