The Determinants of Peak Bone Mass

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WORKSHOP/SYMPOSIUM SUMMARY

The Determinants of Peak Bone Mass Catherine M. Gordon, MD, MSc1, Babette S. Zemel, PhD2, Tishya A. L. Wren, PhD3, Mary B. Leonard, MD, MSCE4, Laura K. Bachrach, MD4, Frank Rauch, MD5, Vicente Gilsanz, MD, PhD3, Clifford J. Rosen, MD6, and Karen K. Winer, MD7

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steoporosis poses a significant health burden for the elderly. Although the medical community recognizes the considerable impact of this disease in adulthood, many primary care providers do not realize that osteoporosis has its origins in childhood and disorders of bone accrual are often ignored. Various factors potentially interfere with gains in bone density and structure during growth and development and add to the risk of osteoporosis in adulthood. Therefore, it is critical to obtain a better understanding of the determinants of bone acquisition, from infancy to early adulthood, and strategies to optimize peak bone mass (PBM). Over one-half of the skeleton is laid down during the teenage years, a period when lifestyle habits may impede optimal bone accrual. The pubertal years are a critical period for bone mass acquisition, but the process by which new tissue produced by the growth plate is turned into metaphyseal bone (endochondral ossification) and the relative roles of androgens, estrogens, and insulin-like growth factors in the adolescent growth spurt requires further investigation. Furthermore, our understanding of the process of modeling, leading to increased bone size and strength, is still lacking. Although there have been significant advances including generation of sex- and racespecific reference data for dual energy x-ray absorptiometry (DXA) bone mineral content (BMC) and areal bone mineral density (areal BMD [aBMD]), large gaps remain in our understanding of bone quality and strength, and in the prevention and treatment of abnormal bone accretion rates in childhood chronic disease. Scientific advances have led to a population of children with chronic illness who live well into their adulthood. Chronic illness poses threats to bone health by interfering with bone accrual and often leads to suboptimal PBM. We recognized the need to account for major advances in the field of pediatric bone health over recent years and, more importantly, the need to identify critical research gaps in this

aBMD BAT BMC BMD CSA CT DMPA DXA EE GCs OCs PBM RCTs vBMD

Areal BMD Brown adipose tissue Bone mineral content Bone mineral density Cross-sectional area Computed tomography Depot medroxyprogesterone acetate Dual energy x-ray absorptiometry Ethinyl estradiol Glucocorticoids Oral contraceptives Peak bone mass Randomized controlled trials Volumetric BMD

area. To address these important issues, a workshop entitled “The Determinants of Peak Bone Mass” was held on November 17-18, 2015 at the National Institutes of Health in Bethesda, Maryland. The workshop was open to the public. This meeting brought together recognized leaders in the field of pediatric and adolescent bone health to discuss the current state of knowledge and identify research priorities. Herein, we summarize highlights of this meeting and discuss advances in our understanding of the development of PBM among children and adolescents. We provide an overview of key research opportunities envisioned to move this field forward.

PBM: When Is It Achieved? Rates of bone mineral accrual follow predictable patterns through childhood and resemble percentile charts for height velocity. Differences in the timing of bone mass accrual are related to sex-specific patterns of pubertal maturation.1 PBM is the amount of bone acquired when accrual ceases or plateaus at some point after completion of growth and development. The greatest gains in bone mass occur approximately 6 months after the adolescent growth spurt,2 but increases in bone mass and density continue for years thereafter. Most estimates of the timing of PBM are based on cross-sectional population surveys from US adolescents and young adults using DXA such as the National Health and Examination Survey.3,4 Estimates of the timing of PBM based on longitudinal changes in DXA-measured aBMD (or 2-dimensional BMD), as were obtained in the Canadian Multicenter Osteoporosis Study, are similar, except for total hip aBMD among females.5 One of the primary aims of Canadian Multicenter Osteoporosis Study has been to identify factors associated with osteoporosis and fracture during adulthood. The study’s longitudinal design adds significant value. Other recent studies identified lifestyle factors that affect PBM during the transition to young adulthood. An early study of college age women found substantial gains in

From the 1Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH; 2Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA; 3Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA; 4Stanford University School of Medicine, Stanford, CA; 5Shriners Hospital for Children, McGill University, Montreal, Canada; 6 Maine Medical Center Research Institute, Scarborough, ME; and 7Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD The workshop was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health Office of the Director, Office of Research on Women’s Health, Office of Dietary Supplements, the National Osteoporosis Foundation, and the American Society for Bone and Mineral Research. C.G. served on the Editorial Board of The Journal of Pediatrics (20112013). The other authors declare no conflicts of interest. 0022-3476/$ - see front matter. © 2016 Elsevier Inc. All rights reserved. http://dx.doi.org10.1016/j.jpeds.2016.09.056

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bone mass and density in the third decade of life (eg, 6.8% increase in lumbar spine aBMD). Gains were associated with dietary intake (calcium/protein ratio) and physical activity.6 A more recent 5-year prospective longitudinal study of young Swedish men, ages 18-24 years, showed that gains in aBMD were related to the timing of adolescent growth spurt and changes in physical activity.7,8 Later timing of the adolescent growth spurt was associated with lower cortical and trabecular volumetric BMD (vBMD) and cortical thickness of the radius and tibia, and lower DXA aBMD of the total body, spine, femoral neck, and radius. Moreover, in follow-up of this cohort, gains in tibial cortical cross-sectional area (CSA) were positively associated with changes in physical activity and adversely affected by initiation of smoking. 9 Quantitative computed tomography (CT) measures of cortical and trabecular bone show very different trajectories of PBM. Trabecular losses in the peripheral skeleton are already occurring among young adults in their early 20s, but cortical losses occur later, well after age 40.10,11 In the axial skeleton, bone acquisition reaches peak values at the time of sexual and skeletal maturity and reported increases in DXA measures of bone are likely due to the influence of soft tissues, rather than to changes in bone acquisition within the vertebral body.12 Thus, the timing of PBM is dependent upon the skeletal site and bone compartment under consideration, sex, maturational timing, and lifestyle factors.

teoporosis has been considerably greater for the axial than appendicular skeleton. Accumulating evidence suggests that diminished bone accrual in girls is the basis for the lower PBM in young women, which, in turn, is a major determinant of their 2- to 4-fold higher incidence of vertebral fractures compared with men. Available data also indicate that sex differences in PBM in the axial skeleton are the consequence of differences in vertebral growth, rather than in bone density.26 The CSA of the lumbar vertebrae is 25% smaller in young women than men, even after accounting for body size. This disparity is also present in children and has most recently been found to be present as early as infancy; newborn girls across races/ethnicities have, on average, 10.6% smaller vertebral cross-sectional dimensions when compared with newborn boys.26 Because the CSA of the vertebral body is a major determinant of its compressive strength, the smaller vertebral CSA of females imparts a mechanical disadvantage that increases the stress within vertebrae for all physical activities, and if such stress persists, the susceptibility for fragility fractures later in life. The smaller female vertebral CSA also results in greater flexion/extension and lateral flexion. Because greater flexibility of the spine may facilitate the lordosis needed to maintain upright posture, it could be hypothesized that fetal load during pregnancy is a selection factor in the evolution of the discrepant spinal morphology between the sexes in humans.

Genetics of PBM

Bone Strength Accrual, Tracking of Bone Mass, and Fracture Risk

Osteoporosis has a strong heritable component,13 as suggested by differences in aBMD for population ancestry groups,1,14 and familial heritability estimates.13,15 Earlier candidate gene and family studies identified the vitamin D receptor,16 collagen 1 alpha 1,17 and low-density lipoprotein receptor-related protein 518,19 as determinants of BMD. In adults, genome-wide association studies have identified 56 loci associated with BMD and 14 loci associated with osteoporotic fracture.20 Many loci are also associated with BMD in childhood, some with sex- and puberty-specific effects,21,22 and their mechanism of action warrants further study. The rare variant, EN1,23,24 and a common variant near SOX6,24 each associate with high bone density in both children and adults,24 suggesting that the risk of osteoporosis may be established during childhood. Recent studies that used a “genetic risk score” based on loci identified in adult bone studies have shown that genetic risk for low BMD in adulthood was associated with decreased bone accretion from age 9 to 17 years.25 Further studies are needed to determine the interaction of genetic predisposition with modifiable factors such as diet and physical activity in determining the timing and magnitude of PBM. Sex Differences in Bone Accrual and Structure An area of progress in osteoporosis research is the identification of the structural basis accounting for much of the variation in bone strength among humans. Progress in elucidating the structural basis for sex differences in the prevalence of os262

Among healthy children, approximately one-half of boys and one-third of girls will sustain a fracture by age 18 years.27 The skeleton is particularly vulnerable to fracture during early adolescence when linear bone growth may outpace bone mineralization, causing a transient increase in bone fragility.28 Children of European vs African ancestry have a greater fracture risk. Although physical activity is critical to building bone, it is noteworthy that more active children have greater exposure to trauma that may cause fractures.29 Bone characteristics during childhood and adolescence are associated with childhood fracture risk. Children with forearm fractures tend to have lower bone mass, areal and vBMD, and cortical thickness, area, and density. A 1 SD decrease in bone mass or density has been associated with a substantial increase in fracture risk.30 Forearm fractures reflect deficits in bone mineral throughout the skeleton, not just at the forearm. Fractures occur when loading exceeds skeletal strength. Strength depends on both geometric properties (size, shape) and material properties (density). The properties contributing most significantly to fracture risk differ depending on the skeletal site. Optimizing bone strength accrual during growth is important for fracture prevention. During growth, vertebral cancellous density is stable in both boys and girls prior to puberty, increasing significantly between the ages of 12 and 17 years for boys and 10 and 15 years for girls.31 Density is similar for black and white children through Tanner stage 3, but diverges with higher density in blacks at Tanner stages 4 Gordon et al

January 2017 and 5.32 Vertebral CSA increases throughout growth and is larger in males than females of similar stature at all ages, even at birth.33 No differences in vertebral CSA are seen based on race. In the appendicular skeleton, cortical bone area at the midshaft of the femur increases during growth, correlated with body weight independent of race and sex.34 Metaphyseal growth is more difficult to characterize.35 In contrast to the axial skeleton, appendicular bone properties do not peak because the periosteum and endosteum continue to expand throughout life.36 Longitudinal growth during the adolescent years is rapid compared with other periods. As the rate of longitudinal growth increases during puberty, the age of the bone structural elements at a given distance to the growth plate decreases, leaving less time for cortical thickening through trabecular coalescence.28 This leads to a discrepancy between older and more stable metaphyseal bone and recently formed bone. A greater volume of newer bone compromises bone strength if challenged with increased mechanical loading. In comparison with the metaphysis, diaphyseal bone develops more in line with the increasing mechanical requirements, presumably because the bone formation rates needed for diaphyseal growth in width are only a fraction of the metaphyseal apposition rates. How local and systemic signals are integrated to achieve site-specific changes in bone structure is not understood. The timing of puberty has a significant impact on bone development and a large number of endocrine and other health-related outcomes.37,38 Delayed puberty is associated with lower bone density at maturity, which may track into adulthood. How hormonal changes during puberty interact with mechanical factors to change bone structure and strength merits further study. Bone measures “track” longitudinally quite strongly from childhood through young adulthood, with a transient decline during early adolescence.39,40 This provides strong evidence that bone status during childhood predicts PBM. However, lifestyle factors such as changes in physical activity, nutrition, and adiposity can alter bone status. Second hand smoke was shown to be associated with osteoporosis in postmenopausal women, which is a potential environmental pathogen that has not yet been evaluated in children.41 Identification of factors that positively or negatively influence bone accrual may provide insights into interventions that may optimize PBM. This may be particularly important for vulnerable patient populations such as those with decreased physical activity and loading of the skeleton because of mobility impairments.42 Research is needed to understand the magnitude and type of bone deficits typical of different patient populations to mitigate fracture risk during childhood and as these patients age.

The Regulation of Bone Acquisition Skeletal growth is driven by myriad endocrine modulators, cytokines, and growth factors, which act both systemically and locally.43 More than one signal likely originates from osteoblasts and osteocytes that regulate insulin sensitivity and secretion, as well as phosphate balance.44,45 The skeletal matrix itself also contains growth factors and peptides that are reThe Determinants of Peak Bone Mass

WORKSHOP/SYMPOSIUM SUMMARY leased during bone remodeling.46 In turn, bone is a recipient of multiple signals not only from the classic calcium regulating hormones (eg, parathyroid hormone, calcitonin, estrogens, and androgens), but also from other tissues, through both endocrine and paracrine pathways. With respect to the latter, neighboring muscle and adipose tissue exert significant control over bone remodeling and in turn, there is an impact on afferent signals from the skeleton back to other tissues. Hence, a major challenge for investigators is to unravel this complex and redundant system. Delineating such systems is made even more challenging by the many processes involved in peak bone acquisition. Peak bone acquisition likely begins before birth, with genetic programming and epigenetic modifications. Recent studies have shown that dietary modifications (caloric- and nutrientspecific) in both rodents and humans can impact that genetic program, leading to subsequent changes in trajectories for skeletal modeling and consolidation.47 Interestingly, genomewide association studies have identified shared determinants from genetic programming that affect the composition of muscle fat and bone.48 In addition to those determinants, epigenetic marks that affect fetal and postnatal cell growth and differentiation can ultimately define body composition in the child.49 Decisions related to cell fate occur in niches that are found in vessels, in muscle and adipose tissue stroma, and most importantly in the bone marrow, which has been a focus of recent investigations. For example, it has been well established that bone marrow in the appendicular skeleton changes from a purely hematopoietic composition to primarily adipogenic during childhood growth.50 This process begins early in life and reaches a peak at the time of maximum bone acquisition, suggesting that there may be an important but poorly defined relationship between adipocytes and osteoblasts during adolescence. Moreover, these changes are very context- and location-specific because increased bone marrow adiposity in the aging individual is paradoxically associated with bone loss.51 Thus, a major challenge for investigators is defining how signals between adipocytes and osteoblasts in situ can impact skeletal growth and acquisition in vivo. One novel approach has been to create artificial bone marrow niches in which all the cellular elements can coexist in a 3-dimensional matrix that mimics skeletal composition.52 It has long been recognized that endocrine signals modulate the timing and magnitude of peak acquisition, although only recently has the role of other tissues interfacing with bone been shown to have additional, yet, important influences on the magnitude of skeletal growth and maintenance. There is no doubt that circulating estrogens, androgens, and growth hormone, secreted in a critical and temporal manner, define specific trajectories for peak bone acquisition during adolescence. However, adipose and muscle mass and composition, also modulated by sex steroids and growth hormone, contribute significantly to final adult bone density. Moreover, with respect to adipose tissue, there may be regulatory determinants that are tissue-specific. For example, recent data from several groups have shown that greater brown adipose tissue (BAT) volume is associated with greater cortical bone density 263

THE JOURNAL OF PEDIATRICS • www.jpeds.com and thickness, as well as higher muscle mass.53,54 The link between BAT and skeletal growth in children remains unknown. Similarly, subcutaneous “white” adipose tissue that surrounds muscle and bone may also be related to higher bone density; on the other hand, higher visceral fat mass, as seen in adolescent type 2 diabetes, is associated with lower trabecular bone volume fraction as measured by CT.55 Interestingly, BAT vs white adipose tissues also differ with respect to their insulin sensitivity and have varying effects on metabolic homeostasis and skeletal acquisition.

Impact of Childhood Chronic Diseases and Glucocorticoid Therapy on Bone Accrual Chronic diseases and their therapies pose threats to musculoskeletal development. The impact may be immediate, resulting in fragility fractures during childhood,56-60 or delayed, because of suboptimal PBM and consequent fractures in adulthood.61,62 Glucocorticoids (GCs) are highly effective for the treatment of many childhood diseases but are associated with adverse effects on osteoblast, osteocyte, osteoclast, and muscle cell metabolism. GCs result in significant reductions in bone formation because of decreased differentiation of osteoblast precursors, impaired osteoblast function, and decreased osteoblast lifespan. 63,64 GC therapy results in early increases in bone resorption as a result of enhanced osteoclastogenesis and osteoclast survival; however, this effect is transient and followed by reductions in osteoclast differentiation and function.65 Finally, GCs adversely affect muscle mass and function through decreased protein synthesis and increased protein catabolism.66 Given the rapid bone accrual that characterizes skeletal modeling during growth, and importance of the anabolic effects of biomechanical loading, the growing skeleton is uniquely vulnerable to the effects of GCs on bone formation and muscle metabolism. Numerous DXA studies reported lower aBMD in children with chronic inflammatory diseases treated with GCs. However, imaging methods that provide insight into site-specific abnormalities in trabecular and cortical vBMD and cortical dimensions (periosteal and endosteal) are needed to understand the impact on bone strength and identify therapeutic targets. Prior DXA studies in children treated with GCs were confounded by GC effects to impair growth, resulting in underestimates of areal BMD for age.67 The differing impact of inhaled vs enteral/parenteral administration on bone health outcomes is also important to consider. A recent systematic review and meta-analysis concluded that ≥12 months of inhaled GCs in children and adults with asthma was not associated with adverse effects on fractures or BMD.68 However, the detrimental effect of inhaled GCs on height, a variable that impacts the interpretation of BMD in pediatric patients, is significant and can persist into adulthood.69-71 Both glucocorticoids and inflammation are associated with decreased trabecular vBMD, periosteal circumference, and consistent bone formation; inflammation is associated with endocortical bone loss consistent with increased bone resorption. The fact that studies in children and adolescents treated 264

Volume 180 with GC demonstrated impaired ability of periosteal expansion to keep pace with linear growth confirms the vulnerability of the growing skeleton. This will likely have lifelong and irreversible implications for fracture risk. Exercise Periods of growth are characterized by high rates of bone modeling and remodeling. Adolescence is considered the best time to strengthen bone because periosteal surfaces are rapidly growing. Physical activity during the rapid growing years of adolescence adds bone mass to periosteal surfaces that enhance bone strength. All physical activity is not necessarily beneficial for bone. Targeted, impact- and muscle-loading physical activities that are moderate-to-high magnitude, rapid and oddimpact (have an effect on the entire circumference of bones, achieved by incorporating motions in many directions) have produced significant results in bone size. Two randomized, controlled trials conducted by Gunter et al72,73 showed that 7-to 8-year-old children who participated in high-impact jumping interventions for 7 months experienced some maintenance of increased BMC years after the cessation of training. This cohort was followed for another 7 years after the cessation of the boxjumping intervention, with benefits to the hip persisting, and jumpers maintained a benefit in hip BMC compared with nonjumpers.74 Further study is necessary to determine if these benefits continue throughout adulthood in the absence of continued exercise.75-77 Contraception Data regarding the effect of combined oral contraceptives (OCs) on bone density among adolescent girls are inconsistent. In one study, OC use by healthy teenage girls did not affect PBM acquisition.78 However, some data suggest that long-term receipt of an oral monophasic contraceptive formulation (ethinyl estradiol 20 mg + desogestrel 0.150 mg) may result in suboptimal PBM.79 The skeletal effects of combined OCs are of particular concern in adolescents compared with adult women.80,81 Initiation of combined OCs within the first 3 years after menarche appears to be of highest concern.81 These preparations may suppress the hypothalamic-pituitary-ovarian axis, thereby decreasing endogenous estradiol production. Ultralow-dose OCs containing 20 mg of ethinyl estradiol (EE) are of most concern, although some studies in adolescents have inherent limitations such as small sample size, inclusion of smokers, and poor accounting for other confounders.82 A recent clinical trial examining the skeletal effect of 20 vs 30 mg EE OCs vs control subjects showed subnormal bone accrual only in the 20 mg EE recipients (compared with other groups).83 Whether changes in BMD are reversible is unknown and merits investigation. Contraception via depot medroxyprogesterone acetate (DMPA) injections is associated with skeletal deficits at the spine and hip among adolescents. DMPA acts on the skeleton mainly through estrogen deficiency.84 However, bone loss in adolescent girls receiving DMPA for contraception is partly or fully reversible following discontinuation of DMPA, with faster recovery at the spine compared with hip.85 DMPA is still Gordon et al

January 2017 recommended for use in adolescents, but with caution given potential deleterious skeletal effects. Both the American Academy of Pediatrics and American Congress of Obstetricians and Gynecologists have published guidelines to increase the use of long-acting reversible contraception in adolescents. Studies in women suggest neither levonorgestrel-releasing intrauterine systems86 nor levonorgestrel intrauterine devices87 to be associated with skeletal losses. The impact on bone accrual in adolescents should be investigated. However, the data that are available are encouraging and suggest the skeletal effects of these implants and intrauterine devices are less than that associated with DMPA. Calcium and Vitamin D Nutritional variables are important modifiable factors that impact bone health. Over 99% of the body’s calcium is found in skeletal stores, serving as a reserve in the face of deficiency and playing an essential role in calcium homeostasis.88 Vitamin D optimizes intestinal calcium absorption and therefore, affects bone mineralization.89 Traditionally, supplementation with these 2 nutrients has been the mainstay of osteoporosis prevention. A 6-year longitudinal assessment of calcium intake on bone in a large diverse study cohort of 1743 children found that dietary calcium had a positive effect, after adjustment for age, height velocity, and physical activity, on bone accrual at the lumbar spine in nonblack females90 with no effect on other ethnic groups or in males. In a recent review,91 of 9 randomized controlled trials (RCTs), all but one found small (1%5%) gains, associated with oral calcium, on bone accrual by DXA. Only 4 of the RCTs, however, used adjustment for body size.92-94 This is noteworthy as longitudinal growth complicates interpretation of changes in bone mass and density variables. Vitamin D is another important nutrient for bone health. Since 2000, 8 RCTs have been conducted, with daily vitamin D doses ranging from 200 to 2000 IU/day and have targeted females ages, 10 and 17 years95-102 and males, ages 11-63 years.95,101 Of note, the mean baseline serum 25-hydroxyvitamin D concentration for all RCTs was between 18 and 48 nmol/L (45 and 120 ng/mL),91 which is lower than the 50 nmol/L (20 ng/mL) accepted threshold for vitamin D sufficiency.103 Four RCTs conducted in Lebanon, Finland, China, and the United Kingdom provide evidence to support the effects of vitamin D supplementation on childhood and adolescent bone mineral accrual to improve hip BMC in females only. In subgroup analyses, the vitamin D effect was more pronounced in prepubertal or early pubertal vs postpubertal girls, as well as in those with a lower compared with higher baseline 25-hydroxyvitamin D. Therefore, there may be a “critical window” during which the skeleton is most receptive to the effects of vitamin D.

Nutritional Deprivation Chronic illness affecting absorption of nutrients such as inflammatory bowel disease or celiac disease may be associated with malnutrition-induced growth failure and abnormal bone The Determinants of Peak Bone Mass

WORKSHOP/SYMPOSIUM SUMMARY accrual. Anorexia nervosa, another form of nutritional deprivation, is associated with decreased fat, muscle, and bone mass and a cascade of hormonal alterations.104,105 Teenage girls with anorexia nervosa have reduced aBMD,106 suppressed bone formation and resorption markers,107 and reduced bone accrual, especially at the lumbar spine.108,109 Some studies suggest that bone structural variables are altered in this disease that may explain the increased fracture risk.110 Adolescent boys with anorexia nervosa also have lower aBMD at multiple skeletal sites.111 Importantly, fracture rate is increased among these adolescents, potentially as high as 7-fold.112 Given the high incidence of eating disorders among contemporary youth, clinical trials are underway to identify pharmacologic strategies to counter bone loss in these young patients.113

Future Directions This National Institutes of Health conference demonstrated the considerable progress made over the last decade to understand the complex factors controlling skeletal growth and acquisition of PBM. Numerous studies have demonstrated that the pace of bone accrual varies by sex, race, and maturation. The discovery that bone accrual tracks over time, in a similar manner to linear growth, has important implications for its potential long-term impact on bone health into adulthood. Over one-half the skeleton is laid down during the teenage years, when onset of chronic disease or unhealthy lifestyle habits may impede optimal bone accrual. Limited studies using peripheral quantitative CT have demonstrated that gains in appendicular cortical bone density and thickness continue into the third decade of life, even though trabecular density may decline over the same interval.10,114-116 The impact of these opposing changes on bone strength is not known. In spite of major scientific advances, the burden of care associated with osteoporosis and fragility fractures continues to grow at a rate exceeding that of inflation. There are multiple bases for this disparity, including our escalating elderly population and the relative ineffectiveness of treatments at the later stages of disease. To overcome current treatment limitations and effectively reduce the costs associated with osteoporosis, research should be geared toward optimizing bone accrual in childhood. PBM is one of the most important factors in preventing osteoporosis; epidemiologic studies suggest that a 10% increase in PBM at the population level would decrease the risk of fracture later in life by 50%.117 Pediatricians who care for patients with chronic illness need more information on how various disorders and their therapies affect bone mass acquisition. Primary bone disorders in children are relatively uncommon. In contrast, unhealthy lifestyle habits or acquired disorders such as asthma, inflammatory bowel disease, or malignancy, and the pharmacologic agents used to treat them represent a more frequent threat to optimal bone accrual and PBM. In the coming years, the research focus should shift to the impact of risk factors and interventions on peak bone strength (as opposed to bone mass or density). Longitudinal studies in children with diabetes mellitus, anorexia nervosa, malignancy, and other chronic disorders are 265

THE JOURNAL OF PEDIATRICS • www.jpeds.com needed to better understand the paracrine and endocrine effects of fat and muscle on PBM. Observations from animal models may also provide insight into human physiology.45 Longitudinal studies using high-resolution modalities are needed to determine how genetic, physiologic, and lifestyle factors influence trabecular and cortical compartments, bone geometry and microarchitecture, and ultimately, bone strength. What are the factors directing this development? When is peak bone strength achieved and how long is it maintained? These studies are necessary to develop strategies to maximize peak bone strength, to intervene in disorders that impede skeletal development, and to determine how long these interventions should last. How long is the window of opportunity to reverse or ameliorate deficits in bone? Which pharmacologic agents might counteract inflammation, immobilization, and other threats to acquisition of bone strength? What is the optimal anticatabolic agent(s), including dose and duration of use? Is there an anabolic agent that is safe for growing patients? What is the role for nonpharmacologic interventions such as mechanical stimulation? Are the effects of anabolic agents used during growth maintained into adulthood? The above knowledge gaps can best be addressed through multidisciplinary collaborations. Multicenter studies have an important role in pediatric clinical trials by enabling investigators to share knowledge and resources and to provide larger numbers of children of various ages from diverse backgrounds to assure more accurate clinical information. Lastly, there is a need to increase awareness among health care providers regarding risk factors for bone fragility from infancy through adolescence. Osteoporosis prevention should begin at birth and pediatricians should be educated about strategies to optimize bone acquisition. The robust DXA reference data generated by the NICHD-funded Bone Mineral Density in Childhood Study, and the evidence that DXA predicts fractures in healthy children and adolescents1,29,40 and those with chronic disease 59,118 represent important advances. However, the utility of DXA is limited in the absence of an evidence-based arsenal of strategies to optimize bone mass and strength. Research support for pediatric bone health has lagged far behind the support for investigations of osteoporosis in adults. The optimization of PBM has lifelong health benefits and warrants significant investment in this research. ■ We acknowledge the important contributions of the workshop speakers: Kathleen Janz, EdD, Ron Rosenfeld, MD (serves as a consultant for OPKO Health Inc, Novo Nordisk, Pfizer, Ferring, Merck, Ascendis, Versartis, and Genexine), Gerard Karsenty, MD, Heidi Kalkwarf, PhD, Madhusmita Misra, MD, Connie Weaver, PhD (receives funding from the Alliance of Potato Research and Education), Richard Lewis, PhD, Joan Lappe, PhD, Jin-Ran Chen, PhD, and Struan Grant, PhD. We also thank Taylor Wallace, PhD, for his support in all aspects of the meeting’s planning and execution and for the generous support of the National Osteoporosis Foundation. Submitted for publication Jul 14, 2016; last revision received Aug 19, 2016; accepted Sep 26, 2016 Reprint requests: Catherine M. Gordon, MD, MSc, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC 4000, Cincinnati, OH 45229. E-mail: [email protected]

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References 1. Zemel BS, Kalkwarf HJ, Gilsanz V, Lappe JM, Oberfield S, Shepherd JA, et al. Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study. J Clin Endocrinol Metab 2011;96:3160-9. 2. Bailey DA, McKay HA, Mirwald RL, Crocker PR, Faulkner RA. A sixyear longitudinal study of the relationship of physical activity to bone mineral accrual in growing children: the university of Saskatchewan bone mineral accrual study. J Bone Miner Res 1999;14:1672-9. 3. Looker AC, Borrud LG, Hughes JP, Fan B, Shepherd JA, Melton L Jr. Lumbar spine and proximal femur bone mineral density, bone mineral content, and bone area: United States, 2005-2008. Vital Health Stat 2012;11:1-132. 4. Kelly T, Wilson KE, Heymsfield SB. Dual energy x-ray absorptiometry body composition reference values from NHANES. PLoS ONE 2009;4:e7038. 5. Berger C, Goltzman D, Langsetmo L, Joseph L, Jackson S, Kreiger N, et al. Peak bone mass from longitudinal data: implications for the prevalence, pathophysiology, and diagnosis of osteoporosis. J Bone Miner Res 2010;25:1948-57. 6. Recker RR, Davies KM, Hinders SM, Heaney RP, Stegman MR, Kimmel DB. Bone gain in young adult women. JAMA 1992;268:2403-8. 7. Kindblom JM, Lorentzon M, Norjavaara E, Hellqvist A, Nilsson S, Mellström D, et al. Pubertal timing predicts previous fractures and BMD in young adult men: the GOOD study. J Bone Miner Res 2006;21: 790-5. 8. 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;24:125-33. 9. Rudäng R, Darelid A, Nilsson M, Nilsson S, Mellström D, Ohlsson C, et al. Smoking is associated with impaired bone mass development in young adult men: a 5-year longitudinal study. J Bone Miner Res 2012;27:2189-97. 10. Riggs B, Melton LJ, Robb RA, Camp JJ, Atkinson EJ, McDaniel L, et al. A population-based assessment of rates of bone loss at multiple skeletal sites: evidence for substantial trabecular bone loss in young adult women and men. J Bone Miner Res 2008;23:205-14. 11. Khosla SS, Melton LJ 3rd, Achenbach SJ, Oberg AL, Riggs BL. Hormonal and biochemical determinants of trabecular microstructure at the ultradistal radius in women and men. J Clin Endocrinol Metab 2006;91:885-91. 12. Wren TA, Kim P, Janicka A, Sanchez M, Gilsanz V. Timing of peak bone mass: discrepancies between CT and DXA. J Clin Endocrinol Metab 2007;92:938-41. 13. Krall EA, Dawson-Hughes B. Heritable and life-style determinants of bone mineral density. J Bone Miner Res 1993;8:1-9. 14. 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;84:4702-12. 15. Seeman EE, Hopper JL, Bach LA, Cooper ME, Parkinson E, McKay J, et al. Reduced bone mass in daughters of women with osteoporosis. N Engl J Med 1989;320:554-8. 16. Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, et al. Prediction of bone density from vitamin D receptor alleles. Nature 1994;367:284-7. 17. Grant SF, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH. Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet 1996;14:203-5. 18. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 2002;346:1513-21. 19. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 2002;70:119.

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