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Bone plays an important role in regulating mineral balance in response to physiologic needs. In addition, bone is subject to a continuous remodeling process to maintain healthy bone mass and growth. Metabolic bone diseases are a heterogeneous group of diseases caused by abnormalities of bone mass, mineral structure homeostasis, bone turnover, or bone growth. In pediatrics, several significant advances have been made in recent years in the diagnosis of metabolic bone diseases (e.g., osteogenesis imperfecta, hyperparathyroidism, rickets, renal osteodystrophy, pediatric osteoporosis, and osteopetrosis). Imaging is fundamental in the diagnosis of these pathologies.

Background There have been new advances in understanding bone remodeling on a molecular level including the RANKL-OPG pathway, leading to advancements in targeted therapeutic intervention. There is however limited data in pediatrics with little known on normative values in healthy children. This is the largest cohort to quantify RANKL, OPG, and RANKL: OPG levels in healthy children as well as study the influence of age, gender, Tanner stage, and BMI in this population. Methods Healthy subjects, 1–21 years of age, were recruited from general pediatric clinics affiliated with CHLA and in collaboration with samples stored from a previously completed study. Healthy children were defined as those with no chronic disease, daily medication, or fractures in the past six months. Free soluble RANKL and OPG levels were quantified using a sandwich ELISA. Results Three hundred samples were collected with overall serum concentrations of RANKL, OPG and RANKL: OPG of 0.28 pmol/L, 3.56 pmol/L and 0.08 pmol/L, respectively. Serum RANKL and RANKL: OPG concentrations were significantly different by age (p = 0.0001 and 0.0027, respectively). There was an overall downward trend by age except in the 11–15-year age group where a slight increase was noted. RANKL concentrations were also significantly different between Tanner stages, with highest concentrations seen at Tanner 3 (p = 0.0481), and zBMI (p = 0.001). OPG was inversely correlated with zBMI, but not influenced by gender, age, or Tanner stage. Conclusion We showed significant difference in RANKL levels by age, Tanner stage, and zBMI. OPG was inversely correlated with zBMI. Insight into circulating levels of RANKL, OPG and RANKL: OPG in healthy children may be a potential tool to better understand disease states in pediatrics. Future studies are needed to evaluate the clinical significance of RANKL and OPG levels for diagnostic and therapeutic purposes in this population.

Introduction Zoledronic acid (ZA) is an intravenous bisphosphonate used to treat pediatric osteoporosis. Adverse events including hypocalcemia and acute phase reaction (APR) are common following first-infusion. The purpose of this report is to describe implementation of a ZA clinical practice guideline and the subsequent process changes to improve adherence to aspects of the protocol related to safety and efficacy. Methods Quality assurance was evaluated by chart review over a 5-year period to compare the prevalence of hypocalcemia and APR to published data. A quality improvement (QI) initiative consisting of process changes including the addition of an endocrine RN to coordinate infusions and a shift to patient/family self-scheduling of infusions was conducted. The effect of the interventions on safety (completion of pre- and post-infusion bloodwork) and efficacy (receipt of all prescribed infusions) outcomes was evaluated. Results Seventy-two patients received 244 infusions over the period. The frequency of hypocalcemia (22%) and APR (31%) was consistent with prior reports. 99% of patients received pre-infusion bloodwork, 78% received post-first-infusion bloodwork, and 47% received all prescribed infusions. QI initiatives increased the percentage of patients receiving post-first-infusion bloodwork from 67 to 79% and those receiving all infusions from 62 to 74%, but fell short of the goal of 90%. Conclusions The implementation of a standardized protocol for ZA use in children was successful in confirming patient eligibility with pre-infusion bloodwork but failed to ensure that patients obtained post-first-infusion bloodwork and received all prescribed infusions. Further efforts to systematize the management of children on ZA are needed. Supplementary Information The online version contains supplementary material available at 10.1007/s00774-021-01214-5.

Numerous forms of osteoporosis in childhood are characterized by low bone turnover (for example, osteoporosis due to neuromuscular disorders and glucocorticoid exposure). Anti-resorptive therapy, traditionally used to treat osteoporosis in the young, is associated with further reductions in bone turnover, raising concerns about the long-term safety and efficacy of such therapy. These observations have led to increasing interest in the role of anabolic therapy to treat pediatric osteoporosis. While growth hormone and androgens appears to be relatively weak anabolic modulators of bone mass, emerging therapies targeting bone formation pathways (anti-transforming growth factor beta antibody and anti-sclerostin antibody) hold considerable promise. Teriparatide remains an attractive option that merits formal study for patients post-epiphyseal fusion, although it must be considered that adult studies have shown its effect is blunted when administered following bisphosphonate therapy. Mechanical stimulation of bone through whole body vibration therapy appears to be much less effective than bisphosphonate therapy for treating osteoporosis in children. New anabolic therapies which target important pathways in skeletal metabolism merit further study in children, including their effects on fracture risk reduction and after treatment discontinuation.

This review summarizes our current knowledge on primary osteoporosis in children with focus on recent genetic findings. Advances in genetic research, particularly next-generation sequencing, have found several genetic loci that associate with monogenic forms of inherited osteoporosis, widening the scope of primary osteoporosis beyond classical osteogenesis imperfecta. New forms of primary osteoporosis, such as those related to WNT1, PLS3, and XYLT2, have identified defects outside the extracellular matrix components and collagen-related pathways, in intracellular cascades directly affecting bone cell function. Primary osteoporosis can lead to severe skeletal morbidity, including abnormal longitudinal growth, compromised bone mass gain, and noticeable fracture tendency beginning at childhood. Early diagnosis and timely care are warranted to ensure the best achievable bone health. Future research will most likely broaden the spectrum of primary osteoporosis, hopefully provide more insight into the genetics governing bone health, and offer new targets for treatment.

Osteoporosis is an under-recognized complication of chronic illness in childhood. This review will summarize recent literature addressing the risk factors, evaluation, and treatment for early bone fragility. Criteria for the diagnosis of pediatric osteoporosis include the presence of low trauma vertebral fractures alone or the combination of low bone mineral density and several long bone fractures. Monitoring for bone health may include screening for vertebral fractures that are common but often asymptomatic. Pharmacologic agents should be offered to those with fragility fractures especially when spontaneous recovery is unlikely. Controversies persist about the optimal bisphosphonate agent, dose, and duration. Newer osteoporosis drugs have not yet been adequately tested in pediatrics, though clinical trials are underway. The prevalence of osteoporosis is increased in children with chronic illness. To reduce the frequency of fragility fractures requires increased attention to risk factors, early intervention, and additional research to optimize therapy and potentially prevent their occurrence.

Objectives:\ud To explore the prevalence and anatomic distribution of vertebral fractures in disease groups investigated for primary and secondary osteoporosis, using vertebral fracture assessment (VFA).\ud \ud Study design:\ud VFA was performed independently by 2 nonradiologists, in 165 children (77 males, 88 females) as part of their investigation for osteoporosis. Vertebral bodies from T6 to L4 were assessed for vertebral fractures using the Genant scoring system. The common readings for the presence of vertebral fractures were used for evaluating the prevalence and anatomic distribution of vertebral fractures.\ud \ud Results:\ud The median age of the subjects was 13.4 years (range, 3.6, 18). Of the 165 children, 24 (15%) were being investigated for primary bone disease, and the remainder had a range of chronic diseases known to affect bone health. Vertebral fractures were identified in 38 (23%) children. The distribution of the vertebral fractures was bimodal, with vertebral fractures peaks centered at T9 and L4. Conditions associated with increased odds for vertebral fractures were inflammatory bowel disease (OR, 3.3; 95% CI, 1.4, 8.0; P = .018) and osteogenesis imperfecta (OR, 2.3; 95% CI, 1.04, 5.8; P = .022). Among children with vertebral fractures, those with Duchenne muscular dystrophy (P = .015) and osteogenesis imperfecta (P = .023) demonstrated higher number of vertebral fractures than the other disease groups.\ud \ud Conclusions:\ud VFA identified the presence of vertebral fractures, in a bimodal distribution, in both primary bone disease and chronic disease groups. VFA is a practical screening tool for identification of vertebral fractures in children and adolescents at risk of fragility fractures.

WNT proteins comprise a 19-member glycoprotein family that act in several developmental and regenerative processes. In bone, WNT proteins regulate osteoblast differentiation and maintain bone health by activating the canonical WNT/β-catenin pathway. We reported a heterozygous missense mutation c.652T>G (p.C218G) in WNT1 exon 4 as the cause for severe early-onset, autosomal dominant osteoporosis. The initial study concerned a large Finnish family with 10 affected adults. Here we report clinical findings of the WNT1 osteoporosis in 8 children and young adults (median age 14 years; range 10 to 30 years) in two families, all with the p.C218G mutation in WNT1. Clinical assessments showed no apparent dysmorphia or features similar to typical osteogenesis imperfecta (OI). Biochemistry revealed no changes in parameters of calcium metabolism and bone turnover markers. Fracture frequencies varied, but all subjects had sustained at least one fracture and 4 had a pathological fracture history. Plain radiographs showed osteopenic appearance, loss in vertebral height, and thin diaphyses of the long bones. Bone densitometry showed the BMD to be below normal median in all subjects and the bone mass deficit seemed to be more severe in older participants. Bone histomorphometry revealed a low turnover osteoporosis in 2 subjects at ages 14 and 16 years. These findings are congruent with earlier findings in adult patients and indicate that WNT1 osteoporosis causes significant skeletal changes already in early childhood and impairs bone mass gain during pubertal years. Genetic testing of children or close relatives of affected individuals is recommended for appropriate preventive measures. © 2016 American Society for Bone and Mineral Research.

Intravenous bisphosphonates (IV BP) have been used to treat children with osteoporosis for many years. Favorable side effect profile and improvements in bone mineral density (BMD) have been demonstrated in patients with osteogenesis imperfecta (OI), a primary form of osteoporosis in pediatrics. Less is known about the safety of IV BP in children with secondary osteoporosis or glucocorticoid-induced osteoporosis (GIO). We aimed to determine the prevalence of both acute and long-term side effects and assess the efficacy of IV BP treatment to increase bone mineral density in pediatric patients with varying presentations of compromised bone health.We conducted a retrospective chart review of pediatric patients (21 years old) treated for osteoporosis with intravenous pamidronate (PAM) or zoledronic acid (ZA) at Cincinnati Children's Hospital Medical Center from 2010 to 2017. Patient demographics, diagnosis, infusion type and dose, acute phase reactions (APR), electrolyte abnormalities, and bone density measurements were collected from the electronic medical records. Diagnoses were grouped into 3 categories: primary osteoporosis, secondary osteoporosis, and GIO. Descriptive characteristics and adverse events were compared among categories. Change in bone mineral density (BMD) over time was compared among groups.123 patients (56% male) received 942 infusions (83% PAM and 17% ZA). APR was reported in 7% of all infusions and more common in secondary osteoporosis (16%, p 0.0001). There was a higher percentage of acute adverse events after the first infusion (27% vs 5%, p 0.0001). Hypocalcemia following IV BP infusions occurred in 7% (27/379) of infusions and was significantly associated with ZA use (p = 0.04). Severity of hypocalcemia was generally mild, requiring intravenous calcium in 3% (13/379) of infusions. Hypophosphatemia occurred frequently, however rarely required intravenous supplementation. In 468 patient years of IV BP exposure, there were no reports of osteonecrosis of the jaw (ONJ) nor atypical femoral fracture (AFF). Lumbar spine (LS) aBMD Z-score 1 year after IV BP initiation increased overall for all groups (p 0.0001) but did not significantly differ for those who did or did not fracture following IV BP treatment.APR due to intravenous BP treatment for pediatric osteoporosis were infrequent and generally mild. APR were more likely to occur in patients with secondary osteoporosis, a group who may require closer monitoring. A higher proportion of hypophosphatemia occurred in the patients with GIO. Long-term serious adverse events including ONJ and AFF were not identified in our patient population. LS aBMD Z-score increased following initiation of IV BP. However, the change in BMD was not associated with risk of fracture during the follow-up interval. These data provide reassurance and suggest that IV BP can be safely used in pediatric patients with osteoporosis.

Osteoporotic fractures are a significant cause of morbidity in acute lymphoblastic leukemia (ALL). Our objective was to determine the incidence and predictors of fractures and recovery from osteoporosis in pediatric ALL over 6 years following glucocorticoid initiation. Vertebral fractures (VF) and vertebral body reshaping were assessed on annual spine radiographs, low-trauma non-VF were recorded at regular intervals and spine bone mineral density (BMD) was captured every 6 months for 4 years and then annually. A total of 186 children with ALL were enrolled (median age 5.3 years; range, 1.3 to 17.0 years). The cumulative fracture incidence was 32.5% for VF and 23.0% for non-VF; 39.0% of children with VF were asymptomatic. No fractures occurred in the sixth year and 71.3% of incident fractures occurred in the first 2 years. Baseline VF, cumulative glucocorticoid dose, and baseline lumbar spine (LS) BMD Z-score predicted both VF and non-VF. Vertebral body reshaping following VF was incomplete or absent in 22.7% of children. Those with residual vertebral deformity following VF were older compared to those without (median age 8.0 years at baseline [interquartile range {IQR}, 5.5 to 9.4] versus 4.8 years [IQR, 3.6 to 6.2], p = 0.04) and had more severe vertebral collapse (median maximum spinal deformity index 3.5 [IQR, 1.0 to 8.0] versus 0.5 [IQR, 0.0 to 1.0], p = 0.01). VF and low LS BMD Z-score at baseline as well as glucocorticoid exposure predicted incident VF and non-VF. Nearly 25% of children had persistent vertebral deformity following VF, more frequent in older children, and in those with more severe collapse. These results suggest the need for trials addressing interventions in the first 2 years of chemotherapy, targeting older children and children with more severe vertebral collapse, because these children are at greatest risk for incident VF and subsequent residual vertebral deformity. © 2018 American Society for Bone and Mineral Research.

Osteoporosis is now increasingly recognized in children due to the increased prevalence of disorders associated with bone loss. Fragility fractures represent the cardinal clinical features of pediatric osteoporosis and children presenting with fragility fractures deserve an accurate assessment to rule out a secondary cause. Indeed, in the pediatric population, a low bone mass is often a consequence of a chronic disease or its treatment; genetic bone disorders represent the cause of only a small fraction of cases. The position statement of the International Society for Clinical Densitometry guides physicians in interpreting densitometric data and making diagnoses of osteoporosis in children. Once a diagnosis of osteoporosis has been made, the aim is to identify children in whom bone status may deteriorate if left untreated. To date, bisphosphonates have represented the mainstay of treatment for pediatric osteoporosis. However, due to the peculiar pathophysiology of osteoporosis in this age group, a pharmacological agent with an anabolic effect on bone may provide clinicians with other therapeutic options in children. Multicenter studies are needed to optimize treatments and define optimal clinical response in treated children.

The ISCD 2007 Pediatric Official Positions define osteoporosis in children on the basis of fracture history and low bone density, adjusted as appropriate for age, gender, and body size. The task force on fracture prediction and osteoporosis definition has reviewed these positions and suggests modifications with respect to vertebral fracture and the definition of a significant fracture history and draws attention to the need to consider degree of trauma as a factor that may modify fracture risk prediction.

Bisphosphonates (BPs) are used most commonly in children with osteogenesis imperfecta, resulting in increased tra- beculae and cortical thickness, increased bone density as measured by DXA (Dual Energy X-ray Absorptiometry), and improved vertebral morphology. Less well documented in controlled trials are decrease in long bone fractures, improved strength and motor function, and decreased pain (1). Outside of children with osteogenesis imperfecta, use of bisphosphonates in children is increasing, all of which is off-label. This is seen in children with other chronic conditions resulting in pediatric osteoporosis and insufficiency fractures. Additional indications include steroid dependency with progressive loss of bone density, avascular necrosis of bone, and chronic regional pain syndrome. This review highlights the potential benefits and risks of the use of bisphosphonates in these unique children at risk for fracture or bone collapse.

Fractures are a frequent source of morbidity in children with disabling conditions. The assessment of bone density in this population is challenging, because densitometry is influenced by dynamic forces affecting the growing skeleton and may be further confounded by positioning difficulties and surgical hardware. First-line treatment for pediatric osteoporosis involves conservative measures, including optimizing the management of underlying conditions, maintaining appropriate calcium and vitamin D intake, encouraging weight-bearing physical activity, and monitoring measurements of bone mineral density. Bisphosphonates are a class of medications that increase bone mineral density by inhibiting bone resorption. Although bisphosphonates are commonly prescribed for treatment of adult osteoporosis, their use in pediatric patients is controversial because of the lack of long-term safety and efficacy data.

Concerns about bone health and potential fragility in children and adolescents have led to a high interest in bone densitometry. Pediatric patients with genetic and acquired chronic diseases, immobility, and inadequate nutrition may fail to achieve expected gains in bone size, mass, and strength, leaving them vulnerable to fracture. In older adults, bone densitometry has been shown to predict fracture risk and reflect response to therapy. The role of densitometry in the management of children at risk of bone fragility is less clear. This clinical report summarizes current knowledge about bone densitometry in the pediatric population, including indications for its use, interpretation of results, and risks and costs. The report emphasizes updated consensus statements generated at the 2013 Pediatric Position Development Conference of the International Society of Clinical Densitometry by an international panel of bone experts. Some of these recommendations are evidence-based, whereas others reflect expert opinion, because data are sparse on many topics. The statements from this and other expert panels provide general guidance to the pediatrician, but decisions about ordering and interpreting bone densitometry still require clinical judgment. The interpretation of bone densitometry results in children differs from that in older adults. The terms “osteopenia” and “osteoporosis” based on bone densitometry findings alone should not be used in younger patients; instead, bone mineral content or density that falls >2 SDs below expected is labeled “low for age.” Pediatric osteoporosis is defined by the Pediatric Position Development Conference by using 1 of the following criteria: ≥1 vertebral fractures occurring in the absence of local disease or high-energy trauma (without or with densitometry measurements) or low bone density for age and a significant fracture history (defined as ≥2 long bone fractures before 10 years of age or ≥3 long bone fractures before 19 years of age). Ongoing research will help define the indications and best methods for assessing bone strength in children and the clinical factors that contribute to fracture risk. The Pediatric Endocrine Society affirms the educational value of this publication.

Administration of oxandrolone, a nonaromatizable testosterone analog, to children for 12 months following severe burn injury has been shown to improve height, increase bone mineral content (BMC), reduce cardiac work, and augment muscle strength. Surprisingly, the increase in BMC persists well beyond the period of oxandrolone administration. This study was undertaken to determine if administration of oxandrolone for 2 years yields greater effects on long-term BMC and bone mineral density (BMD). Patients between 0 and 18 years of age with ≥30% of total body surface area burned were consented to an IRB-approved protocol and randomized to receive either placebo (n = 84) or 0.1 mg/kg oxandrolone orally twice daily for 24 months (n = 35). Patients were followed prospectively from the time of admission until 5 years postburn in a single-center, intent-to-treat setting. Height, weight, BMC, and BMD were recorded annually through 5 years postinjury. The long-term administration of oxandrolone for 16 ± 1 months postburn (range, 12.1-25.2 months) significantly increased whole-body (WB) BMC (p < 0.02) and lumbar spine (LS) BMC (p < 0.05); these effects were significantly pronounced for a longer time in patients who were in growth spurt years (7-18 years). When adjusted for height, sex, and age, LS BMD was found to significantly increase with long-term oxandrolone administration (p < 0.0009). Fewer patients receiving oxandrolone exhibited LS BMD z scores below -2.0 as compared with controls, indicating a significantly reduced risk for future fracture with oxandrolone administration. Long-term oxandrolone patients had significantly greater height velocity than controls throughout the first 2-year postburn (p < 0.05). No adverse side effects were attributed to the long-term administration of oxandrolone. A comparison of the current patients receiving long-term oxandrolone to previously described patients receiving 12 months of oxandrolone revealed that long-term oxandrolone administration imparted significantly greater increases in WB-BMC, WB-BMD, and LS-BMD (p < 0.05). In conclusion, the administration of oxandrolone for up to 24 months to severely burned pediatric patients significantly improves WB BMC, LS BMC, LS BMD, and height velocity. The administration of long-term oxandrolone was more efficacious than administration for 12 months. Additionally, fewer patients in the oxandrolone cohort met the diagnostic criteria for pediatric osteoporosis, pointing to a reduced risk for future bone fracture. This study demonstrates that administering oxandrolone for up to 2 years following severe burn injury results in greater improvements in BMC, BMD, and height velocity.

OBJECTIVES. The purpose of this work was to determine the prevalence of vitamin D deficiency and insufficiency in children with osteopenia or osteoporosis and to evaluate the relationship between serum 25-hydroxyvitamin D levels and bone parameters, including bone mineral density. MATERIALS AND METHODS. Serum 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, parathyroid hormone, and other bone markers, as well as bone mineral density, were obtained for 85 pediatric patients with primary osteoporosis (caused by osteogenesis imperfecta or juvenile idiopathic osteoporosis) and secondary osteopenia or osteoporosis caused by various underlying chronic illnesses. Pearson's correlation was used to assess the relationship between vitamin D levels and different bone parameters. RESULTS. Vitamin D insufficiency (defined as serum 25-hydroxyvitamin D CONCLUSIONS. Vitamin D insufficiency was remarkably common in pediatric patients with primary and secondary osteopenia or osteoporosis. The inverse relationship between 25-hydroxyvitamin D and parathyroid hormone levels suggests a physiologic impact of insufficient vitamin D levels that may contribute to low bone mass or worsen the primary bone disease. We suggest that monitoring and supplementation of vitamin D should be a priority in the management of pediatric patients with osteopenia or osteoporosis.

Although bone mineral density (BMD) as related to T score (comparison with young adult) is well correlated with fracture risk in adults, no such correlation has been confirmed in children. Quadriparetic children have lower BMD than age-matched controls, as well as a higher rate of fragility fracture. This study examines a cohort of children with quadriparesis and other nonambulatory children to correlate BMD with fragility fractures. We hypothesize that fracture in these children is related to BMD as correlated with patient size and that age comparison (Z-score) is less important. Review of all children with a dual-energy x-ray absorptiometry scan from August 2003 to June 2005 identified 101 nonambulatory pediatric patients (excluding children with osteogenesis imperfecta or metabolic bone disease). Sixteen patients had insufficient data, leaving 85 patients, 26 of whom had experienced fragility fractures. Lateral femoral dual-energy x-ray absorptiometry scan was performed on one or both legs, then regions were averaged. Data was evaluated for statistical correlation between BMD and body size as evidenced by body mass index (BMI). Other factors, including age, Z-score, and height and weight independently were secondarily evaluated for correlation with fracture risk. Correlation was demonstrated between history of fracture and BMD when related to BMI (P = 0.002). In conclusion, in these nonambulatory children, the combination of the BMD of the distal femur and BMI correlates well with occurrence of fragility fracture and may relate to fracture risk. This relationship is independent of the child's chronological age and Z-score. This information may be helpful prognostically to define a treatment algorithm for low bone density on a case-by-case basis.

This article reviews the manifestations and risk factors associated with osteoporosis in childhood, the definition of osteoporosis and recommendations for monitoring and prevention. As well, this article discusses when a child should be considered a candidate for osteoporosis therapy, which agents should be prescribed, duration of therapy and side effects. There has been significant progress in our understanding of risk factors and the natural history of osteoporosis in children over the past number of years. This knowledge has fostered the development of logical approaches to the diagnosis, monitoring, and optimal timing of osteoporosis intervention in this setting. Current management strategies are predicated upon monitoring at-risk children to identify and then treat earlier rather than later signs of osteoporosis in those with limited potential for spontaneous recovery. On the other hand, trials addressing the prevention of the first-ever fracture are still needed for children who have both a high likelihood of developing fractures and less potential for recovery. This review focuses on the evidence that shapes the current approach to diagnosis, monitoring, and treatment of osteoporosis in childhood, with emphasis on the key pediatric-specific biological principles that are pivotal to the overall approach and on the main questions with which clinicians struggle on a daily basis. The scope of this article is to review the manifestations of and risk factors for primary and secondary osteoporosis in children, to discuss the definition of pediatric osteoporosis, and to summarize recommendations for monitoring and prevention of bone fragility. As well, this article reviews when a child is a candidate for osteoporosis therapy, which agents and doses should be prescribed, the duration of therapy, how the response to therapy is adjudicated, and the short- and long-term side effects. With this information, the bone health clinician will be poised to diagnose osteoporosis in children and to identify when children need osteoporosis therapy and the clinical outcomes that gauge efficacy and safety of treatment.

Objectives Recent evidence from the 7-year follow-up of the Pediatric Osteoporosis Prevention (POP) study indicates an inverse correlation between years of participation in a physical activity (PA) intervention and fracture risk in children. However, we could not see a statistically significant reduction in fracture risk, which urged for an extension of the intervention. Setting The study was conducted in 4 neighbouring elementary schools, where 1 school functioned as intervention school. Participants We included all children who began first grade in these 4 schools between 1998 and 2012. This resulted in 1339 children in the intervention group and 2195 children in the control group, all aged 6–8 years at the state of the study. Intervention We launched an 8-year intervention programme with 40 min of moderate PA per school day, while the controls continued with the Swedish national standard of 60 min of PA per week. Primary outcome measure We used the regional radiographic archive to register objectively verified fractures and we estimated annual fracture incidences and incidence rate ratios (IRRs). Results During the first year after initiation of the intervention, the fracture IRR was 1.65 (1.05 to 2.08) (mean 95% CI). For each year of the study, the fracture incidence rate in the control group compared with the intervention group increased by 15.7% (5.6% to 26.8%) (mean 95% CI). After 8 years, the IRR of fractures was 52% lower in the intervention group than in the control group (IRR 0.48 (0.25 to 0.91) (mean 95% CI))]. Conclusions Introduction of the school-based intervention programme is associated with a higher fracture risk in the intervention group during the first year followed by a gradual reduction, so that during the eighth year, the fracture risk was lower in the intervention group. Trial registration number NCT00633828.

Progress toward identifying and treating disorders of bone fragility in pediatric patients has been considerable in recent years. This article will summarize several key advances in the management of osteoporosis in children and adolescents.Recommendations from the 2013 pediatric Position Development Conference provide expert guidance for evaluating bone health in younger patients. The diagnosis of pediatric osteoporosis can be made in a child with low-trauma vertebral fractures or a combination of low bone mass and long bone fractures. Management of bone fragility includes optimizing nutrition, activity, and treatment of the underlying disease. Pharmacologic agents can be considered if these measures fail to prevent further bone loss or fractures. Although the efficacy and safety of several intravenous and oral bisphosphonates have been examined, there is still no consensus on the optimal drug, dose, or duration of treatment. Observational studies of children with secondary osteoporosis provide insight into risk factors for fracture or the potential for recovery.Despite advances in the diagnosis and treatment of pediatric osteoporosis, more research is needed. Randomized controlled trials of pharmacologic agents should be defined to target those identified at the highest risk by observational studies.http://links.lww.com/COE/A9

To investigate the influence of physical activity on bone mineral accrual during the adolescent years, we analyzed 6 years of data from 53 girls and 60 boys. Physical activity, dietary intakes, and anthropometry were measured every 6 months and dual-energy X-ray absorptiometry scans of the total body (TB), lumbar spine (LS), and proximal femur (Hologic 2000, array mode) were collected annually. Distance and velocity curves for height and bone mineral content (BMC) were fitted for each child at several skeletal sites using a cubic spline procedure, from which ages at peak height velocity (PHV) and peak BMC velocity (PBMCV) were identified. A mean age- and gender-specific standardized activity (Z) score was calculated for each subject based on multiple yearly activity assessments collected up until age of PHV. This score was used to identify active (top quartile), average (middle 2 quartiles), or inactive (bottom quartile) groups. Two-way analysis of covariance, with height and weight at PHV controlled for, demonstrated significant physical activity and gender main effects (but no interaction) for PBMCV, for BMC accrued for 2 years around peak velocity, and for BMC at 1 year post-PBMCV for the TB and femoral neck and for physical activity but not gender at the LS (all p < 0.05). Controlling for maturational and size differences between groups, we noted a 9% and 17% greater TB BMC for active boys and girls, respectively, over their inactive peers 1 year after the age of PBMCV. We also estimated that, on average, 26% of adult TB bone mineral was accrued during the 2 years around PBMCV.

Dual-energy absorptiometry (DXA) is the current reference standard for assessing pediatric osteoporosis; however due to its areal nature, it has limitations. Thus, quantitative ultrasound (QUS), a modality free of ionizing radiation, has been proposed as a potential surrogate for DXA. To semi-quantitatively assess the diagnostic accuracy of QUS for evaluating pediatric osteoporosis according to the U.S. Preventive Services Task Force guidelines. We retrieved articles on the diagnostic accuracy of quantitative US for assessing abnormal bone quality or quantity in patients of mean age ≤19 years from MEDLINE, EMBASE and Cochrane Library CCTR databases. Evidences were analyzed for reliability, construct and criterion validity, and responsiveness of quantitative US, according to the following questions: (1) How reliable is the acquisition of QUS measurements? (2) Is QUS diagnostically accurate to characterize bone strength and quality in osteoporotic children? (3) Is QUS sensitive to detect changes in bone status over time? (4) Is QUS able to predict future skeletal fractures/degeneration? Three reviewers independently evaluated the quality of reporting and methodological quality using the Standards for Reporting of Diagnostic Accuracy (STARD) and the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tools. Out of 262 retrieved references (215 unique), we included 28 studies (1,963 patients; 807 reported boys and 761 girls, others unspecified; reported mean age, 0–19 years). The mean quality of reporting score was “excellent” in 24/28 (86%) studies; 11/28 (39%) studies had “adequate” research design quality. There is no evidence of the diagnostic value of QUS at the present time despite the overall excellent and adequate research design quality of primary studies. Although QUS can produce reliable measurements, insufficient evidence has been reported to support other clinimetric properties of this technique.

Osteogenesis imperfecta and juvenile osteoporosis are two well-described syndromes of osteoporosis presenting in childhood. There are also several references in the radiology literature to calvarial doughnut lesions (CDLs), areas of radiolucency surrounded by a dense and well-defined area of sclerotic bone, either as an incidental finding or associated with childhood fracture. We have characterized the metabolic abnormalities in a 13-yr-old boy with CDLs and multiple fractures and followed him during his progression through puberty. The patient's paternal grandmother; father; and paternal aunt, uncle, and first cousin were similarly affected, and a mandibular lesion in the uncle was pathologically described as fibrous dysplasia. The subject's physical examination was significant for bony protuberances of the skull and normal hearing, sclearal hue, dentition, and joint flexibility. Radiographs revealed calvarial CDLs and osteopenia which was confirmed by bone mineral density (BMD) testing. Biochemical markers of bone formation and resorption were elevated compared to normal adult and a transiliac crest bone biopsy confirmed high-turnover osteoporosis. Over 6 yr, with no specific therapy, BMD gradually normalized, but the CDLs increased in size, bone turnover remained elevated by biochemical markers, and he continued to fracture. The subject's affected father and maternal grandmother had normal BMD and no history of adult fracture. CDLs with high-turnover osteoporosis should be considered in the differential diagnosis of pediatric osteoporosis. During puberty the BMD normalizes but the high-turnover state persists, and the propensity to fracture eventually decreases in older affected adults. The CDLs may be a variant of fibrous dysplasia, and further study is necessary in order to elucidate the stimulus for increased bone turnover and the familial nature of this syndrome.

Background: Pediatric osteoporosis is uncommon but can result in painful and debilitating insufficiency fractures. Treatment options for osteoporosis in children are few. Bisphosphonate therapy for children has not been approved by the Food and Drug Administration (FDA) in the United States, but its use in that population has been increasing. Randomized controlled studies have not been done because of the small subject pool and the difficulty in randomizing a child with an insufficiency fracture to a placebo arm of a study. This retrospective case-control study of a population of children with primarily neuromuscular disease was done to review changes in bone mineral density as reflected by dual x-ray absorptiometry (DXA) scanning. Methods: Medical records and DXA scans were screened to identify children with low bone density who had been treated with alendronate as well as similar control subjects with low bone density for their age who had not received alendronate. Medication acquisition was confirmed by refill records, and cumulative exposure was calculated. Interval DXA scans were reviewed to correlate bone mineral density change in grams per square centimeter as well as the percent change and percent change over time for both alendronate-treated and control subjects. Results: Twenty-eight alendronate-treated subjects and thirty control subjects met the inclusion criteria. No significant improvement in bone mineral density was seen in the alendronate-treated subjects as compared with the control subjects. Some patients in both groups exhibited marked improvement, with improvement of >31% seen only in the alendronate-treated subjects. Conclusions: Alendronate does not reliably improve bone density in children and young adults with primarily neuromuscular disease and without osteogenesis imperfecta. Individual patients treated with bisphosphonates must be carefully followed to ensure medication compliance and appropriate response. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

In children the diagnosis of osteoporosis is based on fracture history and DXA-derived BMD. Bone biopsy is an invasive but accurate method for studying bone characteristics. In this study we evaluated bone biopsy findings and their correlation with noninvasive measures of bone health. Transiliac bone biopsy was performed on 24 consecutive children (17 boys, median age 12 years, range 6 to 16 years) evaluated for suspected primary osteoporosis. Biopsy findings were compared with normative data and correlated with clinical, radiological, biochemical, and densitometric findings. The patients had sustained altogether 64 nonvertebral fractures (median 2.5) from low- or moderate-energy traumas, and 14 patients (58%) had vertebral fractures. The median lumbar spine BMD Z-score was −1.2 (range −3.1 to +1.0). Hypovitaminosis D was present in 58%. Histomorphometry showed low bone volume in 7 patients and normal bone volume in 17. Bone turnover was high in 7, low in 7, and normal in 10 patients. Histomorphometric findings correlated poorly with fracture history, serum bone turnover markers, and DXA findings. Vitamin D deficiency and low lumbar BMD were associated with high bone turnover in the biopsy. These findings underscore the difficulties in diagnosing pediatric osteoporosis. Bone histomorphometry gives additional information and may be useful when considering bisphosphonate treatment in children with suspected primary osteoporosis. © 2011 American Society for Bone and Mineral Research

Background Children with chronic illnesses are at increased risk for reductions in bone strength and subsequent fractures (osteoporosis), either due to the impact of the underlying condition on skeletal development or due to the osteotoxic effect of medications (e.g., glucocorticoids) used to treat the chronic illness. Bisphosphonates are being administered with increasing frequency to children with secondary osteoporosis; however, the efficacy and harm of these agents remains unclear. Objectives To examine the efficacy and harm of bisphosphonate therapy in the treatment and prevention of secondary osteoporosis in children and adolescents. Search methods We searched the Cochrane Central Register of Controlled Trials (Issue 4, 2006), MEDLINE, EMBASE, CINAHL and ISI Web of Science (inception-December 2006). Further literature was identified through expert contact, key author searches, scanning reference lists of included studies, and contacting bisphosphonate manufacturers. Selection criteria Randomized, quasi-randomized, controlled clinical trials, cohort, and case controls of bisphosphonate(s) in children 0-18 years of age with at least one low-trauma fracture event or reductions in bone mineral density in the context of secondary osteoporosis. Data collection and analysis Two reviewers independently extracted data and assessed quality. Case series were used for supplemental harms-related data. Main results Six RCTs, two CCTs, and one prospective cohort (n=281 children) were included and classified into osteoporosis due to: 1) neuromuscular conditions (one RCT) and 2) chronic illness (five RCTs, two CCTs, one cohort). Bisphosphonates examined were oral alendronate, clodronate, and intravenous (IV) pamidronate. Study quality varied. Harms data from 23 case series (n=241 children) were used. Heterogeneity precluded statistically combining the results. Percent change or Z-score change in lumbar spine areal BMD from baseline were consistently reported. Two studies carried out between-group analyses; one showed no significant difference (using oral alendronate in anorexia nervosa) while the other demonstrated a treatment effect on lumbar spine with IV pamidronate in burn patients. Frequently reported harms included the acute phase reaction, followed by gastrointestinal complaints, and bone/muscle pain. Authors' conclusions The results justify further evaluation of bisphosphonates among children with secondary osteoporosis. However, the evidence does not support bisphosphonates as standard therapy. Short-term (3 years or less) bisphosphonate use appears to be well-tolerated. An accepted criterion for osteoporosis in children, a standardized approach to BMD reporting, and examining functional bone health outcomes (e.g., fracture rates) will allow for appropriate comparisons across studies.

BackgroundWalking and cycling to school could be an important regular source of physical activity in growing children. The aim of this 12 months prospective observational study was thus to evaluate the effect of self-transportation to school on bone mineral accrual and gain in bone width in pre-pubertal children, both traits independently contributing to bone strength.MethodsNinety-seven girls and 133 boys aged 7–9 years were recruited as a part of the Malmö Pediatric Osteoporosis Prevention (POP) Study in order to evaluate the influence of self-selected school transportation for the accrual of bone mineral and bone width. Children who walked or cycled to school were compared with children who went by bus or car. Bone mineral content (BMC) was measured by dual energy X-ray absorptiometry (DXA) in the lumbar spine (L2–L4), third lumbar vertebra (L3) and hip, and bone width was calculated at L3 and femoral neck (FN). Changes during the first 12 months were compared between the groups. Subjective duration of physical activity was estimated by a questionnaire and objective level of everyday physical activity at follow-up by accelerometers worn for four consecutive days. All children remained in Tanner stage 1 throughout the study. Comparisons were made by independent student'st-tests between means, ANCOVA and Fisher's exact tests.ResultsThere were no differences in baseline or annual changes in BMC or bone width when the transportation groups were compared. No differences were detected in objectively measured daily level of physical activity by accelerometer. All children reached above 60 minutes of moderate to intense daily physical activity per day, the international recommended level of daily physical activity according to the United Kingdom Expert Consensus Group.ConclusionThe everyday physical activity in these pre-pubertal children seems to be so high that the school transportation contributes little to their total level of physical activity. As a result, the choice of school transportation seems not to influence the accrual of bone mineral or gain in bone size during a 12-month follow-up period.

This non-randomized prospective controlled study evaluates a daily school-based exercise intervention program of 40 min/school day for 1 year in a population-based cohort of 81 boys aged 7-9 years. Controls were 57 age-matched boys assigned to the general school curriculum of 60 min/week. Bone mineral content (BMC; g) and areal bone mineral density (aBMD; g/cm(2)) were measured with dual X-ray absorptiometry (DXA) of the total body, the third lumbar vertebra (L3) and the femoral neck (FN). Bone width for L3 and FN was calculated from the lumbar spine and hip scan. No differences between the groups were found at baseline in age, anthropometrics or bone parameters. The mean annual gain in L3 BMC was 5.9 percentage points higher (P

The aim of this study was to evaluate a general school-based 1-year exercise intervention program in a population-based cohort of girls at Tanner stage I. Fifty-three girls aged 7–9 years were included. The school curriculum-based exercise intervention program included 40 minutes/school day. Fifty healthy age-matched girls assigned to the general school curriculum of 60 minutes physical activity/week served as controls. Bone mineral content (BMC, g) and areal bone mineral density (aBMD, g/cm2) were measured with dual X-ray absorptiometry (DXA) of the total body (TB), lumbar spine (L2–L4 vertebrae), third lumbar vertebra (L3), femoral neck (FN), and leg. Volumetric bone mineral density (g/cm3) and bone width were calculated at L3 and FN. Total lean body mass and total fat mass were estimated from the TB scan. No differences at baseline were found in age, anthropometrics, or bone parameters when the groups were compared. The annual gain in BMC was 4.7 percentage points higher in the lumbar spine and 9.5 percentage points higher in L3 in cases than in controls (both P < 0.001). The annual gain in aBMD was 2.8 percentage points higher in the lumbar spine and 3.1 percentage points higher in L3 in cases than in controls (both P < 0.001). The annual gain in bone width was 2.9 percentage points higher in L3 in cases than in controls (P < 0.001). A general school-based exercise program in girls aged 7–9 years enhances the accrual of BMC and aBMD and increases bone width.

Objective To assess the value of spinal radiographs in determining the significance of reductions in bone mass or density in chronically ill children. Study design A pediatric scoring method for assessment of osteoporotic vertebral changes, developed on the basis of radiographs of 70 healthy controls and established adult scoring methods, was subsequently used to assess 32 pediatric patients with suspected secondary osteoporosis. Radiographic findings were correlated with bone mineral density (BMD), clinical data, and biochemistry. Results Thirty-two patients (median age 14.1 years) were included. Assessment of spinal radiographs with the developed scoring method found previously undiagnosed spinal compression deformities in 11 patients (34%) of whom 9 were asymptomatic and 8 had lumbar spine (size-corrected) BMD measurements within +/-2.0 SD of the age- and sex-specific norms. Fracture history and cumulative glucocorticoid (GC) dose did not differ between those with and without compression deformities. Conclusions Vertebral compression fractures can be documented in a significant number of chronically ill children and are poorly predicted by single BMD measurements and clinical history. Assessment of vertebral morphology is recommended as an additional tool in the diagnostic workup of pediatric osteoporosis.

Objectives To examine the response to single-day intravenous pamidronate in a heterogeneous population with symptomatic osteoporosis. Study design Patients (n = 18) 6 to 21 years of age, meeting treatment criteria were offered treatment with a single-day infusion of pamidronate every 3 months. Baseline and follow-up data were recorded and compared between persons with risk factors of progressive chronic illness or ongoing glucocorticoid usage (group 1) and persons with neither risk factor (group 2). We also examined the association between changes in urinary N-telopeptide percentile and spinal bone mineral density (BMD). Results Spinal BMD Z score increased in all patients after 6 months of treatment. Although patients had an average of 1.9 fractures in the year preceding treatment, only 2 patients had fractures once treatment began. No significant differences in baseline data were noted between the two groups. However, group 1 had significantly less gain in BMD ( P =.04) than group 2. No evidence of growth impairment was seen, and no association between changes in urinary N-telopeptide percentile and changes in BMD were noted. Conclusions Single-day intravenous infusion of pamidronate is efficacious and well tolerated in a heterogeneous group of pediatric patients with symptomatic osteoporosis. (J Pediatr 2003;142:417-23)