REVIEW URRENT C OPINION
Diagnosis and treatment of pediatric osteoporosis Laura K. Bachrach
Purpose of review 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. Recent findings 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. Summary 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. Video abstract: http://links.lww.com/COE/A9 Keywords bisphosphonates, bone density, fractures, pediatric osteoporosis
INTRODUCTION Threats to bone health are increasingly a pediatric concern. Genetic or acquired disorders can compromise gains in bone quantity and quality leading to osteoporosis early in life [1,2]. Recurrent fractures in otherwise healthy youth may also indicate underlying bone fragility [3,4 ]. The stakes are high to address these early threats to bone health as the foundation for bone health is established during the first 2 decades [5]. Genetic factors determine an estimated 70% of the variability in peak bone mass, but to reach one’s genetic potential requires optimal modifiable factors [5]. The goal of clinical practice is to prevent fractures in at-risk patients before they occur and to reduce the likelihood of their recurrence. Despite advances in the diagnosis and treatment of pediatric osteoporosis, important limitations persist. This review will summarize recent progress in management with a particular focus on publications from the past 2 years. &
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SURROGATE MEASURES IN THE DIAGNOSIS OF PEDIATRIC OSTEOPOROSIS The surrogate measures of bone health used to assess fracture risk in adults are more challenging to interpret in younger patients because they represent a moving target. The skeleton evolves in size and mass until late adolescence or early adulthood when lifetime peak bone mass is achieved. Serum and urine biochemical markers are used to distinguish highturnover from low-turnover bone disorders. Results are affected by myriad factors, including age, Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA Correspondence to Laura K. Bachrach, MD, Department of Pediatrics, Stanford University School of Medicine, Room H314, Stanford Medical Center, Stanford, CA 94035–5208, USA. Tel: +1 650 723 5791; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2014, 21:454–460 DOI:10.1097/MED.0000000000000106 Volume 21 Number 6 December 2014
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KEY POINTS Bone densitometry is only part of a comprehensive skeletal screen for bone fragility. Spine and TBLH are the preferred sites for DXA in most children. Vertebral fractures that occur with low trauma are rare in pediatrics and suggestive of bone fragility. The diagnosis of osteoporosis in pediatrics can based upon vertebral fractures alone or low bone density and multiple long bone fractures. Bisphosphonate therapy is considered reasonable for patients with a clinically significant fracture history.
pubertal stage, nutrition, growth velocity, time of day, and day-to-day variability [6,7]. The mean and range for pediatrics are considerably greater than adult norms until late adolescence. Bone markers have been used to monitor bone turnover in response to disease and pharmacologic therapy, but their value in clinical practice has not been established [6,7]. Bone densitometry has more clinical utility but it also presents problems in interpretation. Valuable guidance for utilizing this diagnostic tool has come from Pediatric Position Development Conferences (PDC) held in 2007 and 2013. Pediatric bone experts reviewed the literature and generated guidelines after rigorously rating the quality of available evidence. The 2013 report which is in print [8 ] and online (http://www.iscd.org/documents/2014/02/ 2013-iscd-official-position-brochure.pdf) addresses five areas: dual energy X-ray absorptiometry (DXA) interpretation and reporting, densitometry in infants and young children, DXA assessment in chronic diseases that may affect the skeleton, quantitative computed tomography, and fracture prediction and the definition of osteoporosis. The PDC recommendations provide practical guidance for evaluating pediatric bone health on the basis of available data and expert opinion when evidence is lacking. The ideal noninvasive technique to assess the growing skeleton would precisely measure the mass and geometry of bone that contribute to bone strength [9]. DXA neither distinguishes cortical from trabecular bone nor does it directly measure volumetric bone mineral density (vBMD) or bone geometry. Despite these limitations, DXA remains the preferred clinical tool to assess bone mineral content (BMC) and areal bone mineral density (aBMD) because of its speed, precision, safety, and robust normative data [8 ]. The antero-posterior &&
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lumbar spine (L1–4) and total body less head (TBLH) are the preferred skeletal sites for measurement in most children. For children aged 0–5 years, the spine BMC and BMD can be measured; whole body measurements are feasible only for those aged 3 years or older. Additional regions of interest using DXA are recommended in special cases. Scans of the lateral distal femur can be valuable in patients with contractures that preclude proper positioning for spine or whole body scans [10]. This site is also helpful in assessing patients with immobilization disorders because bone fragility is greatest in the lower extremities [11]. DXA scans should avoid areas with metal implants, contractures, or vertebrae in which fractures have occurred. The distal radius can be measured in patients who exceed the weight limit for the equipment. Quantitative computed tomography (QCT) measures volumetric BMD, distinguishes between trabecular and cortical bone, and detects bone geometry [9]. Peripheral QCT (pQCT) and highresolution pQCT (HR-pQCT) require less radiation than QCT and provide insights into the separate contributions of bone geometry and mass to bone strength. A study comparing girls with anorexia nervosa (AN) with controls found no significant difference in radius aBMD by DXA. By contrast, HRpQCT detected significant changes in cortical and trabecular microarchitecture in the girls with AN that would predict reduced bone strength [12 ]. At present, QCT, pQCT, and HR-pQCT remain primarily research techniques due to the lack of standardized scanning protocols and limited normative data. They can be used clinically in centers in which appropriate expertise and reference data are available [8 ]. &
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INDICATIONS FOR DENSITOMETRY A variety of primary and secondary disorders have been associated with increased bone fragility [1,8 ]. Osteogenesis imperfecta, Bruck syndrome, and idiopathic juvenile osteoporosis are examples of genetic disorders. The disorders linked to secondary osteoporosis include the inflammatory disorders (cystic fibrosis, rheumatologic disease or inflammatory bowel disease), neuromuscular conditions (muscular dystrophy or cerebral palsy), endocrinopathies (hypogonadism or growth hormone deficiency), under-nutrition (AN or HIV), malignancy, transplantation, and exposure to osteotoxic drugs. The PDC guidelines recommend that the initial DXA exam be performed when the patient might benefit from intervention and when the densitometry results would influence management
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[8 ]. Repeat scans (to monitor disease processes or therapy) should be done no more often than every 6–12 months.
identified microarchitectural deficits at the tibia and radius that discriminated between youth with and without low-trauma fractures of the distal forearm [4 ]. Observations from healthy youth may not apply to chronically ill or immobilized youth. For patients exposed to chronic glucocorticoid therapy [19,20 ] and those with leukemia [21], the risk of fracture is greater at the spine than at the forearm. Low spine BMD by DXA is strongly correlated with these fractures [19,21]. For each standard deviation that BMD Z-score falls below zero, there is an associated 80% increase odds of vertebral compression fracture. Youth with cerebral palsy, Duchenne muscular dystrophy, and other immobilization disorders are at greater risk for lower extremity fractures. In a study of 619 youth with cerebral palsy or Duchenne muscular dystrophy, lateral distal femur aBMD predicted these fractures, whereas the relationship between spine aBMD and fracture risk was unproven [11]. &
INTERPRETATION OF DUAL ENERGY XRAY ABSORPTIOMETRY RESULTS The results of pediatric DXA scans should be compared with norms for age, sex, and race/ethnicity collected from healthy youth using similar equipment and software as that used for the patient. The Bone Mineral Density in Childhood Study provides the best reference data for Hologic (Bedford, Massachusetts, USA) as they were collected from a representative population of healthy youth and summarized using optimal statistical modeling [13]. These data are available on a user-friendly website that calculates Z-scores corrected for age, sex, race/ ethnicity, and height Z-score (http://www.bmdcspu blic.com). Normative data for General Electric-Lunar (Madison, Wisconsin, USA) equipment have been published as well [14]. The interpretation of pediatric densitometry may require additional adjustment, if growth and maturation are delayed. BMD using DXA is a twodimensional measurement that tends to be lower in smaller individuals and greater in taller ones. To address the influence of bone size, the 2013 PDC guidelines recommend adjusting spine data for estimated bone volume (bone mineral apparent density) or height Z-score [8 ]. TBLH should be adjusted for height Z-score. &&
CAN DENSITOMETRY PREDICT PEDIATRIC FRACTURES? The largest studies examining the association of bone density with fracture have been carried out in otherwise healthy youth because they tend to fracture [15 ,16]. An estimated 30–50% of youth will have at least one broken bone by age 16, most commonly in the forearm [17,18]. The best predictors of fracture in these studies have been TBLH BMC corrected for height, weight, and bone area. Youth with smaller bone area and bone mineral for area have an increased fracture risk [15 ]. At best, the ability of DXA alone to predict fracture is limited. A study by Kalkwarf et al. [16] compared a variety of DXA and pQCT parameters of bone mass and size in 224 children with or without radius fractures in the prior month. The area under the curve linking densitometry measures and fracture ranged from 0.56 to 0.59, identifying those with fractures little better than chance alone [16]. Preliminary data indicate that HRpQCT may prove a better noninvasive tool for assessing bone strength. This technique &&
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LATERAL SPINE RADIOGRAPHS Vertebral compression fractures are rare in children and in those occurring without major trauma indicate bone fragility. Vertebral fracture assessment in DXA software is used to identify spine fractures in adults but may not be sufficiently sensitive for use in children [22]. At present, lateral radiographs of the thoracolumbar spine are the gold standard to identify spine fractures in pediatrics [23]. Vertebral compression fractures can occur in chronically ill youth in the absence of very low BMD by DXA. In an illustrative case report, a 10year-old boy with nephrotic syndrome developed back pain after long-term high-dose glucocorticoids [24]. A spine radiograph demonstrated fractures at T7 and T8 and a bone biopsy showed findings consistent with osteoporosis. Spine and whole body aBMD Z-scores were only slightly reduced at 0.5 and 0.4, respectively.
CRITERIA FOR THE DIAGNOSIS OF OSTEOPOROSIS DXA findings alone cannot be used to diagnose osteoporosis in pediatric patients. This is in contrast with postmenopausal women who can be labeled with osteoporosis on the basis of a T-score below 2.5 [25]. T-scores comparing the patient’s DXA results with a young adult reference group should not be used before the age of 20 years. The terms, osteoporosis and osteopenia, should not appear on pediatric DXA reports. Pediatric patients with BMC or aBMD values at or below 2 standard deviations should be described as having low bone mass for age. Volume 21 Number 6 December 2014
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The 2013 PDC guidelines defined the diagnostic criteria for osteoporosis in pediatric patients. A child or teen with one or more vertebral compression fractures occurring without local bone disease or high-energy trauma meets criteria [8 ]. Measuring BMD can add to the assessment of these patients but is not required. Alternatively, osteoporosis can be diagnosed in patients with a combination of low bone density (BMC or aBMD Z-scores < 2) and a significant fracture history (two or more long bone fractures by age the 10 or 3 years or more long bone fractures before age 19 years). &&
doses may be required in patients with obesity or malabsorption disorders [27]. Adequate total body stores of vitamin D have been defined as a serum 25 hydroxy vitamin D concentration of at least 20 ng/ml [26,28] or 30 ng/ml [29] based largely on studies in adults. Unfortunately, nutritional deficits can be overlooked in chronic illness. Studies have found 40% or more of children admitted to pediatric ICU have 25 OH vitamin D concentrations less than 20 ng/ml [30]. Lower vitamin D stores were associated with greater severity of illness. Physical activity has an anabolic effect on the growing skeleton. High-impact activities have been shown to increase bone mass in healthy youth [31 ] but should be avoided in children with bone fragility. Nonetheless, modified activity as tolerated is important to counteract the impact of reduced mobility. Modest gains in aBMD have been reported from studies using static standing, physical therapy, or high frequency vibratory platforms [32]. Replacement of sex steroids and growth hormone for those with documented deficiencies is also appropriate [33]. Growth hormone therapy has been shown to increase aBMD even after final adult height is reached and continued growth hormone replacement into adulthood is recommended for those with low age-adjusted BMC [34]. &
DENSITOMETRY IS PART OF A COMPREHENSIVE BONE HEALTH SCREEN A child or adolescent with low bone mass or lowtrauma fractures warrants a comprehensive evaluation to determine possible primary or secondary causes [1]. This includes a review of chronic illness, medications, nutrition, activity, and fracture history. A family history of hip fractures in elderly relatives or repeated fractures in younger family members should be explored. Recommended laboratory tests include a complete blood count, erythrocyte sedimentation rate, serum calcium, phosphorus, alkaline phosphatase, intact PTH, total 25 hydroxy vitamin D, BUN, creatinine, and celiac screen, as well as urinary calcium to creatinine ratio. Additional tests to consider depending upon the age, physical exam, and history include luteinizing hormone, follicle stimulating hormone, estradiol, testosterone, insulin-like growth factor type I, free T4, and TSH. Genetic screening for osteogenesis imperfecta is commercially available; testing for other genetic disorders, such as inactivating mutations in low-density lipoprotein receptorrelated protein 5, may be available on a research basis. Vertebral fractures may be asymptomatic and a lateral thoracolumbar spine radiograph is indicated for those with back pain, low-trauma fractures of the long bones, or chronic glucocorticoid therapy. A bone biopsy helps distinguish osteomalacia from osteoporosis and low-turnover versus high-turnover bone disease. This procedure is reserved for more severe cases of bone fragility not diagnosed through routine evaluation.
GENERAL MEASURES FOR BONE HEALTH Prevention and treatment of bone fragility should address all potential threats to skeletal health. Calcium from diet and supplements should total 1300 mg/day for ages 9–18 years [26]. Recommended daily intake of vitamin D is a minimum of 600 IU daily after the first year of life, but higher
PHARMACOLOGIC THERAPY When low-trauma fractures occur despite these general measures, the addition of pharmacologic agents should be considered. An anabolic agent would be ideal as pediatric osteoporosis often results from a failure to acquire bone rather than accelerated loss. Synthetic parathyroid hormone (teriparatide) has a black box warning against its use in patients with open growth plates and the benefits of human growth hormone are not established except in growth hormone deficient patients. This limits pharmacologic therapy primarily to antiresorptive agents. Sex hormone therapy (SHT) is indicated for those with hypogonadism as discussed above. The efficacy of SHT to improve BMD or reduce fractures in exercise-associated amenorrhea [35] or eating disorders [36,37] remains uncertain. In light of this, the American College of Sports Medicine has recommended that oral contraceptives be considered in amenorrheic athletes only after age 16 years and if BMD is decreasing despite adequate nutrition and weight gain [35]. One potential explanation for the failure of SHT to improve bone health has been the suppressive effect of high-dose oral estrogens on serum insulinlike growth factor type I. A placebo-controlled study
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in teens with AN found that low-dose transdermal estrogen or very low-dose incremental oral ethinylestradiol resulted in gains in spine and hip aBMD [38]. In another study of a young woman with AN, low-dose oral estrogen and dehydroepiandrosterone maintained spine and whole body aBMD [39] and improved hip geometry as determined by hip structural analysis as compared with placebo [40]. Whether these SHT regimens will result in reduced fracture risk remains to be determined.
BISPHOSPHONATE THERAPY Bisphosphonates have been used to treat osteogenesis imperfecta [41] and a variety of disorders causing secondary osteoporosis for more than 3 decades [42]. There is insufficient evidence to support the routine use of bisphosphonates in these disorders but compassionate use is reasonable for those with fragility fractures. There is no consensus about the optimal agent, dose, and duration of therapy [43]. Pamidronate has been the most extensively used of the bisphosphonates in pediatrics in doses ranging from 4 to 9 mg/kg/year. Randomized dose-response studies have not been performed to establish the optimal dose. The demand for more convenient and less expensive therapy has led to trials with oral bisphosphonates and more potent intravenous agents. In a randomized controlled trial in children with osteogenesis imperfecta, daily oral alendronate resulted in significant gains in spine aBMD versus placebo, but no significant reduction in bone pain and time to first fracture [44]. By contrast, a randomized trial of daily oral risedronate in osteogenesis imperfecta patients resulted in increased spine aBMD and a reduced risk of first or recurrent nonvertebral fractures [45 ] Zoledronic acid is 100–200 times more potent than pamidronate, can be infused more rapidly, and has duration of action for up to 3 years in postmenopausal osteoporosis [46]. Case series from children with secondary osteoporosis have shown gains in aBMD, metacarpal cortical thickness, and vertebral morphology with zoledronic acid given every 3 months [47] or 6 months [48 ] in a dose of 0.1 mg/kg/year. Twice yearly zoledronic acid has also been shown to increase spine aBMD in children with type I osteogenesis imperfecta [49]. Prior to treatment, these children had sustained 73 fractures. During 1–3-year treatment period, six patients had 10 new long bone fractures. Minor adverse reactions are common after the initial dose of bisphosphonates, including fatigue, fever, nausea, and muscle aches. The incidence of hypocalcemia, hypophosphatemia, and &&
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hypomagnesemia can be reduced by ensuring adequate vitamin D and calcium intake. Reducing the initial dose of zoledronic acid from 0.05 to 0.0125–0.025 mg/kg/day has also been suggested [50]. To date, no atypical femur fractures or avascular necrosis of the jaw have been observed in pediatric patients. A concern for potential teratogenic effects has been raised as bisphosphonates may be released from bone for years and readily cross the placenta. A review of 78 fetuses whose mothers had been treated with bisphosphonates prior to or during pregnancy found few serious adverse effects [51]. Prematurity, low birth weight, and transient hypocalcemia were observed. Eight spontaneous abortions and the congenital anomalies were attributed to the underlying maternal disease or other medications. Some experts have recommended that bisphosphonates be discontinued 6–12 months prior to pregnancy [51]. The pediatric experience using denosumab, a monoclonal antibody that inhibits osteoclast activity, is very limited. Four boys with osteogenesis imperfecta type IV resistant to bisphosphonates showed reductions in bone resorption markers during denosumab treatment for 5–33 weeks [52]. Denosumab was reported to reduce bone pain and the size of a bone lesion in one child with fibrous dysplasia [53].
DURATION OF THERAPY The maximal benefits from pamidronate in children are seen at 2–4 years but low-dose maintenance bisphosphonate therapy may be needed until growth is complete in patients with persistent risk factors for osteoporosis such as those with osteogenesis imperfecta [54]. Studies in these patients have shown that diaphyseal BMC is maintained for 2 years after pamidronate is stopped, but new bone added at metaphyseal sites has a lower density. Fractures have occurred at the junction of untreated new bone and regions of older treated bone [43,54].
REFINING WHO TO TREAT It would be ideal to treat high-risk patients before fractures occur and to withhold pharmacologic therapy in those likely to regain bone without medication. To target treatment in this way would require increased knowledge of the natural history of primary and secondary osteoporosis. Observational studies from patients during the first year of glucocorticoid therapy have shown variable risk for vertebral fracture. Incident vertebral fractures occurred in 6% of children with rheumatologic disorders [19] or nephrotic syndrome [20 ] and 16% of children with acute lymphoblastic leukemia &
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[21]. Vertebral deformities were mild in nephrotic syndrome but moderate-to-severe in the others. A 13% cumulative incidence of vertebral fractures has been reported in children with rheumatologic disorders during the first 3 years of glucocorticoid therapy [55 ]. Higher fracture risk was linked to larger glucocorticoid doses, increasing BMI Z-score, decreasing spine aBMD Z-score, and vertebral fractures at the baseline [19,21,55 ]. Bone mass and geometry can recover once chronic illness resolves. A 1-year study using pQCT found that tibial trabecular BMD increased in all patients after chemotherapy for acute lymphoblastic leukemia [56]. Patients who had completed treatment within 6 months of finishing treatment gained cortical bone area but had decreased cortical density. Patients at more than 6-months after therapy at the baseline had stable cortical dimensions and gained cortical density. These observational data can be helpful in targeting potential candidates for future treatment trials. &
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CONCLUSION The diagnosis and treatment of pediatric osteoporosis have advanced in recent years aided by consensus guidelines, robust densitometry norms, and studies of fracture risk in primary and secondary osteoporosis. More is known about the risks and benefits of pharmacologic therapy in younger patients. There is more to be learned, however, about the impact of age, disease, mobility, medications, and other clinical variables on fracture risk independent of bone density. Randomized trials of pharmacologic and nonpharmacologic interventions are needed with efficacy judged by fracture incidence, mobility, and bone pain, as well as aBMD. Only with this knowledge can management of pediatric osteoporosis advance further from expert opinion to evidence-based. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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44. Ward LM, Rauch F, Whyte MP, et al. Alendronate for the treatment of pediatric osteogenesis imperfecta: a randomized placebo-controlled study. J Clin Endocrinol Metab 2011; 96:355–364. 45. Bishop N, Adami S, Ahmed SF, et al. Risedronate in children with osteogen&& esis imperfecta: a randomised, double-blind, placebo-controlled trial. Lancet 2013; 382:1424–1432. In this randomized controlled trial in 147 children with osteogenesis imperfecta, oral risedronate (2.5–5 mg/day) resulted in greater gains in spine aBMD and reduced the risk of long bone fractures by 47%. 46. Grey A, Bolland M, Wattie D, et al. Prolonged antiresorptive activity of zoledronate: a randomized controlled trial. J Bone Miner Res 2010; 25:2251–2255. 47. Simm PJ, Johannesen J, Briody J, et al. Zoledronic acid improves BMD, reduced bone turnover and improves skeletal architecture over 2 years of treatment in children with secondary osteoporosis. Bone 2011; 49:939– 943. 48. Ooi HL, Briody J, Biggin A, et al. Intravenous zoledronic acid given every & 6 months in childhood osteoporosis. Horm Res Paediatr 2013; 80:179– 184. This retrospective study of 27 patients found that twice yearly zoledronic acid (0.05 mg/kg/dose) resulted in increased spine BMD and reshaping of fractured vertebral bodies. 49. Vuorimies I, Toivianen-Salo S, Hero M, Makitie O. Zoledronic acid treatment in children with osteogenesis imperfecta. Horm Res Paediatr 2011; 75:346– 353. 50. Munns CF, Rajab MH, Hong J, et al. Acute phase response and mineral status following low dose intravenous zoledronic acid in children. Bone 2007; 41:366–370. 51. Stathopoulos IP, Liakou CG, Katsalira A, et al. The use of bisphosphonates in women prior to or during pregnancy and lactation. Hormones (Athens) 2011; 10:280–291. 52. Semler O, Netzer C, Hoyer-Kuhn H, et al. First use of the RANKL antibody denosumab in osteogenesis imperfecta type VI. J Musculoskelet Neuronal Interact 2012; 12:183–188. 53. Boyce A, Chong W, Yao J, et al. Denosumab treatment for fibrous dysplasia. J Bone Miner Res 2012; 27:1462–1470. 54. Rauch F, Cornibert S, Cheung M, Glorieux FH. Long-bone changes after pamidronate discontinuation in children and adolescents with osteogenesis imperfecta. Bone 2007; 40:821–827. 55. Leblanc CM, Ma J, Scuccimarri R, et al. A154: glucocorticoid therapy and the & risk of incident vertebral fracture in children with rheumatic disorders. Arthritis Rheumatol 2014; 66:S199–S200. This prospective study of 136 children with rheumatologic disease followed for 3 years from initiation of glucocorticoids found 13% had vertebral fractures with risk related to steroid dose. 56. Mostoufi-Moab S, Brodsky J, Isaacoff EJ, et al. Longitudinal assessment of bone density and structure in childhood survivors of acute lymphoblastic leukemia without cranial radiation. J Clin Endocrinol Metab 2012; 97:3584– 3592.
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Diagnosis and treatment of pediatric osteoporosis Laura K. Bachrach
Purpose of review 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. Recent findings 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. Summary 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. Video abstract: http://links.lww.com/COE/A9 Keywords bisphosphonates, bone density, fractures, pediatric osteoporosis
INTRODUCTION Threats to bone health are increasingly a pediatric concern. Genetic or acquired disorders can compromise gains in bone quantity and quality leading to osteoporosis early in life [1,2]. Recurrent fractures in otherwise healthy youth may also indicate underlying bone fragility [3,4 ]. The stakes are high to address these early threats to bone health as the foundation for bone health is established during the first 2 decades [5]. Genetic factors determine an estimated 70% of the variability in peak bone mass, but to reach one’s genetic potential requires optimal modifiable factors [5]. The goal of clinical practice is to prevent fractures in at-risk patients before they occur and to reduce the likelihood of their recurrence. Despite advances in the diagnosis and treatment of pediatric osteoporosis, important limitations persist. This review will summarize recent progress in management with a particular focus on publications from the past 2 years. &
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SURROGATE MEASURES IN THE DIAGNOSIS OF PEDIATRIC OSTEOPOROSIS The surrogate measures of bone health used to assess fracture risk in adults are more challenging to interpret in younger patients because they represent a moving target. The skeleton evolves in size and mass until late adolescence or early adulthood when lifetime peak bone mass is achieved. Serum and urine biochemical markers are used to distinguish highturnover from low-turnover bone disorders. Results are affected by myriad factors, including age, Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA Correspondence to Laura K. Bachrach, MD, Department of Pediatrics, Stanford University School of Medicine, Room H314, Stanford Medical Center, Stanford, CA 94035–5208, USA. Tel: +1 650 723 5791; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2014, 21:454–460 DOI:10.1097/MED.0000000000000106 Volume 21 Number 6 December 2014
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KEY POINTS Bone densitometry is only part of a comprehensive skeletal screen for bone fragility. Spine and TBLH are the preferred sites for DXA in most children. Vertebral fractures that occur with low trauma are rare in pediatrics and suggestive of bone fragility. The diagnosis of osteoporosis in pediatrics can based upon vertebral fractures alone or low bone density and multiple long bone fractures. Bisphosphonate therapy is considered reasonable for patients with a clinically significant fracture history.
pubertal stage, nutrition, growth velocity, time of day, and day-to-day variability [6,7]. The mean and range for pediatrics are considerably greater than adult norms until late adolescence. Bone markers have been used to monitor bone turnover in response to disease and pharmacologic therapy, but their value in clinical practice has not been established [6,7]. Bone densitometry has more clinical utility but it also presents problems in interpretation. Valuable guidance for utilizing this diagnostic tool has come from Pediatric Position Development Conferences (PDC) held in 2007 and 2013. Pediatric bone experts reviewed the literature and generated guidelines after rigorously rating the quality of available evidence. The 2013 report which is in print [8 ] and online (http://www.iscd.org/documents/2014/02/ 2013-iscd-official-position-brochure.pdf) addresses five areas: dual energy X-ray absorptiometry (DXA) interpretation and reporting, densitometry in infants and young children, DXA assessment in chronic diseases that may affect the skeleton, quantitative computed tomography, and fracture prediction and the definition of osteoporosis. The PDC recommendations provide practical guidance for evaluating pediatric bone health on the basis of available data and expert opinion when evidence is lacking. The ideal noninvasive technique to assess the growing skeleton would precisely measure the mass and geometry of bone that contribute to bone strength [9]. DXA neither distinguishes cortical from trabecular bone nor does it directly measure volumetric bone mineral density (vBMD) or bone geometry. Despite these limitations, DXA remains the preferred clinical tool to assess bone mineral content (BMC) and areal bone mineral density (aBMD) because of its speed, precision, safety, and robust normative data [8 ]. The antero-posterior &&
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lumbar spine (L1–4) and total body less head (TBLH) are the preferred skeletal sites for measurement in most children. For children aged 0–5 years, the spine BMC and BMD can be measured; whole body measurements are feasible only for those aged 3 years or older. Additional regions of interest using DXA are recommended in special cases. Scans of the lateral distal femur can be valuable in patients with contractures that preclude proper positioning for spine or whole body scans [10]. This site is also helpful in assessing patients with immobilization disorders because bone fragility is greatest in the lower extremities [11]. DXA scans should avoid areas with metal implants, contractures, or vertebrae in which fractures have occurred. The distal radius can be measured in patients who exceed the weight limit for the equipment. Quantitative computed tomography (QCT) measures volumetric BMD, distinguishes between trabecular and cortical bone, and detects bone geometry [9]. Peripheral QCT (pQCT) and highresolution pQCT (HR-pQCT) require less radiation than QCT and provide insights into the separate contributions of bone geometry and mass to bone strength. A study comparing girls with anorexia nervosa (AN) with controls found no significant difference in radius aBMD by DXA. By contrast, HRpQCT detected significant changes in cortical and trabecular microarchitecture in the girls with AN that would predict reduced bone strength [12 ]. At present, QCT, pQCT, and HR-pQCT remain primarily research techniques due to the lack of standardized scanning protocols and limited normative data. They can be used clinically in centers in which appropriate expertise and reference data are available [8 ]. &
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INDICATIONS FOR DENSITOMETRY A variety of primary and secondary disorders have been associated with increased bone fragility [1,8 ]. Osteogenesis imperfecta, Bruck syndrome, and idiopathic juvenile osteoporosis are examples of genetic disorders. The disorders linked to secondary osteoporosis include the inflammatory disorders (cystic fibrosis, rheumatologic disease or inflammatory bowel disease), neuromuscular conditions (muscular dystrophy or cerebral palsy), endocrinopathies (hypogonadism or growth hormone deficiency), under-nutrition (AN or HIV), malignancy, transplantation, and exposure to osteotoxic drugs. The PDC guidelines recommend that the initial DXA exam be performed when the patient might benefit from intervention and when the densitometry results would influence management
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[8 ]. Repeat scans (to monitor disease processes or therapy) should be done no more often than every 6–12 months.
identified microarchitectural deficits at the tibia and radius that discriminated between youth with and without low-trauma fractures of the distal forearm [4 ]. Observations from healthy youth may not apply to chronically ill or immobilized youth. For patients exposed to chronic glucocorticoid therapy [19,20 ] and those with leukemia [21], the risk of fracture is greater at the spine than at the forearm. Low spine BMD by DXA is strongly correlated with these fractures [19,21]. For each standard deviation that BMD Z-score falls below zero, there is an associated 80% increase odds of vertebral compression fracture. Youth with cerebral palsy, Duchenne muscular dystrophy, and other immobilization disorders are at greater risk for lower extremity fractures. In a study of 619 youth with cerebral palsy or Duchenne muscular dystrophy, lateral distal femur aBMD predicted these fractures, whereas the relationship between spine aBMD and fracture risk was unproven [11]. &
INTERPRETATION OF DUAL ENERGY XRAY ABSORPTIOMETRY RESULTS The results of pediatric DXA scans should be compared with norms for age, sex, and race/ethnicity collected from healthy youth using similar equipment and software as that used for the patient. The Bone Mineral Density in Childhood Study provides the best reference data for Hologic (Bedford, Massachusetts, USA) as they were collected from a representative population of healthy youth and summarized using optimal statistical modeling [13]. These data are available on a user-friendly website that calculates Z-scores corrected for age, sex, race/ ethnicity, and height Z-score (http://www.bmdcspu blic.com). Normative data for General Electric-Lunar (Madison, Wisconsin, USA) equipment have been published as well [14]. The interpretation of pediatric densitometry may require additional adjustment, if growth and maturation are delayed. BMD using DXA is a twodimensional measurement that tends to be lower in smaller individuals and greater in taller ones. To address the influence of bone size, the 2013 PDC guidelines recommend adjusting spine data for estimated bone volume (bone mineral apparent density) or height Z-score [8 ]. TBLH should be adjusted for height Z-score. &&
CAN DENSITOMETRY PREDICT PEDIATRIC FRACTURES? The largest studies examining the association of bone density with fracture have been carried out in otherwise healthy youth because they tend to fracture [15 ,16]. An estimated 30–50% of youth will have at least one broken bone by age 16, most commonly in the forearm [17,18]. The best predictors of fracture in these studies have been TBLH BMC corrected for height, weight, and bone area. Youth with smaller bone area and bone mineral for area have an increased fracture risk [15 ]. At best, the ability of DXA alone to predict fracture is limited. A study by Kalkwarf et al. [16] compared a variety of DXA and pQCT parameters of bone mass and size in 224 children with or without radius fractures in the prior month. The area under the curve linking densitometry measures and fracture ranged from 0.56 to 0.59, identifying those with fractures little better than chance alone [16]. Preliminary data indicate that HRpQCT may prove a better noninvasive tool for assessing bone strength. This technique &&
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LATERAL SPINE RADIOGRAPHS Vertebral compression fractures are rare in children and in those occurring without major trauma indicate bone fragility. Vertebral fracture assessment in DXA software is used to identify spine fractures in adults but may not be sufficiently sensitive for use in children [22]. At present, lateral radiographs of the thoracolumbar spine are the gold standard to identify spine fractures in pediatrics [23]. Vertebral compression fractures can occur in chronically ill youth in the absence of very low BMD by DXA. In an illustrative case report, a 10year-old boy with nephrotic syndrome developed back pain after long-term high-dose glucocorticoids [24]. A spine radiograph demonstrated fractures at T7 and T8 and a bone biopsy showed findings consistent with osteoporosis. Spine and whole body aBMD Z-scores were only slightly reduced at 0.5 and 0.4, respectively.
CRITERIA FOR THE DIAGNOSIS OF OSTEOPOROSIS DXA findings alone cannot be used to diagnose osteoporosis in pediatric patients. This is in contrast with postmenopausal women who can be labeled with osteoporosis on the basis of a T-score below 2.5 [25]. T-scores comparing the patient’s DXA results with a young adult reference group should not be used before the age of 20 years. The terms, osteoporosis and osteopenia, should not appear on pediatric DXA reports. Pediatric patients with BMC or aBMD values at or below 2 standard deviations should be described as having low bone mass for age. Volume 21 Number 6 December 2014
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The 2013 PDC guidelines defined the diagnostic criteria for osteoporosis in pediatric patients. A child or teen with one or more vertebral compression fractures occurring without local bone disease or high-energy trauma meets criteria [8 ]. Measuring BMD can add to the assessment of these patients but is not required. Alternatively, osteoporosis can be diagnosed in patients with a combination of low bone density (BMC or aBMD Z-scores < 2) and a significant fracture history (two or more long bone fractures by age the 10 or 3 years or more long bone fractures before age 19 years). &&
doses may be required in patients with obesity or malabsorption disorders [27]. Adequate total body stores of vitamin D have been defined as a serum 25 hydroxy vitamin D concentration of at least 20 ng/ml [26,28] or 30 ng/ml [29] based largely on studies in adults. Unfortunately, nutritional deficits can be overlooked in chronic illness. Studies have found 40% or more of children admitted to pediatric ICU have 25 OH vitamin D concentrations less than 20 ng/ml [30]. Lower vitamin D stores were associated with greater severity of illness. Physical activity has an anabolic effect on the growing skeleton. High-impact activities have been shown to increase bone mass in healthy youth [31 ] but should be avoided in children with bone fragility. Nonetheless, modified activity as tolerated is important to counteract the impact of reduced mobility. Modest gains in aBMD have been reported from studies using static standing, physical therapy, or high frequency vibratory platforms [32]. Replacement of sex steroids and growth hormone for those with documented deficiencies is also appropriate [33]. Growth hormone therapy has been shown to increase aBMD even after final adult height is reached and continued growth hormone replacement into adulthood is recommended for those with low age-adjusted BMC [34]. &
DENSITOMETRY IS PART OF A COMPREHENSIVE BONE HEALTH SCREEN A child or adolescent with low bone mass or lowtrauma fractures warrants a comprehensive evaluation to determine possible primary or secondary causes [1]. This includes a review of chronic illness, medications, nutrition, activity, and fracture history. A family history of hip fractures in elderly relatives or repeated fractures in younger family members should be explored. Recommended laboratory tests include a complete blood count, erythrocyte sedimentation rate, serum calcium, phosphorus, alkaline phosphatase, intact PTH, total 25 hydroxy vitamin D, BUN, creatinine, and celiac screen, as well as urinary calcium to creatinine ratio. Additional tests to consider depending upon the age, physical exam, and history include luteinizing hormone, follicle stimulating hormone, estradiol, testosterone, insulin-like growth factor type I, free T4, and TSH. Genetic screening for osteogenesis imperfecta is commercially available; testing for other genetic disorders, such as inactivating mutations in low-density lipoprotein receptorrelated protein 5, may be available on a research basis. Vertebral fractures may be asymptomatic and a lateral thoracolumbar spine radiograph is indicated for those with back pain, low-trauma fractures of the long bones, or chronic glucocorticoid therapy. A bone biopsy helps distinguish osteomalacia from osteoporosis and low-turnover versus high-turnover bone disease. This procedure is reserved for more severe cases of bone fragility not diagnosed through routine evaluation.
GENERAL MEASURES FOR BONE HEALTH Prevention and treatment of bone fragility should address all potential threats to skeletal health. Calcium from diet and supplements should total 1300 mg/day for ages 9–18 years [26]. Recommended daily intake of vitamin D is a minimum of 600 IU daily after the first year of life, but higher
PHARMACOLOGIC THERAPY When low-trauma fractures occur despite these general measures, the addition of pharmacologic agents should be considered. An anabolic agent would be ideal as pediatric osteoporosis often results from a failure to acquire bone rather than accelerated loss. Synthetic parathyroid hormone (teriparatide) has a black box warning against its use in patients with open growth plates and the benefits of human growth hormone are not established except in growth hormone deficient patients. This limits pharmacologic therapy primarily to antiresorptive agents. Sex hormone therapy (SHT) is indicated for those with hypogonadism as discussed above. The efficacy of SHT to improve BMD or reduce fractures in exercise-associated amenorrhea [35] or eating disorders [36,37] remains uncertain. In light of this, the American College of Sports Medicine has recommended that oral contraceptives be considered in amenorrheic athletes only after age 16 years and if BMD is decreasing despite adequate nutrition and weight gain [35]. One potential explanation for the failure of SHT to improve bone health has been the suppressive effect of high-dose oral estrogens on serum insulinlike growth factor type I. A placebo-controlled study
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in teens with AN found that low-dose transdermal estrogen or very low-dose incremental oral ethinylestradiol resulted in gains in spine and hip aBMD [38]. In another study of a young woman with AN, low-dose oral estrogen and dehydroepiandrosterone maintained spine and whole body aBMD [39] and improved hip geometry as determined by hip structural analysis as compared with placebo [40]. Whether these SHT regimens will result in reduced fracture risk remains to be determined.
BISPHOSPHONATE THERAPY Bisphosphonates have been used to treat osteogenesis imperfecta [41] and a variety of disorders causing secondary osteoporosis for more than 3 decades [42]. There is insufficient evidence to support the routine use of bisphosphonates in these disorders but compassionate use is reasonable for those with fragility fractures. There is no consensus about the optimal agent, dose, and duration of therapy [43]. Pamidronate has been the most extensively used of the bisphosphonates in pediatrics in doses ranging from 4 to 9 mg/kg/year. Randomized dose-response studies have not been performed to establish the optimal dose. The demand for more convenient and less expensive therapy has led to trials with oral bisphosphonates and more potent intravenous agents. In a randomized controlled trial in children with osteogenesis imperfecta, daily oral alendronate resulted in significant gains in spine aBMD versus placebo, but no significant reduction in bone pain and time to first fracture [44]. By contrast, a randomized trial of daily oral risedronate in osteogenesis imperfecta patients resulted in increased spine aBMD and a reduced risk of first or recurrent nonvertebral fractures [45 ] Zoledronic acid is 100–200 times more potent than pamidronate, can be infused more rapidly, and has duration of action for up to 3 years in postmenopausal osteoporosis [46]. Case series from children with secondary osteoporosis have shown gains in aBMD, metacarpal cortical thickness, and vertebral morphology with zoledronic acid given every 3 months [47] or 6 months [48 ] in a dose of 0.1 mg/kg/year. Twice yearly zoledronic acid has also been shown to increase spine aBMD in children with type I osteogenesis imperfecta [49]. Prior to treatment, these children had sustained 73 fractures. During 1–3-year treatment period, six patients had 10 new long bone fractures. Minor adverse reactions are common after the initial dose of bisphosphonates, including fatigue, fever, nausea, and muscle aches. The incidence of hypocalcemia, hypophosphatemia, and &&
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hypomagnesemia can be reduced by ensuring adequate vitamin D and calcium intake. Reducing the initial dose of zoledronic acid from 0.05 to 0.0125–0.025 mg/kg/day has also been suggested [50]. To date, no atypical femur fractures or avascular necrosis of the jaw have been observed in pediatric patients. A concern for potential teratogenic effects has been raised as bisphosphonates may be released from bone for years and readily cross the placenta. A review of 78 fetuses whose mothers had been treated with bisphosphonates prior to or during pregnancy found few serious adverse effects [51]. Prematurity, low birth weight, and transient hypocalcemia were observed. Eight spontaneous abortions and the congenital anomalies were attributed to the underlying maternal disease or other medications. Some experts have recommended that bisphosphonates be discontinued 6–12 months prior to pregnancy [51]. The pediatric experience using denosumab, a monoclonal antibody that inhibits osteoclast activity, is very limited. Four boys with osteogenesis imperfecta type IV resistant to bisphosphonates showed reductions in bone resorption markers during denosumab treatment for 5–33 weeks [52]. Denosumab was reported to reduce bone pain and the size of a bone lesion in one child with fibrous dysplasia [53].
DURATION OF THERAPY The maximal benefits from pamidronate in children are seen at 2–4 years but low-dose maintenance bisphosphonate therapy may be needed until growth is complete in patients with persistent risk factors for osteoporosis such as those with osteogenesis imperfecta [54]. Studies in these patients have shown that diaphyseal BMC is maintained for 2 years after pamidronate is stopped, but new bone added at metaphyseal sites has a lower density. Fractures have occurred at the junction of untreated new bone and regions of older treated bone [43,54].
REFINING WHO TO TREAT It would be ideal to treat high-risk patients before fractures occur and to withhold pharmacologic therapy in those likely to regain bone without medication. To target treatment in this way would require increased knowledge of the natural history of primary and secondary osteoporosis. Observational studies from patients during the first year of glucocorticoid therapy have shown variable risk for vertebral fracture. Incident vertebral fractures occurred in 6% of children with rheumatologic disorders [19] or nephrotic syndrome [20 ] and 16% of children with acute lymphoblastic leukemia &
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[21]. Vertebral deformities were mild in nephrotic syndrome but moderate-to-severe in the others. A 13% cumulative incidence of vertebral fractures has been reported in children with rheumatologic disorders during the first 3 years of glucocorticoid therapy [55 ]. Higher fracture risk was linked to larger glucocorticoid doses, increasing BMI Z-score, decreasing spine aBMD Z-score, and vertebral fractures at the baseline [19,21,55 ]. Bone mass and geometry can recover once chronic illness resolves. A 1-year study using pQCT found that tibial trabecular BMD increased in all patients after chemotherapy for acute lymphoblastic leukemia [56]. Patients who had completed treatment within 6 months of finishing treatment gained cortical bone area but had decreased cortical density. Patients at more than 6-months after therapy at the baseline had stable cortical dimensions and gained cortical density. These observational data can be helpful in targeting potential candidates for future treatment trials. &
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CONCLUSION The diagnosis and treatment of pediatric osteoporosis have advanced in recent years aided by consensus guidelines, robust densitometry norms, and studies of fracture risk in primary and secondary osteoporosis. More is known about the risks and benefits of pharmacologic therapy in younger patients. There is more to be learned, however, about the impact of age, disease, mobility, medications, and other clinical variables on fracture risk independent of bone density. Randomized trials of pharmacologic and nonpharmacologic interventions are needed with efficacy judged by fracture incidence, mobility, and bone pain, as well as aBMD. Only with this knowledge can management of pediatric osteoporosis advance further from expert opinion to evidence-based. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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Volume 21 Number 6 December 2014
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