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Fracture Prediction and the Definition of Osteoporosis in Children and Adolescents: The ISCD 2013 Pediatric Official Positions
Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health, vol. 17, no. 2, 275e280, 2014 Ó Copyright 2014 by The International Society for Clinical Densitometry 1094-6950/17:275e280/$36.00 http://dx.doi.org/10.1016/j.jocd.2014.01.004
2013 Pediatric Position Development Conference
Fracture Prediction and the Definition of Osteoporosis in Children and Adolescents: The ISCD 2013 Pediatric Official Positions Nick Bishop,*,1,2,a,b Paul Arundel,1,2,c Emma Clark,3,c Paul Dimitri,1,2,c Joshua Farr,4,c Graeme Jones,5,c Outi Makitie,6,c Craig F. Munns,7,c and Nick Shaw8,c 1
Department of Human Metabolism, Academic Unit of Child Health, University of Sheffield, Sheffield, UK; 2Sheffield Children’s Hospital, Sheffield, UK; 3Academic Rheumatology, Musculoskeletal Unit, University of Bristol, Bristol, UK; 4 College of Medicine, Mayo Clinic, Rochester, MN, USA; 5Musculoskeletal Unit, Menzies Research Institute, Hobart, Australia; 6Pediatric Endocrinology and Metabolic Bone Diseases, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland; 7Bone and Mineral Medicine, The Children’s Hospital at Westmead, Sydney, NSW, Australia; and 8Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham, UK
Abstract 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. Key Words: Dual-energy X-ray absorptiometry; ethnicity; fracture; pediatric; trauma.
half of all childhood fractures affect the forearm (2,5e8). There is a clear relationship, irrespective of bone mass, between fracture frequency and the overall level of physical activity (9), despite the fact that physical activity and exercise are positively associated with bone mass (10e17). In reviewing the existing Positions, the Task Force on fracture prediction and osteoporosis definition collated information from studies that examined the relationship of fracture with a range of factors including genotype, ethnicity, body composition, puberty, antenatal and perinatal events, exercise and physical activity, degree of trauma, diet, and recurrent fractures. With respect to fracture prediction and the definition of osteoporosis, the 2007 Pediatric Position statements are given below, taken from the ISCD Website. Fracture prediction should primarily identify children at risk of clinically significant fractures, such as fracture of long bones in the lower extremities, vertebral compression fractures, or 2 or more long bone fractures of the upper extremities. The diagnosis of osteoporosis in children and adolescents should not be made on the basis of densitometric criteria alone. The diagnosis of osteoporosis requires the presence of both a clinically significant fracture history and low bone
Introduction The usefulness of imaging, in particular dual-energy X-ray absorptiometry (DXA), in the assessment of skeletal wellbeing at all ages is generally accepted, although the ability of DXA alone to predict fracture is limited (1). The effects of variation in body and bone size on DXA measurement of bone mass are covered in the document from Task Force 4, ‘‘Reporting Pediatric Densitometry Results.’’ Fracture frequency is high in children compared with young and middleaged adults (2), reflecting the interacting effects of bone size and mass, physical activity, and possibly other factors. Among healthy children, as many as half of all boys and a third of girls will fracture by age 18, and one-fifth will have 2 or more fractures (3,4). Most fractures are of the upper limb; one-third to Received 01/07/14; Accepted 01/08/14. a
Task Force Chair.
b
Task Force Liaison.
c
Task Force Member.
*Address correspondence to: Nick Bishop, MD, Academic Unit of Child Health, University of Sheffield, Sheffield Children’s Hospital, Western Bank, Sheffield S10 2TH, UK. E-mail: n.j.bishop@ shef.ac.uk
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mineral content (BMC) or bone mineral density (BMD). A clinically significant fracture history is one or more of the following: B B B
Long bone fracture of the lower extremities. Vertebral compression fracture. Two or more long bone fractures of the upper extremities.
Low BMC or BMD is defined as a BMC or areal BMD Z-score that is less than or equal to 2.0, adjusted for age, gender, and body size, as appropriate. The approach of the Task Force has been to review the published literature, focusing in particular on articles published since 2007, to provide evidence that either supports the statements as they stand or suggests that they should be amended.
Methodology Individual task force members were assigned areas of the literature to review and undertook searches using the PubMed and OVID databases from 1966 to 2013. Combinations of terms including those used in the 2007 searches were used (BMD, BMAD, children, adolescents, pediatric, and fracture), along with area-specific terms as indicated previously. Studies were included in the literature set if they included an analysis of the relationship between bone mass/density and fracture. Almost all imaging was by DXA; one recent study used High Resolution peripheral Quantitative Computed Tomography (HRpQCT) to assess variation in microarchitecture in children with fracture according to grades of trauma and is included because of the important insight it provides. The articles pulled together include those used by the 2007 Task Force with an additional 10 articles selected (according to the criteria listed) from those suggested by current Task Force members. The Task Force considered data primarily relating to studies of apparently healthy children. Nevertheless, it is important that each child is evaluated appropriately for the signs and symptoms of diseases known to increase fracture risk. The position statement on bone health in children and adolescents with chronic diseases will address DXA measures in varied diseases.
Position 1 Fracture prediction should primarily identify children at risk of clinically significant fractures, such as fracture of long bones in the lower extremities, vertebral compression fractures, or 2 or more long bone fractures of the upper extremities. The issue that has arisen in considering this Position is the one relating to degree of trauma in relation to assessment of risk. Given sufficient force, any bone will break. The Task Force agreed that it is thus reasonable to exclude fractures occurring as a result of road traffic accidents or falls from above 3 m (10 feet) since fractures are expected to occur in such circumstances irrespective of any other consideration. The association of fractures resulting from mild as opposed to moderate degrees of trauma with variation in bone mass
estimated by DXA has not been systematically studied in children. Recent work published by Farr et al (18) using HRpQCT suggests that microarchitectural deficits likely to result in increased bone fragility are evident in children who suffer a distal forearm fracture (DFF) following mild, but not moderate, trauma compared with non-fracture controls. The deficits at a microarchitectural level and cortical thinning are seen in both the distal radius and distal tibia in children presenting with a DFF where the degree of trauma (per Landin’s modified criteria) is mild, but not in those where the degree of trauma is moderate. Microfinite element analysis in the distal radius HRpQCT images showed that the ‘‘mild trauma’’ DFF cases had reduced bone strength (failure load), compared with the children with no fracture history. This implies in turn that moderate trauma is sufficient to break healthy bones, which are not otherwise at inherently increased risk of fracture. This suggestion is supported by the studies of Clark and others that irrespective of bone mass, fracture risk rises as the amount of vigorous activity rises (9). However, degree of trauma was not discussed in these articles. Thus, consideration should be given to excluding fractures arising from moderate or worse trauma from the Position.
Summary The Task Force agreed that excluding fractures occurring as a result of high-energy trauma is appropriate. However, the differentiation of mild and moderate degrees of trauma is difficult to assess; there are few studies where any attempt has been made to rigorously classify trauma, and only Farr’s study related degree of trauma to microarchitectural findings. Recall of the exact mechanism of trauma might be difficult; unobserved fractures in younger children would be difficult to classify, and there could be issues around fall complexity (e.g., twisting components). In addition, even in children with known bone fragility, moderate trauma does not inevitably result in a fracture. The Task Force agreed that the criteria of Landin should not be used as trauma from skiing and skateboarding accidents were included there as ‘‘mild.’’ The view of the Task Force overall was that fractures were more likely to be of significance in terms of the diagnosis of osteoporosis or for the assessment of future fracture risk if they occurred as a result of simple, mild, or low-energy trauma. However, defining simple and mild/low energy would be a matter for clinical judgment in the individual case. The Task Force was of the view that further studies were needed in this area. The Task Force suggested that the Position not be substantially amended, but the addition of the word ‘‘increased’’ in front of the word ‘‘risk’’ would make the Position more focused. At PDC, further discussion took place regarding the purpose of both fracture risk prediction and the diagnosis of osteoporosis. As the Position Statements are expected to inform clinical practice, it was felt important to reflect the utility of fracture risk prediction and (assumed) osteoporosis in the first Position. The final agreed new Position 1 is: ‘‘Evaluation of bone health should identify children and adolescents who may
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Pediatric Osteoporosis Definition benefit from intervention to decrease their elevated risk of a clinically significant fracture.’’
Position 2 Grade: approvedfair/gooddB/Cdworldwide. In the 2007 Position Statements, the second section of the document addressed the question ‘‘what are the densitometric criteria for the diagnosis of osteoporosis in a child or adolescent?’’ We have altered the flow of the document to reflect a more clinical orientation, and this section lays out the new criteria for the diagnosis of osteoporosis. The previous Position 2 was as follows: ‘‘The diagnosis of osteoporosis in children and adolescents should not be made on the basis of densitometric criteria alone.’’ There was no disagreement from any task force member with this statement and no evidence from the published literature that this should change; however, the ordering of the Positions has been changed, and this Position now becomes the final Position, Position 4, to maintain the emphasis on the clinical aspects of diagnosis and fracture prediction. In the 2007 Position Statements, there was the potential for confusion in that both the Positions referred to ‘‘clinically significant fracture;’’ in Position 1, this was in relation to the risk of subsequent fracture, whereas in the body of Position 2, it was in relation to previous fracture history. 2007 Position 2 reads as follows: The diagnosis of osteoporosis requires the presence of both a clinically significant fracture history and low BMC or BMD. A clinically significant fracture history is one or more of the following: - Long bone fracture of the lower extremities. - Vertebral compression fracture. - Two or more long bone fractures of the upper extremities. - Low BMC or BMD is defined as a BMC or areal BMD Z-score that is less than or equal to 2.0, adjusted for age, gender, and body size, as appropriate.
B
There was no direct disagreement with this statement. However, there were suggestions made with respect to both what constituted a: 1. ‘‘Clinically significant fracture history’’ and 2. The threshold for regarding bone density as being ‘‘low.’’ There was general agreement that a vertebral crush fracture (loss of vertebral height at any point of O20%) was an indicator of osteoporosis unless caused by high-energy trauma. In addition, from discussions in PDC in Baltimore, MD, it became clear that there was support to create a new Position reflecting the importance of vertebral crush fracture as a clinical indicator of osteoporosis. The new Position 2 is, therefore, as follows: ‘‘The finding of one or more vertebral compression (crush) fractures is indicative of osteoporosis, in the absence of local disease or high-energy trauma. In such children and adolescents, measuring BMD adds to the overall assessment of bone health.’’
277 Grade: approvedfairdBdworldwide. The Task Force then addressed the question of ‘‘what is a clinically significant fracture?’’ excluding the vertebral crush fracture as stated previously. We generally agreed (see above) that the lower the level of apparent trauma resulting in a fracture, the more likely it was to be indicative of an underlying propensity to fracture. For apparently healthy children, published data indicate that 15%e20% have more than one fracture, but there has been no systematic evaluation of number of fractures (irrespective of age) in relation to altered microarchitecture, nor any evaluation of number of fractures in relation to vigorous activity and degree of trauma. For children with an underlying disease process, the situation is even less clear. The study of Mayranpaa et al (19) looked at a group of children with a history of any one of: 2 long bone fractures before age 10 yr; 3 long bone fractures before age 16 yr; or one or more vertebral fractures. Among those with vertebral fractures, regarded by most as pathognomonic for osteoporosis, the average lumbar spine bone mineral density Z-score (adjusted for age and sex and excluding damaged vertebrae) was 0.8 0.8. The authors concluded that there was no clear relationship in this ‘‘at risk’’ group of children between low BMD and fracture risk and that a thorough evaluation of the skeleton was indicated after a second ‘‘low-energy’’ fracture. Another issue was the extent to which low BMD is predictive for all fractures, as opposed to upper limb (which is the most frequent site) fractures. The data from the study of Farr quoted previously (18) found similar deficits at both the distal radius and distal tibia, but the majority of DXA-based studies have not discriminated between sites concerning the predictive ability of spine, total body, or hip measurements for fracture. The study of Jones (20) found no relationship between DXA measures at the spine and hip with fractures other than those of the upper limb. The previous Position Statements referenced the work of Ferrari et al (21) in this respect as showing an association of low ultradistal and one-third (33%) radius areal BMD adjusted for age and gender (Z-score) with subsequent DFF in 32 girls older than 8.5 yr; work by Goulding et al (22) following a cohort of 170 girls (82 with fracture) over a 4-yr period failed to show any such association, however. The overall view of the Task Force was that the current criteria, if applied as a screening tool for who should have a DXA scan, were too loose; as many as 34% of children could end up having a scan. The criteria used by Mayranpaa et al (19) (2 or more fractures at age !10 yr, 3 or more at any age, or a vertebral fracture) were debated; however, there are no data to indicate that either the number of fractures or the age thresholds are more or less predictive of future fracture risk/osteoporosis than any other criteria. In summary, the current threshold of 2 long bone fractures, or a lower limb fracture, was felt to be inadequately supported by the literature. More work is needed to define alternative thresholds for fracture frequency/number alongside evaluation of the degree of trauma resulting in those fractures. In addition, further work was needed to evaluate whether additional risk factors should
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278 be included and whether re-fracture at the same site should be considered as recurrent. The Task Force suggested nevertheless that consideration should be given to adopting the Makitie thresholds while further work is undertaken to address the issues raised. A clinically significant fracture history is one or more of the following: - Two or more long bone fractures by age 10 yr; - Three or more long bone fractures at any age up to 16 yr. - Vertebral compression fracture (loss of O20% height at any point).
B
Occurring as a result of ‘‘mild-moderate trauma’’ (i.e., excluding high-energy trauma). Experts at PDC agreed with these statements in broad outline but felt that defining mild as opposed to moderate trauma could not be easily achieved without more published data; this part of the statement was therefore amended as reflected in the final Position 3 (see below). The Task Force also considered whether it was appropriate to change the threshold for BMD/BMC Z-score in this Position. In otherwise healthy children, the population-based data indicate that at age 9 yr the best predictor of fracture over the following 2 yr is whole-body (less head) BMC adjusted for height, weight, and bone area, with each successive adjustment increasing the strength of the combined associations with the outcome of subsequent fracture. Height-age adjustment in the Bone Mineral Density in Childhood Study (BMDCS) accounts for 25%e37% of the variance in BMC/BMD Z-scores (23); however, the stated premise was that an ‘‘appropriate’’ adjustment would result in similar distributions of the adjusted BMC and BMD among short, average, and tall children, not that the height-adjusted BMC/BMD Z-score would have predictive value for fracture outcome. BMDCS also reasonably excluded some children on the basis of fracture history (children 10 yr old with O1 fracture, or O10 yr old with O2 fractures) to target a ‘‘healthy’’ population, but this may have excluded some children who would be at increased risk of future fragility-related fracture. Thus, BMDCS cohort may not be the best one in which to assess the relationship of BMD Z-score (however adjusted) and fracture risk. The work from Jones et al assessing the effect of different adjustments (age, height, weight) on DXA estimates with respect to subsequent fracture risk found no difference when using body size-related measures as opposed to age (20). In the Mayranpaa study (19), BMD was adjusted for Tanner stage/bone age; very few of those with vertebral crush fractures had an adjusted BMD Z-score that was ! 2.0. Task Force members commented that the use of body-size adjusted Z-scores needs to be practicaldthere is no published prediction equation for bone mass based on height, weight, and bone area currently. There was also the comment that hip data were unreliable in younger children and it would therefore be appropriate to restrict the use of the Z-scores to the spine and total body measurements.
Bishop et al.
Summary of Discussion Regarding the Bone Density Threshold At present, it is difficult to justify changing the BMD element of the Position, since there are no data to support a change. However, the available data from apparently healthy children indicate that while a lower bone mass for body size is associated with increased fracture risk, children can have fragile bones with an apparently ‘‘normal’’ bone density as assessed by DXA. In discussion in PDC, the idea was put forward that while a BMC/BMD Z-score of 2.0 was required for the diagnosis, this did not preclude the possibility of bone fragility, as can be seen in children with mild osteogenesis imperfecta, for instance. The agreed new Position 3 therefore reads: ‘‘In the absence of vertebral compression (crush) fractures, the diagnosis of osteoporosis is indicated by the presence of both a clinically significant fracture history and BMD Z-score 2.0. A clinically significant fracture history is one or more of the following: 1. Two or more long bone fractures by age 10 yr; 2. Three or more long bone fractures at any age up to 19 yr. A BMD/BMC Z-score O 2.0 does not preclude the possibility of skeletal fragility and increased fracture risk.’’ Grade: mildly approvedpoordCdworldwide. It was felt important that the statement regarding the use of bone density assessment alone as inappropriate in the diagnosis of osteoporosis in children was retained but moved to become Position 4: ‘‘The diagnosis of osteoporosis in children and adolescents should not be made on the basis of densitometric criteria alone.’’ Grade: strongly approvedpoordCdworldwide.
Additional Areas Reviewed by the Task Force Effects of Ethnicity The studies of apparently healthy children relating bone mass to fracture risk have been of predominantly White children. With respect to fracture frequency and ethnicity, data have been presented in 2 studies that indicate a significantly higher risk of fracture for children of White Caucasian origin, as opposed to children of black African origin of similar age, gender, and bone mass. In the studies of Wren et al (24), based on the BMDCS longitudinal cohort study, white boys who subsequently fractured had higher BMD Z-scores. Thandrayen et al also found substantially higher fracture rates among white as opposed to black African children living in South Africa in a large longitudinal cohort study (25,26). Does this mean that a different BMD threshold should be used for children of black African origin? BMDCS excluded children with a fracture history, as noted above so the sample may have excluded some informative cases, identified as 1.7% of potential participants. This is interesting as others have found that as many as 20% of children who have had
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one fracture will have a second by age 18 yr. Although degree of trauma data was collected, the association of trauma alone or interaction of trauma with other factors was not described in any of the models. In summary, at present, the Task Force does not think there is sufficient information available to amend any of the Positions with respect to ethnicity; some of the reported associations may be the result of differences in physical activity, rather than intrinsic differences in skeletal resistance to fracture. This was agreed by PDC.
increasing fracture risk. Future studies are thus needed to include an assessment/comparison of different body size adjustment techniques with respect to fracture risk, as well as accurately assessing the degree of trauma resulting in fracture. Ethnicity and body fat mass are data that can and should be collected as part of the assessment process and may contribute to the overall assessment of risk.
Obesity
1. Rauch F, Plotkin H, DiMeglio L, et al. 2008 Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2007 Pediatric Official Positions. J Clin Densitom 11(1):22e28. PII: S1094-6950(07)00251-X, http://dx.doi.org/ 10.1016/j.jocd.2007.12.003. 2. Cooper C, Dennison EM, Leufkens HG, et al. 2004 Epidemiology of childhood fractures in Britain: a study using the general practice research database. J Bone Miner Res 19(12):1976e1981. 3. Landin LA. 1983 Fracture patterns in children. Analysis of 8,682 fractures with special reference to incidence, etiology and secular changes in a Swedish urban population 1950-1979. Acta Orthop Scand Suppl 202:1e109. 4. Mayranpaa MK, Makitie O, Kallio PE. 2010 Decreasing incidence and changing pattern of childhood fractures: a population-based study. J Bone Miner Res 25(12):2752e2759, http://dx.doi.org/ 10.1002/jbmr.155. 5. de Putter CE, van Beeck EF, Looman CW, et al. 2011 Trends in wrist fractures in children and adolescents, 1997-2009. J Hand Surg Am 36(11):1810e1815.e2. PII: S0363-5023(11)01010-0, http://dx.doi.org/10.1016/j.jhsa.2011.08.006. 6. Jones G, Boon P. 2008 Which bone mass measures discriminate adolescents who have fractured from those who have not? Osteoporos Int 19(2):251e255, http://dx.doi.org/10.1007/s00198007-0458-1. 7. Landin LA. 1997 Epidemiology of children’s fractures. J Pediatr Orthop B 6(2):79e83. 8. Lyons RA, Delahunty AM, Kraus D, et al. 1999 Children’s fractures: a population based study. Inj Prev 5(2):129e132. 9. Clark EM, Ness AR, Tobias JH. 2008 Vigorous physical activity increases fracture risk in children irrespective of bone mass: a prospective study of the independent risk factors for fractures in healthy children. J Bone Miner Res 23(7):1012e1022, http://dx.doi.org/10.1359/jbmr.080303. 10. Bailey DA, McKay HA, Mirwald RL, et al. 1999 A six-year longitudinal study of the relationship of physical activity to bone mineral accrual in growing children: the university of Saskatchewan bone mineral accrual study. J Bone Miner Res 14(10): 1672e1679. 11. Baxter-Jones AD, Kontulainen SA, Faulkner RA, Bailey DA. 2008 A longitudinal study of the relationship of physical activity to bone mineral accrual from adolescence to young adulthood. Bone 43(6):1101e1107. PII: S8756-3282(08)00599-1, http:// dx.doi.org/10.1016/j.bone.2008.07.245. 12. Detter FT, Rosengren BE, Dencker M, et al. 2013 A 5-year exercise program in pre- and peripubertal children improves bone mass and bone size without affecting fracture risk. Calcif Tissue Int 92(4):385e393, http://dx.doi.org/10.1007/s00223012-9691-5. 13. Gunter K, Baxter-Jones AD, Mirwald RL, et al. 2008 Impact exercise increases BMC during growth: an 8-year longitudinal study. J Bone Miner Res 23(7):986e993, http://dx.doi.org/10. 1359/jbmr.071201. 14. Macdonald HM, Kontulainen SA, Khan KM, McKay HA. 2007 Is a school-based physical activity intervention effective for
The issue of whether BMD is accurate in children who are obese is one that we think still needs addressing, as does the extent to which we adjust for height and weight, or can adjust accurately for them, in children who are very obese. Furthermore, the Task Force was of the view that both underweight and overweight body habitus confers an increased risk of fracture, but again the mechanism by which such associations might lead to skeletal fragility are not clear. At present, the Task Force does not think there is sufficient information available to amend any of the Positions with respect to obesity, although it is recognized that obesity may be a risk factor for fracture. This was agreed by PDC, and together with issues related to trauma and ethnicity flagged as an area for future research (see below).
Future Directions There was a clear view expressed by Task Force members that a fracture occurring as a result of trivial, mild, simple, or low-energy trauma was more likely to reflect an intrinsic skeletal issue resulting in bone fragility. Work is needed to try and more clearly define what is meant by these terms, however, and in particular to determine whether mild/trivial/simple/ low-energy trauma can be readily differentiated from moderate trauma. The ‘‘numbers of fractures by a certain age’’ element also requires further study because at the present time we are suggesting moving from one expert view to another primarily because in the existing Position the thresholds are perceived as being too low (i.e., too many children could end up being scanned if they were applied as screening criteria). We recognize that children with fractures may be apparently healthy but that there is likely to be an increased risk of future fracture in those with underlying diseases affecting the skeleton. These recommendations are presented in the Position Statement considering those disorders. However, we feel that part of our remit is to consider how best to adjust bone density measurements made by DXA in the context of the diagnosis of osteoporosis. Data are again lacking, although suggestions on adjusting for height and height-age Z-score have been made, they are based on an apparently healthy population and are of uncertain relevance to fracture prediction. Similarly, work describing the adjustment for weight, height, and bone area is based on data from an apparently healthy cohort, although there was a clear relationship with reducing body and bone size-adjusted BMC being associated with
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Bishop et al. 21. Ferrari SL, Chevalley T, Bonjour JP, Rizzoli R. 2006 Childhood fractures are associated with decreased bone mass gain during puberty: an early marker of persistent bone fragility? J Bone Miner Res 21(4):501e507. 22. Goulding A, Jones IE, Taylor RW, et al. 2000 More broken bones: a 4-year double cohort study of young girls with and without distal forearm fractures. J Bone Miner Res 15(10): 2011e2018. 23. Zemel BS, Leonard MB, Kelly A, et al. 2010 Height adjustment in assessing dual energy x-ray absorptiometry measurements of bone mass and density in children. J Clin Endocrinol Metab 95(3):1265e1273. PII: jc.2009-2057, http://dx.doi.org/10.1210/ jc.2009-2057. 24. Wren TA, Shepherd JA, Kalkwarf HJ, et al. 2012 Racial disparity in fracture risk between white and nonwhite children in the United States. J Pediatr 161(6):1035e1040. PII: S00223476(12)00879-7, http://dx.doi.org/10.1016/j.jpeds.2012.07.054. 25. Thandrayen K, Norris SA, Micklesfield LK, Pettifor JM. 2011 Heterogeneity of fracture pathogenesis in urban South African children: the birth to twenty cohort. J Bone Miner Res 26(12): 2834e2842, http://dx.doi.org/10.1002/jbmr.491. 26. Thandrayen K, Norris SA, Pettifor JM. 2009 Fracture rates in urban South African children of different ethnic origins: the birth to twenty cohort. Osteoporos Int 20(1):47e52, http://dx.doi.org/ 10.1007/s00198-008-0627-x.
Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health
Volume 17, 2014
2013 Pediatric Position Development Conference
Fracture Prediction and the Definition of Osteoporosis in Children and Adolescents: The ISCD 2013 Pediatric Official Positions Nick Bishop,*,1,2,a,b Paul Arundel,1,2,c Emma Clark,3,c Paul Dimitri,1,2,c Joshua Farr,4,c Graeme Jones,5,c Outi Makitie,6,c Craig F. Munns,7,c and Nick Shaw8,c 1
Department of Human Metabolism, Academic Unit of Child Health, University of Sheffield, Sheffield, UK; 2Sheffield Children’s Hospital, Sheffield, UK; 3Academic Rheumatology, Musculoskeletal Unit, University of Bristol, Bristol, UK; 4 College of Medicine, Mayo Clinic, Rochester, MN, USA; 5Musculoskeletal Unit, Menzies Research Institute, Hobart, Australia; 6Pediatric Endocrinology and Metabolic Bone Diseases, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland; 7Bone and Mineral Medicine, The Children’s Hospital at Westmead, Sydney, NSW, Australia; and 8Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham, UK
Abstract 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. Key Words: Dual-energy X-ray absorptiometry; ethnicity; fracture; pediatric; trauma.
half of all childhood fractures affect the forearm (2,5e8). There is a clear relationship, irrespective of bone mass, between fracture frequency and the overall level of physical activity (9), despite the fact that physical activity and exercise are positively associated with bone mass (10e17). In reviewing the existing Positions, the Task Force on fracture prediction and osteoporosis definition collated information from studies that examined the relationship of fracture with a range of factors including genotype, ethnicity, body composition, puberty, antenatal and perinatal events, exercise and physical activity, degree of trauma, diet, and recurrent fractures. With respect to fracture prediction and the definition of osteoporosis, the 2007 Pediatric Position statements are given below, taken from the ISCD Website. Fracture prediction should primarily identify children at risk of clinically significant fractures, such as fracture of long bones in the lower extremities, vertebral compression fractures, or 2 or more long bone fractures of the upper extremities. The diagnosis of osteoporosis in children and adolescents should not be made on the basis of densitometric criteria alone. The diagnosis of osteoporosis requires the presence of both a clinically significant fracture history and low bone
Introduction The usefulness of imaging, in particular dual-energy X-ray absorptiometry (DXA), in the assessment of skeletal wellbeing at all ages is generally accepted, although the ability of DXA alone to predict fracture is limited (1). The effects of variation in body and bone size on DXA measurement of bone mass are covered in the document from Task Force 4, ‘‘Reporting Pediatric Densitometry Results.’’ Fracture frequency is high in children compared with young and middleaged adults (2), reflecting the interacting effects of bone size and mass, physical activity, and possibly other factors. Among healthy children, as many as half of all boys and a third of girls will fracture by age 18, and one-fifth will have 2 or more fractures (3,4). Most fractures are of the upper limb; one-third to Received 01/07/14; Accepted 01/08/14. a
Task Force Chair.
b
Task Force Liaison.
c
Task Force Member.
*Address correspondence to: Nick Bishop, MD, Academic Unit of Child Health, University of Sheffield, Sheffield Children’s Hospital, Western Bank, Sheffield S10 2TH, UK. E-mail: n.j.bishop@ shef.ac.uk
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mineral content (BMC) or bone mineral density (BMD). A clinically significant fracture history is one or more of the following: B B B
Long bone fracture of the lower extremities. Vertebral compression fracture. Two or more long bone fractures of the upper extremities.
Low BMC or BMD is defined as a BMC or areal BMD Z-score that is less than or equal to 2.0, adjusted for age, gender, and body size, as appropriate. The approach of the Task Force has been to review the published literature, focusing in particular on articles published since 2007, to provide evidence that either supports the statements as they stand or suggests that they should be amended.
Methodology Individual task force members were assigned areas of the literature to review and undertook searches using the PubMed and OVID databases from 1966 to 2013. Combinations of terms including those used in the 2007 searches were used (BMD, BMAD, children, adolescents, pediatric, and fracture), along with area-specific terms as indicated previously. Studies were included in the literature set if they included an analysis of the relationship between bone mass/density and fracture. Almost all imaging was by DXA; one recent study used High Resolution peripheral Quantitative Computed Tomography (HRpQCT) to assess variation in microarchitecture in children with fracture according to grades of trauma and is included because of the important insight it provides. The articles pulled together include those used by the 2007 Task Force with an additional 10 articles selected (according to the criteria listed) from those suggested by current Task Force members. The Task Force considered data primarily relating to studies of apparently healthy children. Nevertheless, it is important that each child is evaluated appropriately for the signs and symptoms of diseases known to increase fracture risk. The position statement on bone health in children and adolescents with chronic diseases will address DXA measures in varied diseases.
Position 1 Fracture prediction should primarily identify children at risk of clinically significant fractures, such as fracture of long bones in the lower extremities, vertebral compression fractures, or 2 or more long bone fractures of the upper extremities. The issue that has arisen in considering this Position is the one relating to degree of trauma in relation to assessment of risk. Given sufficient force, any bone will break. The Task Force agreed that it is thus reasonable to exclude fractures occurring as a result of road traffic accidents or falls from above 3 m (10 feet) since fractures are expected to occur in such circumstances irrespective of any other consideration. The association of fractures resulting from mild as opposed to moderate degrees of trauma with variation in bone mass
estimated by DXA has not been systematically studied in children. Recent work published by Farr et al (18) using HRpQCT suggests that microarchitectural deficits likely to result in increased bone fragility are evident in children who suffer a distal forearm fracture (DFF) following mild, but not moderate, trauma compared with non-fracture controls. The deficits at a microarchitectural level and cortical thinning are seen in both the distal radius and distal tibia in children presenting with a DFF where the degree of trauma (per Landin’s modified criteria) is mild, but not in those where the degree of trauma is moderate. Microfinite element analysis in the distal radius HRpQCT images showed that the ‘‘mild trauma’’ DFF cases had reduced bone strength (failure load), compared with the children with no fracture history. This implies in turn that moderate trauma is sufficient to break healthy bones, which are not otherwise at inherently increased risk of fracture. This suggestion is supported by the studies of Clark and others that irrespective of bone mass, fracture risk rises as the amount of vigorous activity rises (9). However, degree of trauma was not discussed in these articles. Thus, consideration should be given to excluding fractures arising from moderate or worse trauma from the Position.
Summary The Task Force agreed that excluding fractures occurring as a result of high-energy trauma is appropriate. However, the differentiation of mild and moderate degrees of trauma is difficult to assess; there are few studies where any attempt has been made to rigorously classify trauma, and only Farr’s study related degree of trauma to microarchitectural findings. Recall of the exact mechanism of trauma might be difficult; unobserved fractures in younger children would be difficult to classify, and there could be issues around fall complexity (e.g., twisting components). In addition, even in children with known bone fragility, moderate trauma does not inevitably result in a fracture. The Task Force agreed that the criteria of Landin should not be used as trauma from skiing and skateboarding accidents were included there as ‘‘mild.’’ The view of the Task Force overall was that fractures were more likely to be of significance in terms of the diagnosis of osteoporosis or for the assessment of future fracture risk if they occurred as a result of simple, mild, or low-energy trauma. However, defining simple and mild/low energy would be a matter for clinical judgment in the individual case. The Task Force was of the view that further studies were needed in this area. The Task Force suggested that the Position not be substantially amended, but the addition of the word ‘‘increased’’ in front of the word ‘‘risk’’ would make the Position more focused. At PDC, further discussion took place regarding the purpose of both fracture risk prediction and the diagnosis of osteoporosis. As the Position Statements are expected to inform clinical practice, it was felt important to reflect the utility of fracture risk prediction and (assumed) osteoporosis in the first Position. The final agreed new Position 1 is: ‘‘Evaluation of bone health should identify children and adolescents who may
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Pediatric Osteoporosis Definition benefit from intervention to decrease their elevated risk of a clinically significant fracture.’’
Position 2 Grade: approvedfair/gooddB/Cdworldwide. In the 2007 Position Statements, the second section of the document addressed the question ‘‘what are the densitometric criteria for the diagnosis of osteoporosis in a child or adolescent?’’ We have altered the flow of the document to reflect a more clinical orientation, and this section lays out the new criteria for the diagnosis of osteoporosis. The previous Position 2 was as follows: ‘‘The diagnosis of osteoporosis in children and adolescents should not be made on the basis of densitometric criteria alone.’’ There was no disagreement from any task force member with this statement and no evidence from the published literature that this should change; however, the ordering of the Positions has been changed, and this Position now becomes the final Position, Position 4, to maintain the emphasis on the clinical aspects of diagnosis and fracture prediction. In the 2007 Position Statements, there was the potential for confusion in that both the Positions referred to ‘‘clinically significant fracture;’’ in Position 1, this was in relation to the risk of subsequent fracture, whereas in the body of Position 2, it was in relation to previous fracture history. 2007 Position 2 reads as follows: The diagnosis of osteoporosis requires the presence of both a clinically significant fracture history and low BMC or BMD. A clinically significant fracture history is one or more of the following: - Long bone fracture of the lower extremities. - Vertebral compression fracture. - Two or more long bone fractures of the upper extremities. - Low BMC or BMD is defined as a BMC or areal BMD Z-score that is less than or equal to 2.0, adjusted for age, gender, and body size, as appropriate.
B
There was no direct disagreement with this statement. However, there were suggestions made with respect to both what constituted a: 1. ‘‘Clinically significant fracture history’’ and 2. The threshold for regarding bone density as being ‘‘low.’’ There was general agreement that a vertebral crush fracture (loss of vertebral height at any point of O20%) was an indicator of osteoporosis unless caused by high-energy trauma. In addition, from discussions in PDC in Baltimore, MD, it became clear that there was support to create a new Position reflecting the importance of vertebral crush fracture as a clinical indicator of osteoporosis. The new Position 2 is, therefore, as follows: ‘‘The finding of one or more vertebral compression (crush) fractures is indicative of osteoporosis, in the absence of local disease or high-energy trauma. In such children and adolescents, measuring BMD adds to the overall assessment of bone health.’’
277 Grade: approvedfairdBdworldwide. The Task Force then addressed the question of ‘‘what is a clinically significant fracture?’’ excluding the vertebral crush fracture as stated previously. We generally agreed (see above) that the lower the level of apparent trauma resulting in a fracture, the more likely it was to be indicative of an underlying propensity to fracture. For apparently healthy children, published data indicate that 15%e20% have more than one fracture, but there has been no systematic evaluation of number of fractures (irrespective of age) in relation to altered microarchitecture, nor any evaluation of number of fractures in relation to vigorous activity and degree of trauma. For children with an underlying disease process, the situation is even less clear. The study of Mayranpaa et al (19) looked at a group of children with a history of any one of: 2 long bone fractures before age 10 yr; 3 long bone fractures before age 16 yr; or one or more vertebral fractures. Among those with vertebral fractures, regarded by most as pathognomonic for osteoporosis, the average lumbar spine bone mineral density Z-score (adjusted for age and sex and excluding damaged vertebrae) was 0.8 0.8. The authors concluded that there was no clear relationship in this ‘‘at risk’’ group of children between low BMD and fracture risk and that a thorough evaluation of the skeleton was indicated after a second ‘‘low-energy’’ fracture. Another issue was the extent to which low BMD is predictive for all fractures, as opposed to upper limb (which is the most frequent site) fractures. The data from the study of Farr quoted previously (18) found similar deficits at both the distal radius and distal tibia, but the majority of DXA-based studies have not discriminated between sites concerning the predictive ability of spine, total body, or hip measurements for fracture. The study of Jones (20) found no relationship between DXA measures at the spine and hip with fractures other than those of the upper limb. The previous Position Statements referenced the work of Ferrari et al (21) in this respect as showing an association of low ultradistal and one-third (33%) radius areal BMD adjusted for age and gender (Z-score) with subsequent DFF in 32 girls older than 8.5 yr; work by Goulding et al (22) following a cohort of 170 girls (82 with fracture) over a 4-yr period failed to show any such association, however. The overall view of the Task Force was that the current criteria, if applied as a screening tool for who should have a DXA scan, were too loose; as many as 34% of children could end up having a scan. The criteria used by Mayranpaa et al (19) (2 or more fractures at age !10 yr, 3 or more at any age, or a vertebral fracture) were debated; however, there are no data to indicate that either the number of fractures or the age thresholds are more or less predictive of future fracture risk/osteoporosis than any other criteria. In summary, the current threshold of 2 long bone fractures, or a lower limb fracture, was felt to be inadequately supported by the literature. More work is needed to define alternative thresholds for fracture frequency/number alongside evaluation of the degree of trauma resulting in those fractures. In addition, further work was needed to evaluate whether additional risk factors should
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278 be included and whether re-fracture at the same site should be considered as recurrent. The Task Force suggested nevertheless that consideration should be given to adopting the Makitie thresholds while further work is undertaken to address the issues raised. A clinically significant fracture history is one or more of the following: - Two or more long bone fractures by age 10 yr; - Three or more long bone fractures at any age up to 16 yr. - Vertebral compression fracture (loss of O20% height at any point).
B
Occurring as a result of ‘‘mild-moderate trauma’’ (i.e., excluding high-energy trauma). Experts at PDC agreed with these statements in broad outline but felt that defining mild as opposed to moderate trauma could not be easily achieved without more published data; this part of the statement was therefore amended as reflected in the final Position 3 (see below). The Task Force also considered whether it was appropriate to change the threshold for BMD/BMC Z-score in this Position. In otherwise healthy children, the population-based data indicate that at age 9 yr the best predictor of fracture over the following 2 yr is whole-body (less head) BMC adjusted for height, weight, and bone area, with each successive adjustment increasing the strength of the combined associations with the outcome of subsequent fracture. Height-age adjustment in the Bone Mineral Density in Childhood Study (BMDCS) accounts for 25%e37% of the variance in BMC/BMD Z-scores (23); however, the stated premise was that an ‘‘appropriate’’ adjustment would result in similar distributions of the adjusted BMC and BMD among short, average, and tall children, not that the height-adjusted BMC/BMD Z-score would have predictive value for fracture outcome. BMDCS also reasonably excluded some children on the basis of fracture history (children 10 yr old with O1 fracture, or O10 yr old with O2 fractures) to target a ‘‘healthy’’ population, but this may have excluded some children who would be at increased risk of future fragility-related fracture. Thus, BMDCS cohort may not be the best one in which to assess the relationship of BMD Z-score (however adjusted) and fracture risk. The work from Jones et al assessing the effect of different adjustments (age, height, weight) on DXA estimates with respect to subsequent fracture risk found no difference when using body size-related measures as opposed to age (20). In the Mayranpaa study (19), BMD was adjusted for Tanner stage/bone age; very few of those with vertebral crush fractures had an adjusted BMD Z-score that was ! 2.0. Task Force members commented that the use of body-size adjusted Z-scores needs to be practicaldthere is no published prediction equation for bone mass based on height, weight, and bone area currently. There was also the comment that hip data were unreliable in younger children and it would therefore be appropriate to restrict the use of the Z-scores to the spine and total body measurements.
Bishop et al.
Summary of Discussion Regarding the Bone Density Threshold At present, it is difficult to justify changing the BMD element of the Position, since there are no data to support a change. However, the available data from apparently healthy children indicate that while a lower bone mass for body size is associated with increased fracture risk, children can have fragile bones with an apparently ‘‘normal’’ bone density as assessed by DXA. In discussion in PDC, the idea was put forward that while a BMC/BMD Z-score of 2.0 was required for the diagnosis, this did not preclude the possibility of bone fragility, as can be seen in children with mild osteogenesis imperfecta, for instance. The agreed new Position 3 therefore reads: ‘‘In the absence of vertebral compression (crush) fractures, the diagnosis of osteoporosis is indicated by the presence of both a clinically significant fracture history and BMD Z-score 2.0. A clinically significant fracture history is one or more of the following: 1. Two or more long bone fractures by age 10 yr; 2. Three or more long bone fractures at any age up to 19 yr. A BMD/BMC Z-score O 2.0 does not preclude the possibility of skeletal fragility and increased fracture risk.’’ Grade: mildly approvedpoordCdworldwide. It was felt important that the statement regarding the use of bone density assessment alone as inappropriate in the diagnosis of osteoporosis in children was retained but moved to become Position 4: ‘‘The diagnosis of osteoporosis in children and adolescents should not be made on the basis of densitometric criteria alone.’’ Grade: strongly approvedpoordCdworldwide.
Additional Areas Reviewed by the Task Force Effects of Ethnicity The studies of apparently healthy children relating bone mass to fracture risk have been of predominantly White children. With respect to fracture frequency and ethnicity, data have been presented in 2 studies that indicate a significantly higher risk of fracture for children of White Caucasian origin, as opposed to children of black African origin of similar age, gender, and bone mass. In the studies of Wren et al (24), based on the BMDCS longitudinal cohort study, white boys who subsequently fractured had higher BMD Z-scores. Thandrayen et al also found substantially higher fracture rates among white as opposed to black African children living in South Africa in a large longitudinal cohort study (25,26). Does this mean that a different BMD threshold should be used for children of black African origin? BMDCS excluded children with a fracture history, as noted above so the sample may have excluded some informative cases, identified as 1.7% of potential participants. This is interesting as others have found that as many as 20% of children who have had
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one fracture will have a second by age 18 yr. Although degree of trauma data was collected, the association of trauma alone or interaction of trauma with other factors was not described in any of the models. In summary, at present, the Task Force does not think there is sufficient information available to amend any of the Positions with respect to ethnicity; some of the reported associations may be the result of differences in physical activity, rather than intrinsic differences in skeletal resistance to fracture. This was agreed by PDC.
increasing fracture risk. Future studies are thus needed to include an assessment/comparison of different body size adjustment techniques with respect to fracture risk, as well as accurately assessing the degree of trauma resulting in fracture. Ethnicity and body fat mass are data that can and should be collected as part of the assessment process and may contribute to the overall assessment of risk.
Obesity
1. Rauch F, Plotkin H, DiMeglio L, et al. 2008 Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2007 Pediatric Official Positions. J Clin Densitom 11(1):22e28. PII: S1094-6950(07)00251-X, http://dx.doi.org/ 10.1016/j.jocd.2007.12.003. 2. Cooper C, Dennison EM, Leufkens HG, et al. 2004 Epidemiology of childhood fractures in Britain: a study using the general practice research database. J Bone Miner Res 19(12):1976e1981. 3. Landin LA. 1983 Fracture patterns in children. Analysis of 8,682 fractures with special reference to incidence, etiology and secular changes in a Swedish urban population 1950-1979. Acta Orthop Scand Suppl 202:1e109. 4. Mayranpaa MK, Makitie O, Kallio PE. 2010 Decreasing incidence and changing pattern of childhood fractures: a population-based study. J Bone Miner Res 25(12):2752e2759, http://dx.doi.org/ 10.1002/jbmr.155. 5. de Putter CE, van Beeck EF, Looman CW, et al. 2011 Trends in wrist fractures in children and adolescents, 1997-2009. J Hand Surg Am 36(11):1810e1815.e2. PII: S0363-5023(11)01010-0, http://dx.doi.org/10.1016/j.jhsa.2011.08.006. 6. Jones G, Boon P. 2008 Which bone mass measures discriminate adolescents who have fractured from those who have not? Osteoporos Int 19(2):251e255, http://dx.doi.org/10.1007/s00198007-0458-1. 7. Landin LA. 1997 Epidemiology of children’s fractures. J Pediatr Orthop B 6(2):79e83. 8. Lyons RA, Delahunty AM, Kraus D, et al. 1999 Children’s fractures: a population based study. Inj Prev 5(2):129e132. 9. Clark EM, Ness AR, Tobias JH. 2008 Vigorous physical activity increases fracture risk in children irrespective of bone mass: a prospective study of the independent risk factors for fractures in healthy children. J Bone Miner Res 23(7):1012e1022, http://dx.doi.org/10.1359/jbmr.080303. 10. Bailey DA, McKay HA, Mirwald RL, et al. 1999 A six-year longitudinal study of the relationship of physical activity to bone mineral accrual in growing children: the university of Saskatchewan bone mineral accrual study. J Bone Miner Res 14(10): 1672e1679. 11. Baxter-Jones AD, Kontulainen SA, Faulkner RA, Bailey DA. 2008 A longitudinal study of the relationship of physical activity to bone mineral accrual from adolescence to young adulthood. Bone 43(6):1101e1107. PII: S8756-3282(08)00599-1, http:// dx.doi.org/10.1016/j.bone.2008.07.245. 12. Detter FT, Rosengren BE, Dencker M, et al. 2013 A 5-year exercise program in pre- and peripubertal children improves bone mass and bone size without affecting fracture risk. Calcif Tissue Int 92(4):385e393, http://dx.doi.org/10.1007/s00223012-9691-5. 13. Gunter K, Baxter-Jones AD, Mirwald RL, et al. 2008 Impact exercise increases BMC during growth: an 8-year longitudinal study. J Bone Miner Res 23(7):986e993, http://dx.doi.org/10. 1359/jbmr.071201. 14. Macdonald HM, Kontulainen SA, Khan KM, McKay HA. 2007 Is a school-based physical activity intervention effective for
The issue of whether BMD is accurate in children who are obese is one that we think still needs addressing, as does the extent to which we adjust for height and weight, or can adjust accurately for them, in children who are very obese. Furthermore, the Task Force was of the view that both underweight and overweight body habitus confers an increased risk of fracture, but again the mechanism by which such associations might lead to skeletal fragility are not clear. At present, the Task Force does not think there is sufficient information available to amend any of the Positions with respect to obesity, although it is recognized that obesity may be a risk factor for fracture. This was agreed by PDC, and together with issues related to trauma and ethnicity flagged as an area for future research (see below).
Future Directions There was a clear view expressed by Task Force members that a fracture occurring as a result of trivial, mild, simple, or low-energy trauma was more likely to reflect an intrinsic skeletal issue resulting in bone fragility. Work is needed to try and more clearly define what is meant by these terms, however, and in particular to determine whether mild/trivial/simple/ low-energy trauma can be readily differentiated from moderate trauma. The ‘‘numbers of fractures by a certain age’’ element also requires further study because at the present time we are suggesting moving from one expert view to another primarily because in the existing Position the thresholds are perceived as being too low (i.e., too many children could end up being scanned if they were applied as screening criteria). We recognize that children with fractures may be apparently healthy but that there is likely to be an increased risk of future fracture in those with underlying diseases affecting the skeleton. These recommendations are presented in the Position Statement considering those disorders. However, we feel that part of our remit is to consider how best to adjust bone density measurements made by DXA in the context of the diagnosis of osteoporosis. Data are again lacking, although suggestions on adjusting for height and height-age Z-score have been made, they are based on an apparently healthy population and are of uncertain relevance to fracture prediction. Similarly, work describing the adjustment for weight, height, and bone area is based on data from an apparently healthy cohort, although there was a clear relationship with reducing body and bone size-adjusted BMC being associated with
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