Peripheral quantitative computed tomography (pQCT) for the assessment of bone strength in most of bone affecting conditions in developmental age: a review

With rising life expectancy, CF has been associated with an increased prevalence of low BMD [151, 152]. However, whereas well-recognized in adults, osteopenia and increased fracture rates due to CF are not well-characterized in paediatric age. Subjects with CF show a reduced aBMD, or BMC when adjusted for lean tissue mass (LTM, proxy for muscle) [97, 153]: while prior to puberty, BMC is not compromised for the associated LTM, however, lower BMC for LTM emerged in pubertal females [153]. Besides, we have clear evidence suggesting that bone mineral gain is reduced compared to normal accretion rates during adolescent growth, potentially leading to a suboptimal PBM [153‐155]. Additionally, CF specific factors cause reduced areal BMD, such as malnutrition and vitamin D deficiency secondary to pancreatic insufficiency, immobility, corticosteroid therapy and chronic inflammation [151, 152, 156].

A study conducted in children with CF showed that they had lower weight-, height-, BMI-, and whole LBM-Z and tibial length; in CF females, after adjustment for BMI-Z-score and muscleCSA, lower total and trabecular vBMD was shown, whereas the males had lower cortical, muscleCSA, and fatCSA, and their trabecular vBMD deficit approached significance. The occurrence of these differences in CF youth highlights the importance of instituting measures to optimize peak bone mass early in the course of CF [157].

In another study, CF patients showed lower whole body BMC (WBBMC) than controls with larger differences at older ages. Periosteal and endosteal circumferences were smaller in CF. Positive relationships of CoA and bone strength with age were attenuated with CF. Children with CF have similar WBBMC relative to lean mass as controls. Cortical bone area and bone strength were less in CF group compared to controls, with greater differences in older children [98].

Finally, another study evaluating pQCT parameters in children and adolescents with CF, showed that pre-pubertal males had greater trabecular vBMD and total vBMD at 4 % tibia, and greater total vBMD at 4 % radius. Pre-pubertal females with CF had greater total vBMD at 66 % tibia and radius, and cortical vBMD at the radius. At puberty, the CF cohort had less BMC at 4 % tibia, and smaller muscleCSA at 66 % tibia. Pubertal CF females had a smaller bone CSA at 4 % tibia, and lower SSI at the tibia and radius sites. Bone strength parameters were not compromised prior to puberty in this CF cohort. At puberty, the bone phenotype changed for this CF cohort, showing several deficits compared to the controls. However, bone strength was adapting to the mechanical demands of the muscle [99].

In literature we have found only four papers regarding pQCT in children with inflammatory bowel disease (IBD), mainly paediatric populations of Crohn’s disease (CD) [101, 102, 104, 105]. CD and ulcerative colitis patients present multiple risk factors responsible for an impaired bone accrual, such as poor growth, delayed pubertal development, malnutrition, cachexia [158]. Moreover, elevated inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-6 [159, 160], as well as glucocorticoid therapy impair bone formation, causing reduced BMD [161].

Most of the previous studies of BMD in IBD has been relied using DXA [162‐165], and children with CD diagnosis should undergo DXA assessment of lumbar spine BMD at diagnosis, and annually thereafter [166].

Studies using pQCT in CD showed a marked reduction of trabecular vBMD and cortical dimensions at diagnosis [105]. Therefore, in these patients, following diagnosis and treatment of pediatric CD, the trabecular vBMD improved significantly, whereas deficits in cortical dimensions progressed [105]. In a recent paper, the comparison of pQCT and DXA revealed important differences in the associations with auxological and disease-related factors, stressing the fact that the measures of spine BMD may not capture disease and treatment effects on trabecular bone in IBD patients [167].

Vitamin D (25(OH)D) deficiency and insufficiency are highly prevalent among children and adolescents. 25(OH)D level is significantly correlated with bone density and bone quality key parameters. Further interventional studies are warranted to define the role of vitamin D supplementation for the improvement of bone health among adolescents. Three hundred thirty-three girls and 230 boys (12–16 years old) with normal health were recruited in summer and winter separately from local schools. Serum 25(OH)D level, bone density and quality parameters by DXA and HR-pQCT, dietary calcium intake, and physical activity level were assessed. Sixty-four point seven percent and 11.4 % of subjects resulted insufficient [25(OH)D ≤ 50 nmol/L] and deficient [25(OH)D <25 nmol/L], respectively. The mean level of serum 25(OH)D in summer was significantly higher than that in winter, without obvious gender difference. In girls, aBMD and BMC of bilateral femoral necks, CoA, CoTh, total vBMD, and trabecular thickness were significantly correlated with 25(OH)D levels. In boys, aBMD of bilateral femoral necks, BMC of the dominant femoral neck, CoA, CoTh, total vBMD, trabecular vBMD, BV/TV, and trabecular separation were significantly correlated with 25(OH)D levels [168].

In a study evaluating with pQCT 46 preterm children (31 appropriate-for-gestational-age, AGA, and 15 small-for-gestational-age, SGA) at mean age 10.1 years and 27 years later, preterm AGA individuals had similar BMC and BMD height-adjusted Z-scores in adulthood compared to controls, whereas preterm SGA individuals had lower distal forearm BMC and BMD height-adjusted Z-scores in adulthood than both controls and preterm AGA individuals. Moreover, preterm SGA individuals had lower gain from childhood to adulthood in distal forearm BMC height-adjusted Z-scores than controls. In tibial CSA Z-score and SSI Z-score, where all measurements were lower than controls. Preterm SGA individuals are at increased risk of reaching low adult bone mass, at least partly due to a deficit in the accrual of bone mineral during growth. In our cohort, we were unable to find a similar risk in preterm AGA individuals [169].

In 135 girls and 123 boys some authors have studied whether greater pre-pubertal adiposity (defined as BMI ≥ 85^th percentile for age and sex) was associated with subsequent timing of maturation and bone strength during adolescence. BMI was negatively associated with age of maturation. Overweight (OW) versus healthy-weight (HW) girls had significantly greater SSI, while OW versus HW boys had significantly greater bone strength at the tibia and femoral neck, but not radius. Analyses were repeated using biological age, which yielded reduced parameter estimates for girls but similar results for boys. Differences were no longer present following adjustment for lean mass in girls while differences at the tibia were sustained in boys. These findings demonstrate sex- and site-specific differences in the associations between adiposity, maturation and bone strength [170].

Interestingly, childhood overweight appear to be consistently associated with larger long bone cross-sections in both sexes. However, overweight in childhood may also lead to higher trabecular density in women and somewhat lower cortical density in men. Specific mechanisms underlying these associations are not known.

Total cross-sectional (ToA) and CoA at the distal and shaft sites and cortical (shaft CoD) and trabecular (distal TrD) bone density of the nonweight-bearing radius and weight-bearing tibia were evaluated with pQCT. Despite being taller in adolescence, the adult body height of overweight children was similar. In both sexes, childhood overweight was consistently associated with 5-10 % larger ToA at all bone sites measured in adulthood. CoA did not show such a consistent pattern. Women, who were overweight in childhood, had ~5 % denser TrD with no difference in CoD. In contrast, TrD in men who were overweight in childhood was not different, but their CoD was ~1 % lower [171]. In another study involving 302 NW and 143 OW children, at baseline, all bone measures (bone area, total BMD, bone strength index [BSI], SSI, and muscleCSA were significantly greater in OW compared with HW children, with the exception of BMDcort. Over 16 months, total BMD increased more in the OW children, SSI was low when adjusted for body fat in the OW group, suggesting that in OW children bone strength may be not adapt to body fat excess [172].

A study involving 31 perinatally HIV-infected youth aged 3–18 years, used pQCT assessing muscleCSA, total and cortical bone area, cortical BMD and thickness and SSI at the tibial shaft. Thirty and 18 participants returned at 12 and 24 months, respectively. At baseline, height and muscleCSA were reduced in HIV-infected patients. BMC Z-scores adjusted for height and lean mass were lower than controls at all sites except the lumbar spine. Bone area and SSI Z-scores were not different from zero after adjusting for tibial length and muscleCSA. In contrast, cortical BMD Z-scores were greater in HIV-infected youth. Z-scores for all bone outcomes showed positive trends over time in those subjects. Although HIV infection may be associated with bone mass deficits during growth, bone geometry and strength appear adapted to muscle force. Further, deficits in bone mass may dissipate over time in this population [150].

Short-stature homeobox (SHOX) gene haploinsufficiency may cause skeletal dysplasia including Léri–Weill Dyschondrosteosis (LWD), a syndrome presenting the triad of low height, mesomelic disproportion and Madelung’s deformity of the wrist. Bone microarchitecture and estimated strength in adult SHOX mutation carriers have not been examined.

Twenty two SHOX mutation carriers’ bone status weas compared to 22 healthy subjects by DXA and pQCT. Areal BMD and T-scores showed no significant differences between cases and controls. Total radius area was smaller in cases than controls (p < 0.01). Radius cortical bone area (p = 0.01) and thickness (p < 0.01) as well as total density (p < 0.01) were higher in SHOX mutation carriers compared to controls. Radius trabecular bone area were smaller in SHOX mutation carriers. Tibia trabecular thickness was lower in cases (p = 0.01). These results remained significant after adjustment for differences in body height and when restricting analyses to females. There were no differences in BMD, radius and tibia cortical porosity or FEA failure load between groups. A segment of cortical bone defect was identified in the distal radius adjacent to ulna in five unrelated SHOX mutation carriers. Despite a different bone geometry in radius and tibia, subjects with a SHOX mutation presented no differences in BMD or failure load compared to controls, suggesting that mutations in SHOX gene may have an impact on bone microarchitecture albeit not bone strength [149].

In 22 girls with Turner syndrome (TS) pQCT of the radius showed that total vBMD Z-score and trabecular vBMD Z-score were not significantly different between the TS group and controls. A significant reduction in cortical vBMD and a trend in CoTh at the proximal radius was noted in the TS group, suggesting that cortical density may be reduced with sparing of trabecular bone, possibly predisposing to fracture [139].

Whether higher production of glucocorticoids (GCs) within the physiological range may affect bone status in healthy children is unknown. Because dietary protein intake affects both bone and GCs, we examined the association of urinary measures of glucocorticoid status and cortical bone in healthy non-obese children, after assessment of protein intake. Subjects studied (n = 175, 87 males, aged 6 to 18 years) had two 24-h urine samples collected. After controlling for several covariates and especially urinary nitrogen (the biomarker of protein intake) cortisol secretion ∑C21 was inversely associated with all analyzed pQCT measures of bone quality. ∑C21 also predicted a higher endosteal and lower periosteal circumference, explaining both a smaller CoA and, together with lower BMD, a lower SSI. Therefore higher GC levels, even within the physiological range, appear to exert negative influences on bone modeling and remodeling during growth. Our physiological data also suggest a relevant role of cortisone as the direct source for intracrine-generated cortisol by bone cell 11beta-HSD1 [173].

Children with rheumatic diseases showed significantly reduced trabecular bone mineral density and total BMD in comparison to controls, whereas cortical BMD did not differ significantly between the groups. BMD did not correlate with duration of disease or steroid medication [109].

Children with JIA have decreased skeletal size, muscle mass, trabecular bone density, cortical bone geometry, and strength. Not surprisingly, these bone abnormalities are more pronounced in children with greater disease severity. In fact, in a study involving 48 children with JIA, a decreased tibia trabecular bone density, cortical bone size and strength, and muscle mass was reported. The tibia diaphysis was narrower with decreased muscle mass, but normal, size-adjusted bone mineral in all subtypes indicated a localized effect of bone JIA. Patients exposed to glucocorticoids and MTX or to glucocorticoids or MTX alone had greatly reduced trabecular density, cortical bone geometry properties, BMC, muscle mass, and bone strength [49].

Another study evaluating tibia pQCT in 101 JIA patients and 830 healthy control subjects, disclosed that muscleCSA and SSI Z-scores were significantly lower in patients with polyarticular JIA and those with SpA. Trabecular vBMD Z-scores were significantly lower in patients with polyarticular JIA, those with systemic JIA, and those with SpA. Significant predictors of musculoskeletal deficits included active arthritis in the previous 6 months (muscleCSA), temporomandibular joint disease (muscleCSA and SSI), functional disability (muscleCSA and vBMD), short stature (vBMD), infliximab exposure (vBMD), and JIA duration (SSI). The SSI was significantly reduced relative to muscleCSA in patients with JIA after adjustment for age and limb length. Marked deficits in vBMD and bone strength occur in JIA in association with severe and longstanding disease. Contrary to the findings of previous studies, bone deficits were greater than expected relative to the muscleCSA, which illustrates the importance of adjusting for age and bone length [108].

Finally, in a study evaluating 245 children, adolescents, and young adults, 166 of whom longitudinally evaluated, showed that, in comparison with controls, JIA patients presented musculoskeletal deficits, with significantly lower levels of trabecular bone mineral density (TrabBMD), muscleCSA, and SSI. In contrast, JIA showed fatCSA significantly higher than controls [14].

In 56 female JSLE patients, reduced density and strength parameters and microarchitecture alterations of cortical and trabecular bones were observed. Patients with vertebral fracture (VF) exhibited a significant decrease in trabecular bone parameters solely at the distal radius (Total.BMD; Trabecular.BMD [TrbBMD]; bone volume (BV)/trabecular volume (TV); apparent modulus) and higher scores for disease damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI)). A logistic regression univariate analysis revealed that TrbBMD and SLICC/ACR-DI were independent risk factors for VF, The study demonstrates bone microstructure and strength deficits in JSLE patients, particularly at the distal radius, and the association between VF and trabecular radius alterations [113].

In another study, involving fifty-six patients with JSLE (mean age 18.5 ± 5.7 years), 46 of these longitudinally revaluated and compared with age- and sex- matched healthy controls, disclosed that JSLE patients had significantly lower TrbBMD, SSI, but not muscleCSA and CBA values, while CortBMD and fatCSA were significantly increased. At longitudinal evaluation, TrbBMD, fatCSA, but not muscleCSA and CBA, remained lower in patients, but SSI and CortBMD were not significantly different between patients and controls. JSLE subjects present a reduced peak bone mass with high risk of osteoporosis in early adulthood. To reduce the risk, close monitoring of BMD, better control of disease activity, physical exercise and dietary intake of calcium and vitamin D are advocated to ameliorate the loss of bone mass. In patients with proved osteoporosis, therapeutic approaches including bisphosphonates should be considered [114]. In fact, in a recent study evaluating 43 JSLE patients, 138 JIA patients and 79 controls, JSLE patients had a higher CortBMD than controls and JIA patients. However, JSLE and JIA patients had a significantly reduced TrbBMD compared to controls, with no differences between JSLE and JIA. In addition, JIA patients showed a significantly reduced muscleCSA compared to JSLE and controls. Conversely, fatCSA was significantly increased both in JIA and JSLE patients when compared to controls, with no differences between the JSLE and JIA groups. Analogous results were observed in the polar resistance to stress (SSI). On longitudinal evaluation, contrary to CortBMD, the difference between BMAD SDS, TrbBMD, muscleCSA and fatCSA remains unchanged; in JSLE patients, SSI is stable in comparison to JIA and controls without any difference between the two groups. The evaluation of bone density and structure parameters in JSLE patients highlights significant differences compared with JIA patients and controls. These data might indicate a different pathogenesis of bone damage in the two entities, and suggest a different diagnostic and therapeutic approach to improve the peak bone mass [115].

Children with haemophilia are at risk of suboptimal bone mass accrual and low BMD. We recently demonstrated that although BMD in Finnish haemophilic children was within the normal range, their whole-body BMD was significantly lower and hypercalciuria more prevalent than in controls. A case-control study aimed to assess bone structure and strength by pQCT at radius in 29 physically active haemophilic children (mean age 12.2 years) and 46 age-matched controls. Children with haemophilia had decreased total BMD Z-score at the distal radius (P ≤ 0.001), but increased cortical bone density at the proximal radius (P ≤ 0.001). Total bone area at the proximal radius was significantly lower in patients (P = 0.002), whereas there were no differences in cortical bone area or in polar SSI, between the patients and controls. Patients with mild to moderate haemophilia and on-demand treatment had inferior bone strength compared to those with moderate to severe haemophilia and prophylaxis. Altered skeletal development in haemophilic patients assessed in the radius, resulted in smaller bone size and higher cortical bone density. Importantly, bone strength at the radius appears equal to healthy children, therefore exercise seems to have a beneficial effect on bone health in these patients [118].

Twenty nine children with nephrotic syndrome (NS) compared to 29 age- and sex- matched healthy controls, presented similar height, but a higher weight (p = 0.022) and a greater body fat percentage SDS (p = 0.008). Tibial trabecular and cortical vBMD were similar between the two groups but bone CSA was significantly greater in NS group at both the metaphysis and diaphysis (p = 0.014). Endosteal and periosteal circumferences were greater in children with NS than controls (both p < 0.01), resulting in reduced CoTh (p = 0.018), but similar cortical CSA. There were no associations between cumulative glucocorticoid (GC) exposure, duration of NS or number of relapses and any bone parameter. Tibial bone CSA was increased in children with NS, and this could be interpreted as a compensatory response to increased body weight. Defects in trabecular BMD were not identified in this cohort of children with NS [131].

A recent study aimed to examine changes in vBMD and cortical structure over 1 year in 56 NS children and to identify associations with concurrent GC exposure and growth. Tibia pQCT scans were obtained at enrolment, and at 6 and 12 months. Sex, race, and age-specific Z-scores were generated for trabecular vBMD (TrbBMD-Z), cortical vBMD (CortBMD-Z), and cortical area (CortArea-Z) based on >650 reference participants. CortArea-Z was further adjusted for tibia length-for-age Z-score. Quasi-least squares regression was used to identify determinants of changes in pQCT Z-scores. At enrolment, mean TrbBMD-Z (-0.54 ± 1.32) was significantly lower (p = 0.0001) and CortBMD-Z (0.73 ± 1.16, p < 0.0001) and CortArea-Z (0.27 ± 0.91, p = 0.03) significantly greater in NS versus reference participants. Fortyeight (86 %) participants were treated with GC over the study interval (median dose 0.29 mg/kg/day). On average, TrbBMD-Z and CortBMD-Z did not change significantly; however, CortArea-Z decreased (p = 0.003). Greater GC dose (p < 0.001), lesser increases in tibia length (p < 0.001), and lesser increases in CortArea-Z (p = 0.003) were independently associated with greater increases in CortBMD-Z. Greater increases in tibia length were associated with greater declines in CortArea-Z (p < 0.01), unlike in reference participants (interaction p < 0.02). Thus, GC therapy was associated with increases in CortBMD-Z, potentially related to suppressed bone formation and greater secondary mineralization. Conversely, greater growth and expansion of CortArea-Z (ie, new bone formation) were associated with declines in CortBMD-Z. Greater linear growth was associated with impaired expansion of CoA in NS [128].

In another study regarding stage 4–5 chronic kidney disease (CKD) children, LS and WB DXA and tibia pQCT scans were obtained in 88 cases and >650 healthy controls, aged 5–21 years. Sex- and race-specific Z-scores were generated for BMD and BMC by DXA, relative to age and adjusted for height Z-score (LS-BMD-Z and WBBMC-Z), and compared to pQCT TrbBMD-Z for age and CortBMC-Z for age and tibia length. LS-BMD-Z (p < 0.0001) and TrbBMD-Z (p < 0.0001) were greater in CKD, and WBBMC-Z (p < 0.0001) and CortBMC-Z (p < 0.0001) were lower, compared to controls. Z-scores were correlated at trabecular (LS-BMD-Z and TrbBMD-Z: R = 0.36) and cortical (WBBMC-Z and CortBMC-Z: R = 0.64) sites in CKD, similarly to controls. LS and WB DXA suggested greater trabecular BMD and lower cortical BMC in CKD, consistent with pQCT results; however, correlations were modest. Studies are needed to identify methods that predict fracture in childhood CKD [127].