Areal Bone Mineral Density Z-scores Research Articles

Increase in lumbar spine but not distal radius bone mineral density in adults after pancreas kidney transplantation

Osteoporosis occurs in every third individual after simultaneous pancreas kidney transplantation (SPKT). Currently used bone measures insufficiently predict their fracture risk. Lumbar spine Trabecular bone score (TBS) and distal radius areal and volumetric bone mineral density (BMD) were monitored for the first time in patients with type 1 diabetes and chronic renal failure after SPKT with steroid-sparing protocol. In 33 subjects (mean age 43.4 ± 9.8 years), dual-energy X-ray absorptiometry and peripheral quantitative computed tomography were performed just after SPKT (baseline) and one and three years later. While TBS Z-scores increased (−1.1 ± 1.2 and −0.3 ± 1.0; p˂0.001, at baseline and year three, respectively), trabecular volumetric BMD Z-scores at distal radius metaphysis did not change during the study (−1.3 ± 1.3 and −1.3 ± 1.0; p = 0.38). Similarly, areal BMD Z-scores increased at lumbar spine, total hip and femoral neck (all p < 0.01), but not at the distal radius. SPKT induced bone measures' improvement at lumbar spine and hip but not at distal radius. Before suggesting changes in current clinical care, predictive value of individual bone measures or its combination for fracture risk assessment remains to be elucidated.

Risk Factors Associated with Incident Vertebral Fractures in Steroid-treated Males with Duchenne Muscular Dystrophy.

Prevention of fractures is an unmet need in glucocorticoid (GC)-treated Duchenne muscular dystrophy. This study explored factors associated with incident vertebral fractures (VFs) to inform future fracture prevention efforts. VFs were evaluated prospectively at study baseline and 12 months on lateral spine radiographs in participants aged 4 to 25 years with Duchenne muscular dystrophy. Clinical factors were analyzed for their association with the change in Spinal Deformity Index (sum of the Genant-defined VF grades from T4 to L4) between baseline and 12 months. Thirty-eight males were evaluated (mean ± SD age at baseline 11.0 ± 3.6 years; mean ± SD GC duration at baseline 4.1 ± 3.1 years; 74% ambulatory). Nine of 38 participants (24%) had 17 incident VFs, of which 3/17 VFs (18%) were moderate/severe. Participants with 12-month incident VF had lower mean ± SD baseline lumbar spine areal bone mineral density Z-scores (-2.9 ± 1.0 vs -1.9 ± 1.1; P = .049) and lower total body less head areal bone mineral density Z-scores (-3.1 ± 1.2 vs -1.6 ± 1.7; P = .036). Multivariable linear regression showed that at least 1 VF at baseline (P < .001), a higher number of antecedent non-VF (P < .001), and greater bone age delay at baseline (P = .027) were significant predictors of an increase in the Spinal Deformity Index from baseline to 12 months. The observation that ≥ 1 prevalent VF and/or non-VF were the strongest predictors of incident VFs at 12 months supports the need for prevention of first fractures in this high-risk setting. Bone age delay, a marker of GC exposure, may assist in the prioritization of patients in efforts to prevent first fractures.

Non-linear association of body composition and its components with bone density in Iranian children and adolescents.

Peak bone mass is established during childhood and adolescence. One of the important factors influencing predicted bone mass tracking in childhood and adolescence is alteration in the body composition during this growth period. This study aimed to evaluate the associations of the components of overall body mass with areal bone mineral density Z-score in children and adolescents. In this cross-sectional study, 478 healthy Iranian children and adolescents (237 girls and 241 boys) who had DXA measures participated. We evaluated the linearity of associations using generalized additive models. Children's mean age was14 years with a range of 9-18 years, and 49.6% were girls. We found an increase in aBMD Z-score with increasing overall body mass (r = 0.25, p < 0.001). We observed this association with fat-free mass and total fat mass up to the 60th (~30 Kg) and 75th percentile (~12.5 Kg) [0.051 (95% CI, 0.027-0.075) increase in aBMD Z-score per 1 Kg increase in fat-free mass and 0.079 (95% CI, 0.044-0.114) increase in aBMD Z-score per 1 Kg increase in the total fat mass]. The correlation between Z-score of overall body mass and its components with aBMD Z-score was strongly positive. (P value < 0.001 for all) CONCLUSION: The findings of this study showed that children with greater overall body mass had higher aBMD Z-score. In addition, this study adds to a growing literature, suggesting that the relationship between body composition and BMD may be influenced by the pattern of fat and fat-free mass distribution in population.

Sequential Therapy With Recombinant Human IGF-1 Followed by Risedronate Increases Spine Bone Mineral Density in Women With Anorexia Nervosa

Anorexia nervosa is complicated by low bone mineral density (BMD) and increased fracture risk associated with low bone formation and high bone resorption. The spine, particularly its trabecular component as measured by lateral spine dual-energy x-ray absorptiometry (DXA), is most severely affected. Low BMD and bone formation are associated with relative insulin-like growth hormone-1 (IGF-1) deficiency. Our objective was to determine whether bone anabolic therapy with off-label recombinant human (rh)IGF-1 followed by antiresorptive therapy with risedronate would increase BMD more than risedronate alone or placebo in women with anorexia nervosa. We conducted a 12-month, randomized, placebo-controlled study of 90 ambulatory women with anorexia nervosa and low areal BMD (aBMD) (Z- or T-score <-1.0). Participants were randomized to 1 of 3 groups: 6 months of rhIGF-1 (starting dose 30 mcg/kg SQ BID) followed by 6 months of risedronate (35mg PO weekly) (“rhIGF-1/Risedronate”) (n=33), 12 months of risedronate (35mg PO weekly) (“Risedronate”) (n=33), or double placebo (“Placebo”) (n=16). Participants received calcium 1200 mg and vitamin D 800 IU daily. rhIGF-1 was titrated to maintain IGF-1 levels within the age-adjusted normal range. Main outcome measures were aBMD at the spine [1° endpoint: postero-anterior (PA) spine BMD], hip, and radius by DXA, and vertebral, tibial, and radial volumetric BMD (vBMD) and estimated strength by multi-detector computed tomography (MDCT) or high-resolution peripheral quantitative CT (HR-pQCT). At baseline, mean age [28 ± 7 y (mean ± SD)], BMI (18.5 ± 1.9 kg/m2), and BMD were similar among groups. At 12 months, mean PA spine aBMD was higher in the rhIGF-1/Risedronate (p=0.03), and trended towards being higher in the Risedronate (p=0.08), group than the Placebo group. Mean lateral spine aBMD was higher in the rhIGF-1/Risedronate than either the Risedronate (p=0.002) or Placebo (p=0.04) groups. From baseline to 12 months, mean PA and lateral spine aBMD increased by 1.9 ± 0.6% and 4.2 ± 1.0% in the rhIGF-1/Risedronate (p<0.05), 1.7 ± 0.8% and 1.7 ± 1.0% in the Risedronate (p=NS), and decreased by 0.3 ± 0.8% and 1.1 ± 1.3% in the Placebo (p=NS), groups, respectively. Areal BMD Z-scores did not normalize in any group. At 12 months, vertebral vBMD by MDCT was higher (p<0.05), and vertebral strength trended towards being higher, in the rhIGF-1/Risedronate than Placebo group. Neither hip or radial BMD, nor radial or tibial estimated strength, by HR-pQCT differed among groups. rhIGF-1 was well tolerated. In conclusion, sequential therapy of 6 months of rhIGF-1 followed by 6 months of risedronate increased lateral spine aBMD, the site most severely affected in women with anorexia nervosa, more than risedronate or placebo. These data suggest that strategies that are anabolic and antiresorptive to bone may be most effective in increasing BMD in women with anorexia nervosa.

SUN-535 Impact of Route of Estrogen Administration on Bone Turnover Markers in Oligoamenorrheic Athletes and Mediators of these Effects

Transdermal, but not oral, estrogen replacement improves bone mineral density (BMD) in athletes with oligo-amenorrhea (OA). Our objective was to determine mechanisms that may explain the impact of route of estrogen administration on bone outcomes. Whereas IGF-1 is bone anabolic, sclerostin, preadipocyte factor-1 (Pref-1) and brain derived neurotropic factor (BDNF) inhibit bone formation, and an effect of estrogen on these factors has been demonstrated in other populations. However, few studies have examined the impact of route of estrogen administration on these factors in adolescents and young adults. Further, it is unclear how the route of estrogen administration impacts bioavailable testosterone, which in turn may impact bone outcomes in young oligo-amenorrheic women. 73 OA 14-25 years old received (i) a 17β-estradiol transdermal patch continuously with cyclic oral micronized progesterone (PATCH), (ii) a combined ethinyl estradiol and desogestrel pill (PILL), or (iii) no estrogen/progesterone (NONE) for 12-months. We evaluated fasting morning levels of a marker of bone formation [N-terminal propeptide of type 1 procollagen (P1NP)], a marker of bone resorption [N-telopeptide (NTX)], IGF-1, insulin-like growth factor binding protein 3 (IGFBP3), total testosterone, estradiol, sex hormone-binding globulin (SHBG), sclerostin, Pref-1, BDNF, calcium, 25(OH) vitamin D, and parathyroid hormone (PTH) at baseline and 12-months. Groups did not differ for age, weight, exercise activity or markers of bone formation at baseline. We have previously reported increases in areal BMD Z-scores at the spine and femoral neck in the PATCH compared to PILL and NONE groups (Ackerman et al: BJSM Oct. 2018). Over 12 months, between group analysis showed greatest decreases of P1NP in the PILL group (p=0.03) associated with a decrease in IGF-1 and IGF1/IGFBP-3 ratio (r=0.33, p≤0.05), and an increase in SHBG (r=-0.28;p=0.02). Within group analysis showed that sclerostin, Pref-1 and BDNF decreased in the PATCH group over 12 months (p=0.01, 0.01 and 0.04 respectively). PATCH group had the greatest increases in estradiol (p=0.0009), and estradiol increases were associated with increases in BMD. Groups did not differ for changes in NTX. Transdermal 17β-estradiol does not cause the decrease in IGF-1 and SHBG observed with oral ethinyl estradiol. It leads to decreases in sclerostin, Pref-1 and BDNF. These effects may mediate the beneficial effects of transdermal estrogen on bone in young women.

The long-term impact of very preterm birth on adult bone mineral density

IntroductionPreterm infants are at increased risk of osteopenia of prematurity due to insufficient bone mineral accretion. Data on long term effects of prematurity on bone health are conflicting. This study aimed to compare bone mineral density (BMD) in young adults born very preterm and full-term controls and to examine factors associated with long-term bone health. MethodsThis observational cross-sectional study enrolled 101 young adults (18–29 years) born <29 weeks of gestation and 95 sex- and age-matched full-term controls. Participants underwent dual-energy X-ray absorptiometry to measure areal BMD and body composition. Generalized estimated equations were used to compare groups adjusting for height Z-score, lean body mass and fat mass. ResultsAdults born preterm were shorter and lighter than full-term controls. Areal BMD was reduced at the lumbar spine, the femoral neck and whole body in the preterm versus full-term group, but after adjustment, areal BMD Z-score was only significantly lower at the femoral neck by −0.3 unit (95% confidence interval −0.6 to −0.0). Low BMD (Z-score ≤ −1 standard deviation) at any site was observed in 53% of adults born preterm versus 28% of full-term controls, but this was not statistically significantly different. We did not identify any neonatal factors associated with lower BMD within the preterm group. ConclusionsVery preterm birth is associated with lower areal BMD at the femoral neck in young adulthood, even after accounting for body size. Whether this will translate into higher risk of osteoporotic fractures later in life remains unknown.

Bone health measures in glucocorticoid-treated ambulatory boys with Duchenne muscular dystrophy

Osteoporosis is a major problem in boys with Duchenne Muscular Dystrophy (DMD), attributable to muscle weakness and glucocorticoid therapy. Consensus regarding bone health assessment and management is lacking. Lumbar spine areal bone mineral density (defined as bone mass per area of bone) by dual-energy X-ray absorptiometry (DXA) is frequently the primary measure used, but has limitations for boys with DMD. We retrospectively studied 292 ambulant glucocorticoid-treated boys with DMD categorized by functional mobility score, FMS 1, 2 or 3. We assessed DXA whole body and lumbar spine areal bone mineral density and content Z-scores adjusted for age and height, lateral distal femur areal bone mineral density Z-scores, frequency of fractures, and osteoporosis by International Society for Clinical Densitometry 2013 criteria. Whole body and femoral DXA indices decreased, while spine fractures increased, with declining motor function. Lumbar spine areal bone mineral density Z-scores appeared to improve with declining motor function. Bone mineral content Z-scores were consistently lower than corresponding bone mineral density Z-scores. Our findings highlight the complexity of assessing bone health in boys with DMD. Bone health indices worsened with declining motor function in ambulant boys, but interpretation was affected by measure and skeletal site examined. Whole body bone mineral content may be a valuable measure in boys with DMD. Lumbar spine areal bone mineral density Z-score as an isolated measure could be misleading. Comprehensive management of osteoporosis in boys with DMD should include vertebral fracture assessment.

Abnormal Bone Acquisition With Early-Life HIV Infection: Role of Immune Activation and Senescent Osteogenic Precursors.

Chronic immune activation associated with human immunodeficiency virus (HIV) infection may have negative consequences on bone acquisition in individuals infected with HIV early in life. Bone mineral density (BMD) and microarchitecture were characterized in 38 HIV-infected men on antiretroviral therapy (18 perinatally-infected, 20 adolescence-infected) and 20 uninfected men age 20 to 25 years by dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HRpQCT). Flow cytometry was utilized to measure CD4+/CD8+ activation (HLADR+CD38+) and senescence (CD28-CD57+) and to quantify circulating osteogenic precursor (COP) cells in peripheral blood mononuclear cells using antibodies to RUNX2 and osteocalcin (OCN). Telomere lengths were measured in sorted COP cells using qPCR. DXA-derived areal BMD Z-scores and HRpQCT-derived volumetric BMD (vBMD) measures were lower in HIV-infected than uninfected men. Proportion of activated and senescent CD4+ and CD8+ T cells were higher in HIV-infected than uninfected men. The percentage of COP cells (mean ± SE) was lower in HIV-infected than uninfected (0.19% ± 0.02% versus 0.43% ± 0.06%; p < 0.0001) men, and also lower in perinatally-infected than adolescence-infected men (0.15% ± 0.02% versus 0.22% ± 0.03%; p < 0.04). A higher proportion of COP cells correlated with higher bone stiffness, a measure of bone strength, whereas a higher proportion of activated CD4+ T cells correlated with lower BMD and stiffness and lower proportion of COP cells. T cell activation with HIV-infection was associated with decreased numbers of osteogenic precursors as well as lower peak bone mass and bone strength. © 2016 American Society for Bone and Mineral Research.

Intravenous Bisphosphonate Therapy of Young Children With Osteogenesis Imperfecta: Skeletal Findings During Follow Up Throughout the Growing Years.

Cyclical intravenous bisphosphonate therapy is widely used to treat children with osteogenesis imperfecta (OI), but little is known about long-term treatment outcomes. We therefore reviewed 37 children with OI (OI type I, n = 1; OI type III, n = 14; and OI type IV, n = 22) who started intravenous bisphosphonate therapy before 5 years of age (median 2.2 years; range, 0.1 to 4.8 years), and who had a subsequent follow-up period of at least 10 years (median 14.8 years; range, 10.7 to 18.2 years), during which they had received intravenous bisphosphonate treatment (pamidronate or zoledronic acid) for at least 6 years. During the observation period, the mean lumbar spine areal bone mineral density Z-score increased from -6.6 (SD 3.1) to -3.0 (SD 1.8), and weight Z-score increased from -2.3 (SD 1.5) to -1.7 (SD 1.7) (p < 0.001 and p = 0.008). At the time of the last assessment, patients with OI type IV had significantly higher height Z-scores than a control group of patients matched for age, gender, and OI type who had not received bisphosphonates. Patients had a median of six femur fractures (range, 0 to 18) and five tibia fractures (range, 0 to 17) during the follow-up period. At baseline, 35% of vertebra were affected by compression fractures, whereas only 6% of vertebra appeared compressed at the last evaluation (p < 0.001), indicating vertebral reshaping during growth. Spinal fusion surgery was performed in 16 patients (43%). Among the 21 patients who did not have spinal fusion surgery, 13 had scoliosis with a curvature ranging from 10 to 56 degrees. In conclusion, long-term intravenous bisphosphonate therapy was associated with higher Z-scores for lumbar spine areal bone mineral density and vertebral reshaping, but long-bone fracture rates were still high and the majority of patients developed scoliosis.

Skeletal characteristics associated with homozygous and heterozygous WNT1 mutations

Recent reports have shown that homozygous or compound heterozygous mutations in WNT1 can give rise to severe bone fragility resembling osteogenesis imperfecta, whereas heterozygous WNT1 mutations have been found in adults with dominant early-onset osteoporosis. Here we assessed the effects of WNT1 mutations in four children with recessive severe bone fragility and in heterozygous family members. In vitro studies using the Topflash luciferase reporter system showed that two WNT1 missense mutations that were observed in these families, p.Cys143Phe and p.Val355Phe, decreased the ability of WNT1 to stimulate WNT signaling by >90%. Analyses of iliac bone samples revealed no major abnormalities in bone mineralization density distribution, an indicator of material bone properties, whereas a shift towards higher bone mineralization density is characteristic of classical osteogenesis imperfecta caused by mutations in COL1A1/COL1A2. Intravenous bisphosphonate treatment of four children with homozygous or compound heterozygous WNT1 mutations was associated with increasing lumbar spine areal bone mineral density z-scores, as measured by dual energy X-ray absorptiometry, but the effect was smaller than what had previously been reported for children with classical osteogenesis imperfecta. Family members with heterozygous WNT1 mutation tended to have low bone mass. Three of these heterozygous individuals had radiographic signs of vertebral fractures. These observations suggest that more effective treatment approaches are needed for children with recessive WNT1-related bone fragility and that a systematic work-up for osteoporosis is warranted for WNT1 mutation carriers in these families.

Osteogenesis imperfecta type V: marked phenotypic variability despite the presence of the IFITM5 c.−14C>T mutation in all patients

BackgroundOsteogenesis imperfecta (OI) type V is an autosomal dominant bone fragility disorder that we had described a decade ago. Recent research has shown that OI type V is caused by...

Prevalence of Vertebral Compression Fractures and Associated Factors in Children and Adolescents with Severe Juvenile Idiopathic Arthritis

Vertebral fractures occur in patients with juvenile idiopathic arthritis (JIA), but data on their frequency and causes are scarce. Our cross-sectional study evaluated prevalence of compression fractures and associated factors in a high-risk pediatric population with severe JIA. Children and adolescents with a history of treatment-resistant polyarticular-course JIA for ≥ 5 years or systemic arthritis for ≥ 3 years were recruited. Clinical examination, dietary recall, laboratory measurements, bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry, and spinal radiography were performed. Our study included 50 patients (41 girls), of whom 6 (12%) had systemic arthritis, with a median age of 14.8 years (range 7.0-18.7 yrs) and median disease duration of 10.2 years (range 3.9-16.8 years). Ninety-four percent had used systemic glucocorticoids (GC); the median total duration of GC treatment was 7.1 years (range 0-15.5 yrs). The median weight-adjusted cumulative GC dose for the preceding 3 years was 72 mg/kg (range 0-911 mg/kg). The median bone age-corrected lumbar spine and whole-body areal BMD Z-scores were -0.8 and -1.0, respectively. Twenty-two percent had vertebral fractures, mostly thoracic. Compression fractures were associated with high disease activity, high body mass index (BMI), and high recent cumulative GC dose, but not with disease duration or BMD. Thirty percent had sustained at least 1 peripheral low energy fracture. Twenty-six percent were deemed to have significantly compromised bone health. Severe JIA is associated with a significant risk of vertebral compression fractures. Associated factors include high disease activity, high BMI, and high recent GC exposure. Further studies are needed to establish optimal prevention and treatment guidelines.

Low bone mass and high material bone density in two patients with Loeys-Dietz syndrome caused by transforming growth factor beta receptor 2 mutations

Loeys-Dietz syndrome (LDS) is a rare autosomal-dominant connective tissue disorder caused by heterozygous mutations in the genes encoding transforming growth factor beta receptor 1 or 2 (TGFBR1 or TGFBR2). Although an association between LDS and osteoporosis has been reported, the skeletal phenotype regarding bone mass is not well characterized. Here, we report on two LDS patients with mutations in TGFBR2. Patient 1 was a 24-year-old man who had a total of three fractures involving the left radius, the left metacarpal, and the right femur. At the age of 14 years, lumbar spine areal bone mineral density Z-score was -4.0 and iliac bone histomorphometry showed elevated bone turnover (bone formation rate per bone surface: 91 µm³/µm²/year; age-matched control values 37 [10], mean [SD]) and mildly low trabecular bone volume per tissue volume (17.2%; age-matched control values 25.7 [5.3]). Bone mineralization density distribution (BMDD) in trabecular bone was increased (Ca(Peak) 22.70 wt% Ca; age-matched control values 21.66 [0.52]). Patient 2, a 17-year-old girl, suffered from diffuse bone pain but had not sustained fractures. At 14 years of age, her lumbar spine areal bone mineral density Z-score was -3.4. Iliac bone histomorphometry at that age confirmed low bone mass (bone volume to tissue volume 10.1%, same control values as above) and high bone turnover (bone formation rate per bone surface 70 µm³/µm²/year). BMDD in trabecular bone was significantly shifted toward increased mineralization (Ca(Peak) 22.36 wt% Ca). Thus, it appears that LDS can be associated with low bone mass and high bone turnover but increased matrix mineralization of trabecular bone.

Alendronate for the Treatment of Pediatric Osteogenesis Imperfecta: A Randomized Placebo-Controlled Study

Information on the use of oral bisphosphonate agents to treat pediatric osteogenesis imperfecta (OI) is limited. The objective of the investigation was to study the efficacy and safety of daily oral alendronate (ALN) in children with OI. We conducted a multicenter, double-blind, randomized, placebo-controlled study. One hundred thirty-nine children (aged 4-19 yr) with type I, III, or IV OI were randomized to either placebo (n = 30) or ALN (n = 109) for 2 yr. ALN doses were 5 mg/d in children less than 40 kg and 10 mg/d for those 40 kg and greater. Spine areal bone mineral density (BMD) z-score, urinary N-telopeptide of collagen type I, extremity fracture incidence, vertebral area, iliac cortical width, bone pain, physical activity, and safety parameters were measured. ALN increased spine areal BMD by 51% vs. a 12% increase with placebo (P < 0.001); the mean spine areal BMD z-score increased significantly from -4.6 to -3.3 (P < 0.001) with ALN, whereas the change in the placebo group (from -4.6 to -4.5) was insignificant. Urinary N-telopeptide of collagen type I decreased by 62% in the ALN-treated group, compared with 32% with placebo (P < 0.001). Long-bone fracture incidence, average midline vertebral height, iliac cortical width, bone pain, and physical activity were similar between groups. The incidences of clinical and laboratory adverse experiences were also similar between the treatment and placebo groups. Oral ALN for 2 yr in pediatric patients with OI significantly decreased bone turnover and increased spine areal BMD but was not associated with improved fracture outcomes.

Osteosclerosis in two brothers with autosomal dominant pseudohypoparathyroidism type 1b: bone histomorphometric analysis

Pseudohypoparathyroidism (PHP) is a heterogeneous disorder characterized by hypocalcemia and hyperphosphatemia resulting from selective renal resistance to parathyroid hormone (PTH). One autosomal dominant form of PHP type 1b (PHP-Ib) is most frequently caused by a maternally inherited 3-kb deletion within STX16, the gene encoding syntaxin 16. To date, increased bone mineral density (BMD) has been described only in PHP type 1a, and there is a lack of detailed information on bone histomorphometry in PHP-Ib. The objective of this report was to present trans-iliac static and dynamic histomorphometry in two brothers with the 3-kb deletion in the STX16 region and elevated BMD. Observational study of two brothers (age 18.0 and 22.7 years) with the 3-kb STX16 deletion and increased BMD. The brothers had elevated PTH (146 pg/ml (15.6 pmol/l) and 102 pg/ml (10.9 pmol/l); normal: 10-64 pg/ml (1.1-6.8 pmol/l)) and striking osteosclerosis (lumbar spine areal BMD Z-scores: +5.4 and +4.9). Bone histomorphometry showed marked elevations in cortical width for both brothers (241 and 209% of the mean result expected for age), with elevations in the bone formation rate on the endocortical (119 and 260% of the healthy mean) and trabecular (220 and 190% of mean) surfaces. Our findings suggest that PTH in this PHP-Ib genotype can increase cortical thickness due to its anabolic effect on endocortical bone, and underscore the heterogeneity in the skeletal phenotype among patients with PHP-Ib.

Short- and Long-Term Outcome of Patients with Pseudo-Vitamin D Deficiency Rickets Treated with Calcitriol

Pseudo-vitamin D deficiency rickets (PDDR; OMIM 264700) is a rare autosomal recessive disorder caused by mutations in the CYP27B1 gene, leading to an inability to synthesize 1α,25-dihydroxyvitamin D(3) (calcitriol). The long-term (>1 yr) effects of calcitriol replacement treatment have not been reported. Thirty-nine patients (20 females) with PDDR received calcitriol for periods of 2.0-26 yr. In 21 patients, data were available at diagnosis and during the first 2 yr of treatment with calcitriol. Twenty-five patients had reached their final height at the time of this analysis. The most common presenting features were active rickets, neurological signs, and short stature. Treatment with calcitriol resulted in the normalization of biochemical parameters and mean lumbar spine areal bone mineral density z-scores within 3 months, whereas height z-scores increased more gradually. As to long-term effects, adult patients who had received calcitriol before the pubertal growth spurt (n = 11) had normal height, whereas patients who were treated with calcitriol only after puberty (n = 14) on average were short (height z-score -2.2). Lumbar spine areal bone mineral density z-scores were normal in all patients who had achieved final height. Nine women had 19 pregnancies, which all were without complications. All newborns were eucalcemic at birth. Treatment with calcitriol started in infancy results in short- and long-term correction of all clinical, biochemical, and radiological abnormalities related to PDDR.

Vertebral fractures despite normal spine bone mineral density in a boy with nephrotic syndrome

Glucocorticoids (GCs) are associated with fragility fractures in children with various chronic illnesses. The impact of GCs on bone health in children with nephrotic syndrome (NS) is less well understood. Here we report skeletal findings in a 10-year-old boy with steroid-sensitive NS who presented with back pain due to vertebral fractures 5 years after NS diagnosis. Spine radiographs showed a Genant grade 2 fracture at T7 and a grade 1 fracture at T8. Dual-energy X-ray absorptiometry (DXA) revealed a lumbar spine areal bone mineral density (BMD) Z-score of -0.5 and a total body areal BMD Z-score of -0.4. Quantitative transiliac bone histomorphometry revealed low trabecular bone volume and cortical width but no osteomalacia. Our findings show the potential for significant bone morbidity due to osteoporosis in steroid-sensitive NS treated with intermittent GC therapy and emphasize that vertebral fractures may be an underrecognized complication. Furthermore, our report highlights that vertebral fractures can be associated with normal spine areal BMD in this context, suggesting that DXA-based, anteroposterior areal BMD should not be relied upon exclusively for assessing bone health and disease in children with steroid-sensitive NS.

Adverse interaction of low-calcium diet and low 25(OH)D levels on lumbar spine mineralization in late-pubertal girls

No consensus has been reached on the serum 25-hydroxyvitamin D [25(OH)D] levels required to ensure optimal bone health around menarche. We searched for a possible interaction of 25(OH)D levels and calcium intake on lumbar spine mineralization and on biologic features of bone metabolism in healthy late-pubertal girls. Lumbar spine parameters (ie, area, mineral content, and density) and calcium intake were evaluated in 211 healthy white adolescent girls at pubertal stages IV-V (11 to 16.9 years), together with biologic markers of calcium and bone metabolism and with International External Quality Assessment Scheme for Vitamin D Metabolite (DEQAS)-validated serum 25(OH)D levels. A high prevalence of 25(OH)D levels ≤ 30 nmol/L (41%), ≤ 40 nmol/L (61%), and ≤ 50 nmol/L (70%) was found during winter-spring. Parathyroid hormone (PTH) levels were inversely associated with 25(OH)D levels (p = .0021). In contrast, lumbar spine mineral content and density were not associated with 25(OH)D, excepted when calcium intake was below 600 mg/day (p = .0081). Girls with such low calcium intake and 25(OH)D levels of 40 nmol/L or less (9% of the cohort) had a 0.4 to 0.7 SD lower mean areal bone mineral density Z-score than girls with higher calcium intake and/or higher 25(OH)D status. The adverse association between lumbar spine mineralization and combined calcium deficiency-low 25(OH)D levels remained significant in the 91 girls who could be followed over 4 years after their initial evaluation. We conclude that low 25(OH)D levels (≤40 nmol/L) are observed frequently during winter-spring in late-pubertal European girls, which may exacerbate the negative impact of calcium deficiency on lumbar spine mineralization.

Reduced Bone Density in Children on Long-Term Warfarin

Vitamin K is essential for development of normal bone density and achieving adequate peak bone mass in childhood and is thought to be important in preventing the development of osteoporosis in later life. Warfarin, a vitamin K antagonist, is being used with greater frequency in children. The long-term effect of warfarin on bone density of children is not known. We performed a case control study survey of bone density in children on long-term warfarin (n=17, average duration of warfarin treatment 8.2 y) compared with randomly selected controls (n=321). There was a marked reduction in bone mineral apparent density of lumbar spine between patients and controls [patients 0.10 g/cm3; 95% confidence interval (CI), 0.93-0.11 g/cm3, controls 0.12 g/cm3; 95% CI, 0.11-0.12 g/cm3, p<0.001). The lumbar spine areal bone mineral density Z-score of patients was reduced compared with controls [patients, -1.96 (95% CI, -2.52 to -1.40). This difference persisted after adjustment for age and body size. The etiology for the reduced bone density is likely to be multifactorial, however, screening of children on long-term warfarin for reduced bone density should be considered.