Karen K. Winer

Height Adjustment in Assessing Dual Energy X- Ray Absorptiometry Measurements of Bone Mass and Density in Children

CONTEXT In children, bone mineral content (BMC) and bone mineral density (BMD) measurements by dual-energy x-ray absorptiometry (DXA) are affected by height status. No consensus exists on how to adjust BMC or BMD (BMC/BMD) measurements for short or tall stature. OBJECTIVE The aim of this study was to compare various methods to adjust BMC/BMD for height in healthy children. DESIGN Data from the Bone Mineral Density in Childhood Study (BMDCS) were used to develop adjustment methods that were validated using an independent cross-sectional sample of healthy children from the Reference Data Project (RDP). SETTING We conducted the study in five clinical centers in the United States. PARTICIPANTS We included 1546 BMDCS and 650 RDP participants (7 to 17 yr of age, 50% female). INTERVENTION No interventions were used. MAIN OUTCOME MEASURES We measured spine and whole body (WB) BMC and BMD Z-scores for age (BMC/BMD(age)), height age (BMC/BMD(height age)), height (BMC(height)), bone mineral apparent density (BMAD(age)), and height-for-age Z-score (HAZ) (BMC/BMD(haz)). RESULTS Spine and WB BMC/BMD(age)Z and BMAD(age)Z were positively (P < 0.005; r = 0.11 to 0.64) associated with HAZ. Spine BMD(haz) and BMC(haz)Z were not associated with HAZ; WB BMC(haz)Z was modestly associated with HAZ (r = 0.14; P = 0.0003). All other adjustment methods were negatively associated with HAZ (P < 0.005; r = -0.20 to -0.34). The deviation between adjusted and BMC/BMD(age) Z-scores was associated with age for most measures (P < 0.005) except for BMC/BMD(haz). CONCLUSIONS Most methods to adjust BMC/BMD Z-scores for height were biased by age and/or HAZ. Adjustments using HAZ were least biased relative to HAZ and age and can be used to evaluate the effect of short or tall stature on BMC/BMD Z-scores.

Revised Reference Curves for Bone Mineral Content and Areal Bone Mineral Density According to Age and Sex for Black and Non-Black Children: Results of the Bone Mineral Density in Childhood Study

CONTEXT Deficits in bone acquisition during growth may increase fracture risk. Assessment of bone health during childhood requires appropriate reference values relative to age, sex, and population ancestry to identify bone deficits. OBJECTIVE The objective of this study was to provide revised and extended reference curves for bone mineral content (BMC) and areal bone mineral density (aBMD) in children. DESIGN The Bone Mineral Density in Childhood Study was a multicenter longitudinal study with annual assessments for up to 7 yr. SETTING The study was conducted at five clinical centers in the United States. PARTICIPANTS Two thousand fourteen healthy children (992 males, 22% African-Americans) aged 5-23 yr participated in the study. INTERVENTION There were no interventions. MAIN OUTCOME MEASURES Reference percentiles for BMC and aBMD of the total body, lumbar spine, hip, and forearm were obtained using dual-energy x-ray absorptiometry for Black and non-Black children. Adjustment factors for height status were also calculated. RESULTS Extended reference curves for BMC and aBMD of the total body, total body less head, lumbar spine, total hip, femoral neck, and forearm for ages 5-20 yr were constructed relative to sex and age for Black and non-Black children. Curves are similar to those previously published for 7-17 year olds. BMC and aBMD values were greater for Black vs. non-Black children at all measurement sites. CONCLUSIONS We provide here dual-energy x-ray absorptiometry reference data on a well-characterized cohort of 2012 children and adolescents. These reference curves provide the most robust reference values for the assessment and monitoring of bone health in children and adolescents in the literature to date.

Synthetic human parathyroid hormone 1-34 replacement therapy: a randomized crossover trial comparing pump versus injections in the treatment of chronic hypoparathyroidism.

CONTEXT Vitamin D therapy for hypoparathyroidism does not restore PTH-dependent renal calcium reabsorption, which can lead to renal damage. An alternative approach, PTH 1-34 administered twice daily, provides acceptable long-term treatment but is associated with nonphysiological serum calcium fluctuation. OBJECTIVE Our objective was to compare continuous PTH 1-34 delivery, by insulin pump, with twice-daily delivery. RESEARCH DESIGN AND METHODS In a 6-month, open-label, randomized, crossover trial, PTH 1-34 was delivered by pump or twice-daily sc injection. After each 3-month study period, serum and 24-h urine mineral levels and bone turnover markers were measured daily for 3 d, and 24-h biochemical profiles were determined for serum minerals and 1,25-dihydroxyvitamin D(3) and for urine minerals and cAMP. STUDY PARTICIPANTS AND SETTING: Eight patients with postsurgical hypoparathyroidism (mean ± sd age 46 ± 5.6 yr) participated at a tertiary care referral center. RESULTS Pump vs. twice-daily delivery of PTH 1-34 produced less fluctuation in serum calcium, a more than 50% reduction in urine calcium (P = 0.002), and a 65% reduction in the PTH dose to maintain eucalcemia (P < 0.001). Pump delivery also produced higher serum magnesium level (P = 0.02), normal urine magnesium, and reduced need for magnesium supplements. Finally, pump delivery normalized bone turnover markers and significantly lowered urinary cross-linked N-telopeptide of type 1 collagen and pyridinium crosslinks compared with twice-daily injections (P < 0.05). CONCLUSION Pump delivery of PTH 1-34 provides the closest approach to date to physiological replacement therapy for hypoparathyroidism.

Comparison of fingerstick hemoglobin A1c levels assayed by DCA 2000 with the DCCT/EDIC central laboratory assay: results of a Diabetes Research in Children Network (DirecNet) Study.

Abstract:  Background:  The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) high‐performance liquid chromatography (HPLC) method for measuring hemoglobin A1c (HbA1c) serves as a reference standard against which other assays are compared. The DCA 2000® + Analyzer (Bayer Inc., Tarrytown, NY, USA), which uses an immunoassay, is a very popular device for measuring HbA1c levels in pediatric diabetes practices.

Long-Term Treatment of 12 Children with Chronic Hypoparathyroidism: A Randomized Trial Comparing Synthetic Human Parathyroid Hormone 1-34 versus Calcitriol and Calcium

CONTEXT Hypoparathyroidism is among the few hormonal insufficiency states not treated with replacement of the missing hormone. This is the first randomized controlled study in children comparing treatment with synthetic human PTH 1-34 and calcitriol. OBJECTIVE The primary objective was to assess the efficacy and safety of long-term PTH 1-34 vs. calcitriol treatment in the maintenance of normal serum calcium values and renal calcium excretion in children with hypoparathyroidism. SETTING The study was conducted at a clinical research center. SUBJECTS Subjects included 12 children aged 5-14 yr with chronic hypoparathyroidism and without severe renal or hepatic insufficiency. STUDY DESIGN The study was a 3-yr randomized parallel trial comparing twice-daily calcitriol (plus calcium and cholecalciferol in four daily doses) vs. s.c. PTH 1-34 treatment, with weekly or biweekly monitoring of serum and urine calcium. RESULTS Mean predose serum calcium levels were maintained at, or just below, the normal range, and urine calcium levels remained in the normal range throughout the 3-yr study, with no significant differences between treatment groups. Creatinine clearance, corrected for body surface area, did not differ between groups and remained normal throughout the study. Markers of bone turnover were mildly elevated during PTH 1-34 therapy and remained within the normal range during calcitriol therapy. Mean bone mineral density Z-scores at the anterior-posterior lumbar spine, femoral neck, distal radius, and whole body remained within the normal range and did not differ between groups throughout the study. Similarly, height and weight percentiles did not differ between treatment groups and remained normal throughout the 3-yr follow-up. CONCLUSION We conclude that PTH 1-34 therapy is safe and effective in maintaining stable calcium homeostasis in children with hypoparathyroidism. Additionally, PTH 1-34 treatment allowed normal skeletal development because there were no differences in bone mineral accrual, linear growth, or weight gain between the two treatment arms over the 3-yr study period.

Effects of Once Versus Twice-Daily Parathyroid Hormone 1–34 Therapy in Children with Hypoparathyroidism

CONTEXT Hypoparathyroidism is among the few hormonal insufficiency states not treated with replacement of the missing hormone. Long-term conventional therapy with vitamin D and analogs may lead to nephrocalcinosis and renal insufficiency. OBJECTIVE Our objective was to compare the response of once-daily vs. twice-daily PTH 1-34 treatment in children with hypoparathyroidism. SETTING The study was conducted at a clinical research center. SUBJECTS Fourteen children ages 4-17 yr with chronic hypoparathyroidism were studied. STUDY DESIGN This was a randomized cross-over trial, lasting 28 wk, which compared two dose regimens, once-daily vs. twice-daily PTH1-34. Each 14-wk study arm was divided into a 2-wk inpatient dose-adjustment phase and a 12-wk outpatient phase. RESULTS Mean predose serum calcium was maintained at levels just below the normal range. Repeated serum measures over a 24-h period showed that twice-daily PTH 1-34 increased serum calcium and magnesium levels more effectively than a once-daily dose. This was especially evident during the second half of the day (12-24 h). PTH 1-34 normalized mean 24-h urine calcium excretion on both treatment schedules. This was achieved with half the PTH 1-34 dose during the twice-daily regimen compared with the once-daily regimen (twice-daily, 25 +/-15 microg/d vs. once-daily, 58 +/- 28 microg/d; P < 0.001). CONCLUSIONS We conclude that a twice-daily PTH 1-34 regimen provides a more effective treatment of hypoparathyroidism compared with once-daily treatment because it reduces the variation in serum calcium levels and accomplishes this at a lower total daily PTH 1-34 dose. The results showed, as in the previous study of adult patients with hypoparathyroidism, that a twice-daily regimen produced significantly improved metabolic control compared with once-daily PTH 1-34.

Age at Onset of Puberty Predicts Bone Mass in Young Adulthood

OBJECTIVE To determine whether the commencement and length of puberty influences dual x-ray absorptiometry (DXA) values of bone mineral content (BMC) and bone mineral density (BMD) in the axial and appendicular skeleton at skeletal maturity. STUDY DESIGN From the Bone Mineral Density in Childhood Study, we identified children who began puberty and completed sexual and skeletal development and examined whether the timing and length of puberty influence DXA values of BMC and BMD at skeletal maturity. RESULTS A total of 78 girls and 85 boys began puberty and completed skeletal maturity; 4.4 ± 0.8 and 4.5 ± 0.8 years later, respectively. Multiple linear regression analyses indicated that the age of onset of puberty was a strong negative predictor of DXA bone measurements at skeletal maturity, independent of bone values at the beginning of puberty, and the length of puberty. This negative relation was observed for all BMC and BMD measurements at all skeletal sites, in both boys and girls (all P < .0001). In contrast, length of puberty had no relation to any measures of bone. CONCLUSIONS In healthy adolescent males and females, bone mass and bone density at skeletal maturity are inversely related to the timing of puberty.

Fibroblast Growth Factor‐23 Is Regulated by 1α,25‐Dihydroxyvitamin D

Serum FGF‐23 regulation was studied in patients with hypoparathyroidism or pseudohypoparathyroidism treated with calcitriol. Serum FGF‐23 levels changed in parallel in response to changes in serum 1,25‐D, suggesting that FGF‐23 may be regulated by 1,25‐D. In addition, the phosphaturic effect of FGF‐23 may be diminished in the absence of PTH action on the kidney.

PTH(1-34) Replacement Therapy in a Child With Hypoparathyroidism Caused by a Sporadic Calcium Receptor Mutation

Autosomal dominant hypocalcemia (ADH) is an inherited form of hypoparathyroidism caused by activating mutations in the calcium‐sensing receptor (CaR). Treatment with PTH(1–34) may be superior to conventional therapy but is contraindicated in children, and long‐term effects on the skeleton are unknown. The patient is a 20‐yr‐old female with ADH treated with PTH continuously since 6 yr and 2 mo of age. A bone biopsy was obtained for histomorphometry and quantitative backscattered electron imaging (qBEI). Her data were compared with one age‐, sex‐, and length of hypoparathyroidism‐matched control not on PTH and two sex‐matched ADH controls before and after 1 yr of PTH. The patients growth was normal. Hypercalciuria and hypermagnesuria persisted despite normal or subnormal serum calcium and magnesium levels. Nephrocalcinosis, without evidence of impaired renal function, developed by 19 yr of age. Cancellous bone volume was dramatically elevated in the patient and in ADH controls after 1 yr of PTH. BMD distribution (BMDD) by qBEI of the patient and ADH controls was strikingly shifted toward lower mineralization compared with the non‐ADH control. Moreover, the ADH controls exhibited a further reduction in mineralization after 1 yr of PTH. These findings imply a role for CaR in bone matrix mineralization. There were no fractures or osteosarcoma. In conclusion, long‐term PTH replacement in a child with ADH was not unsafe, increased bone mass without negatively impacting mineralization, and improved serum mineral control but did not prevent nephrocalcinosis. Additionally, this may be the first evidence of a role for CaR in human bone.

Longitudinal Assessment of Neuroanatomical and Cognitive Differences in Young Children with Type 1 Diabetes: Association with Hyperglycemia

Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain.