Low bone mineral density and reduced bone-specific alkaline phosphatase in 5q spinal muscular atrophy type 2 and type 3: A 2-year prospective study of bone health.

AIM: Individuals with spinal muscular atrophy (SMA) are at risk of developing skeletal problems. This study investigated bone mineral density (BMD), bone turnover markers and motor function in children and adolescents with SMA type 2 and type 3 over a two-year period. The effect of nusinersen was studied in a subgroup. METHODS: Single-centre study, including 20 patients, 2-18 years, of whom ten patients received nusinersen treatment. BMD was measured by dual-energy X-ray absorptiometry. RESULTS: All patients had low BMD levels at baseline; mean Z-score -2.3 for total body less head (TBLH) and -2.9 for total hip left (THL). Significant correlations were found both at baseline and for the follow-up change for motor function and Z-scores (TBLH and THL). For the whole study group, reduced bone formation and unchanged bone resorption, assessed by bone-specific alkaline phosphatase (BALP) (p = 0.0006, ES = -0.83) and C-terminal cross-linking telopeptide of type I collagen (CTX), respectively, were found over the study period. However, BALP decreased less in the nusinersen treatment group, which suggests a positive development on bone mass in these patients. CONCLUSION: Bone health evaluation is important in follow-up programmes for SMA patients. Further investigations are warranted for individuals on survival motor neuron-targeted treatments.

Bone mass and biomarkers in young women with anorexia nervosa: a prospective 3-year follow-up study.

INTRODUCTION: Anorexia nervosa (AN) increases the risk of impaired bone health, low areal bone mineral density (aBMD), and subsequent fractures. This prospective study investigated the long-term effects of bone and mineral metabolism on bone and biomarkers in 22 women with AN. MATERIALS AND METHODS: Body composition and aBMD were measured by dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography. Total and free 25-hydroxyvitamin D (25OHD), C-terminal collagen cross-links (CTX), osteocalcin, bone-specific alkaline phosphatase (BALP), leptin, sclerostin, and oxidized/non-oxidized parathyroid hormone (PTH) were analyzed before and after 12 weeks of intensive nutrition therapy and again 3 years later. An age-matched comparison group of 17 healthy women was recruited for the 3-year follow-up. RESULTS: Body mass index (BMI) and fat mass increased from baseline to 3 years in women with AN. Sclerostin decreased during nutrition therapy and further over 3 years, indicating reduced bone loss. CTX was elevated at baseline and after 12 weeks but decreased over 3 years. BALP increased during nutrition therapy and stabilized over 3 years. Free 25OHD was stable during treatment but decreased over 3 years. Non-oxidized PTH was stable during treatment but increased over 3 years. Trabecular volumetric BMD in AN patients decreased during the first 12 weeks and over 3 years despite stable BMI and bone biomarkers implying increased BMD. CONCLUSION: Our findings highlight the importance of early detection and organized long-term follow-up of bone health in young women with a history of AN.

Impaired renal clearance among Swedish adolescents born preterm.

AIM: To determine whether adolescents born before 28 gestational weeks have an increased risk for renal impairment. METHODS: Swedish infants, born before 28 gestational weeks in 2001 and 2002, were identified from a local register. A total of 16 children, 12 females and 4 males, were examined at 16-17 years of age with 51 Cr-EDTA clearance. A comparison group (n = 26) was used. RESULTS: Most study participants (n = 13) had normal blood pressure; one individual had hypertension stage 1. All study participants had results within the reference interval for ionised calcium, parathyroid hormone, intact fibroblast growth factor-23 and for urinary albumin-to-creatinine ratio. Four out of 16 participants (25%) had a 51 Cr-EDTA clearance less than 90 ml/min/1.73 m2 , indicating a reduced kidney function. Measured 51 Cr-EDTA clearance values were significantly lower in the study group than in the comparison group (p = 0.0012). Five study participants (31%) were referred for further investigations. CONCLUSION: Swedish children born before 28 gestational weeks have an increased risk of renal impairment later in life, suggesting that the kidney function in these individuals should be assessed, at least once, during adolescence.

Sclerostin: From Molecule to Clinical Biomarker.

Sclerostin, a glycoprotein encoded by the SOST gene, is mainly produced by mature osteocytes and is a critical regulator of bone formation through its inhibitory effect on Wnt signaling. Osteocytes are differentiated osteoblasts that form a vast and highly complex communication network and orchestrate osteogenesis in response to both mechanical and hormonal cues. The three most commonly described pathways of SOST gene regulation are mechanotransduction, Wnt/ß-catenin, and steroid signaling. Downregulation of SOST and thereby upregulation of local Wnt signaling is required for the osteogenic response to mechanical loading. This review covers recent findings concerning the identification of SOST, in vitro regulation of SOST gene expression, structural and functional properties of sclerostin, pathophysiology, biological variability, and recent assay developments for measuring circulating sclerostin. The three-dimensional structure of human sclerostin was generated with the AlphaFold Protein Structure Database applying a novel deep learning algorithm based on the amino acid sequence. The functional properties of the 3-loop conformation within the tertiary structure of sclerostin and molecular interaction with low-density lipoprotein receptor-related protein 6 (LRP6) are also reviewed. Second-generation immunoassays for intact/biointact sclerostin have recently been developed, which might overcome some of the reported methodological obstacles. Sclerostin assay standardization would be a long-term objective to overcome some of the problems with assay discrepancies. Besides the use of age- and sex-specific reference intervals for sclerostin, it is also pivotal to use assay-specific reference intervals since available immunoassays vary widely in their methodological characteristics.

Pharmacologic epigenetic modulators of alkaline phosphatase in chronic kidney disease.

PURPOSE OF REVIEW: In chronic kidney disease (CKD), disturbance of several metabolic regulatory mechanisms cause premature ageing, accelerated cardiovascular disease (CVD), and mortality. Single-target interventions have repeatedly failed to improve the prognosis for CKD patients. Epigenetic interventions have the potential to modulate several pathogenetic processes simultaneously. Alkaline phosphatase (ALP) is a robust predictor of CVD and all-cause mortality and implicated in pathogenic processes associated with CVD in CKD. RECENT FINDINGS: In experimental studies, epigenetic modulation of ALP by microRNAs or bromodomain and extraterminal (BET) protein inhibition has shown promising results for the treatment of CVD and other chronic metabolic diseases. The BET inhibitor apabetalone is currently being evaluated for cardiovascular risk reduction in a phase III clinical study in high-risk CVD patients, including patients with CKD (ClinicalTrials.gov Identifier: NCT02586155). Phase II studies demonstrate an ALP-lowering potential of apabetalone, which was associated with improved cardiovascular and renal outcomes. SUMMARY: ALP is a predictor of CVD and mortality in CKD. Epigenetic modulation of ALP has the potential to affect several pathogenetic processes in CKD and thereby improve cardiovascular outcome.

Does Whole-Body Vibration Treatment Make Children's Bones Stronger?

PURPOSE OF REVIEW: To summarize the last 10 years of literature regarding the effects of whole-body vibration (WBV) on bone in children, and if WBV results in increased bone acquisition. RECENT FINDINGS: WBV intervention appears to be a safe intervention with beneficial effects on bone mass in some diseases and syndromes, but there is still low evidence for WBV in clinical practice. The positive effects on muscle strength, balance, and walking speed are more conclusive. One of the takeaways of this review is that well-trained individuals may not further improve bone mass with WBV; thus, interventions are more beneficial in pediatric individuals with Down syndrome or severe motor disabilities with low bone mass and reduced activity levels. WBV appears to be a safe non-pharmacological anabolic approach to increase bone mass in some pediatric populations; however, longer (> 6 months) and larger prospective studies are needed to elucidate the efficacy of WBV on bone health in young individuals.

Intensive weight gain therapy in patients with anorexia nervosa results in improved serum tartrate-resistant acid phosphatase (TRAP) 5a and 5b isoform protein levels.

AIM: Tartrate-resistant acid phosphatase (TRAP) exists as isoforms 5a and 5b. TRAP 5a is a biomarker of chronic inflammation and influences adipose tissue and 5b associates with bone metabolism/pathologies. The aim was to investigate the association of serum TRAP 5a/5b isoforms with fat and bone markers and anthropometric parameters in patients with anorexia nervosa (AN) during weight gain therapy. METHODS: Twenty-five Swedish female AN patients, age 16-24 years, were treated for 12 weeks with a high-energy diet with six meals daily. Serum TRAP 5a/5b, markers of fat/glucose metabolism, markers of bone resorption and formation were measured. Parameters of bone and body composition were assessed by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. RESULTS: BMI increased from median 15.4 kg/m2 to 19.0 kg/m2, p < 0.0001. TRAP 5a and 5a/5b ratio increased but TRAP 5b decreased during the study. TRAP Δ5a and Δ5b correlated with Δinsulin and Δadiponectin, respectively. TRAP 5b correlated with trabecular density at start but not at week 12. At 12 weeks, TRAP 5b correlated with CTX, and Δ decrease in TRAP 5b correlated to Δ increase in bone-specific alkaline phosphatase. CONCLUSIONS: This clinical interventional study resulted in increased BMI in patients with AN. The decreased TRAP 5b protein levels confirm a role for TRAP 5b as a marker of bone resorption, whereas increased TRAP 5a seemed to derive from systemic changes in bone as well as metabolic changes. The combined detection of TRAP 5a and TRAP 5b in serum could be an indicator of improved bone metabolism. LEVEL OF EVIDENCE: Level III, prospective interventional cohort study.

Long-term follow-up of biomarkers of vascular calcification after switch from traditional hemodialysis to online hemodiafiltration.

Rapid progression of vascular calcification (VC) in hemodialysis (HD) patients is caused by several factors including inflammation and an imbalance between active inducers and inhibitors of VC. Growing evidence shows that online hemodiafiltration (ol-HDF), a combination of diffusive and convective solute transport, has positive effects on the uremic environment that affects patients on dialysis. However, we recently reported that serum 25-hydroxyvitamin D (25(OH)D) decreased after a switch from HD to ol-HDF. As a consequence of this finding, the present study was undertaken to investigate if inducers and inhibitors of VC (i.e. the inactive matrix Gla protein fractions dp-ucMGP and t-ucMGP, fetuin-A, Gla-rich protein (GRP), osteopontin (OPN), bone-specific alkaline phosphatase (BALP), and osteoprotegerin (OPG)) also are affected by ol-HDF. This non-comparative prospective study comprised 35 prevalent patients who were investigated 6, 12, and 24 months after their switch from HD to ol-HDF. Most patients had increased levels of the calcification inhibitors OPN and OPG; and of the inactive calcification inhibitor dp-ucMGP during the study period irrespective of the dialysis modality. BALP and t-ucMGP were mostly within the reference interval, but fetuin-A was mostly below the reference interval during the study period. OPN was significantly associated with BALP and parathyroid hormone, r = 0.62 and r = 0.65 (p < .001), respectively. In conclusion, in contrast to decreased 25(OH)D levels, no differences were found for any of the measured biomarkers of VC following the switch from HD to ol-HDF. Further studies are needed to elucidate how these biomarkers can contribute to calcification risk assessment.

Randomised study of children with obesity showed that whole body vibration reduced sclerostin.

AIM: New strategies are required to increase physical activity and improve metabolic profiles in children with obesity. We studied the effect of whole body vibration (WBV) on children with obesity on biochemical markers of energy and bone metabolism, anthropometric measurements, muscle parameters and calcaneal bone mineral density (BMD). METHODS: This was a randomised, prospective, controlled study of 30 children with a median age of 13 years (range 7-17) at Queen Silvia Children's Hospital, Gothenburg, Sweden, from 2013 to 2015. The target for the intervention group was to perform WBV three times a week for 12 weeks, and the study parameters were assessed at baseline and 12 weeks. RESULTS: The 16 in the WBV group achieved 51% of the planned activity, mainly at home, and were compared with 14 controls. Sclerostin, bone-specific alkaline phosphatase and carboxy-terminal collagen cross-links decreased in the WBV group (p < 0.05) and balance improved (p < 0.006), but osteocalcin and insulin remained unchanged. Anthropometric data, muscle strength and calcaneal BMD did not differ between the groups. CONCLUSION: WBV did not affect most of the clinical parameters in children with obesity, but the reduction in sclerostin implies that it had direct effects on osteocytes, which are key players in bone mechanotransduction.

A 3-year longitudinal study of skeletal effects and growth in children after kidney transplantation.

This prospective study investigated growth and skeletal development for 3 years after kidney transplantation in pediatric patients, 3.4-15.0 years of age. Growth, BMD, bone resorption markers (CTX and TRACP5b), bone formation markers (PINP, ALP, and osteocalcin), PTH, and vitamin D were assessed at start, 3, 12, and 36 months after transplantation. Median GFR was 63 (range 37-96) mL/min/1.73 m2 after 3 years. The median height SDS increased from -1.7 to -1.1, and median BMI SDS increased from -0.1 to 0.6 over 3 years, which shows that transplantation had a favorable outcome on growth. Fat mass increased after transplantation at all time points, whereas lean mass increased after 1 year and 3 years. Total BMC increased at all time points. No changes were observed for total BMD. Bone resorption markers decreased initially after 3 months and remained stable throughout the study, whereas the bone formation markers decreased initially, but successively increased over the study period. In conclusion, this study demonstrates that height SDS and BMI SDS increased, along with the increased formation markers that reveal a positive bone acquisition after kidney transplantation, which was reflected by the significant increase in total body BMC.

Consistent production of high quality PHA using activated sludge harvested from full scale municipal wastewater treatment - PHARIO.

Production of polyhydroxyalkanoate (PHA) biopolymers by mixed microbial cultures concurrent to wastewater treatment is a valorization route for residual organic material. This development has been at pilot scale since 2011 using industrial and municipal organic residuals. Previous experience was the basis for a PHA production demonstration project: PHARIO. PHARIO was centred on processing surplus activated sludge biomass from the Bath full-scale municipal wastewater treatment plant in the Netherlands to produce PHA. Full-scale surplus activated sludge was fed to a pilot facility to produce PHA rich biomass using fermented volatile fatty acid (VFA) rich liquors from industry or primary sludge sources. A PHA rich biomass with on average 0.41 gPHA/gVSS was obtained with reproducible thermal properties and high thermal stability. A routine kilogram scale production was established over 10 months and the polymer material properties and market potential were evaluated. Surplus full-scale activated sludge, over four seasons of operations, was a reliable raw material to consistently and predictably produce commercial quality grades of PHA. Polymer type and properties were systematic functions of the mean co-polymer content. The mean co-polymer content was predictably determined by the fermented feedstock composition. PHARIO polymers were estimated to have a significantly lower environmental impact compared to currently available (bio)plastics.

Bone Alkaline Phosphatase and Tartrate-Resistant Acid Phosphatase: Potential Co-regulators of Bone Mineralization.

Phosphorylated osteopontin (OPN) inhibits hydroxyapatite crystal formation and growth, and bone alkaline phosphatase (BALP) promotes extracellular mineralization via the release of inorganic phosphate from the mineralization inhibitor inorganic pyrophosphate (PPi). Tartrate-resistant acid phosphatase (TRAP), produced by osteoclasts, osteoblasts, and osteocytes, exhibits potent phosphatase activity towards OPN; however, its potential capacity as a regulator of mineralization has not previously been addressed. We compared the efficiency of BALP and TRAP towards the endogenous substrates for BALP, i.e., PPi and pyridoxal 5'-phosphate (PLP), and their impact on mineralization in vitro via dephosphorylation of bovine milk OPN. TRAP showed higher phosphatase activity towards phosphorylated OPN and PPi compared to BALP, whereas the activity of TRAP and BALP towards PLP was comparable. Bovine milk OPN could be completely dephosphorylated by TRAP, liberating all its 28 phosphates, whereas BALP dephosphorylated at most 10 phosphates. OPN, dephosphorylated by either BALP or TRAP, showed a partially or completely attenuated phosphorylation-dependent inhibitory capacity, respectively, compared to native OPN on the formation of mineralized nodules. Thus, there are phosphorylations in OPN important for inhibition of mineralization that are removed by TRAP but not by BALP. In conclusion, our data indicate that both BALP and TRAP can alleviate the inhibitory effect of OPN on mineralization, suggesting a potential role for TRAP in skeletal mineralization. Further studies are warranted to explore the possible physiological relevance of TRAP in bone mineralization.

Vitamin D status in young Swedish women with anorexia nervosa during intensive weight gain therapy.

PURPOSE: Anorexia nervosa (AN) is associated with reduced bone mass and an increased fracture risk. The aim was to evaluate the vitamin D status and the association with body mass index (BMI), fat mass and bone mineral density (BMD) in patients with severe AN during a prospective intervention study of intensive nutrition therapy. METHODS: This study comprised 25 Swedish female AN patients (20.1 ± 2.3 years), who were treated as inpatients for 12 weeks with a high-energy diet. Serum 25-hydroxyvitamin D (25(OH)D), calcium, phosphate and parathyroid hormone (PTH) were measured. BMD and body composition were assessed by dual-energy X-ray absorptiometry at study start and after 12 weeks. RESULTS: Twenty-two patients completed the study. The mean weight gain was 9.9 kg and BMI (mean ± SD) increased from 15.5 ± 0.9 to 19.0 ± 0.9 kg/m2, P < 0.0001. Fat mass increased from median 12 to 27 %. The median serum 25(OH)D level was 84 nmol/L at baseline, which decreased to 76 nmol/L, P < 0.05. PTH increased from median 21.9 to 30.0 ng/L, P < 0.0001. BMC increased during the study period, P < 0.001. CONCLUSIONS: Serum 25(OH)D levels were adequate both at study start and completion, however, nominally decreased after the 12-week nutritional intervention. PTH increased subsequently, which coincide with the decreased 25(OH)D levels. The reduction in 25(OH)D could be due to an increased storage of vitamin D related to the increase in fat mass since vitamin D is sequestered in adipose tissue.

Glycation Contributes to Interaction Between Human Bone Alkaline Phosphatase and Collagen Type I.

Bone is a biological composite material comprised primarily of collagen type I and mineral crystals of calcium and phosphate in the form of hydroxyapatite (HA), which together provide its mechanical properties. Bone alkaline phosphatase (ALP), produced by osteoblasts, plays a pivotal role in the mineralization process. Affinity contacts between collagen, mainly type II, and the crown domain of various ALP isozymes were reported in a few in vitro studies in the 1980s and 1990s, but have not attracted much attention since, although such interactions may have important implications for the bone mineralization process. The objective of this study was to investigate the binding properties of human collagen type I to human bone ALP, including the two bone ALP isoforms B1 and B2. ALP from human liver, human placenta and E. coli were also studied. A surface plasmon resonance-based analysis, supported by electrophoresis and blotting, showed that bone ALP binds stronger to collagen type I in comparison with ALPs expressed in non-mineralizing tissues. Further, the B2 isoform binds significantly stronger to collagen type I in comparison with the B1 isoform. Human bone and liver ALP (with identical amino acid composition) displayed pronounced differences in binding, revealing that post-translational glycosylation properties govern these interactions to a large extent. In conclusion, this study presents the first evidence that glycosylation differences in human ALPs are of crucial importance for protein-protein interactions with collagen type I, although the presence of the ALP crown domain may also be necessary. Different binding affinities among the bone ALP isoforms may influence the mineral-collagen interface, mineralization kinetics, and degree of bone matrix mineralization, which are important factors determining the material properties of bone.

Bone alkaline phosphatase isoforms in hemodialysis patients with low versus non-low bone turnover: a diagnostic test study.

BACKGROUND: Renal osteodystrophy encompasses the bone histologic abnormalities seen in patients with chronic kidney disease (CKD). The bone-specific alkaline phosphatase (bALP) isoform B1x is exclusively found in serum of some patients with CKD. STUDY DESIGN: The aim of this cross-sectional diagnostic test study was to examine the relationship between serum bALP isoform activity and histomorphometric parameters of bone in patients with CKD receiving maintenance hemodialysis. SETTINGS & PARTICIPANTS: Anterior iliac crest bone biopsy samples from 40 patients with CKD were selected on the basis of bone turnover for histomorphometric analysis. There were samples from 20 patients with low and 20 with non-low bone turnover. INDEX TEST: In serum, bALP, bALP isoforms (B/I, B1x, B1, and B2), and parathyroid hormone (PTH) were measured. REFERENCE TEST: Low bone turnover was defined by mineral apposition rate < 0.36µm/d. Non-low bone turnover was defined by mineral apposition rate ≥ 0.36µm/d. OTHER MEASUREMENTS: PTH. RESULTS: B1x was found in 21 patients (53%) who had lower median levels of bALP, 18.6 versus 46.9U/L; B/I, 0.10 versus 0.22 µkat/L; B1, 0.40 versus 0.88 µkat/L; B2, 1.21 versus 2.66 µkat/L; and PTH, 49 versus 287pg/mL, compared with patients without B1x (P<0.001). 13 patients (65%) with low bone turnover and 8 patients (40%) with non-low bone turnover (P<0.2) had detectable B1x. B1x correlated inversely with histomorphometric parameters of bone turnover. Receiver operating characteristic curves showed that B1x can be used for the diagnosis of low bone turnover (area under the curve [AUC], 0.83), whereas bALP (AUC, 0.89) and PTH (AUC, 0.85) are useful for the diagnosis of non-low bone turnover. LIMITATIONS: Small number of study participants. Requirement of high-performance liquid chromatography methods for measurement of B1x. CONCLUSIONS: B1x, PTH, and bALP have similar diagnostic accuracy in distinguishing low from non-low bone turnover. The presence of B1x is diagnostic of low bone turnover, whereas elevated bALP and PTH levels are useful for the diagnosis of non-low bone turnover.

Short-term changes in bone formation markers following growth hormone (GH) treatment in short prepubertal children with a broad range of GH secretion.

OBJECTIVES: Growth hormone (GH) promotes longitudinal growth and bone modelling/remodelling. This study investigated the relationship between levels of bone formation markers and growth during GH treatment in prepubertal children with widely ranging GH secretion levels. METHODS: The study group comprised 113 short prepubertal children (mean age ± SD, 9·37 ± 2·13 years; 99 boys) on GH treatment (33·0 ± 0·06 µg/kg/day) for 1 year. Blood samples were taken at baseline and 1 and 2 weeks, 1 and 3 months, and 1 year after treatment start. Intact amino-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (BALP) and osteocalcin were measured using an automated IDS-iSYS immunoassay system. RESULTS: Intact amino-terminal propeptide of type I procollagen (PINP), BALP and osteocalcin, increased in the short-term during GH treatment. PINP after 1 week (P = 0·00077), and BALP and osteocalcin after 1 month (P < 0·0001 and P = 0·0043, respectively). PINP levels at 1 and 3 months correlated positively, and osteocalcin levels at 1 week and percentage change after 1 month correlated negatively, with first year growth response. No significant correlations were found between BALP and first year growth. Multiple regression analysis showed that bone marker levels together with auxological data and insulin-like growth factor binding protein-3 explained the variation in first year growth response to 36% at start, 32% after 2 weeks and 48% at 3 months. CONCLUSION: Short-term increases in levels of the bone formation markers PINP, BALP and osteocalcin showed different temporal patterns, but all correlated with first year growth response during GH treatment. These markers may be a useful addition to existing prediction models for growth response.

In the backwater of convective dialysis: decreased 25-hydroxyvitamin D levels following the switch to online hemodiafiltration.

BACKGROUND/AIMS: Vitamin D deficiency and elevated serum fibroblast growth factor-23 (FGF23) levels are hallmark features and surrogate markers of adverse clinical outcomes in patients with chronic kidney disease (CKD). Convection of molecules over the dialysis membrane during online hemodiafiltration (ol-HDF) increases the removal of larger waste molecules compared with traditional high-flux hemodialysis (HD). The primary aim of this study was to explore the long-term impact of ol-HDF on serum 25(OH)D and FGF23. METHOD: An observational, prospective, noncomparator study including 35 patients who were switched from HD to ol-HDF. Serum 25(OH)D and FGF23 were measured at baseline (i.e., time of switch to ol-HDF) and at 6, 12, and 24 months. RESULTS: At follow-up time points, there was a significant reduction in serum 25(OH)D compared with baseline (p<0.0001) whereas FGF23 was unaltered (p>0.05). The decrease in 25(OH)D was more prominent in individuals with higher baseline 25(OH)D levels. CONCLUSION: Ol-HDF may lower systemic 25(OH)D levels by convective mechanisms although the clinical significance remains unknown. Further controlled studies are warranted to replicate these findings in larger patient cohorts.

Bone and fat mass in relation to postnatal levels of insulin-like growth factors in prematurely born children at 4 y of age.

BACKGROUND: Children born prematurely may be at risk of developing osteopenia. This study investigated whether insulin-like growth factors (IGFs) in the early postnatal period influence bone mass and body composition in prematurely born children. METHODS: A total of 74 control (gestational age >36 wk; n = 37) and preterm (gestational age <32 wk; n = 37) infants were investigated (mean age ± SD: 4.59 ± 0.31 y). Bone mineral density, body composition, and markers of bone and mineral metabolism were investigated in relation to postnatal IGF levels. RESULTS: After adjusting for confounders, we found no differences in bone mass, but significantly less lean mass, increased fat mass, and increased osteocalcin levels in ex-preterm infants. Forward stepwise multiple analysis revealed that higher late postnatal IGF-II levels predict lumbar spine bone mineral content (P < 0.05) and lean mass (P < 0.05). When the birth weight standard deviation score was included in the analysis, higher early postnatal IGF-I levels predicted both lumbar spine bone mineral density and bone mineral content (P < 0.05). Higher early postnatal IGF binding protein-3 (P < 0.01) predicted increased fat mass at 4-y follow-up. CONCLUSION: Ex-preterm children have normal bone mass but different body composition compared with full-term controls. Higher early IGF-I and late postnatal IGF-II concentrations are positive predictors of lumbar spine bone mass.

Limosilactobacillus reuteri 6475 and Prevention of Early Postmenopausal Bone Loss: A Randomized Clinical Trial.

Importance: Daily supplementation with the probiotic Limosilactobacillus reuteri ATCC PTA 6475 (L reuteri) vs placebo has previously been demonstrated to reduce bone loss in an estrogen deficiency mice model and older women, although the magnitude of the effect was small. We hypothesized that long-term treatment with L reuteri could result in clinically relevant skeletal benefits in postmenopausal osteoporosis. Objective: To evaluate whether daily supplementation with L reuteri vs placebo could reduce early postmenopausal bone loss and whether the effects remained or increased over time during 2 years of treatment. Design, Setting, and Participants: A double-blind, randomized, placebo-controlled clinical trial was conducted between December 4, 2019, and October 6, 2022, at a single center in Gothenburg, southwestern Sweden. Participants were recruited by online advertisements, and letters were sent to 10 062 women aged 50 to 60 years. Responding women (n = 752) underwent telephone screening, resulting in 292 women being invited to a screening visit. Of those who were screened, 239 women met all inclusion criteria and had no exclusion criteria. Interventions: Capsules with L reuteri in 2 doses, 5 × 108 (low dose) or 5 × 109 (high dose) colony-forming units, taken twice daily or placebo were administered. All capsules also included cholecalciferol, 200 IU. Main Outcomes and Measures: The primary outcome was the relative change in tibia total volumetric bone mineral density (vBMD) over 2 years. Secondary outcomes included relative change in areal BMD of the lumbar spine and total hip, bone turnover markers C-terminal telopeptide cross-links of collagen type I and type I procollagen intact N-terminal propeptide, as well as tibia trabecular bone volume fraction and cortical vBMD. Both intention-to-treat and per-protocol analyses were conducted. Results: A total of 239 postmenopausal women (median age, 55 [IQR, 53-56] years) were included. Tibia vBMD (primary outcome), hip and spine vBMD, and tibia cortical area and BMD decreased significantly in all groups, with no group-to-group differences (percent change tibia vBMD high dose vs placebo least-squares means, -0.08 [95 CI, -0.85 to 0.69] and low dose vs placebo least-squares means, -0.22 [95% CI, -0.99 to 0.55]). There were no significant treatment effects on any other predefined outcomes. A prespecified sensitivity analysis found a significant interaction between body mass index (BMI) and treatment effect at 2 years. No significant adverse effects were observed. Conclusions and Relevance: In this randomized clinical trial of 239 early postmenopausal women, supplementation with L reuteri had no effect on bone loss or bone turnover over 2 years. The observed interaction between BMI and treatment effect warrants further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT04169789.

Demographic and disease-related factors impact bone turnover and vitamin D in children with hemato-oncological diseases.

Children with hemato-oncological diseases may have significant skeletal morbidity, not only during and after treatment but also at the time of diagnosis before cancer treatment. This study was designed to evaluate the vitamin D status and circulating bone metabolic markers and their determinants in children at the time of diagnostic evaluation for hemato-oncological disease. This cross-sectional study included 165 children (91 males, median age 6.9 yr range 0.2-17.7 yr). Of them, 76 patients were diagnosed with extracranial or intracranial solid tumors, 83 with leukemia, and 6 with bone marrow failure. Bone metabolism was assessed by measuring serum 25OHD, PTH, bone alkaline phosphatase, intact N-terminal propeptide of type I procollagen, and C-terminal cross-linked telopeptide of type I collagen. Vitamin D deficiency was found in 30.9% of children. Lower 25OHD levels were associated with older age, lack of vitamin D supplementation, season outside summer, and a country of parental origin located between latitudes -45° and 45°. Children diagnosed with leukemia had lower levels of markers of bone formation and bone resorption than those who had solid tumors or bone marrow failure. In conclusion, vitamin D deficiency was observed in one-third of children with newly diagnosed cancer. Bone turnover markers were decreased in children with leukemia, possibly because of the suppression of osteoblasts and osteoclasts by leukemic cells. The identification of patients with suboptimal vitamin D status and compromised bone remodeling at cancer diagnosis may aid in the development of supportive treatment to reduce the adverse effects of cancer and its treatment.