Cross-sectional studies of the causal link between asthma and osteoporosis: insights from Mendelian randomization and bioinformatics analysis.

The study, using data from Chongqing, China, and employing Mendelian randomization along with bioinformatics, establishes a causal link between asthma and osteoporosis, beyond glucocorticoid effects. Asthma may contribute to osteoporosis by accelerating bone turnover through inflammatory factors, disrupting the coupling between osteoblasts and osteoclasts, ultimately leading to osteoporosis. INTRODUCTION: Asthma and osteoporosis are prevalent health conditions with substantial public health implications. However, their potential interplay and the underlying mechanisms have not been fully elucidated. Previous research has primarily focused on the impact of glucocorticoids on osteoporosis, often overlooking the role of asthma itself. METHODS: We conducted a multi-stage stratified random sampling in Chongqing, China and excluded individuals with a history of glucocorticoid use. Participants underwent comprehensive health examinations, and their clinical data, including asthma status, were recorded. Logistic regression and Mendelian randomization were employed to investigate the causal link between asthma and osteoporosis. Furthermore, bioinformatics analyses and serum biomarker assessments were conducted to explore potential mechanistic pathways. RESULTS: We found a significant association between asthma and osteoporosis, suggesting a potential causal link. Mendelian Randomization analysis provided further support for this causal link. Bioinformatics analyses revealed that several molecular pathways might mediate the impact of asthma on bone health. Serum alkaline phosphatase levels were significantly elevated in the asthma group, suggesting potential involvement in bone turnover. CONCLUSION: Our study confirms a causal link between asthma and osteoporosis and highlights the importance of considering asthma in osteoporosis prediction models. It also suggests that asthma may accelerate osteoporosis by increasing bone turnover through inflammatory factors, disrupting the coupling between osteoblasts and osteoclasts, ultimately leading to bone loss.

Twenty-four months of follow-up in women with rebound-associated vertebral fractures after discontinuation of denosumab: a single-centre case series.

Evidence on the management of rebound-associated vertebral fractures after denosumab discontinuation is scarce. This study describes seven patients retreated with denosumab, teriparatide or zoledronate for 24 months. Their bone mineral density remained stable or improved and no new fractures occurred suggesting that all three options might be adequate for their treatment. PURPOSE: To describe the densitometric and biochemical changes achieved with osteoactive treatment after 24 months of follow-up in patients who suffered rebound-associated vertebral fractures (RAVFs) after Dmab discontinuation, and to report the occurrence of new vertebral and non-vertebral fractures. METHODS: Patients with RAVFs who received retreatment (RT) for 24 months were included. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry at the lumbar spine (LS), femoral neck (FN) and total hip (TH), along with C-terminal cross-linked telopeptide of type I collagen, osteocalcin, and bone alkaline phosphatase. Data were collected at the start of the RT and after 24 months. RESULTS: Seven female patients were included. RT consisted in Dmab (n = 3), teriparatide (TPT) (n = 3) and zoledronate (Zol) (n = 1). At 24 months, the mean BMD change was 2.2% at LS, 6.8% at FN and 3.8% at TH in the Dmab group, 7.5% at LS, 1.4% at FN and 3.7% at TH in the TPT group and, 5.0% at LS, 0.6% at FN and 3.9% at TH in the patient with Zol. After 24 months of follow-up, no patient suffered new fractures. CONCLUSION: In this series of patients with RAVFs, we did not observe any new fractures and the BMD remained stable after 24 months of RT. Future studies are needed to evaluate the most suitable treatment approach after RAVFs but these preliminary data suggest that all denosumab, zoledronate and teriparatide might be adequate options.

The relationship between length of denosumab treatment for postmenopausal osteoporosis and serum TRAcP5b measured six months after the last injection.

To test the hypothesis that during treatment with denosumab osteomorphs and precursors recycle to higher number of osteoclasts with time, we measured TRAcP5b in serum taken 6 months after the last injection in postmenopausal women treated for 1-10 years. Serum TRAcP5b values were not related to time of exposure to denosumab. PURPOSE: In women with postmenopausal osteoporosis the aetiology of the observed inverse relationship between duration of denosumab (Dmab) therapy and bone loss after its discontinuation is currently unknown. In studies in mice inhibition of RANKL is associated with an increase in osteomorphs and osteoclast precursors that recycle into osteoclasts and may accumulate with time. We hypothesized that longer inhibition of RANKL by Dmab will be followed by the synchronous formation of a larger number of osteoclasts after stopping treatment. To test this hypothesis, we measured serum TRAcP5b, a marker of osteoclast numbers, in postmenopausal women treated with Dmab for different periods of time up to 10 years. METHODS: TRAcP5b, C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at 6.0 months ± 15 days after last Dmab injection in 59 women who had received Dmab for 4.0 ± 2.3 years (range 1-10 years). Of these, 38 were treatment naïve (group 1) and 21 had received other treatments prior Dmab (group 2). RESULTS: Duration of Dmab treatment was not related to serum TRAcP5b values or to TRAcP5b/CTX ratio either in the whole cohort or in each of the two groups separately. In contrast, serum TRAcP5b values were significantly correlated with serum CTX values (rs = 0.619; p < 0.001), but not with serum P1NP values or BMD at all skeletal sites. CONCLUSION: Our observations indicate that serum TRAcP5b, measured at 6 months after a Dmab injection, is not a useful early marker for time-dependent increased accumulation of osteoclasts in humans and for identification of patients at risk for a higher rebound increase in bone resorption.

B vitamins and bone health: a meta-analysis with trial sequential analysis of randomized controlled trials.

Our study showed that B vitamins did not have significant effect on fracture incidence, bone mineral density, and bone turnover markers. However, the research data of B vitamins on bone mineral density and bone turnover markers are limited, and more clinical trials are needed to draw sufficient conclusions. PURPOSE: The objective of this study was to identify the efficacy of B vitamin (VB) (folate, B6, and B12) supplements on fracture incidence, bone mineral density (BMD), and bone turnover markers (BTMs). METHODS: A comprehensive search was performed in PubMed, MEDLINE, EMBASE, Cochrane databases, and ClinicalTrials.gov up to September 4, 2023. The risk of bias was assessed according to Cochrane Handbook and the quality of evidence was assessed according to the GRADE system. We used trial sequential analysis (TSA) to assess risk of random errors and Stata 14 to conduct sensitivity and publication bias analyses. RESULTS: Data from 14 RCTs with 34,700 patients were extracted and analyzed. The results showed that VBs did not significantly reduce the fracture incidence (RR, 1.06; 95% CI, 0.95 - 1.18; p = 0.33; I2 = 40%) and did not affect BMD in lumbar spine and femur neck. VBs had no significant effect on bone specific alkaline phase (a biomarker for bone formation), but could increase the serum carboxy-terminal peptide (a biomarker for bone resorption) (p = 0.009; I2 = 0%). The TSA showed the results of VBs on BMD and BTMs may not be enough to draw sufficient conclusions due to the small number of sample data included and needed to be demonstrated in more clinical trials. The inability of VBs to reduce fracture incidence has been verified by TSA as sufficient. Sensitivity analysis and publication bias assessment proved that our meta-analysis results were stable and reliable, with no significant publication bias. CONCLUSIONS: Available evidence from RCTs does not support VBs can effectively influence osteoporotic fracture risk, BMD, and BTMs. TRIAL REGISTRATION: PROSPERO registration number: CRD42023427508.

Bone mineral density, turnover, and microarchitecture assessed by second-generation high-resolution peripheral quantitative computed tomography in patients with Sheehan's syndrome.

Sheehan's syndrome (SS) is a rare but well-characterized cause of hypopituitarism. Data on skeletal health is limited and on microarchitecture is lacking in SS patients. PURPOSE: We aimed to explore skeletal health in SS with bone mineral density (BMD), turnover, and microarchitecture. METHODS: Thirty-five patients with SS on stable replacement therapy for respective hormone deficiencies and 35 age- and BMI-matched controls were recruited. Hormonal profile and bone turnover markers (BTMs) were measured using electrochemiluminescence assay. Areal BMD and trabecular bone score were evaluated using DXA. Bone microarchitecture was assessed using a second-generation high-resolution peripheral quantitative computed tomography. RESULTS: The mean age of the patients was 45.5 ± 9.3 years with a lag of 8.3 ± 7.2 years prior to diagnosis. Patients were on glucocorticoid (94%), levothyroxine (94%), and estrogen-progestin replacement (58%). None had received prior growth hormone (GH) replacement. BTMs (P1NP and CTX) were not significantly different between patients and controls. Osteoporosis (26% vs. 16%, p = 0.01) and osteopenia (52% vs. 39%, p = 0.007) at the lumbar spine and femoral neck (osteoporosis, 23% vs. 10%, p = 0.001; osteopenia, 58% vs. 29%, p = 0.001) were present in greater proportion in SS patients than matched controls. Bone microarchitecture analysis revealed significantly lower cortical volumetric BMD (vBMD) (p = 0.02) at the tibia, with relative preservation of the other parameters. CONCLUSION: Low areal BMD (aBMD) is highly prevalent in SS as compared to age- and BMI-matched controls. However, there were no significant differences in bone microarchitectural measurements, except for tibial cortical vBMD, which was lower in adequately treated SS patients.

Pre-treatment bone turnover does not influence the level of the response to alendronate in postmenopausal osteoporosis at the bone tissue level.

PURPOSE: The main effect of anti-resorptive agents such as bisphosphonates is a reduction of bone resorption, with a consequent marked decrease of bone turnover. This post-hoc analysis investigated the changes of histomorphometric parameters of bone turnover after alendronate (ALN), according to the baseline turnover. METHODS: Ninety postmenopausal women underwent a transiliac bone biopsy before and after 6 (n = 44) or 12 (n = 46) months of treatment with ALN (70 mg/week). The dynamic parameters reflecting the bone formation and bone turnover were mineralizing surface (MS/BS; %), bone formation rate (BFR/BS; µm3/µm2/d), and activation frequency (Ac.f; /yr). Biochemical markers sPINP and the sCTX were assessed before treatment and after 3, 6, and 12 months. Subjects were divided into quartiles based on the baseline values of BFR/BS. RESULTS: At baseline, MS/BS and Ac.f were significantly different (p < 0.0001) among the BFR quartiles. sCTX and sP1NP were not significantly different among quartiles. After ALN treatment, MS/BS was not significantly different among quartiles but Ac.f remained significantly lower in the first quartile compared to the third and fourth ones (p < 0.03). The absolute value of the difference between pre- and post-treatment significantly correlated with the baseline BFR/BS but when expressed in percent of the baseline value, the magnitude of the diminutions of MS/BS, Ac.f, sCTX, and sP1NP was similar in the four baseline BFR quartiles. CONCLUSION: The percentage response to ALN appeared independent of the baseline level of bone turnover. After treatment, the bone turnover tended to be similar in all BFR quartiles. This analysis investigated the influence of baseline turnover measured by bone histomorphometry on the effect of alendronate. When expressed in percent of pre-treatment values, the decreases of histomorphometric parameters and biochemical markers of bone turnover were independent of the baseline turnover.

Graded Replacement of Carbohydrate-Rich Breakfast Products with Dairy Products: Effects on Postprandial Aminoacidemia, Glycemic Control, Bone Metabolism, and Satiety.

BACKGROUND: Postprandial metabolic responses following dairy consumption have mostly been studied using stand-alone dairy products or milk-derived nutrients. OBJECTIVE: Assessing the impact of ingesting dairy products as part of a common breakfast on postprandial aminoacidemia, glycemic control, markers of bone metabolism, and satiety. METHODS: In this randomized, crossover study, 20 healthy young males and females consumed on 3 separate occasions an iso-energetic breakfast containing no dairy (NO-D), 1 dairy (ONE-D), or 2 dairy (TWO-D) products. Postprandial concentrations of amino acids, glucose, insulin, glucagon-like peptide-1 (GLP-1), calcium, parathyroid hormone (PTH), and markers of bone formation (P1NP) and resorption (CTX-I) were measured before and up to 300 min after initiating the breakfast, along with VAS-scales to assess satiety. RESULTS: Plasma essential and branched-chained amino acids availability (expressed as total area under the curve (tAUC)) increased in a dose-dependent manner (P<0.05 for all comparisons). Plasma glucose tAUCs were lower in ONE-D and TWO-D compared with NO-D (P<0.05 for both comparisons). Plasma GLP-1 tAUC increased in a dose-dependent manner (P<0.05 for all comparisons), whereas no differences were observed in plasma insulin tAUC between conditions (P>0.05 for all comparisons). Serum calcium tAUCs were higher in ONE-D and TWO-D compared with NO-D (P<0.05 for both comparisons), along with lower PTH tAUCs in ONE-D and TWO-D compared with NO-D (P=0.001 for both comparisons). In accordance, serum CTX-I concentrations were lower in the late postprandial period in ONE-D and TWO-D compared with NO-D (P<0.01 for both comparisons). No differences were observed in P1NP tAUCs between conditions (P>0.05). The tAUC for satiety was higher in TWO-D compared with NO-D and ONE-D (P<0.05 for both comparisons). CONCLUSIONS: Iso-energetic replacement of a carbohydrate-rich breakfast component with one serving of dairy improves postprandial amino acid availability, glycemic control, and bone metabolism. Adding a second serving of dairy in lieu of carbohydrates augments postprandial amino acid and GLP-1 concentrations while further promoting satiety. This study was registered at https://doi.org/10.1186/ISRCTN13531586 with Clinical Trial Registry number ISRCTN13531586.

Bone Turnover Markers and Wnt Signaling Modulators in Early Complex Regional Pain Syndrome. A Pre-specified Observational Study.

To explore serum levels of some bone turnover markers and the involvement of the Wnt signaling in CRPS-1. Query ID="Q1" Text="Please check and confirm whether the edit made to the article title is in order." We conducted an observational study on patients with early CRPS-1 recruited before any treatment. Clinical measures were assessed together with biochemical evaluation. Values of sclerostin, DKK1, CTX-I, and P1NP were compared with sex-age-matched healthy controls (HCs). We enrolled 34 patients diagnosed with CRPS-1 (mean age 59.3 ± 10.6 years, Male/Female 10/24), median disease duration = 2 weeks (IQR 1-5); median VAS score = 76 (IQR 68-80). Foot localization was slightly more frequent than hand localization (18/16). No statistically significant difference was found between CRPS-1 patients and HCs for CTX-I (0.3 ± 0.1 ng/ml vs 0.3 ± 0.1, p = 0.140), while mean serum values of P1NP were significantly higher in CRPS-1 patients compared to HCs (70.0 ± 38.8 ng/ml vs 50.1 ± 13.6, p = 0.005). Mean levels of sclerostin and DKK1 were lower in CRPS-1 patients vs HCs (sclerostin 28.4 ± 10.8 pmol/l vs 34.1 ± 11.6, p = 0.004; DKK1 12.9 ± 10.8 pmol/l vs 24.1 ± 11.9, p = 0.001). No statistically significant difference was found for all biochemical assessments in a subgroup of fracture-induced CRPS-1. No statistically significant differences were observed according to disease localization, disease duration, presence of hyperalgesia, allodynia, sudomotor alterations, and mild or moderate/severe swelling. No significant correlation emerged between sclerostin, DKK1 levels, baseline VAS score, or McGill Pain Questionnaire score. Bone involvement in early CRPS-1 does not seem to rely on increased osteoclast activity. Conversely, a serum marker of bone formation resulted increased. Both Sclerostin and DKK1 showed decreased values, probably suggesting a widespread osteocyte loss of function.Trial registration number: Eudract Number: 2014-001156-28.

Resolution of PTHrP-Mediated Hypercalcemia Following Treatment with Dual BRAF/MEK Inhibition for BRAFV600E-Positive Metastatic Ameloblastoma.

Ameloblastoma is a rare odontogenic tumor which may be complicated by hypercalcemia in advanced disease. Tumoral parathyroid hormone-related peptide (PTHrP) production and local osteolysis from paracrine factors have been proposed as mechanisms. Mitogen-activated protein kinase (MAPK) inhibitors have been successfully used in ameloblastomas with BRAF V600E mutation to reduce symptoms and decrease tumor burden. Serum calcium has been observed to normalize following treatment with MAPK inhibitors; however, the response of PTHrP and markers of bone turnover has not been reported. We describe a case of a 55-year-old female with PTHrP-mediated hypercalcemia secondary to BRAF V600E-positive ameloblastoma with pulmonary metastases. Following treatment with dabrafenib and trametinib, the patient experienced the regression of pulmonary lesions and normalization of serum calcium, PTHrP, and markers of bone turnover. Tissue samples of ameloblastoma carrying BRAF V600E mutation are more likely to express PTHrP than tissue samples carrying wild-type BRAF. In our case, resolution of PTHrP-mediated hypercalcemia following initiation of BRAF/MEK inhibition provides additional evidence that the MAPK pathway contributes to PTHrP synthesis. It also raises the question of whether MAPK inhibitors would be effective in treating PTHrP-mediated hypercalcemia associated with other malignancies harboring BRAF V600E mutation.

Glucagon-like Peptide-1 Receptor Agonists and Diabetic Osteopathy: Another Positive Effect of Incretines? A 12 Months Longitudinal Study.

Diabetic osteopathy is a frequent complication in patients with type 2 diabetes mellitus (T2DM). The association between T2DM and increased fracture risk has led to study the impact of new antidiabetic drugs on bone metabolism. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin mimetic drugs which have many pleiotropic properties. The relationship between GLP-1RAs and bone is very complex: while in vitro and animal studies have demonstrated a protective effect on bone, human studies are scarce. We led a 12 months longitudinal study evaluating bone changes in 65 patients withT2DM for whom a therapy with GLP-1RAs had been planned. Fifty-four T2DM patients completed the 12-month study period; of them, 30 had been treated with weekly dulaglutide and 24 with weekly semaglutide. One-year therapy with GLP-1RAs resulted in a significant reduction in weight and BMI. Bone mineral density (BMD), bone metabolism, trabecular bone score (TBS), adiponectin, and myostatin were evaluated before and after 12 months of GLP-1RAs therapy. After 12 months of therapy bone turnover markers and adiponectin showed a significant increase, while myostatin values showed a modest but significant reduction. BMD-LS by DXA presented a significant reduction while the reduction in BMD-LS by REMS was not significant and TBS values showed a marginal increase. Both DXA and REMS techniques showed a modest but significant reduction in femoral BMD. In conclusion, the use of GLP-1RAs for 12 months preserves bone quality and reactivates bone turnover. Further studies are needed to confirm whether GLP-1RAs could represent a useful therapeutic option for patients with T2DM and osteoporosis.

Bone health in SATB2-associated syndrome: Results from a large prospective cohort and recommendations for surveillance.

Alterations in SATB2 result in SATB2-associated syndrome (SAS; Glass syndrome, OMIM 612313), an autosomal dominant multisystemic disorder predominantly characterized by developmental delay, craniofacial anomalies, and growth retardation. The bone phenotype of SAS has been less explored until recently and includes a variety of skeletal deformities, increased risk of low bone mineral density (BMD) with a propensity to fractures, and other biochemical abnormalities that suggest elevated bone turnover. We present the results of ongoing surveillance of bone health from 32 individuals (47% females, 3-18 years) with molecularly-confirmed SAS evaluated at a multidisciplinary clinic. Five individuals (5/32, 16%) were documented to have BMD Z-scores by DXA scans of -2.0 SD or lower and 7 more (7/32, 22%) had Z-scores between -1 and - 2 SD at the lumbar spine or the total hip. Alkaline phosphatase levels were found to be elevated in 19 individuals (19/30, 63%) and determined to correspond to bone-specific alkaline phosphatase elevations when measured (11/11, 100%). C-telopeptide levels were found to be elevated when adjusted by age and gender in 6 individuals (6/14, 43%). Additionally, the two individuals who underwent bone cross-sectional geometry evaluation by peripheral quantitative computed tomography were documented to have low cortical bone density for age and sex despite concurrent DXA scans that did not have this level of decreased density. While we could not identify particular biochemical abnormalities that predicted low BMD, the frequent elevations in markers of bone formation and resorption further confirmed the increased bone turnover in SAS. Based on our results and other recently published studies, we propose surveillance guidelines for the skeletal phenotype of SAS.

Long-term effects of denosumab on bone mineral density and turnover markers in patients undergoing hemodialysis.

INTRODUCTION: Denosumab, a fully human anti-RANKL monoclonal antibody, is a widely used osteoporosis treatment that is increasingly being used in patients undergoing dialysis; however, its long-term efficacy and safety in these patients remain unknown. MATERIALS AND METHODS: This observational study comprised individuals aged ≥ 20 years undergoing hemodialysis and receiving denosumab. After denosumab administration, we analyzed the long-term changes in bone mineral density (BMD) and levels of bone turnover markers (BTMs) and calcium. RESULTS: The study included 45 patients who have been receiving denosumab for a median duration of 3.8 (interquartile range, 2.5-6.7) years. Tartrate-resistant acid phosphatase 5b (TRACP-5b) levels decreased from a median of 595 (434-778) mU/dL at baseline to 200 (141-430) mU/dL after 6 months of denosumab administration (P < 0.001) and remained low thereafter. Similarly, bone-specific alkaline phosphatase (BAP) levels decreased from a median of 18.2 (15.9-25.8) µg/L at baseline to 12.4 (9.9-15.6) µg/L after 6 months (P < 0.001) and remained low thereafter. Meanwhile, BMD, as assessed with dual energy X-ray absorptiometry and measured at the distal 1/3 of the radius, did not decrease (0.465 ± 0.112 g/cm2 at baseline vs. 0.464 ± 0.112 g/cm2 after administration; P = 0.616). Regarding hypocalcemia, corrected calcium levels reached were the lowest at 7 days after administration and normalized within 30 days. CONCLUSION: The study showed long-term suppression of TRACP-5b and BAP levels and sustaining BMD after denosumab administration over an extended period in patients undergoing hemodialysis.

Effects of partial replacement of red and processed meat with non-soya legumes on bone and mineral metabolism and amino acid intakes in BeanMan randomised clinical trial.

The transition towards more plant-based diets may pose risks for bone health such as low vitamin D and Ca intakes. Findings for the contribution of animal and plant proteins and their amino acids (AA) to bone health are contradictory. This 6-week clinical trial aimed to investigate whether partial replacement of red and processed meat (RPM) with non-soya legumes affects AA intakes and bone turnover and mineral metabolism in 102 healthy 20-65-year-old men. Participants were randomly assigned to diet groups controlled for RPM and legume intake (designed total protein intake (TPI) 18 E%): the meat group consumed 760 g RPM per week (25 % TPI) and the legume group consumed non-soya legume-based products (20 % TPI) and 200 g RPM per week, the upper limit of the Planetary Health Diet (5 % TPI). No differences in bone (bone-specific alkaline phosphatase; tartrate-resistant acid phosphatase 5b) or mineral metabolism (25-hydroxyvitamin D; parathyroid hormone; fibroblast growth factor 23; phosphate and Ca) markers or Ca and vitamin D intakes were observed between the groups (P > 0·05). Methionine and histidine intakes were higher in the meat group (P ≤ 0·042), whereas the legume group had higher intakes of arginine, asparagine and phenylalanine (P ≤ 0·013). Mean essential AA intakes in both groups met the requirements. Increasing the proportion of non-soya legumes by reducing the amount of RPM in the diet for 6 weeks did not compromise bone turnover and provided on average adequate amounts of AA in healthy men, indicating that this ecologically sustainable dietary change is safe and relatively easy to implement.

Effect of vitamin D supplementation or fortification on bone turnover markers in women: a systematic review and meta-analysis.

Vitamin D is a vital indicator of musculoskeletal health, as it plays an important role through the regulation of bone and mineral metabolism. This meta-analysis was performed to investigate the effects of vitamin D supplementation/fortification on bone turnover markers in women. All human randomised clinical trials reported changes in bone resorption markers (serum C-terminal telopeptide of type-I collagen (sCTX) and urinary type I collagen cross-linked N-telopeptide (uNTX)) or bone formation factors (osteocalcin (OC), bone alkaline phosphatase (BALP) and procollagen type-1 intact N-terminal propeptide (P1NP)) following vitamin D administration in women (aged ≥ 18 years) were considered. Mean differences (MD) and their respective 95 % CI were calculated based on fixed or random effects models according to the heterogeneity status. Subgroup analyses, meta-regression models, sensitivity analysis, risk of bias, publication bias and the quality of the included studies were also evaluated. We found that vitamin D supplementation had considerable effect on sCTX (MD: -0·038, n 22) and OC (MD: -0·610, n 24) with high heterogeneity and uNTX (MD: -8·188, n 6) without heterogeneity. Our results showed that age, sample size, dose, duration, baseline vitamin D level, study region and quality of studies might be sources of heterogeneity in this meta-analysis. Subgroup analysis also revealed significant reductions in P1NP level in dose less than 600 µg/d and larger study sample size (>100 participants). Moreover, no significant change was found in BALP level. Vitamin D supplementation/fortification significantly reduced bone resorption markers in women. However, results were inconsistent for bone formation markers.

Vitamin D and vitamin K status in postmenopausal women with normal and low bone mineral density.

OBJECTIVES: Vitamin D and K are believed to promote bone health, but existing evidence is controversial. This study aimed to measure several metabolites of both vitamins by liquid chromatography tandem mass spectrometry (LC-MS/MS) in a cohort of postmenopausal women with low and normal bone mineral density (BMD). METHODS: Vitamin metabolites (25-hydroxyvitamin D (25[OH]D), 24,25-dihydroxyvitamin D (24,25(OH)2D), phylloquinone (K1), menaquinone-4 (MK-4) and MK-7) were measured in 131 serum samples by LC-MS/MS. The vitamin D metabolite ratio (VMR) was calculated. Parathyroid hormone (PTH), type I procollagen-N-terminal-peptide (PINP) and C-terminal telopeptides of type I collagen (CTX-I) were measured by immunoassay. Dual X-ray absorptiometry was performed to identify participants with normal (T-score>-1) and low (T-score<-1) BMD. RESULTS: Mean age was 58.2±8.5 years. BMD was normal in 68 and low in 63 women. Median (interquartile range) for 25(OH)D and total vitamin K concentrations were 53.5 (39.6-65.9) nmol/L and 1.33 (0.99-2.39) nmol/L. All vitamin metabolites were comparable in individuals with normal and low BMD. Furthermore, BMD and trabecular bone score were comparable in participants with adequate and inadequate vitamin status (at least one criterion was met: 25(OH)D <50 nmol/L, 24,25(OH)2D <3 nmol/L, VMR <4 %, total vitamin K <0.91 nmol/L). PTH, but not PINP or CTX-I, was inversely correlated with 25(OH)D, 24,25(OH)2D and VMR. Synergistic effects between vitamin D and K were not observed. CONCLUSIONS: Vitamin D and K status is not related to BMD and trabecular bone quality in postmenopausal women. Inverse associations were only seen between vitamin D metabolites and PTH.

Meat consumption and the risk of hip fracture in women and men: two prospective Swedish cohort studies.

PURPOSE: To study the association between meat intake (predominantly red and processed meats) and the risk of hip fracture, as well as the association between meat intake and biomarkers of inflammation, oxidative stress, bone turnover, body composition, and bone mineral density (BMD). METHODS: Data from the Swedish Mammography Cohort and the Cohort of Swedish men (n = 83,603, 54% men) with repeated investigations and their respective clinical sub-cohorts was utilised. Incident hip fractures were ascertained through individual linkage to registers. Associations were investigated using multivariable Cox and linear regression analyses. RESULTS: During up to 23 years of follow-up (mean 18.2 years) and 1,538,627 person-years at risk, 7345 participants (2840 men) experienced a hip fracture. Each daily serving of meat intake conferred a hazard ratio (HR) of 1.03 (95% confidence interval [CI] 1.00; 1.06) for hip fracture. In quintile 5, compared to quintile 2, the HR was 1.11 (95% CI 1.01; 1.21) among all participants. In the sub-cohorts, meat intake was directly associated with circulating levels of interleukin-6, C-reactive protein, leptin, ferritin, parathyroid hormone, and calcium. CONCLUSION: A modest linear association was found between a higher meat intake and the risk of hip fractures. Our results from the sub-cohorts further suggest that possible mechanisms linking meat intake and hip fracture risk may be related to the regulation of bone turnover, subclinical inflammation, and oxidative stress. Although estimates are modest, limiting red and processed meat intake in a healthy diet is advisable to prevent hip fractures.

Chronic kidney disease mineral bone disorder in childhood and young adulthood: a 'growing' understanding.

Chronic kidney disease (CKD) mineral and bone disorder (MBD) comprises a triad of biochemical abnormalities (of calcium, phosphate, parathyroid hormone and vitamin D), bone abnormalities (turnover, mineralization and growth) and extra-skeletal calcification. Mineral dysregulation leads to bone demineralization causing bone pain and an increased fracture risk compared to healthy peers. Vascular calcification, with hydroxyapatite deposition in the vessel wall, is a part of the CKD-MBD spectrum and, in turn, leads to vascular stiffness, left ventricular hypertrophy and a very high cardiovascular mortality risk. While the growing bone requires calcium, excess calcium can deposit in the vessels, such that the intake of calcium, calcium- containing medications and high calcium dialysate need to be carefully regulated. Normal physiological bone mineralization continues into the third decade of life, many years beyond the rapid growth in childhood and adolescence, implying that skeletal calcium requirements are much higher in younger people compared to the elderly. Much of the research into the link between bone (de)mineralization and vascular calcification in CKD has been performed in older adults and these data must not be extrapolated to children or younger adults. In this article, we explore the physiological changes in bone turnover and mineralization in children and young adults, the pathophysiology of mineral bone disease in CKD and a potential link between bone demineralization and vascular calcification.

Maternal APOE ε2 as a possible risk factor for elevated prenatal Pb levels.

Lead (Pb) is a global contaminant associated with multiple adverse health effects. Humans are especially vulnerable during critical developmental stages. During pregnancy, exposure to Pb can occur through diet and release from maternal bones. Apolipoprotein E gene (APOE) variants (ɛ2, ɛ3, ɛ4 alleles) may influence sex steroid hormones, bone metabolism, and Pb kinetics. We examined the interplay among maternal APOE (mAPOE) genotypes, fetal sex, parity, and Pb in maternal and cord blood (mB-Pb, CB-Pb) using linear regression models. Our study involved 817 pregnant women and 772 newborns with measured adequate levels of zinc and selenium. We compared carriers of the ε2 and ε4 alleles to those with the ε3/ε3 genotype. The geometric means (range) of mB-Pb and CB-Pb were 11.1 (3.58 - 87.6) and 9.31 (1.82 - 47.0) ng/g, respectively. In cases with female fetuses, the maternal mAPOE ε2 allele was associated with higher, while the mAPOE ε4 allele was associated with lower mB-Pb and CB-Pb levels. Nulliparity increased the strength of the observed associations. These findings highlight the significance of mAPOE genetics, fetal sex, and parity in prenatal Pb kinetics. Notably, the maternal ε2 allele may increase the risk of Pb exposure.

Fat as a Friend or Foe of the Bone.

PURPOSE OF REVIEW: The objective of this review is to summarize the literature on the prevalence and diagnosis of obesity and its metabolic profile, including bone metabolism, focusing on the main inflammatory and turnover bone mediators that better characterize metabolically healthy obesity phenotype, and to summarize the therapeutic interventions for obesity with their effects on bone health. RECENT FINDINGS: Osteoporosis and fracture risk not only increase with age and menopause but also with metabolic diseases, such as diabetes mellitus. Thus, patients with high BMI may have a higher bone fragility and fracture risk. However, some obese individuals with healthy metabolic profiles seem to be less at risk of bone fracture. Obesity has become an alarming disease with growing prevalence and multiple metabolic comorbidities, resulting in a significant burden on healthcare and increased mortality. The imbalance between increased food ingestion and decreased energy expenditure leads to pathological adipose tissue distribution and function, with increased secretion of proinflammatory markers and harmful consequences for body tissues, including bone tissue. However, some obese individuals seem to have a healthy metabolic profile and may not develop cardiometabolic disease during their lives. This healthy metabolic profile also benefits bone turnover and is associated with lower fracture risk.

Correlation of serum DKK1 level with skeletal phenotype in children with osteogenesis imperfecta.

PURPOSE: We aim to detect serum DKK1 level of pediatric patients with OI and to analyze its relationship with the genotype and phenotype of OI patients. METHODS: A cohort of pediatric OI patients and age-matched healthy children were enrolled. Serum levels of DKK1 and bone turnover biomarkers were measured by enzyme-linked immunosorbent assay. Bone mineral density (BMD) was measured by Dual-energy X-ray absorptiometry. Pathogenic mutations of OI were detected by next-generation sequencing and confirmed by Sanger sequencing. RESULTS: A total of 62 OI children with mean age of 9.50 (4.86, 12.00) years and 29 healthy children were included in this study. The serum DKK1 concentration in OI children was significantly higher than that in healthy children [5.20 (4.54, 6.32) and 4.08 (3.59, 4.92) ng/mL, P < 0.001]. The serum DKK1 concentration in OI children was negatively correlated with height (r = - 0.282), height Z score (r = - 0.292), ALP concentration (r = - 0.304), lumbar BMD (r = - 0.276), BMD Z score of the lumbar spine and femoral neck (r = - 0.32; r = - 0.27) (all P < 0.05). No significant difference in serum DKK1 concentration was found between OI patients with and without vertebral compression fractures. In patients with spinal deformity (22/62), serum DKK1 concentration was positively correlated with SDI (r = 0.480, P < 0.05). No significant correlation was observed between serum DKK1 concentration and the annual incidence of peripheral fractures, genotype and types of collagen changes in OI children. CONCLUSION: The serum DKK1 level was not only significantly elevated in OI children, but also closely correlated to their skeletal phenotype, suggesting that DKK1 may become a new biomarker and a potential therapeutic target of OI.