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Background: Biochemical bone turnover markers are useful tools to assess bone remodeling. C-terminal telopeptide of type I collagen (ß-CTX) has been recommended as a reference marker for bone resorption in research studies.Methods: We describe the results of a multicenter study for routine clinical laboratory assays for ß-CTX in serum and plasma. Four centers (Athens GR, Copenhagen DK, Liege BE and Sheffield UK) collected serum and plasma (EDTA) samples from 796 patients presenting to osteoporosis clinics. Specimens were analyzed in duplicate with each of the available routine clinical laboratory methods according to the manufacturers' instructions. Passing-Bablok regressions, Bland-Altman plots, V-shape evaluation method, and Concordance correlation coefficient for ß-CTX values between serum and plasma specimens and between methods were used to determine the agreement between results. A generalized linear model was employed to identify possible variables that affected the relationship between the methods. Two pools of serum were finally prepared and sent to the four centers to be measured in 5-plicates on 5 consecutive days with the different methods.Results: We identified significant variations between methods and between centers although comparison results were generally more consistent in plasma compared to serum. We developed univariate linear regression equations to predict Roche Elecsys®, IDS-iSYS, or IDS ELISA ß-CTX results from any other assay and a multivariable model including the site of analysis, the age, and weight of the patient. The coefficients of determination (R2) increased from approximately 0.80 in the univariate model to approximately 0.90 in the multivariable one, with the site of analysis being the major contributing factor. Results observed on the pools also suggest that long-term storage could explain the difference observed with the different methods on serum.Conclusion: Our results show large within- and between-assay variation for ß-CTX measurement, particularly in serum. Stability of the analyte could be one of the explanations. More studies should be undertaken to overcome this problem. Until harmonization is achieved, we recommend measuring ß-CTX by the same assay on EDTA plasma, especially for research purposes in large pharmacological trials where samples can be stored for long periods before they are assayed. [ABSTRACT FROM AUTHOR]

A correction to this paper has been published: https://doi.org/10.1007/s00223-021-00839-y [ABSTRACT FROM AUTHOR]

The anti-fibroblast growth factor 23 monoclonal antibody burosumab corrects hypophosphatemia in adults with X-linked hypophosphatemia (XLH) and improves pain, stiffness, physical function, and fatigue. This post hoc subgroup analysis used data from the 24-week placebo-controlled period of a phase 3 study in 134 adults with XLH (ClinicalTrials.gov NCT02526160), to assess whether the benefits of burosumab are evident in 14 clinically relevant subgroups defined by baseline demographic and functional criteria, including sex, Brief Pain Inventory-short form (BPI-SF) Average And Worst Pain, region, race, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) Stiffness, Physical Function and Pain domains and total score, use of opioid/other pain medication, active fractures/pseudo-fractures, and 6-min walk test distance. There were no statistically significant interactions between any of the subgroups and treatment arm for any endpoint. Higher proportions of subjects achieved mean serum phosphate concentration above the lower limit of normal (the primary endpoint) with burosumab than with placebo in all subgroups. For the key secondary endpoints (WOMAC Stiffness and Physical Function; BPI-SF Worst Pain) individual subgroup categories showed improvements with burosumab relative to placebo. For additional efficacy endpoints, burosumab was favored in some subgroups but differences were not significant and confidence intervals were wide. For some endpoints the treatment effect is small at 24 weeks in all subjects. This subgroup analysis shows that burosumab was largely superior to placebo across endpoints in the 14 clinically relevant subgroup variables at 24 weeks and is likely to benefit all symptomatic adults with active XLH., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alterations in musculoskeletal health with advanced age contribute to sarcopenia and decline in bone mineral density (BMD) and bone strength. This decline may be modifiable via dietary supplementation. To test the hypothesis that a specific oral nutritional supplement can result in improvements in measures of bone health. Participants (n 380) were participants of the PROVIDE study, a 13-week, multicenter, randomized, controlled, double-blind, 2 parallel-group study among non-malnourished older participants (≥ 65 years) with sarcopenia [determined by Short Physical Performance Battery (SPPB; 0-12) scores between 4 and 9, and a low skeletal muscle mass index (SMI; skeletal muscle mass/BW × 100) ≤ 37% in men and ≤ 28% in women using bioelectric impedance analysis] Supplementation of a vitamin D, calcium and leucine-enriched whey protein drink that comprises a full range of micronutrients (active; 2/day) was compared with an iso-caloric control. Serum 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), biochemical markers of bone formation (osteocalcin; OC, procollagen type 1 amino-terminal propeptide; P1NP) and resorption (carboxy-terminal collagen crosslinks; CTX), insulin like growth factor 1 (IGF-1) and total-body BMD were analysed pre- and post-intervention. Serum 25(OH)D concentrations increased from 51.1 ± 22.9 nmol/L (mean ± SD) to 78.9 ± 21.1 nmol/L in the active group (p < 0.001 vs. control). Serum PTH showed a significant treatment difference (p < 0.001) with a decline in the active group, and increase in the control group. Serum IGF-1 increased in the active group (p < 0.001 vs. control). Serum CTX showed a greater decline in the active group (p = 0.001 vs. control). There were no significant differences in serum OC or P1NP between groups during the intervention. Total body BMD showed a small (0.02 g/cm 2 ; ~ 2%) but significant increase in the active group after supplementation (p = 0.033 vs. control). Consuming a vitamin D, calcium and leucine-enriched whey protein supplement for 13 weeks improved 25(OH)D, suppressed PTH and had small but positive effects on BMD, indicative of improved bone health, in sarcopenic non-malnourished older adults.

Burosumab, a fully human monoclonal antibody to FGF23, is the only approved treatment for X-linked hypophosphatemia (XLH), a rare genetic disorder characterized by renal phosphate wasting and substantial cumulative musculoskeletal morbidity. During an initial 24-week randomized, controlled trial, 134 adults with XLH received burosumab 1 mg/kg (n = 68) or placebo (n = 66) every 4 weeks. After 24 weeks, all subjects received open-label burosumab until week 48. This report describes the efficacy and safety of burosumab during the open-label treatment period. From weeks 24-48, serum phosphorus concentrations remained normal in 83.8% of participants who received burosumab throughout and were normalized in 89.4% who received burosumab after placebo. By week 48, 63.1% of baseline fractures/pseudofractures healed fully with burosumab, compared with 35.2% with burosumab after placebo. In both groups, burosumab was associated with clinically significant and sustained improvement from baseline to week 48 in scores for patient-reported outcomes of stiffness, pain, physical function, and total distance walked in 6 min. Rates of adverse events were similar for burosumab and placebo. There were no fatal adverse events or treatment-related serious adverse events. Nephrocalcinosis scores did not change from baseline by more than one grade at either week 24 or 48. These data demonstrate that in participants with XLH, continued treatment with burosumab is well tolerated and leads to sustained correction of serum phosphorus levels, continued healing of fractures and pseudofractures, and sustained improvement in key musculoskeletal impairments.

High-resolution peripheral quantitative computed tomography (HR-pQCT) is increasingly being used in the research setting to assess the effects of osteoporosis treatments and disease on trabecular and cortical bone compartments. Further in-depth study of HR-pQCT measurement variables is essential to ensure study strength and statistical confidence when designing large multicenter studies. Duplicate HR-pQCT examinations of the distal radius and tibia were performed in 180 healthy men and women ages 16-18, 30-32, and >70 years. HR-pQCT images were processed using standard and extended cortical bone analysis techniques. Biomechanical properties of bone were assessed using finite element analysis. Percent root mean square coefficient of variation (RMSCV) was calculated for each measurement variable. Age, site, and gender influences on measurement variability were investigated using variance ratio tests. Smaller precision errors were observed for densitometric (0.2-5.5%) than for microstructural (1.2-7.0%), extended cortical bone (3.4-20.3%), and biomechanical (0.3-9.9%) measures at both the radius and tibia. Tibial measurements (RMSCVs = 0.2-7.4%) tended to be more precise than radial measurements (RMSCVs = 0.7-20.3%). Variability was influenced by age, site, and gender (all p < 0.05). HR-pQCT measurements for the tibia were more precise than those for the radius, and this may be explained by the larger bone volumes examined and the reduced likelihood of movement artifact. The greater measurement variability observed for older volunteers may be due to the loss of bone density and microstructural integrity with age.

Proton pump inhibitors are taken by millions of patients for prevention and treatment of gastroesophageal diseases. Case-control studies have suggested that use of omeprazole is associated with an increased risk of hip fractures. The aim of this prospective study was to assess the risk of vertebral fractures in postmenopausal women using omeprazole. We studied 1,211 postmenopausal women enrolled in the Osteoporosis and Ultrasound Study from the general population. Information on omeprazole and other risk factors for fractures including prevalent fractures and bone mineral density was obtained at baseline. Vertebral fractures were assessed on X-rays obtained at baseline and at the end of the 6-year follow-up and analyzed centrally. At baseline, 5% of this population was using omeprazole. Age-adjusted rates for vertebral fractures were 1.89 and 0.60 for 100 person-years for omeprazole users and nonusers, respectively (P = 0.009). In the multivariate analysis, omeprazole use was a significant and independent predictor of vertebral fractures (RR = 3.50, 95% CI 1.14-8.44). The other predictors were age higher than 65 years (RR = 2.34, 95% CI 1.02-5.34), prevalent vertebral fractures (RR = 3.62, 95% CI 1.63-8.08), and lumbar spine T score

Periprosthetic bone loss is an important factor that limits implant survival after total hip arthroplasty (THA). In a randomized trial we previously reported that pamidronate therapy prevented periprosthetic bone loss and decreased urinary excretion of N-telopeptide collagen cross-links over the first 6 months after THA, but had no apparent effect on free deoxypyridinoline excretion (J Bone Miner Res 2001; 16:556-564). In this study we investigated this discrepant observation that pamidronate reduced conjugated cross-link excretion but had no effect on free cross-links. Free and total deoxypyridinoline (DPD) were assayed by reverse-phase high-performance liquid chromatography (HPLC) and by immunosorbent assay (ELISA) at preoperative baseline and at week 6 after surgery in 46 subjects who had taken part in the trial. Randomly selected, 22 subjects received a single 90 mg intravenous infusion of pamidronate and 24 received placebo. Acute rises in free and total DPD occurred in both study groups at week 6 (P < 0.05). Total DPD excretion was lower in the pamidronate group than in the placebo group when measured by both HPLC and ELISA (P < 0.05). No difference in free DPD was found between groups. A rise in the ratio of free to total DPD occurred in the pamidronate group at week 6 (P = 0.03), but not in the placebo group. Pamidronate treatment suppresses excretion of total DPD. This is consistent with the effect of pamidronate on other turnover markers and periprosthetic bone loss after THA. Urinary-free DPD is a poor marker of response to treatment as the ratio of free-to-total cross-links is affected by amino-bisphosphonate therapy.