Real-world effects, safety, and predictors of the effectiveness of romosozumab in primary and secondary osteoporosis: An observational study.

Romosozumab is an anti-sclerostin antibody that increases bone formation and decreases bone resorption. It became available for patients at high risk of osteoporotic fractures in Japan in 2019. The aim of this study was to clarify the clinical effects, safety, and predictors of the effectiveness of 12 months of romosozumab therapy. The study had an observational pre-post design and included 460 patients. Romosozumab was administered at a dose of 210 mg subcutaneously every 4 weeks for 12 months. The incidence of new fractures, safety, and changes in bone mineral density (BMD) and bone turnover markers were recorded. New fractures occurred in 11 cases (3.0 %). Nine patients (2.0 %) experienced cardiovascular events, which were fatal in 3 (0.65 %). Percent changes in BMD at the spine and total hip at 12 months from baseline were +7.7 % and +1.8 %, respectively. Romosozumab had better effects in patients with good renal function, low spine BMD, and high TRACP-5b at baseline and low TRACP-5b or high P1NP after 1 month of treatment. The percent change in spine BMD at 12 months was significantly lower in patients transitioning from denosumab than in those not previously treated with other anti-osteoporosis agents. Romosozumab is considered to be relatively safe in patients with primary osteoporosis compared to those with secondary osteoporosis. Romosozumab resulted in larger increases in spine BMD in patients with primary osteoporosis who were not previously treated with other anti-osteoporosis therapies and those with low spine BMD at the start of treatment.

Predictive value of bone turnover markers and thyroid indicators for bone metabolism in GD patients after treatment.

Purpose: To investigate the relationship between bone turnover markers (BTMs) and thyroid indicators in Graves' disease (GD) and to further assess predictive value of changes in early stage retrospectively. Methods: We studied 435 patients with GD and 113 healthy physical examiners retrospectively and followed up these two groups of patients after 6 months. We investigated the correlations between BTMs and other 15 observed factors, and analyzed the predictive value of FT3 and FT4 before and after treatment (FT3-P/FT3-A, FT4-P/FT4-A) on whether BTMs recovered. Results: The levels of thyroid hormones and BTMs in GD group were significantly higher than those in control group (P < 0.05) and decreased after 6 months of treatment. FT3, W, Ca and ALP were independent factors in predicting the elevation of OST. Duration of disease, FT3, TSH and ALP were independent factors in predicting the elevation of P1NP. Age, duration of disease, TRAb and ALP were independent factors in predicting the elevation of CTX-1. The AUC of FT3-P/FT3-A and FT4-P/FT4-A for predicting OST recovery were 0.748 and 0.705 (P < 0.05), respectively, and the cut-off values were 0.51 and 0.595. There was no predictive value for P1NP and CTX-1 recovery (P > 0.05). Conclusion: BTMs were abnormally elevated in GD and were significantly correlated with serum levels of FT3, FT4, TRAb, Ca, and ALP. FT3 decreased more than 51% and FT4 dropped more than 59.5% after 6 months of treatment were independent predictors for the recovery of BTMs in GD.

Bone Turnover Markers, n-Terminal Propeptide of Type I Procollagen and Tartrate-Resistant Acid Phosphatase Type 5b, for Predicting Castration Resistance in Prostate Cancer.

Bone is a common site of prostate cancer metastasis. Bone turnover markers n-terminal propeptide of type I procollagen (P1NP) and tartrate-resistant acid phosphatase type 5b (TRACP-5b) are highly sensitive to bone remodeling activity. However, their prognostic significance as markers of prostate cancer is unknown. This study retrospectively examined the usefulness of P1NP and TRACP-5b as prognostic biomarkers. Castration-resistant prostate cancer recurrence-free survival (CFS) was estimated using the Kaplan-Meier method. A predictive model for CFS was constructed using multivariate analysis. This study enrolled 255 patients diagnosed with prostate cancer at Kanazawa University Hospital. The median follow-up was 115.1 months. Patients with both high serum P1NP and TRACP-5b levels, defined as having a poor bone turnover category (BTC), had significantly shorter CFS. Multivariate analysis identified Gleason score, metastasis, and BTC poor as predictors for castration resistance in prostate cancer. Using these three factors, a prognostic model was established, categorizing patients into low-risk (no or one factor) and high-risk (two or three factors) groups. In the low-risk group, the median CFS was not reached, contrasting with 19.1 months in the high-risk group (hazard ratio, 32.23, p < 0.001). Combining P1NP and TRACP-5b may better predict castration resistance.

Effects of Exogenous GIP and GLP-2 on Bone Turnover in Individuals With Type 2 Diabetes.

CONTEXT: Individuals with type 2 diabetes (T2D) have an increased risk of bone fractures despite normal or increased bone mineral density. The underlying causes are not well understood but may include disturbances in the gut-bone axis, in which both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are regulators of bone turnover. Thus, in healthy fasting participants, both exogenous GIP and GLP-2 acutely reduce bone resorption. OBJECTIVE: The objective of this study was to investigate the acute effects of subcutaneously administered GIP and GLP-2 on bone turnover in individuals with T2D. METHODS: We included 10 men with T2D. Participants met fasting in the morning on 3 separate test days and were injected subcutaneously with GIP, GLP-2, or placebo in a randomized crossover design. Blood samples were drawn at baseline and regularly after injections. Bone turnover was estimated by circulating levels of collagen type 1 C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), sclerostin, and PTH. RESULTS: GIP and GLP-2 significantly reduced CTX to (mean ± SEM) 66 ± 7.8% and 74 ± 5.9% of baseline, respectively, compared with after placebo (P = .001). In addition, P1NP and sclerostin increased acutely after GIP whereas a decrease in P1NP was seen after GLP-2. PTH levels decreased to 67 ± 2.5% of baseline after GLP-2 and to only 86 ± 3.4% after GIP. CONCLUSION: Subcutaneous GIP and GLP-2 affect CTX and P1NP in individuals with T2D to the same extent as previously demonstrated in healthy individuals.

Effect of Anamorelin, a Ghrelin Receptor Agonist, on Muscle and Bone in Adults With Osteosarcopenia.

CONTEXT: Anamorelin, a ghrelin receptor agonist known to stimulate the pulsatile release of GH from the pituitary, has the potential to improve musculoskeletal health in adults with osteosarcopenia. OBJECTIVE: To determine the effect of anamorelin treatment for 1 year on muscle mass and strength and on biochemical markers of bone turnover in adults with osteosarcopenia (OS). DESIGN: Randomized, placebo-controlled, 1-year anamorelin intervention trial. SETTING: The Bone Metabolism Laboratory at the USDA Nutrition Center at Tufts University. PARTICIPANTS: 26 men and women, age 50 years and older, with OS. MAIN OUTCOME MEASURES: Muscle mass by D3-creatine dilution and lean body mass (LBM) and bone mineral density (BMD) by dual-energy X-ray absorptiometry, muscle strength, serum IGF-1, and bone turnover markers, serum procollagen 1 intact N-terminal (P1NP), and C-terminal telopeptide (CTX). RESULTS: Anamorelin did not have a significant effect on muscle mass or LBM; it significantly increased knee flexion torque at 240°/s by 20% (P = .013) and had a similar nonstatistically significant effect on change in knee extension; it increased bone formation (P1NP) by 75% (P = .006) and had no significant effect on bone resorption (CTX) or BMD. Serum IGF-1 increased by 50% in the anamorelin group and did not change in the placebo group (P = .0001 for group difference). CONCLUSION: In this pilot study, anamorelin did not significantly alter muscle mass; however, it may potentially improve lower extremity strength and bone formation in addition to increasing circulating IGF-1 levels in adults with OS. Further study of anamorelin in this population is warranted.

Increased bone resorption that outpaces increased bone formation: An important pathology of rapidly destructive coxarthrosis.

Rapid joint destruction caused by rapidly destructive coxarthrosis (RDC) can increase surgical complexity and intraoperative blood loss. This single-center retrospective study investigates osteoporosis-related biomarkers for early RDC diagnosis and explores new treatment targets. We included 398 hip joints from patients who underwent total hip arthroplasty, examining medical records for preoperative patient demographics, bone mineral density of the hip and lumbar spine from dual-energy X-ray absorptiometry scans, and osteoporosis-related biomarkers including TRACP-5b, total P1NP, intact parathyroid hormone, and homocysteine. We compared RDC and osteoarthritis (OA) patients, and univariate analysis showed that RDC patients were older (p < 0.001) and had lower serum levels of albumin (p < 0.001) and higher serum levels of TRACP-5b, total P1NP (p < 0.001), and homocysteine (p = 0.006). Multivariable analysis showed that the ratio of serum TRACP-5b to total P1NP had a more significant difference in RDC patients than in OA patients (p = 0.04). Serum TRACP-5b levels were negatively correlated with the time between RDC onset and blood collection, and Japanese Orthopedic Association pain score. Receiver operating characteristic curve analysis revealed that the ratio of serum TRACP-5b to total P1NP had the highest area under the curve value. This study is the first to demonstrate that the ratio of serum TRACP-5b to total P1NP-increased bone resorption that outpaces increased bone formation-is significantly elevated in patients with RDC and that TRACP-5b is higher in the early stages of RDC. Inhibiting serum levels of TRACP-5b, activated osteoclasts, during early RDC may suppress disease progression.

Parathyroidectomy Improves Bone Density in Women With Primary Hyperparathyroidism and Preoperative Osteopenia.

CONTEXT: Osteoporosis and/or bone fractures are indications of parathyroidectomy in primary hyperparathyroidism (PHPT), especially in women. However, the benefit of surgery in patients with osteopenia remains unclear. OBJECTIVE: To evaluate bone mineral density (BMD) and bone remodeling biomarkers changes 1 year after parathyroidectomy in women with PHPT. DESIGN: In the prospective, monocentric, observational prospective cohort with primary hyperparathyroidism patients (CoHPT) cohort, women operated for sporadic PHPT since 2016 with ≥1 year follow-up were included. BMD (dual-X ray absorptiometry) and bone remodeling biomarkers [cross-linked C-telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), and bone-specific alkaline phosphatases] were assessed before and 1 year after parathyroidectomy. SETTING: Referral center. PATIENTS: A total of 177 women with PHPT (62.5 ± 13.3 years, 83.1% menopausal, 43.9% osteopenic, and 45.1% osteoporotic) were included. INTERVENTION: Parathyroidectomy. MAIN OUTCOME MEASURE: BMD change between before and 1 year after parathyroidectomy. RESULTS: Parathyroidectomy resulted in significant increase in BMD and decrease in serum bone remodeling biomarker concentrations. In the 72 patients with baseline osteopenia, mean BMD significantly increased at the lumbar spine [+0.05 g/cm2 (95% confidence interval [CI], 0.03-0.07)], the femoral neck [+0.02 g/cm2 (95% CI 0.00-0.04)], the total hip [+0.02 g/cm2 (95% CI 0.01-0.02)], and the forearm [+0.01 (95% CI 0.00-0.02)], comparable to osteoporotic patients. Among osteopenic patients, those with individual BMD gain (>0.03 g/cm2) at ≥1 site had higher preoperative serum CTX, P1NP, and urine calcium concentrations than those without improvement. CONCLUSION: Parathyroidectomy significantly improved BMD and remodeling biomarkers in women with osteopenia, thereby supporting the benefit of parathyroidectomy in these patients. Preoperative serum CTX and P1NP concentrations could be useful to predict expected BMD gain.

Night shift work and serum markers of bone turnover in male shift workers.

Night shift work is related to sleep disorders, disruption of circadian rhythm and low serum levels of vitamin D. It is known that all these conditions can adversely affect bone mass. The rate of bone turnover can be assessed through the measurement of molecules called bone turnover markers, including C-terminal telopeptide fragment of type I collagen (CTX) and procollagen type I N-terminal propeptide (P1NP). In this study, we evaluated the serum levels of CTX, P1NP and 25-Hydroxy Vitamin D in 82 male subjects (42 daytime workers and 40 night shift workers) to assess the possible risk of osteoporosis in male shift workers. Serum levels of CTX and P1NP were found to be higher in night shift workers than in daytime workers. No significant difference was found in vitamin D levels between night shift and daytime workers. The increased CTX and P1NP levels reveal a higher rate of bone turnover in night shift workers and thus a possible increased risk of osteoporosis in this category of workers compared with daytime workers. In view of this, our results highlight the importance of further studies investigating the bone health in male night shift workers.

The short-term effects of CGRP monoclonal antibodies on bone turnover: A prospective cohort study.

BACKGROUND: Calcitonin gene-related peptide monoclonal antibodies (CGRP mAb) are an effective treatment of migraine however may have possible off-target effects. Pre-clinical studies implicate CGRP in several aspects of bone turnover and homeostasis. The clinical effect of CGRP mAb on bone turnover is not known, however. METHODS: Between June 2021 and July 2022, a multi-centre prospective cohort study was undertaken with eligible patients undergoing paired testing of the validated bone turnover markers procollagen type I N-terminal propeptide (P1NP) and serum C-terminal telopeptide of type I collagen (CTX) prior to and at least three months following administration of a CGRP mAb. RESULTS: A total of 45 patients with a mean age of 41.8 (SD 11.9) were included in the final analysis, all of whom received a ligand-targeting CGRP mAb. Administration of a CGRP mAb was associated with a statistically significant increase in P1NP from 44.5 microg/L to 51.5 microg/L (p = 0.004), but no significant change in CTX. CONCLUSION: In otherwise homeostatic conditions, short-term administration of a CGRP mAb is associated with increased P1NP, a bone formation marker but not with increased CTX, a bone resorption marker. Further study is required to validate these findings over longer time periods, in a larger cohort, and in pre-existing states of increased calcium stress and bone-turnover.

Impact of Intravenous Iron Substitution on Serum Phosphate Levels and Bone Turnover Markers-An Open-Label Pilot Study.

The association between intravenous iron substitution therapy and hypophosphatemia was previously reported in patients with iron deficiency anemia. However, the extent of hypophosphatemia is thought to depend on the type of iron supplementation. We hypothesized that the intravenous application of ferric carboxymaltose and iron sucrose leads to a different longitudinal adaptation in serum phosphate levels. In this open-label pilot study, a total of 20 patients with inflammatory bowel diseases or iron deficiency anemia were randomly assigned to one of two study groups (group 1: ferric carboxymaltose, n = 10; group 2: iron sucrose, n = 10). Serum values were controlled before iron substitution therapy, as well as 2, 4, and 12 weeks after the last drug administration. The primary objective of the study was the longitudinal evaluation of serum phosphate levels after iron substitution therapy with ferric carboxymaltose and iron sucrose. The secondary objective was the longitudinal investigation of calcium, 25-hydroxyvitamin D (25(OH)D), intact parathyroid hormone, procollagen type 1 amino-terminal propeptide (P1NP), beta-CrossLaps (CTX), hemoglobin (Hb), iron, ferritin, and transferrin saturation levels. Two weeks after drug administration, phosphate levels were significantly lower (p < 0.001) in group 1 and ferritin levels were significantly higher (p < 0.001) in group 1. Phosphate levels (0.8-1.45 mmol/L) were below the therapeutic threshold and ferritin levels (10-200 ng/mL for women and 30-300 ng/mL for men) were above the therapeutic threshold in group 1. P1NP (15-59 µg/L) and CTX (<0.57 ng/mL) levels were above the therapeutic threshold in group 2. Four weeks after drug administration, significant differences were still observed between both study groups for phosphate (p = 0.043) and ferritin (p = 0.0009). All serum values except for Hb were within the therapeutic thresholds. Twelve weeks after drug administration, no differences were observed in all serum values between both study groups. Hb values were within the therapeutic threshold in both study groups. Serum 25(OH)D levels did not differ between both study groups throughout the whole study period and remained within the therapeutic threshold.

Reference intervals for plasma ß-CTX and P1NP in children: A systematic review and pooled estimates.

OBJECTIVE: Reference intervals for plasma P1NP and ß-CTX in children and adolescents from several studies have recently been published. The aim of this study was to combine the available data into a set of reference intervals for use in clinical laboratories. DESIGN AND METHODS: A systematic literature search for primary studies reporting reference intervals for plasma P1NP and ß-CTX in infants, children and adolescents using the Roche methods was carried out. Reference limits were extracted. For each year of age, mean upper and lower reference limits were calculated, weighted by the number of subjects in each study, and were plotted against age. Proposed reference limits were developed from the weighted mean data with age partitions determined pragmatically. RESULTS: Reference limits for clinical use for females to 25 years and males to 18 years, based on the weighted mean reference data, are presented. Ten studies contributed to the pooled analysis. The proposed reference limits are identical for males and females <9 years age, prior to the pubertal growth spurt. For ß-CTX, the weighted mean reference limits showed relatively constant values during the pre-pubertal years but a marked increase during puberty before a rapid decline towards adult values. Those for P1NP showed high values declining rapidly in the first 2 years of life, followed by a modest increase during early puberty. Limited published information for late adolescent and young adult subjects was noted. CONCLUSIONS: The proposed reference intervals may be useful for clinical laboratories reporting these bone turnover markers measured by the Roche assays.

The efficacy of alendronate for the treatment of thalassemia-associated osteoporosis: a randomized controlled trial.

Background: With adequate blood transfusion and iron chelation, thalassemia patients have a longer life expectancy and experience long-term metabolic complications, including osteoporosis, fractures, and bone pain. Alendronate, an oral bisphosphonate, is currently used to treat various types of osteoporosis. However, the efficacy for the treatment of thalassemia-associated osteoporosis remains unclear. Methods: We conducted a randomized controlled trial to evaluate the efficacy of alendronate for the treatment of osteoporosis in thalassemia patients. Patients were included if they were males (18-50 years) or premenopausal females with low bone mineral density (BMD) (Z-score < -2.0 SD) or positive vertebral deformities from vertebral fracture analysis (VFA). Stratified randomization was performed according to sex and transfusion status. Patients were 1:1 allocated to receive once weekly alendronate 70 mg orally or placebo for a total duration of 12 months. BMD and VFA were re-evaluated at 12 months. Markers of bone resorption (C-terminal crosslinking telopeptide of type I collagen; CTX) and bone formation (Procollagen type I N-terminal propeptide; P1NP), and pain scores were measured at baseline, 6 months, and 12 months. The primary outcome was the change of BMD. The secondary endpoints were changes in bone turnover markers (BTM) and pain scores. Results: A total of 51 patients received the study drug, 28 patients were assigned to receive alendronate and 23 patients to receive placebo. At 12 months, patients in the alendronate group had significant improvement of BMD at L1-L4 compared to their baseline (0.72 ± 0.11 vs 0.69 ± 0.11 g/cm2, p = 0.004), while there was no change in the placebo group (0.69 ± 0.09 vs 0.70 ± 0.06 g/cm2, p = 0.814). There was no significant change of BMD at femoral neck in both groups. Serum BTMs were significantly decreased among patients receiving alendronate at 6 and 12 months. The mean back pain score was significantly reduced compared to the baseline in both groups (p = 0.003). Side effects were rarely found and led to a discontinuation of the study drug in 1 patient (grade 3 fatigue). Conclusion: Alendronate 70 mg orally once weekly for 12 months effectively improves BMD at L-spine, reduces serum BTMs, and alleviates back pain in thalassemia patients with osteoporosis. The treatment was well tolerated and had a good safety profile.

An Increase in Plasma Sodium Levels Is Associated With an Increase in Osteoblast Function in Chronic SIAD.

CONTEXT: Hyponatremia is associated with increased risk for osteoporosis. Preclinical studies in untreated hyponatremia suggest osteoclast upregulation, whereas a clinical study showed improved osteoblast function after hyponatremia normalization in hospitalized patients with syndrome of inappropriate antidiuresis (SIAD). OBJECTIVE: This work aimed to investigate the effect of an increase in sodium on bone turnover, that is, the ratio of the osteoblast marker procollagen type 1 N-terminal propeptide (P1NP) to the osteoclast marker cross-linked C-terminal telopeptide of type 1 collagen (CTX), in outpatients with chronic SIAD. METHODS: A predefined secondary analysis was conducted of the 2-month double-blind, crossover, placebo-controlled SANDx Trial (NCT03202667) performed from December 2017 to August 2021. Participants included 11 outpatients with chronic SIAD: 6 women, median age 73 years, who received a 4-week treatment with 25-mg empagliflozin or placebo. Main outcome measures included the relationship between the change in bone formation index (BFI), defined as P1NP/CTX, and the change in plasma sodium levels. RESULTS: Changes in sodium were positively correlated with changes in BFI and P1NP (BFI: ρ=.55; P < .001; P1NP: ρ=.45; P = .004) but not with CTX (P = .184) and osteocalcin (P = .149). A sodium increase of 1 mmol/l was associated with an increase of 5.21 in BFI (95% CI, 1.41-9.00; P = .013) and with an increase of 1.48 µg/l in P1NP (95% CI, .26-2.62; P = .03). The effect of sodium change on bone markers was independent of the study medication empagliflozin. CONCLUSION: An increase in plasma sodium levels in outpatients with chronic hyponatremia due to SIAD, even when mild, was associated with an increase in bone formation index (P1NP/CTX) triggered by an increase in P1NP, a surrogate marker of osteoblast function.

Bone turnover following high-impact exercise is not modulated by collagen supplementation in young men: A randomized cross-over trial.

INTRODUCTION: We assessed whether collagen supplementation augments the effects of high-impact exercise on bone turnover and whether a higher exercise frequency results in a greater benefit for bone metabolism. METHODS: In this randomized, cross-over trial, 14 healthy males (age 24 ± 4 y, BMI 22.0 ± 2.1 kg/m2) performed 5-min of high-impact exercise once (JUMP+PLA and JUMP+COL) or twice daily (JUMP2+COL2) during a 3-day intervention period, separated by a 10-day wash out period. One hour before every exercise bout participants ingested 20 g hydrolysed collagen (JUMP+COL and JUMP2+COL2) or a placebo control (JUMP+PLA). Blood markers of bone formation (P1NP) and resorption (CTXI) were assessed in the fasted state before the ingestion of the initial test drinks and 24, 48, and 72 h thereafter. In JUMP+PLA and JUMP+COL, additional blood samples were collected in the postprandial state at 1, 2, 3, 4, 5 and 13 h after ingestion of the test drink. RESULTS: In the postprandial state, serum P1NP concentrations decreased marginally from 99 ± 37 to 93 ± 33 ng/mL in JUMP+COL, and from 97 ± 32 to 92 ± 31 ng/mL in JUMP+PLA, with P1NP levels having returned to baseline levels after 13 h (time-effect, P = 0.053). No differences in serum P1NP concentrations were observed between JUMP+PLA and JUMP+COL (time x treatment, P = 0.58). Serum CTX-I concentrations showed a ~ 50 % decline (time, P < 0.001) in the postprandial state in JUMP+COL (0.9 ± 0.3 to 0.4 ± 0.2 ng/mL) and JUMP+PLA (0.9 ± 0.3 to 0.4 ± 0.2 ng/mL), with no differences between treatments (time x treatment, P = 0.17). Fasted serum P1NP concentrations increased ~8 % by daily jumping exercise (time-effect, P < 0.01), with no differences between treatments (time x treatment, P = 0.71). Fasted serum CTX-I concentrations did not change over time (time-effect, P = 0.41) and did not differ between treatments (time x treatment, P = 0.58). CONCLUSIONS: Five minutes of high-impact exercise performed daily stimulates bone formation during a 3-day intervention period. This was indicated by an increase in fasted serum P1NP concentrations, rather than an acute increase in post-exercise serum P1NP concentrations. Collagen supplementation or an increase in exercise frequency does not further increase serum P1NP concentrations. The bone resorption marker CTX-I was not affected by daily short-duration high-impact exercise with or without concurrent collagen supplementation.

Acarbose diminishes postprandial suppression of bone resorption in patients with type 2 diabetes.

AIMS: The alpha-glucosidase inhibitor acarbose is an antidiabetic drug delaying assimilation of carbohydrates and, thus, increasing the amount of carbohydrates in the distal parts of the intestines, which in turn increases circulating levels of the gut-derived incretin hormone glucagon-like peptide 1 (GLP-1). As GLP-1 may suppress bone resorption, acarbose has been proposed to potentiate meal-induced suppression of bone resorption. We investigated the effect of acarbose treatment on postprandial bone resorption in patients with type 2 diabetes and used the GLP-1 receptor antagonist exendin(9-39)NH2 to disclose contributory effect of acarbose-induced GLP-1 secretion. METHODS: In a randomised, placebo-controlled, double-blind, crossover study, 15 participants with metformin-treated type 2 diabetes (2 women/13 men, age 71 (57-85 years), BMI 29.7 (23.6-34.6 kg/m2), HbA1c 48 (40-74 mmol/mol)/6.5 (5.8-11.6 %) (median and range)) were subjected to two 14-day treatment periods with acarbose and placebo, respectively, separated by a six-week wash-out period. At the end of each period, circulating bone formation and resorption markers were assessed during two randomised 4-h liquid mixed meal tests (MMT) with infusions of exendin(9-39)NH2 and saline, respectively. Glucagon-like peptide 2 (GLP-2) was also assessed. RESULTS: Compared to placebo, acarbose impaired the MMT-induced suppression of CTX as assessed by baseline-subtracted area under curve (P = 0.0037) and nadir of CTX (P = 0.0128). During acarbose treatment, exendin(9-39)NH2 infusion lowered nadir of CTX compared to saline (P = 0.0344). Neither parathyroid hormone or the bone formation marker procollagen 1 intact N-terminal propeptide were affected by acarbose or GLP-1 receptor antagonism. Acarbose treatment induced a greater postprandial GLP-2 response than placebo treatment (P = 0.0479) and exendin(9-39)NH2 infusion exacerbated this (P = 0.0002). CONCLUSIONS: In patients with type 2 diabetes, treatment with acarbose reduced postprandial suppression of bone resorption. Acarbose-induced GLP-1 secretion may contribute to this phenomenon as the impairment was partially reversed by GLP-1 receptor antagonism. Also, acarbose-induced reductions in other factors reducing bone resorption, e.g. glucose-dependent insulinotropic polypeptide, may contribute.

A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis.

Background & Aims: Efruxifermin has shown clinical efficacy in patients with non-alcoholic steatohepatitis (NASH) and F1-F3 fibrosis. The primary objective of the BALANCED Cohort C was to assess the safety and tolerability of efruxifermin in patients with compensated NASH cirrhosis. Methods: Patients with NASH and stage 4 fibrosis (n = 30) were randomized 2:1 to receive efruxifermin 50 mg (n = 20) or placebo (n = 10) once-weekly for 16 weeks. The primary endpoint was safety and tolerability of efruxifermin. Secondary and exploratory endpoints included evaluation of non-invasive markers of liver injury and fibrosis, glucose and lipid metabolism, and changes in histology in a subset of patients who consented to end-of-study liver biopsy. Results: Efruxifermin was safe and well-tolerated; most adverse events (AEs) were grade 1 (n = 7, 23.3%) or grade 2 (n = 19, 63.3%). The most frequent AEs were gastrointestinal, including transient, mild to moderate diarrhea, and/or nausea. Significant improvements were noted in key markers of liver injury (alanine aminotransferase) and glucose and lipid metabolism. Sixteen-week treatment with efruxifermin was associated with significant reductions in non-invasive markers of fibrosis including Pro-C3 (least squares mean change from baseline [LSMCFB] -9 µg/L efruxifermin vs. -3.4 µg/L placebo; p = 0.0130) and ELF score (-0.4 efruxifermin vs. +0.4 placebo; p = 0.0036), with a trend towards reduced liver stiffness (LSMCFB -5.7 kPa efruxifermin vs. -1.1 kPa placebo; n.s.). Of 12 efruxifermin-treated patients with liver biopsy after 16 weeks, 4 (33%) achieved fibrosis improvement of at least one stage without worsening of NASH, while an additional 3 (25%) achieved resolution of NASH, compared to 0 of 5 placebo-treated patients. Conclusions: Efruxifermin appeared safe and well-tolerated with encouraging improvements in markers of liver injury, fibrosis, and glucose and lipid metabolism following 16 weeks of treatment, warranting confirmation in larger and longer term studies. Lay summary: Cirrhosis resulting from non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease, represents a major unmet medical need. Currently there are no approved drugs for the treatment of NASH. This proof-of-concept randomized, double-blind clinical trial demonstrated the potential therapeutic benefit of efruxifermin treatment compared to placebo in patients with cirrhosis due to NASH. Clinical Trial Number: NCT03976401.

Evaluation of preoperative procollagen type 1 N-terminal peptide and collagen type 1 C-telopeptide levels in the prediction of postoperative hypocalcemia in patients undergoing parathyroidectomy due to primary hyperparathyroidism.

PURPOSE: This study is aimed at investigating the role of preoperative procollagen type 1 N-terminal peptide (P1NP) and collagen type 1 C-telopeptide (CTx) levels in predicting the development of postoperative hypocalcemia in primary hyperparathyroidism (PHPT). METHODS: In this prospective observational study, preoperative complaints of patients with primary hyperparathyroidism and their urea, creatinine, glomerular filtration rate (GFR), calcium, albumin, urinary calcium, parathyroid hormone, and bone mineral density (BMD) were recorded. P1NP and CTx levels were analyzed in blood samples taken the day before surgery, and their relationship with calcium levels obtained on the first postoperative day was examined. RESULTS: The median age was 53 years for patients who developed hypocalcemia and 62 years for those who did not develop hypocalcemia (p = 0.01). The urea, creatinine, and GFR values were determined as 22 mcg/dl, 0.61 mcg/dl, and 105 ml/min, respectively, for the hypocalcemia group (Group 1) and 30.5 mcg/dl, 0.74 mcg/dl, and 90 ml/min, respectively, for the non-hypocalcemia group (Group 2) (p = 0.02, 0.001, and 0.01, respectively). The BMD femur Z-score was - 0.1 in Group 1 and 0.8 in the Group 2 (p = 0.02). The mean CTx values were 4.14 pg/dl and 1.98 pg/dl (p = 0.036), and the mean P1NP values were 252.84 mcg/dl and 269.04 mcg/dl (p = 0.427) for Groups 1 and 2, respectively. According to multivariate analysis, only CTx was a significant independent predictor of hypocalcemia (odds ratio 1.739). CONCLUSION: CTx level is a significant factor in predicting the risk of developing early postoperative hypocalcemia in patients scheduled for surgery due to primary hyperparathyroidism.

Reversing the imbalance in bone homeostasis via sustained release of SIRT-1 agonist to promote bone healing under osteoporotic condition.

The imbalance of bone homeostasis is the root cause of osteoporosis. However current therapeutic approaches mainly focus on either anabolic or catabolic pathways, which often fail to turn the imbalanced bone metabolism around. Herein we reported that a SIRT-1 agonist mediated molecular therapeutic strategy to reverse the imbalance in bone homeostasis by simultaneously regulating osteogenesis and osteoclastogenesis via locally sustained release of SRT2104 from mineral coated acellular matrix microparticles. Immobilization of SRT2104 on mineral coating (MAM/SRT) harnessing their electrostatic interactions resulted in sustained release of SIRT-1 agonist for over 30 days. MAM/SRT not only enhanced osteogenic differentiation and mineralization, but also attenuated the formation and function of excessive osteoclasts via integrating multiple vital upstream signals (ß-catenin, FoxOs, Runx2, NFATc1, etc.) in vitro. Osteoporosis animal model also validated that it accelerated osteoporotic bone healing and improved osseointegration of the surrounding bone. Overall, our work proposes a promising strategy to treat osteoporotic bone defects by reversing the imbalance in bone homeostasis using designated small molecule drug delivery systems.

Peptide modified geniposidic acid targets bone and effectively promotes osteogenesis.

Background: Geniposidic acid (GPA), one of the active components of Eucommia ulmoides, promote bone formation and treat osteoporosis by activating farnesoid X receptor (FXR). However, GPA has low oral availability and lack of bone targeting in the treatment of bone related diseases. With the development of modern technology, small molecules, amino acids, or aptamers are used for biological modification of drugs and target cells in bone tissue, which has become the trend of bone targeted research. Methods: In this study, SDSSD (an osteoblast-targeting peptide) were modified in GPA using Fmoc solid-phase synthesis technique to form a new SDSSD-GPA conjugate (SGPA). The bone targeting of SGPA was evaluated using in vivo imaging and cell co-culture. In vitro, the effect of SGPA on cytotoxicity, osteoblastic activity, and mineralization ability were studied in mouse primary osteoblasts (OBs). In vivo, the therapeutic effect of SGPA on osteoporosis using an ovariectomized (OVX) mouse model. The bone mass, histomorphometry, serum biochemical parameters, and the molecular mechanism were evaluated. Results: SGPA was enriched in OBs and tends to accumulate in bone tissue. In vitro, SGPA significantly enhanced the osteogenic activity and mineralization of OBs compared with GPA. In vivo, SGPA enhanced serum BALP and P1NP levels, increased the trabecular bone mass of the mice, and SGPA administration have a higher bone mineralization deposition rate than the GPA-treated mice. Moreover, SGPA significantly activated FXR and Runt-related transcription factor 2 (RUNX2). Conclusions: Collectively, SGPA is enriched into OBs, and promotes bone formation by activating FXR-RUNX2 signalling, effectively treating osteoporosis at relatively low doses. The translational potential of this article: This study demonstrates a more efficient and safe application of GPA in treating osteoporosis, provide a new concept for the bone targeted application of natural compounds.

The prevalence and treatment of osteoporosis in patients undergoing total hip arthroplasty and the levels of biochemical markers of bone turnover.

AIMS: Osteoporosis is common in total hip arthroplasty (THA) patients. It plays a substantial factor in the surgery's outcome, and previous studies have revealed that pharmacological treatment for osteoporosis influences implant survival rate. The purpose of this study was to examine the prevalence of and treatment rates for osteoporosis prior to THA, and to explore differences in osteoporosis-related biomarkers between patients treated and untreated for osteoporosis. METHODS: This single-centre retrospective study included 398 hip joints of patients who underwent THA. Using medical records, we examined preoperative bone mineral density measures of the hip and lumbar spine using dual energy X-ray absorptiometry (DXA) scans and the medications used to treat osteoporosis at the time of admission. We also assessed the following osteoporosis-related biomarkers: tartrate-resistant acid phosphatase 5b (TRACP-5b); total procollagen type 1 amino-terminal propeptide (total P1NP); intact parathyroid hormone; and homocysteine. RESULTS: The prevalence of DXA-proven hip osteoporosis (T-score ≤ -2.5) among THA patients was 8.8% (35 of 398). The spinal osteoporosis prevalence rate was 4.5% (18 of 398), and 244 patients (61.3%; 244 of 398) had osteopenia (-2.5 < T-score ≤ -1) or osteoporosis of either the hip or spine. The rate of pharmacological osteoporosis treatment was 22.1% (88 of 398). TRACP-5b was significantly lower in the osteoporosis-treated group than in the untreated group (p < 0.001). CONCLUSION: Osteoporosis is common in patients undergoing THA, but the diagnosis and treatment for osteoporosis were insufficient. The lower TRACP-5b levels in the osteoporosis-treated group - that is, osteoclast suppression - may contribute to the reduction of the postoperative revision rate after THA.Cite this article: Bone Joint Res 2022;11(12):873-880.