Bone Turnover Marker for the Evaluation of Skeletal Remodelling in Autosomal Recessive Osteopetrosis after Haematopoietic Stem Cell Transplantation: A Case Report.

Background: Autosomal recessive osteopetrosis (ARO) is a rare genetic disorder of bone metabolism, primarily affecting the remodelling function of osteoclasts. Haematopoietic stem cell transplantation (HSCT) is the first-line treatment for ARO. Traditional tools for the assessment of therapeutic response, such as measuring donor chimerism, do not provide information on bone remodelling. The use of bone turnover markers (BTMs) might be ideal. Here, we report a case of a paediatric ARO patient undergoing successful HSCT. Methods: For the evaluation of donor-derived osteoclast activity and skeletal remodelling throughout the transplantation, the bone resorption marker ß-CTX (ß-C-terminal telopeptide) was used. Results: The low baseline level of ß-CTX markedly increased after transplantation and remained in the elevated range even after 3 months. Donor-derived osteoclast activity reached its new baseline level around the 50th percentile range after 5 months and proved to be stable during the 15-month follow-up time. The apparent increase of the baseline osteoclast activity after HSCT was in consonance with the radiographic improvement of the disease phenotype and the correction of bone metabolic parameters. Despite the successful donor-derived osteoclast recovery, craniosynostosis developed, and reconstructive surgery had to be performed. Conclusions: The use of ß-CTX may be of aid in assessing osteoclast activity throughout the transplantation. Further studies could help to establish the extended BTM profile of ARO patients using the available osteoclast- and osteoblast-specific markers.

Changes in bone turnover markers in patients without bone metastases receiving immune checkpoint inhibitors: An exploratory analysis.

Immune checkpoint inhibitors (ICIs) has revolutionized the treatment of different advanced solid tumors, but most patients develop severe immune-related adverse events (irAEs). Although a bi-directional crosstalk between bone and immune systems is widely described, the effect of ICIs on the skeleton is poorly investigated. Here, we analyze the changes in plasma levels of type I collagen C-terminal telopeptide (CTX-I) and N-terminal propeptide of type I procollagen (PINP), reference makers of bone turnover, in patients treated with ICIs and their association with clinical outcome. A series of 44 patients affected by advanced non-small cell lung cancer or renal cell carcinoma, without bone metastases, and treated with ICIs as monotherapy were enrolled. CTX-I and PINP plasma levels were assessed at baseline and after 3 months of ICIs treatment by ELISA kits. A significant increase of CTX-I with a concomitant decreasing trend towards the reduction of PINP was observed after 3 months of treatment. Intriguingly, CTX-I increase was associated with poor prognosis in terms of treatment response and survival. These data suggest a direct relationship between ICIs treatment, increased osteoclast activity and potential fracture risk. Overall, this study reveals that ICIs may act as triggers for skeletal events, and if confirmed in larger prospective studies, it would identify a new class of skeletal-related irAEs.

3-Hydroxybutyrate administration elevates plasma parathyroid hormone in a pilot human randomized, controlled, cross over trial.

CONTENT: Ketone bodies, in particular 3-hydroxybutyrate (3OHB), are known to possess important energetic and signaling capacities. There is a growing block of evidence, that ketogenic dieting (KD), fasting, and sodium glucose transporter 2 inhibitor (SGLT2i) treatment are associated with hyperparathyroidism and negative bone health. OBJECTIVE: We aimed to study the effect of exogenous 3OHB administration on bone metabolism, specifically the effect on parathyroid hormone (PTH) and calcium/phosphate homeostasis. DESIGN: A randomized, controlled, cross over study with two arms: i) saline infusion and ii) 3OHB infusion. SETTING: The study was conducted at Aarhus University Hospital. PARTICIPANTS: We examined eight healthy human subjects aged 50-70 years. INTERVENTION: Continuous intravenous DL-3OHB-NaCl infusion or 0.9% NaCl was administered for 390 min. MAIN OUTCOME MEASURES: The study was designed to test the impact of 3OHB on PTH, calcium-phosphate, C-terminal Telopeptide (CTX), and Procollagen I N-terminal Propeptide (PINP). The study was a post hoc study. RESULTS: The PTH concentration increased by 25% with a concomitant drop in phosphate of 30% in the 3OHB group. 3OHB infusion increased concentrations of CTX by 5%, without changes in PINP and albumin corrected calcium concentrations. CONCLUSION: In conclusion, 3OHB administration increases PTH concentration and markers of bone resorption. These findings suggest a possible negative effect on bone health, which needs to be determined in future studies.

Influence of receptor activator of nuclear factor kappa B ligand, osteoprotegerin and interleukin-33 on bone metabolism in patients with long-standing ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic disease with periods of remission and recurrences. Dysfunction of the local immune response leads to chronic inflammation within the large intestine which triggers morphological changes in the intestinal wall as well as induces the synthesis of numerous factors that have an adverse impact on the bone metabolism. The aim of the study was to determine the expression of RANKL, OPG and IL-33 in mucosal biopsies of UC patients with long disease duration as well as serum level of these cytokines in the context of bone density and bone metabolism. MATERIALS AND METHODS: The UC group consisted of 56 patients with average disease duration of 16y. The control group comprised 37 healthy individuals. Local expression of cytokines was assessed in the biopsies of colonic mucosa by the real-time PCR and immunohistochemistry (IHC), and their serum concentration was measured by ELISA. RESULTS: The increased bone resorption observed in patients with UC was reflected by low bone density and high serum level of C-terminal telopeptide (CTX). Mucosal RANKL expression and serum concentration were similar in UC group and healthy subjects, however, UC patients had higher local expression of OPG and serum OPG concentration. Increased IL-33 gene expression was observed only in UC at the mRNA level. We propose that bone resorption in UC patients despite OPG up-regulation could be caused by IL-33-induced mucosal synthesis of a potent proinflammatory cytokine, such as TNF-α, known as a possible inducer of osteoclastogenesis in the way independent of RANKL.