ERN BOND: The key European network leveraging diagnosis, research, and treatment for rare bone conditions.

There is no universally accepted definition for rare diseases: in Europe a disease is considered to be rare when affecting fewer than 1 in 2000 people. European Reference Networks (ERNs) have been the concrete response to address the unmet needs of rare disease patients and many pan-European issues in the field, reducing inequities, and significantly increasing accessibility to high-quality healthcare across Europe. ERNs are virtual networks, involving centres and patient representatives with the general scope to facilitate discussion on complex cases requiring highly specialised competences and trained expertise. ERN BOND - the European Reference Network on rare BONe Diseases - is one of these 24 approved networks with the specific ongoing mission to implement measures facilitating multidisciplinary, holistic, continuous, patient-centred, and participative care provision to patients, and supporting them in the full realisation of their fundamental human rights. ERN BOND includes in 2023 a total of 53 centres of expertise from 20 European countries. Its governing structure installed in March 2017 includes decision-making, operative and consultative committees, which comprise experts in the field and patient representatives ensuring patient's voice and perspectives are taken into account. Over the years, ERN BOND has worked hard to achieve its mission and valuably contribute to the advancement of diagnosis, management, treatment, and research in rare diseases. The network activities are mainly related to (i) the provision of care which collectively involves averagely 2800 patients diagnosed per year, (ii) the development of education for and training of the healthcare personnel consisting until now in the realisation of 7 thematic workshops and 19 webinars, (iii) the dissemination and exchange and spread of knowledge via network's website (https://ernbond.eu/), social media channels, and newsletters, (iv) the management of related data through a disease registry currently mapping over 2300 cases and recording over 600 reported cases, and (v) the enhancement of research which now include two clinical trials endorsed by the network. ERN BOND represents therefore an unprecedented move to improve the healthcare management of patients suffering from rare bone diseases through European collaborations. This network, through the support from the European Health Programme, will continue to pursue its efforts to achieve its goals, always maintaining the patients and their families at the centre of healthcare services.

Low wintertime pre-diagnostic vitamin D status is associated with an increased risk of internal malignancies in kidney transplant recipients.

Low serum 25-hydroxyvitamin D (25OHD) concentrations have been associated with increased cancer risk, but the relative importance of seasonality, i.e. high summer concentrations versus low winter concentrations, is unclear. We investigated this issue in a high risk group: kidney transplant recipients with known increased risk of cancer and low vitamin D statuses. We examined the relationship between registered concentrations of 25OHD binned by quarter and subsequent risk of internal malignancy or cutaneous squamous cell carcinoma in 1112 kidney transplant recipients. Hazard ratios for internal malignancies were significantly increased with lower pre-diagnostic 25OHD concentrations in the first quarter of the year (January-March); a 1.4 fold increase (95%CI 1.1;1.7) per 10 nmol L-1 decrease in 25OHD. Except for women in April-June (1.3 (1.01;1.7) per 10 nmol L-1 decrease) pre-diagnostic 25OHD concentrations in the other quarters were not statistically significantly associated with internal malignancies. Higher 25OHD concentrations tended to be associated with the development of cutaneous squamous cell carcinomas, independent of the time of the year. Our study indicates that low wintertime 25OHD concentrations are associated with an increased risk of internal malignancies and that transplant recipients may benefit from wintertime vitamin D supplementation. Our findings need further corroboration, but suggest that the lowest concentrations of vitamin D, which occur in winter, are important for the risk of internal malignancies.

Effects of up to 15 years of recombinant human GH (rhGH) replacement on bone metabolism in adults with growth hormone deficiency (GHD): the Leiden Cohort Study.

BACKGROUND: Growth hormone deficiency (GHD) in adulthood may be associated with a decreased bone mineral density (BMD), a decreased bone mineral content (BMC) and an increased fracture risk. Recombinant human GH (rhGH) replacement induces a progressive increase in BMD for up to 5-7 years of treatment. Data on longer follow-up are, however, scarce. METHODS: Two hundred and thirty-adult GHD patients (mean age 47·1 years, 52·6% female), of whom 88% patients had adult-onset (AO) GHD, receiving rhGH replacement for ≥5 years were included in the study. Most patients had multiple pituitary hormone deficiencies. Bone turnover markers, BMC and BMD and T-scores at the lumbar spine and femoral neck were evaluated at baseline, and after 5, 10 and 15 years of rhGH replacement. In addition, clinical fracture incidence was assessed. RESULTS: Mean lumbar spine BMD, lumbar spine BMC and T-scores gradually increased during the first 10 years of rhGH replacement and remained stable thereafter. Largest effects of rhGH supplementation were found in men. In the small subset of patients using bisphosphonates, use of bisphosphonates did not impact additional beneficial effects in the long term. Low baseline BMD positively affected the change in BMD and BMC over time, but there was a negative effect of high GH dose at 1 year on the change in BMD and BMC over time. Clinical fracture incidence during long-term rhGH replacement was 20.1/1000 py. CONCLUSIONS: Fifteen years of rhGH replacement in GHD adults resulted in a sustained increase in BMD values at the lumbar spine, particularly in men, and stabilization of BMD values at the femoral neck. Clinical fracture incidence was suggested not to be increased during long-term rhGH replacement.

The role of vitamin D in human fracture healing: a systematic review of the literature.

INTRODUCTION: Vitamin D is essential for bone mineralization and for the subsequent maintenance of bone quality. Mineralization is part of hard callus formation and bone remodelling, processes, which are part of fracture healing. We provide a comprehensive review of the literature to summarize and clarify if possible, the cellular effects of vitamin D and its clinical involvement in the process of fracture healing in human. MATERIAL AND METHODS: We conducted a literature search in PubMed, Embase (OVID version), and Web of Science. RESULTS: A total of 75 in vitro and 30 in vivo studies were found with inconsistent results about the cellular effect of vitamin D on fracture involved inflammatory cells, cytokines, growth factors, osteoblasts, osteoclasts and on the process of mineralization. With only five in vitro studies performed on material derived from a fracture site and one in vivo study in fracture patients, the exact cellular role remains unclear. Seven studies investigated the circulating vitamin D metabolites in fracture healing. Although it appears that 25(OH)D and 24,25(OH)2D3 are not affected by the occurrence of a fracture, this might not be the case with serum concentrations of 1,25(OH)2D3. The potential clinical effect of vitamin D deficiency is only described in one case series and three case controlled studies, where the results tend to show no effect of a vitamin D deficiency. No clinical studies were found investigating solely vitamin D supplementation. Two clinical studies found a positive effect of vitamin D supplementation and calcium, of increased bone mineral density or respectively increased fracture callus area at the fracture site. One study found indirect evidence that vitamin D and calcium promoted fracture healing. CONCLUSION: Despite these results, and the presumed beneficial effect of vitamin D supplementation in deficient patients, clinical studies that address the effects of vitamin D deficiency or supplementation on fracture healing are scarce and remain inconclusive. We conclude that vitamin D has a role in fracture healing, but the available data are too inconsistent to elucidate how and in what manner.

Absorption of the oral bisphosphonate alendronate in osteoporotic patients with Crohn's disease.

The absorption of bisphosphonates from the gut is poor. The question arises whether the absorption of alendronate, and thus its bioavailability, is further altered by the local inflammatory process in patients with Crohn's disease, thereby potentially affecting clinical outcome when used in the treatment of osteoporosis. To address this question, urinary excretion of alendronate was evaluated 3 months and 6 months after start of treatment with oral alendronate at a dose of 10 mg/day in 19 osteoporotic patients with stable Crohn's disease, 12 of whom had an intestinal resection. Biochemical parameters of bone turnover and BMD were also measured at start and at 6 months. Thirteen patients had been previously treated with glucocorticoids and five were currently using them. The average 24-h urinary excretion of alendronate was 0.5-0.6% of the dose administered, a figure comparable to that reported for osteoporotic patients without gut pathology. There was a significant decrease from baseline in urine N-telopeptides of collagen cross-links (NTx)/creatinine (60%) associated with an increase in lumbar spine BMD of already 2% after 6 months of treatment. Our data suggest that in patients with Crohn's disease, alendronate is adequately absorbed from the intestine and retained in the skeleton. This adequacy is confirmed by appropriate suppression of bone resorption and increase in lumbar spine BMD. These data hold significant implications for the clinical management of patients with Crohn's disease and osteoporosis.