Disease Manifestations and Complications in Dutch X-Linked Hypophosphatemia Patients.

X-linked hypophosphatemia (XLH) is the most common monogenetic cause of chronic hypophosphatemia, characterized by rickets and osteomalacia. Disease manifestations and treatment of XLH patients in the Netherlands are currently unknown. Characteristics of XLH patients participating in the Dutch observational registry for genetic hypophosphatemia and acquired renal phosphate wasting were analyzed. Eighty XLH patients, including 29 children, were included. Genetic testing, performed in 78.8% of patients, showed a PHEX mutation in 96.8%. Median (range) Z-score for height was - 2.5 (- 5.5; 1.0) in adults and - 1.4 (- 3.7; 1.0) in children. Many patients were overweight or obese: 64.3% of adults and 37.0% of children. All children received XLH-related medication e.g., active vitamin D, phosphate supplementation or burosumab, while 8 adults used no medication. Lower age at start of XLH-related treatment was associated with higher height at inclusion. Hearing loss was reported in 6.9% of children and 31.4% of adults. Knee deformities were observed in 75.0% of all patients and osteoarthritis in 51.0% of adult patients. Nephrocalcinosis was observed in 62.1% of children and 33.3% of adults. Earlier start of XLH-related treatment was associated with higher risk of nephrocalcinosis and detection at younger age. Hyperparathyroidism longer than six months was reported in 37.9% of children and 35.3% of adults. This nationwide study confirms the high prevalence of adiposity, hearing loss, bone deformities, osteoarthritis, nephrocalcinosis and hyperparathyroidism in Dutch XLH patients. Early start of XLH-related treatment appears to be beneficial for longitudinal growth but may increase development of nephrocalcinosis.

Bone material strength index as measured by in vivo impact microindentation is normal in subjects with high-energy trauma fractures.

Bone material properties were assessed using impact microindentation in patients with high-energy trauma fractures. Compared to patients with low-energy trauma fractures, bone material strength index was significantly higher in patients with high-energy trauma fractures, and did not differ between patients with osteopenia and those with osteoporosis within each trauma group. INTRODUCTION: Impact microindentation (IMI) is a technique to assess tissue-level properties of bone at the tibia. Bone material strength index (BMSi), measured by IMI, is decreased in patients with low-energy trauma fractures, independently of areal bone mineral density (aBMD), but there is no information about BMSi in patients with high-energy trauma fractures. In the present study, we evaluated tissue-level properties of bone with IMI in patients with high-energy trauma fractures. METHODS: BMSi was measured 3.0 months (IQR 2.0-5.8) after the fracture in 40 patients with high-energy trauma and 40 age- and gender-matched controls with low-energy trauma fractures using the OsteoProbe® device. RESULTS: Mean age of high- and low-energy trauma patients was 57.7 ± 9.1 and 57.2 ± 7.7 years, respectively (p = 0.78). Fracture types were comparable in high- vs low-energy trauma patients. Lumbar spine (LS)-aBMD, but not femoral neck (FN)-aBMD, was higher in high- than in low-energy trauma patients (LS 0.96 ± 0.13 vs 0.89 ± 0.13 g/cm2, p = 0.02; FN 0.75 ± 0.09 vs 0.72 ± 0.09 g/cm2, p = 0.09). BMSi was significantly higher in high- than in low-energy trauma patients (84.4 ± 5.0 vs 78.0 ± 4.6, p = 0.001), also after adjusting for aBMD (p = 0.003). In addition, BMSi did not differ between patients with osteopenia and those with osteoporosis within each trauma group. CONCLUSION: Our data demonstrate that BMSi and LS-aBMD, but not FN-aBMD, are significantly higher in high-energy trauma patients compared to matched controls with similar fractures from low-energy trauma. Further studies of non-osteoporotic patients with high-energy trauma fracture with measurements of BMSi are warranted to determine whether IMI might help in identifying those with reduced bone strength.

Extent of Extraskeletal Manifestations of Fibrous Dysplasia/McCune-Albright Syndrome in Patients with Mazabraud's Syndrome.

Mazabraud's syndrome (MZB) is a rare condition in which fibrous dysplasia of bone/the McCune-Albright syndrome (FD/MAS) co-exists with intramuscular myxomas. Both FD and the myxomas harbor the GNAS-mutation. Recent studies have shown that extraskeletal, GNAS-related features are associated with a more severe phenotype of FD/MAS. However, patients with MZB are often only seen by orthopedic surgeons. We therefore evaluated MZB patients seen in tertiary referral centers from the Netherlands (LUMC), USA (National Institutes of Health) and France (INSERM UMR 1033 (Lyos), Hôpital Edouard Herriot). All FD/MAS patients known in these centers with an additional diagnosis of a myxoma were included. Demographic information and data on disease extent and extraskeletal manifestations of FD/MAS such as precocious puberty (PP) or café-au-lait patches (CAL) were retrieved from patient's medical records. Thirty MZB patients were included: 20 women (67%) and 10 men (33%). Patients received a diagnosis of MZB (median 42 years, range 16-19) significantly later than the diagnosis of FD/MAS (median 30 years, range 0-60), p < 0.01. Twenty-six patients were diagnosed with polyostotic disease (87%). In 97% the myxoma was located near the skeletal FD lesion. The combination of MZB and MAS was made in 13 patients in whom PP (n = 7), CAL (n = 7), GH-excess (n = 3) and hyperthyroidism (n = 3) were present. Other extraskeletal features were (multinodular) goiter (n = 2) and thyroid cysts (n = 1). Furthermore, in this cohort of patients with MZB several (pre-)malignant tumors were observed; ductal carcinoma in situ of the breast in 3 patients (10%), breast cancer in 1 patient (3.3%), intra pancreatic mucinous neoplasms in 3 patients (10%) and liver adenomas in 2 patients (6.6%). A total of 47% of patients with MZB had an additional extraskeletal feature such as an endocrinopathy. In MZB, 87% of patients suffer from polyostotic FD, 43% of patients have extraskeletal GNAS-features such as an hyperfunctioning endocrinopathy and 30% (pre-)malignant tumors. We therefore advocate that MZB patients should undergo a complete screening and long-term follow-up for extent of bone disease, but also extraskeletal GNAS features of FD/MAS.

Increased Prevalence of Malignancies in Fibrous Dysplasia/McCune-Albright Syndrome (FD/MAS): Data from a National Referral Center and the Dutch National Pathology Registry (PALGA).

Malignant transformation of fibrous dysplasia lesions has been reported in patients with fibrous dysplasia/McCune-Albright syndrome (FD/MAS). Recently, we have observed an increased risk for breast cancer. In this study, the prevalence of skeletal and extraskeletal malignancies in patients with FD/MAS in the Netherlands was assessed by analyzing data from our cohort of FD/MAS patients, the Dutch Pathology Registry (PALGA), and the Netherlands Cancer Registry (NCR). We extracted data on sex, age at diagnosis of FD/MAS, type of FD/MAS, type of malignancy, and age at diagnosis of malignancy and histology of bone and malignant tissue when available, including GNAS-mutation analysis from patients' medical records. Standardized Morbidity Ratios (SMRs) with 95% confidence intervals were calculated. Twelve malignancies were identified in the LUMC FD/MAS cohort and 100 in the PALGA cohort. In this cohort, SMR was increased for osteosarcoma (19.7, 95% CI 3.5-48.9), cervical cancer (4.93, 95%CI 1.7-8.2), thyroid cancer (3.71, 95% CI 1.1-7.8), prostate cancer (3.08, 95% CI 1.8-4.6), and melanoma (2.01, 95%CI 1.2-3.1). SMRs for pancreatic cancer or hepatocellular carcinoma could not be calculated due to low numbers. The small number of malignancies identified in our FD/MAS cohort precluded the calculation of SMRs for our cohort specifically. Our findings show that patients with FD/MAS appear to have an increased risk for osteosarcoma, cervical, thyroid, and prostate cancer and melanoma. However, these data should be interpreted with caution, as true incidence rates of the identified malignancies may be influenced by the inclusion of only patients with histologically confirmed FD/MAS. The etiology of this increased risk for malignancies still needs to be elucidated.

The Polygenic and Monogenic Basis of Paediatric Fractures.

PURPOSE OF REVIEW: Fractures are frequently encountered in paediatric practice. Although recurrent fractures in children usually unveil a monogenic syndrome, paediatric fracture risk could be shaped by the individual genetic background influencing the acquisition of bone mineral density, and therefore, the skeletal fragility as shown in adults. Here, we examine paediatric fractures from the perspective of monogenic and complex trait genetics. RECENT FINDINGS: Large-scale genome-wide studies in children have identified ~44 genetic loci associated with fracture or bone traits whereas ~35 monogenic diseases characterized by paediatric fractures have been described. Genetic variation can predispose to paediatric fractures through monogenic risk variants with a large effect and polygenic risk involving many variants of small effects. Studying genetic factors influencing peak bone attainment might help in identifying individuals at higher risk of developing early-onset osteoporosis and discovering drug targets to be used as bone restorative pharmacotherapies to prevent, or even reverse, bone loss later in life.

Treatments of osteoporosis increase bone material strength index in patients with low bone mass.

Effects on bone material properties of two-year antiosteoporotic treatment were assessed using in vivo impact microindentation (IMI) in patients with low bone mineral density (BMD) values. Antiresorptive treatment, in contrast to vitamin D ± calcium treatment alone, induced BMD-independent increases in bone material strength index, measured by IMI, the magnitude of which depended on pretreatment values. INTRODUCTION: Bone material strength index (BMSi), measured by IMI in vivo, is reduced in patients with fragility fractures, but there is no information about changes in values during long-term therapy. In the present study, we assessed changes in BMSi in patients receiving antiosteoporotic treatments for periods longer than 12 months. METHODS: We included treatment-naive patients with low bone mass who had a BMSi measurement with OsteoProbe® at presentation and consented to a repeat measurement after treatment. RESULTS: We studied 54 patients (34 women), median age 58 years, of whom 30 were treated with bisphosphonates or denosumab (treatment group) and 24 with vitamin D ± calcium alone (control group). There were no differences in clinical characteristics between the two groups with the exception of a higher number of previous fragility fractures in the treatment group. Baseline hip BMD and BMSi values were lower in the treatment group. After 23.1 ± 6.6 months, BMSi increased significantly in the treatment group (82.4 ± 4.3 vs 79.3 ± 4.1; p < 0.001), but did not change in the control group (81.5 ± 5.2 vs 82.2 ± 4.1; p = 0.35). Changes in BMSi with antiresorptives were inversely related with baseline values (r = - 0.43; p = 0.02) but not with changes in BMD. Two patients in the control group with large decreases in BMSi values sustained incident fractures. CONCLUSION: In patients at increased fracture risk, antiresorptive treatments induced BMD-independent increases in BMSi values, the magnitude of which depended on pretreatment values.

Parathyroidectomy versus cinacalcet for tertiary hyperparathyroidism; a retrospective analysis.

INTRODUCTION: Tertiary hyperparathyroidism (tHPT), i.e., persistent HPT after kidney transplantation, affects 17-50% of transplant recipients. Treatment of tHPT is mandatory since persistently elevated PTH concentrations after KTx increase the risk of renal allograft dysfunction and osteoporosis. The introduction of cinacalcet in 2004 seemed to offer a medical treatment alternative to parathyroidectomy (PTx). However, the optimal management of tHPT remains unclear. METHODS: A retrospective analysis was performed on patients receiving a kidney transplantation (KT) in two academic centers in the Netherlands. Thirty patients undergoing PTx within 3 years of transplantation and 64 patients treated with cinacalcet 1 year after transplantation for tHPT were included. Primary outcomes were serum calcium and PTH concentrations 1 year after KT and after PTx. RESULTS: Serum calcium normalized in both the cinacalcet and the PTx patients. PTH concentrations remained above the upper limit of normal (median 22.0 pmol/L) 1 year after KT, but returned to within the normal range in the PTx group (median 3.7 pmol/L). Side effects of cinacalcet were difficult to assess; minor complications occurred in three patients. Re-exploration due to persistent tHPT was performed in three (10%) patients. CONCLUSION: In patients with tHPT, cinacalcet normalizes serum calcium, but does not lead to a normalization of serum PTH concentrations. In contrast, PTx leads to a normalization of both serum calcium and PTH concentrations. These findings suggest that PTx is the treatment of choice for tHPT.

Illness Perceptions are Associated with Quality of Life in Patients with Fibrous Dysplasia.

Fibrous dysplasia (FD) is a rare bone disorder in which normal bone is replaced by fibrous tissue resulting in pain, deformities, pathological fractures or asymptomatic disease. Illness perceptions are patients' cognitions and emotions about their illness and its treatment, which may impact on Quality of Life (QoL). Here, we explore illness perceptions in patients with FD compared to other disorders, identify factors associated with illness perceptions and evaluate their relationship with QoL. Ninety-seven out of 138 eligible patients from the LUMC FD cohort completed the Illness Perception Questionnaire-Revised (IPQ-R) and the Short Form-36 (SF-36). Age, Gender, Skeletal Burden Score (SBS), FGF-23 levels, type of FD and SF-36 scores were analysed for an association with illness perceptions. We observed significant (p < 0.01) differences in patients' illness perceptions between FD subtypes in the domains: identity, timeline acute/chronic and consequences. Patients with craniofacial FD reported to perceive more consequences (p = 0.022). High SBS was associated with perceiving more negative consequences and attributing the cause of FD to psychological factors (p < 0.01), and high FGF-23 levels with attributing more symptoms to the disease and perceiving more consequences (p < 0.01). The IPQ-R domain identity, timeline acute/chronic, timeline cyclical, consequences, emotional representations and treatment control were significantly associated with impairments in QoL. Illness perceptions in patients with FD relate to QoL, differ from those in patients with other disorders, and are associated with disease severity. Identifying and addressing maladaptive illness perceptions may improve quality of life in patients with FD.

Passive Coping Strategies Are Associated With More Impairment In Quality Of Life In Patients With Fibrous Dysplasia.

Impairments in quality of life (QoL) have been reported in patients with fibrous dysplasia (FD). Here, we examine coping strategies in FD and assess whether these coping strategies are associated with QoL and disease severity. Ninety-two patients (66% females) filled out the Utrecht Coping List (UCL), Short Form-36, and the Brief Pain Inventory (BPI). Coping strategies of patients with FD were compared with reference data from a random sample of Dutch women and patients with chronic pain. Compared to healthy adults, patients expressed more emotions (p < 0.01). Compared to patients with chronic pain, patients with FD used more active coping strategies (p < 0.001), and sought more distraction (p = 0.01) and more social support (p < 0.001). Using more passive coping strategies was associated with more impairment in social function, physical role, mental health, vitality (all p < 0.001), and general health (p < 0.01). Using more avoidant coping strategies was associated with worse mental health and less vitality (both p < 0.01). More expression of emotions was associated with worse mental health (p < 0.01). Type and clinical severity of FD were not associated with coping behavior. Patients with FD have different coping strategies compared to random Dutch reference populations with or without pain. In FD, using more passive coping strategies was associated with more impairment in several aspects of QoL. There was no relationship between coping behavior and clinical characteristics, pointing to biomedical variables not determining the way patients cope with their illness. Recognition of less effective coping strategies can be helpful in the understanding and adaptation of these coping strategies, improving personalized clinical care, with the ultimate goal to improve QoL in patients with FD.

Bone material strength index as measured by impact microindentation is low in patients with fractures irrespective of fracture site.

We evaluated the relationship between bone material strength index (BMSi) and fragility fractures, including vertebral fractures. Our data showed that BMSi is low in all fracture patients with low bone mass, independently of whether patients sustained a vertebral or a non-vertebral fracture. INTRODUCTION: Impact microindentation (IMI) is a new technique for the measurement of tissue level properties of cortical bone in vivo. Previous studies showed an association between BMSi and non-vertebral fractures, but an association with vertebral fractures is still being debated. The objective of this paper was to evaluate the relationship between BMSi and different types of fragility fractures, including vertebral fractures. METHODS: In this cross-sectional study, we measured BMSi in patients of both sexes with different types of fragility fractures and low bone mass with the IMI method using the Osteoprobe®. Vertebral fractures were diagnosed and graded on lateral spine radiographs. RESULTS: A total of 132 patients were included in the study, of whom 101 patients (65 women) had sustained a low energy fracture and 31 (mean age 57.7 ± 9.9 years) had no history or radiological evidence for a fracture. Of the fracture patients, 53 (mean age 62.8 ± 8.3 years) had only non-vertebral fractures (VF-/Fx+), 34 (mean age 62.8 ± 9.9 years) had vertebral and non-vertebral fractures (VF+/Fx+), and 14 (mean age 64.7 ± 9.3 years) had only vertebral fractures (VF+/Fx-). BMSi values, adjusted for age and BMD, were similar for all three groups of fracture patients (78.9 ± 0.7, 78.3 ± 0.9, and 78.4 ± 1.4, respectively; p = 0.866). BMSi values were not associated with number or severity of vertebral fractures. CONCLUSION: Our data demonstrate that BMSi is low in fracture patients with low bone mass, irrespective of whether they sustained a vertebral fracture or a non-vertebral fracture.

Value and potential limitations of vertebral fracture assessment (VFA) compared to conventional spine radiography: experience from a fracture liaison service (FLS) and a meta-analysis.

We evaluated the value of VFA in the identification of vertebral fractures using a retrospective study and a meta-analysis. Performance of VFA was adequate in the meta-analysis although this was not demonstrated in our centre. We recommend checking the performance of VFA tools before exclusively relying on this tool. INTRODUCTION: Vertebral fractures are traditionally diagnosed using conventional radiographs of the spine. Vertebral fracture assessment (VFA) has been advocated as an alternative tool in the diagnosis of these fractures. METHODS: We conducted a retrospective study as well as a systematic review and a meta-analysis to evaluate the performance of VFA compared to conventional spinal radiography in patients who had sustained a fracture and thus at risk for osteoporosis. A risk of bias analysis was also performed. RESULTS: The diagnostic study included 542 patients (25% male) with fractures. The sensitivity of low-radiation VFA to detect a patient with a vertebral fracture ≥ Genant grade 2 was 0.77 and its specificity 0.80. Two hundred ninety-seven (55%) patients had ≥1 and 135(25%) ≥3 unevaluable vertebrae. The systematic review identified 16 studies including a total of 3238 subjects (19% male) with a mean age range of 45 to 74 years. Seven studies had a low risk of bias and 9 had an intermediate risk, mainly due to not consecutively including patients. The pooled sensitivity of VFA to detect a patient with a vertebral fracture ≥Genant grade 2 was 0.84 (95% CI, 0.72-0.92) and specificity 0.90 (95% CI, 0.84-0.94). CONCLUSIONS: Our findings from the meta-analysis suggest an adequate performance of VFA for the detection of vertebral fractures. However, we could not demonstrate these findings in our center, especially the specificity. Our data advocate caution with exclusively relying on VFA in the assessment of vertebral fractures without identifying performance and potential limitations of the technique.

Rothmund-Thomson syndrome and osteoma cutis in a patient previously diagnosed as COPS syndrome.

We present a patient with poikiloderma, severe osteoporosis and a mild intellectual disability. At the age of 9 years, this patient was proposed to suffer from a novel disease entity designated as calcinosis cutis, osteoma cutis, poikiloderma and skeletal abnormalities (COPS) syndrome. At the age of 35, he was diagnosed with Hodgkin's lymphoma. Recently, biallelic pathogenic variants in the RECQL4 gene were detected (c.1048_1049delAG and c.1391-1G>A), confirming a diagnosis of Rothmund-Thomson syndrome (RTS). In the brother of this patient, who had a milder phenotype, a similar diagnosis was made. CONCLUSION: We conclude that COPS syndrome never existed as a separate syndrome entity. Instead, osteoma cutis may be regarded as a novel feature of RTS, whereas mild intellectual disability and lymphoma may be underreported parts of the phenotype. What is new: • Osteoma cutis was not a known feature in Rothmund-Thomson patients. • Intellectual disability may be considered a rare feature in RTS; more study is needed. What is known: • RTS is a well-described syndrome caused by mutations in the RECQL4 gene. • Patients with RTS frequently show chromosomal abnormalities like, e.g. mosaic trisomy 8.

The Dutch multidisciplinary guideline osteoporosis and fracture prevention, taking a local guideline to the international arena.

BACKGROUND: In 2018, a grant was provided for an evidence-based guideline on osteoporosis and fracture prevention based on 10 clinically relevant questions. METHODS: A multidisciplinary working group was formed with delegates from Dutch scientific and professional societies, including representatives from the patient's organization and the Dutch Institute for Medical Knowledge. The purpose was to obtain a broad consensus among all participating societies to facilitate the implementation of the updated guideline. RESULTS: Novel recommendations in our guideline are as follows: - In patients with an indication for DXA of the lumbar spine and hips, there is also an indication for VFA. - Directly starting with anabolic drugs (teriparatide or romosozumab) in patients with a very high fracture risk; - Directly starting with zoledronic acid in patients 75 years and over with a hip fracture (independent of DXA); - Directly starting with parenteral drugs (denosumab, teriparatide, zoledronic acid) in glucocorticoid-induced osteoporosis with very high fracture risk; - A lifelong fracture risk management, including lifestyle, is indicated from the start of the first treatment. CONCLUSION: In our new multidisciplinary guideline osteoporosis and fracture prevention, we developed 5 "relatively new statements" that are all a crucial step forward in the optimization of diagnosis and treatment for fracture prevention. We also developed 5 flowcharts, and we suppose that this may be helpful for individual doctors and their patients in daily practice and may facilitate implementation.

Venous thromboembolism in Cushing syndrome: results from an EuRRECa and Endo-ERN survey.

Background: Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). Objective: The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis. Design and methods: A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022. Results: Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3-30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Conclusion: Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed. Significance statement: The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

Expression of RANKL in breast cancer tissue in patients with fibrous dysplasia/McCune-Albright syndrome.

BACKGROUND: In fibrous dysplasia/McCune-Albright syndrome (FD/MAS), mosaic mutations in the GNAS gene lead to locally abnormal bone turnover. Additionally, patients with FD/MAS, particularly with thoracic lesions, have an increased risk for breast cancer. Development and progression of breast cancer has been associated with expression of Receptor Activator of NF-κB ligand (RANKL) in mammary tissue, and due to the GNAS mutation, RANKL is systemically increased in patients with FD/MAS. Yet it is unknown whether breast cancer in FD/MAS is also dependent on RANKL. We hypothesized that the GNAS mutation might induce RANKL overproduction and an oncogenic niche in mammary tissue, and examined RANKL expression in breast cancer tissue of patients with FD/MAS compared to controls. METHODS: Nine patients with FD/MAS and breast cancer were included and clinical data were retrieved. Patients were matched to controls with breast cancer without FD/MAS based on age and tumor type. Three pregnant breast cancer patients were included as positive controls. Immunohistochemical detection of RANKL was performed on formalin-fixed paraffin-embedded breast cancer specimens. Staining intensity was classified as weak, moderate or intense. The area of positive RANKL staining divided by the total ductal-lobular area was assessed (positive area percentage, PAP). Number of patients with RANKL expression was compared between FD/MAS and control group by chi-square (χ2) test, the PAP by Mann-Whitney U test (MWU). RESULTS: RANKL expression was observed in 3 patients with FD/MAS (38 %), mainly in healthy tissue, and none of the control patients (χ2p = 0.055). The FD/MAS group demonstrated considerably more intense staining than the control group, comparable to positive controls. The median PAP was 0.64 % (range 0.14-2.04 %) in the 3 FD/MAS patients with RANKL expression, 0.01 % (Q1-Q3: 0.0003-0.514 %) in the entire FD/MAS group, 0.006 % (Q1-Q3: 0.001-0.012 %) in the control group (MWU = 0.574), and 0.19 % (0.08-0.32 %) in the pregnant patients. All patients with FD/MAS and RANKL expression had thoracic bone lesions, but no correlation was observed between RANKL expression and presence of the GNAS mutation or FD disease burden. CONCLUSIONS: The triad of a higher number of patients, higher positive area percentage and stronger intensity in the FD/MAS compared to the control group indicates that RANKL may be upregulated in mammary tissue in a subset of patients with FD/MAS, which may explain the increased risk for breast cancer, although the clinical significance remains unclear. Further research is needed to establish risk profiles for the development of RANKL-positive breast cancer and to improve early screening and treatment.

Clinical value of RANKL, OPG, IL-6 and sclerostin as biomarkers for fibrous dysplasia/McCune-Albright syndrome.

BACKGROUND: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare genetic bone disease caused by a somatic mutation in the GNAS gene. Currently used bone turnover markers (BTMs) do not correlate with the clinical picture and are not useful to predict or monitor therapy success. This study assessed the correlation of RANKL, OPG, RANKL/OPG ratio, IL-6 and sclerostin with the classic BTMs alkaline phosphatase (ALP), procollagen type 1 propeptide (P1NP) and beta crosslaps (CTX), with pain, skeletal burden score (SBS) and response to bisphosphonate or denosumab treatment. METHODS: Ninety-six serum samples of adult patients >18 years of age with any subtype of FD/MAS were included from the biobank facility of the Leiden University Medical Center, Center for Bone Quality between 2015 and 2021. Standard laboratory assessments were assessed as part of usual care. The concentrations of potential biomarkers RANKL, OPG, sclerostin, IL-6 were analyzed. Data on FD/MAS subtype, age, pain, treatment history and treatment response were retrieved from the electronic patient files. Baseline characteristics were summarized by descriptive statistics. Correlations of the concentrations of the potential biomarkers with classic bone turnover markers, SBS and pain scores were cross-sectionally assessed by Spearman rank order correlation. Correction for multiple testing was performed by Benjamini and Hochberg False Discovery Rate. A sensitivity analyses was performed by excluding patients with SBS below 15 and patients using antiresorptive medication at the time of blood withdrawal or within the wash-out period. In patients treated with bisphosphonates or denosumab after blood withdrawal, pre-treatment concentrations were compared in patients with and without therapy response by Mann Whitney U test. RESULTS: The median age of the patients was 41.2 (Q1-Q3 25.9-52.2) years, 62.5 % was female. Median SBS was 2.5 (Q1-Q3 0.5-7.8). RANKL level correlated weakly with ALP (Spearman rho 0.309, p = 0.004, n = 84), but not with P1NP or CTX. The RANKL/OPG ratio, OPG, IL-6 and sclerostin did not correlate with ALP, P1NP or CTX. None of the potential biomarkers correlated with SBS or pain. Results of the sensitivity analyses were comparable. Pre-treatment biomarker levels were similar in patients with and without improvement in pain scores following bisphosphonate therapy. Pre-treatment RANKL and sclerostin were comparable between patients with and without improvement in pain scores after denosumab therapy. Pre-treatment IL-6 level and the RANKL/OPG ratio seemed to be higher in patients with response to denosumab (IL-6: median 0.64 (Q1-Q3 0.53-0.74) pg/mL, n = 6, RANKL/OPG: median 0.062 (Q1-Q3 0.016-0.331), n = 5) compared to patients without response (IL-6: median 0.35 (0.20-0.54) pg/mL, n = 5, RANKL/OPG: 0.027 (0.024-0.046), n = 4). Pre-treatment IL-6 correlated with the improvement in maximum pain scores (rho 0.962, p < 0.001, n = 9) and average pain scores (rho 0.895, p = 0.001, n = 9) reported during denosumab therapy. CONCLUSION: Increased concentrations of RANKL, IL-6, sclerostin and of the RANKL/OPG ratio do not indicate severity of FD/MAS, as no correlation was observed of these potential biomarkers with the classic BTMs and SBS. Biomarker levels did not correlate with pain and had no value in predicting bisphosphonate treatment response. These biomarkers are not superior over the currently used methods of assessing ALP, P1NP and CTX or evaluating SBS to establish disease extent or activity and provide no reliable results. Yet, possibly pre-treatment IL-6 and the RANKL/OPG ratio may have some predictive value for clinical response to denosumab. Therefore, studies investigating disease activity and treatment response should include lesional imaging and patient-reported outcome measures.

Diagnostic and therapeutic practices in adult chronic nonbacterial osteomyelitis (CNO).

BACKGROUND: Chronic nonbacterial osteomyelitis (CNO) is a rare, and impactful auto-inflammatory bone disease occurring in children and adults. Clinical care for CNO is challenging, as the condition lacks validated classification criteria and evidence-based therapies. This study aimed to map the current diagnostic and therapeutic practices for CNO in adults, as a first step towards a standardized disease definition and future consensus treatment plans. METHODS: A primary survey was spread among global rheumatological/bone networks and 57 experts as identified from literature (May 2022), covering terminology, diagnostic tools (clinical, radiological, biochemical) and treatment steps. A secondary survey (sent to primary survey responders in August 2022) further queried key diagnostic features, treatment motivations, disease activity and treatment response monitoring. RESULTS: 36 and 23 physicians completed the primary and secondary survey respectively. Diagnosis was mainly based on individual physician assessment, in which the combination of chronic relapsing-remitting bone pain with radiologically-proven osteitis/osteomyelitis, sclerosis, hyperostosis and increased isotope uptake on bone scintigraphy were reported indicative of CNO. Physicians appeared more likely to refer to the condition as synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome in the presence of joint and skin pathology. MRI was most frequently performed, and the preferred diagnostic test for 47%. X-rays were second-most frequently used, although considered least informative of all available tools. Typical imaging features reported were hyperostosis, osteitis, osteosclerosis, bone marrow edema, while degeneration, soft tissue calcification, and ankylosis were not regarded characteristic. Inflammation markers and bone markers were generally regarded unhelpful for diagnostic and monitoring purposes and physicians infrequently performed bone biopsies. Management strategies diverged, including indications for treatment, response monitoring and declaration of remission. Step-1 treatment consisted of non-steroidal anti-inflammatory drugs/COX-2 inhibitors (83%). Common step 2-3 treatments were pamidronate, methotrexate, and TNF-a-inhibition (anti-TNFα), the latter two regarded especially convenient to co-target extra-skeletal inflammation in SAPHO syndrome. Overall pamidronate and anti-TNFα and were considered the most effective treatments. CONCLUSIONS: Following from our survey data, adult CNO is a broad and insufficiently characterized disease spectrum, including extra-osseous features. MRI is the favoured imaging diagnostic, and management strategies vary significantly. Overall, pamidronate and anti-TNFα are regarded most successful. The results lay out current practices for adult CNO, which may serve as backbone for a future consensus clinical guideline.

Electronic reporting of rare endocrine conditions within a clinical network: results from the EuRRECa project.

Objective: The European Registries for Rare Endocrine Conditions (EuRRECa, eurreb.eu) includes an e-reporting registry (e-REC) used to perform surveillance of conditions within the European Reference Network (ERN) for rare endocrine conditions (Endo-ERN). The aim of this study was to report the experience of e-REC over the 3.5 years since its launch in 2018. Methods: Electronic reporting capturing new encounters of Endo-ERN conditions was performed monthly through a bespoke platform by clinicians registered to participate in e-REC from July 2018 to December 2021. Results: The number of centres reporting on e-REC increased to a total of 61 centres from 22 countries. A median of 29 (range 11, 45) paediatric and 32 (14, 51) adult centres had reported cases monthly. A total of 9715 and 4243 new cases were reported in adults (age ≥18 years) and children, respectively. In children, sex development conditions comprised 40% of all reported conditions and transgender cases were most frequently reported, comprising 58% of sex development conditions. The median number of sex development cases reported per centre per month was 0.6 (0, 38). Amongst adults, pituitary conditions comprised 44% of reported conditions and pituitary adenomas (69% of cases) were most commonly reported. The median number of pituitary cases reported per centre per month was 4 (0.4, 33). Conclusions: e-REC has gained increasing acceptability over the last 3.5 years for capturing brief information on new encounters of rare conditions and shows wide variations in the rate of presentation of these conditions to centres within a reference network. Significance statement Endocrinology includes a very wide range of rare conditions and their occurrence is often difficult to measure. By using an electronic platform that allowed monthly reporting of new clinical encounters of several rare endocrine conditions within a defined network that consisted of several reference centres in Europe, the EuRRECa project shows that a programme of e-surveillance is feasible and acceptable. The data that have been collected by the e-reporting of rare endocrine conditions (e-REC) can allow the continuous monitoring of rare conditions and may be used for clinical benchmarking, designing new studies or recruiting to clinical trials.

European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders.

This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders (PARAT) in 2019, were discussed during two virtual workshops in 2021, and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosing to familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represent areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT, need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborns children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed for a broader clinical audience, and were developed with focus on endocrinologists in training.

The effect of osteoporosis and its treatment on fracture healing a systematic review of animal and clinical studies.

INTRODUCTION: Osteoporosis is characterised by low bone mass and micro-architectural deterioration of bone structure. Its treatment is directed at the processes of bone formation or resorption, that are of utmost importance in fracture healing. We provide a comprehensive review of the literature aiming to summarize and clarify the effects of osteoporosis and its treatment on fracture healing. MATERIAL AND METHODS: A literature search was conducted in PubMed and Embase (OVID version). In vivo animal and human studies on long bone fractures were included. A total of 93 articles were included for this review; 23 studies on the effect of osteoporosis (18 animal and 5 clinical studies) and 70 studies on the effect of osteoporosis treatment (41 animal, 26 clinical studies and 3 meta-analyses) on fracture healing. RESULTS: In animal fracture models osteoporosis was associated with decreased callus formation and bone growth, bone mineral density, biomechanical strength and delayed cellular and differentiation processes during fracture healing. Two large databases identified osteoporosis as a risk factor for non-union whereas three other studies did not. One of those three studies however found a prolonged healing time in patients with osteoporosis. Anti-osteoporosis medication showed inconsistent effects on fracture healing in both non-osteoporotic and osteoporotic animal models. Only the parathyroid hormone and anti-resorption medication were related to improved fracture healing and delayed remodelling respectively. Clinical studies performed in predominantly hip and distal radius fracture patients showed no effect of bisphosphonates on fracture healing. Parathyroid hormone reduced time to union in several clinical trials performed in mainly hip fracture patients, but this did not result in decreased delayed or non-union rates. CONCLUSION: Evidence that substantiates the negative influence of osteoporosis on fracture healing is predominantly from animal studies and to a lesser extent from clinical studies, since convincing clinical evidence lacks. Bisphosphonates and parathyroid hormone may be used during fracture healing, since no clear negative effect has been shown. Parathyroid hormone might even decrease time to fracture union, without decreasing union rate.