Analysis of circulating osteoclast and osteogenic precursors in patients with Gorham-Stout disease.

PURPOSE: Gorham-Stout disease is a very rare disorder characterized by progressive bone erosion and angiomatous proliferation; its etiopathogenesis is still unknown, and diagnosis is still performed by exclusion criteria. The alteration of bone remodeling activity has been reported in patients; in this study, we characterized circulating osteoclast and osteogenic precursors that could be important to better understand the osteolysis observed in patients. METHODS: Flow cytometry analysis of PBMC (Peripheral Blood Mononuclear Cells) was performed to characterize circulating osteoclast and osteogenic precursors in GSD patients (n = 9) compared to healthy donors (n = 55). Moreover, ELISA assays were assessed to evaluate serum levels of bone markers including RANK-L (Receptor activator of NF-κB ligand), OPG (Osteoprotegerin), BALP (Bone Alkaline Phosphatase) and OCN (Osteocalcin). RESULTS: We found an increase of CD16-/CD14+CD11b+ and CD115+/CD14+CD11b+ osteoclast precursors in GSD patients, with high levels of serum RANK-L that could reflect the increase of bone resorption activity observed in patients. Moreover, no significant alterations were found regarding osteogenic precursors and serum levels of BALP and OCN. CONCLUSION: The analysis of circulating bone cell precursors, as well as of RANK-L, could be relevant as an additional diagnostic tool for these patients and could be exploited for therapeutic purposes.

ECHOCARDIOGRAPHIC FINDINGS IN PATIENTS WITH NORMOCALCEMIC PRIMARY HYPERPARATHYROIDISM COMPARED WITH FINDINGS IN HYPERCALCEMIC PRIMARY HYPERPARATHYROID PATIENTS AND CONTROL SUBJECTS.

OBJECTIVE: There are no data regarding echocardiographic parameters in patients with normocalcemic primary hyperparathyroidism (NCPHPT). We compared the echocardiographic findings in postmenopausal women with NCPHPT with those in patients with hypercalcemic primary hyperparathyroidism (PHPT) and controls. METHODS: Seventeen consecutive Caucasian postmenopausal women with NCPHPT were compared with 20 women with hypercalcemic PHPT and 20 controls. Obesity, diabetes, kidney failure, and previous cardiovascular diseases were considered exclusion criteria. Each patient underwent biochemical evaluation, bone mineral density scan, and echocardiographic measurements. Patients with parathyroid disorders underwent kidney ultrasound evaluation. RESULTS: Patients with PHPT had significantly higher mean total serum calcium, ionized calcium, 24-hour urinary calcium, and parathyroid hormone and lower mean phosphorus levels compared with those in the controls (all P < .05). The only differences between patients with NCPHPT and PHPT were significantly lower mean total serum calcium, ionized calcium, and 24-hour urinary calcium and higher phosphorus levels in patients with NCPHPT (all P < .05). The only biochemical difference between patients with NCPHPT and the controls was a higher level of mean parathyroid hormone in patients with NCPHPT. There were no differences in cardiovascular risk factors between patients with NCPHPT and PHPT and the controls. Hypertension was the most frequent cardiovascular risk factor, diagnosed in 65% of patients with PHPT. This high prevalence was not statistically significant compared with that observed in patients with NCPHPT (59%) and in the controls (30%). Echocardiography parameters were not different between patients with NCPHPT and PHPT and the controls when subdivided according to the presence of hypertension (ANOVA followed by Bonferroni correction). CONCLUSION: In a population with a low cardiovascular risk, we found no differences in cardiovascular risk factors and echocardiographic parameters between patients with NCPHPT and PHPT and the controls.

Investigating subtle kidney injury in primary hyperparathyroidism by means of sensitive and specific biomarkers.

OBJECTIVE: Kidney involvement is a common complication in primary hyperparathyroidism (PHPT). No study so far has assessed the prevalence of kidney injury developing before the reduction in glomerular filtration rate (GFR) in PHPT. The study was aimed at establishing the potential role of biomarkers of kidney injury in detecting subtle renal damage in patients with PHPT. DESIGN: Cross-sectional study. PATIENTS: A total of 69 postmenopausal patients with PHPT and 41 healthy age- and sex-matched subjects were studied. Exclusion criteria were as follows: GFR < 30 mL/min, chronic inflammatory disease, nephrotic syndrome, infection, malignancy, heart failure, recent exposure to iodinated contrast media or nonsteroidal anti-inflammatory drugs. MEASUREMENTS: We measured a panel of sensitive biomarkers of kidney injury in PHPT vs controls. RESULTS: Mean FGF23 and Klotho were higher in PHPT (72 ± 48 and 811 ± 366 pg/mL, respectively) than controls (53 ± 23.5 and 668.6 ± 17; P < .02 and P < .05). Urine KIM-1/uCr was significantly higher in PHPT (1.4-6  ± 1.3-6 ) than controls (9.2-7  ± 7-7 ; P < .05); this was particularly evident in the CrCl 60-89 mL/min category (1.36  ± 97 vs 8.2-7  ± 3.6-7 ; P < .02). Mean values of urine NGAL/uCr were higher in PHPT with (n = 28) compared to those without kidney stones (n = 35; 1.8-5  ± 1.4-5 and 1-5  ± 8-6 ; P < .0001). We found significant positive associations between urine NGAL/uCr and Ca (R = .292, P < .02) and urine KIM1/uCr and PTH (R = .329, P < .01). CONCLUSIONS: We propose the utilization of these molecules, particularly urine KIM-1/uCr and urine NGAL/uCr ratios for the assessment of subtle kidney injury in patients with PHPT. These molecules are elevated in tubular necrosis and have potential role in the development of kidney damage in PHPT, according to the severity of the disease.

Safety maximization of percutaneous transthoracic needle biopsy with ultrasound guide in subpleural lesions in the evaluation of pulmonary consolidation.

The study by Kiranantawat et al. "Clinical role, safety and diagnostic accuracy of percutaneous transthoracic needle biopsy in the evaluation of pulmonary consolidation" highlights how "pulmonary consolidation can be safely evaluated with CT-guided percutaneous needle biopsy". Even if we agree about the role of CT guidance, we would like to point out how Thoracic Ultrasound could be better than CT for biopsy of subpleural lesions that could easily be detected and reached with this "real-time" and quicker technique.

Prevalence of Chronic Hypoparathyroidism in a Mediterranean Region as Estimated by the Analysis of Anonymous Healthcare Database.

Epidemiological data on prevalence and incidence of chronic hypoparathyroidism are still scarce. This study aimed to establish prevalence of chronic hypoparathyroidism and incidence of surgical hypoparathyroidism using the analysis of electronic anonymous public health care database. Data referred to a 5-year period (2009-2013, Region of Tuscany, Italy, as a sample representative of the whole Mediterranean/European population, estimated mean population: 3,750,000 inhabitants) were retrieved by the analysis of pharmaceutical distribution dataset, containing data related to drugs reimbursed by public health system, hospital discharge and procedures codes, and ICD9 exemption codes for chronic diseases. The application of a specific algorithm was applied to indirectly identify people with chronic hypoparathyroidism as assuming chronic therapy with active vitamin D metabolites (AVDM). The number of people taking AVDM for a period equal to or longer than 6 months till the end of the study period, with ICD9 exemption code for hypoparathyroidism, and with a disease-related discharge code were identified. Within this restricted group, patients with chronic kidney disease and osteoporosis were excluded. The indirect estimate of chronic hypoparathyroidism in a European Mediterranean subpopulation by means of the analysis of chronic therapy with AVDM was 27/100,000 inhabitants (female:male ratio = 2.2:1), with a mean age of 63.5 ± 16.7 years. The risk of developing hypoparathyroidism after neck surgery was 1.5%. While the epidemiological approaches based on disease code and hospital discharge code greatly underestimates the prevalence of hypoparathyroidism, the indirect estimate of this disease through the analysis of prescriptions of AVDM in a European region is in line with the results of studies performed in other regions of the world.

A Challenging Case of Tumor-Induced Osteomalacia: Pathophysiological and Clinical Implications.

We investigated the usefulness of fibroblast growth factor 23 (FGF23) intraoperative assay to monitor tumor resection in patients with oncogenic osteomalacia. A 33-year-old man with 5 years' history of lumbar and pelvis pain together with multiple vertebral fractures was admitted to our hospital. He was diagnosed with ankylosing spondylitis 1 year before. Laboratory investigation showed low tubular reabsorption of phosphate (0.41 mmol/L) despite chronic hypophosphatemia (0.39/L). Increased plasma values of FGF23 (673 pg/mL; n.v. < 95 pg/mL) were also observed. A full-body CT scan showed two suspicious areas in the head of the right femur and in the right tibia; however, the Octreoscan™ showed an increased uptake of the tracer only in the femur. We decided to remove first the head femur lesion and perform intraoperative FGF23 assay to confirm tumor resection; if this had been unsuccessful, we would have extended the operation to excise the second bone lesion. FGF23 basal values and 10, 60, and 225 min after excision of the femoral head were 423, 127, 56, and 30 pg/mL, respectively. The brisk fall of FGF23 values suggested that the head femur lesion was responsible for the syndrome. Histological examination revealed a mesenchymal highly vascular tumor. This is the first report showing the possibility of intraoperative FGF23 assay to monitor tumor resection in patients with tumor-induced osteomalacia.

Diagnostic accuracy of 3T magnetic resonance imaging in the preoperative localisation of parathyroid adenomas: comparison with ultrasound and 99mTc-sestamibi scans.

OBJECTIVES: To evaluate the diagnostic performance of 3TMRI in comparison with ultrasound (US) and 99mTc-sestamibi scan for presurgical localisation of parathyroid adenomas (PTAs) in patients with primary hyperparathyroidism (PHPT). METHODS: Fifty-seven patients affected by PHPT were prospectively enrolled and underwent US, 99mTc-sestamibi and 3TMRI. T2-weighted and post-contrast T1-weighted Iterative decomposition of water and fat with Echo Asymmetry and Least squares estimation (IDEAL) sequences were acquired. Diagnostic performance of US, 99mTc-sestamibi and MRI in localising PTAs to correct quadrant were compared according to surgical and pathological findings. RESULTS: According to surgical findings, US correctly localised 41/46 PTAs (sensitivity of 89.1%; specificity 97.5%; PPV 93.1% and NPV 95.6%); 99mTc-sestamibi correctly localised 38/46 PTAs (sensitivity 83.6%, specificity 98.3%, PPV 95% and NPV 93.7%). US and 99mTc-sestamibi combined had a sensitivity of 93.4% (43/46 PTAs), specificity of 98.3%, PPV 95% and NPV 98.3%. MRI correctly localised 45/46 PTAs (sensitivity 97.8%; specificity 97.5%; PPV 93.7% and NPV 99.2%). MRI was able to detect six adenomas missed by 99mTc-sestamibi and two adenomas missed by US. MRI and US were able to detect all enlarged parathyroid glands in patients with multiglandular disease. MRI identified six of seven ectopic adenomas. CONCLUSIONS: Our study demonstrated high diagnostic performance of 3T MRI in the preoperative PTAs quadrant localisation, as well as in patients with multiglandular disease and ectopic PTAs. MRI may be preferred to adequately select patient candidates for minimally invasive parathyroidectomy (MIP). KEY POINTS: • PTA(s) quadrant localisation by 3TMRI was more accurate than US+99mTc-sestamibi. • MRI identified all enlarged glands in multiglandular disease similarly to US. • MRI identified 6/7 ectopic PTAs similarly to 99mTc-sestamibi. • Presurgical PTA(s) localisation by 3TMRI select the optimal candidates for MIP.

Adverse effects of media reports on the treatment of osteoporosis.

PURPOSE: The review focused on the role that media reporting plays in the level of public awareness about osteoporosis and its influence on osteoporosis treatment decisions. METHODS: We reviewed the literature on the role of media on three main aspects influencing patient adherence to osteoporosis treatment: the awareness of osteoporosis as a major health problem, the perception of the effectiveness of osteoporosis medications, and the fear of adverse effects with osteoporosis medications. RESULTS: A review of the literature confirmed what is routinely observed in clinical practice-that media report can strongly influence the level of awareness of osteoporosis and fracture risk. Inadequate and/or incorrect information on osteoporosis in the media are associated with a low level of awareness of the disease. High-risk patients may have a poor understanding of the need for treatment. Alarming information in the media over the last 2 decades regarding effectiveness and safety of long-term osteoporosis treatment is associated with reduction in the use of osteoporosis medications. CONCLUSIONS: There is a gap between the application of clinical recommendations and patient perceptions of osteoporosis and its treatment. There is a need for better education of patients and practitioners aimed at recognizing the serious consequences of fractures and understanding the expected benefits and potential risks of treatment. Media reports that disseminate evidence-based information on the balance of benefits and risks could help to reduce the osteoporosis treatment gap and mitigate the crisis in osteoporosis care.

The Epidemiology of Hypoparathyroidism in Italy: An 8-Year Register-Based Study.

Hypoparathyroidism is a rare endocrine disorder, but few studies have focused on the epidemiology and hospital management of the disease and none has been performed in Italy. We investigated the prevalence of different forms of hypoparathyroidism among hospitalized patients in Italy during an 8-year period. This study is designed as a retrospective register-based study. We retrieved data from the "Record of Hospital Discharge" (SDO) of the Italian Health Ministry, from the year 2006 to 2013 and analyzed the codes corresponding to hypoparathyroidism-related diagnoses. The inpatient prevalence of the disease was also calculated after excluding repeated hospitalizations. Overall, 27,692 hospitalization episodes for hypoparathyroidism were identified during the entire period (72.2% in women and 27.8% in men; mean age 49.5 ± 22.9 years). The mean length of stay was 7.4 ± 9.8 days (25.9% of the episodes requiring less than 3 days of stay). The mean hospitalization rate for hypoparathyroidism was 5.9/100,000 inhabitants per year and there was a significant decrease during the period of 2006-2013 (p < 0.0001). The mean hospitalization rate for postsurgical hypoparathyroidism was 1.4/100,000 inhabitants per year and the trend showed a significant reduction during the years (p < 0.0001). The mean prevalence of hypoparathyroidism among inpatients was 5.3/100,000 inhabitants per year, and there was a significant decrease over the years (p < 0.0001). Hypoparathyroidism, particularly the postsurgical form of the disease, is not an uncommon condition among hospitalized patients in Italy. We observed a tendency to a decrease in the frequency of hospitalization during the period 2006-2013.

Effect of a single intravenous zoledronic acid administration on biomarkers of acute kidney injury (AKI) in patients with osteoporosis: a pilot study.

AIMS: The pilot study was designed to evaluate the early effect of intravenous (i.v.) zoledronic acid (ZA) on renal function. METHODS: Five mg i.v. ZA was administered to 23 patients with osteoporosis (17 women and 6 men, mean age 73 ± 7 SD years). Urinary NGAL, KIM-1, and MCP-1, plasma (p) MCP-1 and serum (s) IL-18, serum calcium (sCa), Creatinine clearance (CrCl), parathyroid hormone (PTH), plasma C-terminal FGF23 (pFGF23), serum (s) Klotho, calcium excretion (CaEx) and renal threshold phosphate concentration/GFR (TmPO4 /GFR) were assessed at baseline, 24 h and Day 30 after administration. RESULTS: There was a significant decrease in sCa and CaEx at 24 h (-4.1 ± 2.8%, P < 0.01 and -28 ± 59%, P < 0.05, respectively) and Day 30 (-3.9 ± 4%, P < 0.001 and -26 ± 43%, P < 0.01) and a significant increase in PTH (79.8 ± 95.8%) at Day 30 (P < 0.001) compared to baseline. TmPO4 /GFR decreased significantly at 24 h and Day 30 (-8.6 ± 15.9%, P < 0.05 and -11.3 ± 13.5%, P < 0.001) compared to baseline. We observed no difference in the concentration of pFGF23, sKlotho and urinary AKI biomarkers at any time points. Mean levels of sIL-18 and pMCP-1 increased significantly at 24 h (44 ± 88%; P < 0.01 and 198 ± 237%; P < 0.001) and returned to baseline at Day 30. CONCLUSIONS: Our pilot study suggests that there is no direct acute effect of ZA on kidney function. The increase in plasma MCP-1 and serum IL-18 concentration could be associated with the stimulation of immunity mechanisms occurring soon after the administration of the drug. Secondary hyperparathyroidism develops shortly after the infusion of ZA and is maintained even after 1 month.

Oral calcidiol is a good form of vitamin D supplementation.

Vitamin D supplementation represents an important topic in the field of metabolic bone disease. Calcidiol, the 25-hydroxy-vitamin D [25(OH)D], is the form of vitamin D most recently introduced in clinical practice. Advantages of the use of calcidiol derive from the pharmacokinetic properties and are related to the possibility of use in patients with liver disease, obese patients, patients with intestinal malabsorption, secondary hyperparathyroidism associated with chronic kidney disease as well as to avoid any possible toxic effect when high doses are used. The ADDI-D study demonstrated the efficacy and safety of calcidiol at the daily dose of 20 or 40 µg and 125 µg/week. In particular, the daily dose of 40 µg can be suggested as an alternative in severely deficient patients, as it has demonstrated to ensure higher vitamin D levels, compared to the 20 µg/day and the weekly 125 µg dose. The last can be an option when issues with compliance to the supplementation are present.

Update on vitamin D: pros and cons.

Controversies on vitamin D currently represent a challenging topic in mineral metabolism research. In particular, current guidelines on vitamin D supplementation did not report consistent recommendation and the issue related to beneficial vs harmful effects of loading vitamin D doses did not lead to any firm universal conclusion. Finally, serum and clinical outcomes of vitamin D supplementation, particularly as far as extra-skeletal effect of the hormone, need to be further investigated.

Bone loss after discontinuation of denosumab: the devil is in the details.

A 47-year-old postmenopausal woman with osteoporosis was treated with denosumab, which was discontinued due to side effects. She was therefore transitioned to a yearly intravenous infusion of zoledronic acid. An increase in bone turnover markers together with bone loss at the lumbar spine was observed before the second infusion, suggesting an overshooting of bone resorption due to denosumab discontinuation. On physical examination, the patient was restless and reported having lost about 10 kg since the last visit. A solitary left inferior thyroid nodule was noted on neck palpation. Circulating thyroid hormone levels were elevated, with suppressed thyroid-stimulating hormone. A thyroid scan showed increased uptake in the left inferior nodule with suppression of the remainder of the thyroid gland. A diagnosis of hyperthyroidism due to toxic adenoma was made. The patient was treated with radioactive iodine ablation, with consequent complete normalization of thyroid function. She continued yearly treatment with zoledronic acid. She remained clinically well with no further fractures. Bone turnover markers were appropriately suppressed and bone mineral density increased in the spine and hip. This case illustrates how the overshooting phenomenon following denosumab discontinuation may be compounded by the development of secondary conditions, which can result in suboptimal response to antiresorptive osteoporosis medications.

Nutrition, Vitamin D, and Calcium in Elderly Patients before and after a Hip Fracture and Their Impact on the Musculoskeletal System: A Narrative Review.

Hip fractures are a major health issue considerably impacting patients' quality of life and well-being. This is particularly evident in elderly subjects, in which the decline in bone and muscle mass coexists and predisposes individuals to fall and fracture. Among interventions to be implemented in hip fractured patients, the assessment and management of nutritional status is pivotal, particularly in subjects older than 65. Nutrition plays a central role in both primary and secondary preventions of fracture. An adequate protein intake improves muscle mass and strength and the intestinal absorption of calcium. Other nutrients with recognized beneficial effects on bone health are calcium, vitamins D, K, and C, potassium, magnesium, folate, and carotenoids. With reference to calcium, results from longitudinal studies showed that the consumption of dairy foods has a protective role against fractures. Moreover, the most recent systematic reviews and meta-analyses and one umbrella review demonstrated that the combination of calcium and vitamin D supplementation significantly reduces hip fracture risk, with presumed higher efficacy in older and institutionalized subjects. Owing to these reasons, the adequate intake of calcium, vitamin D, protein, and other macro and micronutrients has been successfully implemented in the Fracture Liaison Services (FLSs) that represent the most reliable model of management for hip fracture patients. In this narrative review, papers (randomized controlled trials, prospective and intervention studies, and systematic reviews) retrieved by records from three different databases (PubMed, Embase, and Medline) have been analyzed, and the available information on the screening, assessment, and management of nutritional and vitamin D status and calcium intake in patients with hip fractures is presented along with specific prevention and treatment measures.

Effect of 2 Years of Monthly Calcifediol Administration in Postmenopausal Women with Vitamin D Insufficiency.

BACKGROUND: We assessed the long-term (24 months) efficacy and safety of monthly calcifediol (0.266 mg) in the correction and maintenance of total 25(OH)D levels in postmenopausal women with basal values <30 ng/mL. METHODS: We initially enrolled 45 consecutive patients during the period September 2019-September 2020. After an initial visit, patients were instructed to return at 3, 6, 9, 12 and 24 months for measuring serum total 25(OH)D, ionised calcium, creatinine and isoenzyme of alkaline phosphatase (bALP). Here, we report only the per-protocol analysis, because the COVID-19 pandemic precluded adherence to the scheduled visits for some patients. RESULTS: The patients' mean age was 62.4 ± 9.0 years. Mean basal 25(OH)D levels were 20.5 ± 5.3 ng/mL. There was a continuous increase of mean 25(OH)D values (p for trend < 0.001). However, mean values at month 24 (36.7 ± 15.9) were not significantly different in respect to values at month 12 (41.2 ± 11.18). At 24 months, only 1 out 19 patients had a value <20 ng/mL. There was a significant decrease with time of mean values of bALP (p < 0.0216), with no significant changes between 12 and 24 months. No significant changes were observed as far as ionised calcium or creatinine were concerned. CONCLUSIONS: The long-term administration of calcifediol maintains stable and sustained 25(OH)D concentrations, with no safety concerns.