Romosozumab versus parathyroid hormone receptor agonists: which osteoanabolic to choose and when?

Osteoanabolic agents are used as a first line treatment in patients at high fracture risk. The PTH receptor 1 (PTH1R) agonists teriparatide (TPTD) and abaloparatide (ABL) increase bone formation, bone mineral density (BMD), and bone strength by activating PTH receptors on osteoblasts. Romosozumab (ROMO), a humanized monoclonal antibody against sclerostin, dramatically but transiently stimulates bone formation and persistently reduces bone resorption. Osteoanabolic agents increase BMD and bone strength while being more effective than antiresorptives in reducing fracture risk in postmenopausal women. However, direct comparisons of the antifracture benefits of osteoanabolic therapies are limited. In a direct comparison of TPTD and ABL, the latter resulted in greater BMD increases at the hip. While no differences in vertebral or non-vertebral fracture risk were observed between the two drugs, ABL led to a greater reduction of major osteoporotic fractures. Adverse event profiles were similar between the two agents except for hypercalcemia, which occurred more often with TPTD. No direct comparisons of fracture risk reduction between ROMO and the PTH1R agonists exist. Individual studies have shown greater increases in BMD and bone strength with ROMO compared with TPTD in treatment-naive women and in women previously treated with bisphosphonates. Some safety aspects, such as a history of tumor precluding the use of PTH1R agonists, and a history of major cardiovascular events precluding the use of ROMO, should also be considered when choosing between these agents. Finally, convenience of administration, reimbursement by national health systems and length of clinical experience may influence patient choice.

Restless leg syndrome as a complication of primary hyperparathyroidism: insights from a retrospective study.

INTRODUCTION: Restless leg syndrome (RLS) is an invalidating neurological disorder with a complex, largely unknown pathophysiology. While RLS is observed in Parkinson's disease and in renal failure, idiopathic cases are common. Limited reports associate RLS with parathyroid hormone (PTH). This study analyzes a cohort of patients with primary hyperparathyroidism (PHPT) and chronic post-surgical hypoparathyroidism (hypo PTH), to investigate RLS prevalence, and associated risk factors. METHODS: Ninety-five patients (54 PHPT, 41 hypo PTH) were consecutively enrolled at the bone metabolism outpatient clinic. The revised IRLSSG diagnostic criteria were used to diagnose RLS, with assessments conducted through face-to-face interviews and neurological examination. When RLS was confirmed, the RLS severity scale was applied. Retrospective records included calcium-phosphate metabolism-related parameters, surgery details, renal lithiasis, fragility fractures, and densitometric features (T-score). RESULTS: RLS was diagnosed in 22.2% PHPT patients, compared to 4.9% of patients with hypo PTH (p = 0.02). Of RLS diagnosed patients, 91.7% had a history of parathyroidectomy, compared to 47.6% of patients without RLS (p = 0.01). Most of the operated patients reported that surgery determined an improvement of symptoms; however, mean score severity of RLS at our evaluation was 15/40, defined as moderate. PTH and calcium levels were not statistically associated to the presence of RLS. CONCLUSION: Our study suggests that PHPT may be one of the etiologies of RLS. Parathyroidectomy alleviates symptoms in the vast majority of the cases but does not remove them.

Real-Time Evaluation of Thyroid Cytology Using New Digital Microscopy Allows for Sample Adequacy Assessment, Morphological Classification, and Supports Molecular Analysis.

Thyroid cytological examination, a key tool in preoperative thyroid nodule evaluation, is specific and accurate; some drawbacks are due to inadequate or indeterminate cytological reports and there is a need for an innovative approach overcoming the limits of traditional cytological diagnostics. Fluorescence laser confocal microscopes (FCM) is a new optical technique for allowing immediate digital imaging of fresh unfixed tissues and real-time assessment of sample adequacy and diagnostic evaluation for small biopsies and cytological samples. Currently, there are no data about the use of FCMs in the field of thyroid nodular pathology. The aims of this study were to test FCM technology for evaluating the adequacy of FNA samples at the time of the procedure and to assess the level of concordance between FCM cytological evaluations, paired conventional cytology, and final surgical histology. The secondary aim was to define the integrity of nucleic acids after FCM evaluation through NGS molecular analysis. Sample adequacy was correctly stated. Comparing FCM evaluation with the final histology, all cases resulting in malignant or suspicious for malignancy at FCM, were confirmed to be carcinomas (PPV 100%). In conclusion, we describe a successful application of FCM in thyroid preoperative cytological evaluation, with advantages in immediate adequacy assessment and diagnostic information, while preserving cellular specimens for permanent morphology and molecular analysis, thus improving timely and accurate patient management.

Management of Hypoparathyroidism.

Hypoparathyroidism (HypoPT) is a rare disorder characterized by hypocalcemia in the presence of a low or inappropriately normal parathyroid hormone level. HypoPT is most commonly seen after neck surgery, which accounts for approximately 75% of cases, whereas approximately 25% have HypoPT due to nonsurgical causes. In both groups of patients, conventional therapy includes calcium and active vitamin D analogue therapy aiming to maintain serum calcium concentration in the low normal or just below the normal reference range and normalize serum phosphorus, magnesium concentrations, and urine calcium levels. The limitations of conventional therapy include wide fluctuations in serum calcium, high pill burden, poor quality of life, and renal complications. Parathyroid hormone (PTH) replacement therapy may improve the biochemical profile in those in whom conventional therapy proves unsatisfactory. Based on a systematic review and meta-analysis of the literature, the panel made a graded recommendation suggesting conventional therapy as first line therapy rather than administration of PTH (weak recommendation, low quality evidence). When conventional therapy is deemed unsatisfactory, the panel considers use of PTH. Because pregnancy and lactation are associated with changes in calcium homeostasis, close monitoring is required during these periods with appropriate adjustment of calcium and active vitamin D analogue therapy to ensure that serum calcium remains in the mid to low normal reference range in order to avoid maternal and fetal complications. Emerging therapies include molecules with prolonged PTH action as well as different mechanisms of action that may significantly enhance drug efficacy and safety. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Efficacy of radiofrequency and laser thermal ablation in solving thyroid nodule-related symptoms and cosmetic concerns. A systematic review and meta-analysis.

Several studies have showed good/excellent results of thermal-ablation (TA) to reduce volume of benign thyroid nodule (TN). Nevertheless, no systematic review has reported information about clinical achievements with TA. Being the latter of high interest, this systematic review was undertaken to achieve high evidence about the efficacy of TA in reducing TN-related symptoms and cosmetic concerns. Radiofrequency (RFA) and laser (LA) therapies were considered. A comprehensive literature search of online databases was performed on January 2022 looking for studies reporting clinical results obtained by RFA or LA in terms of VAS (namely, Visual Analogic Scale) and cosmetic concerns. Initially, 318 records were found and 14 were finally included in the meta-analysis. VAS data were available in all RFA studies and the pooled mean reduction was of 3.09 points with significant heterogeneity. Cosmetic score data were available in 11 RFA studies and the pooled mean reduction was of 1.45 with significant heterogeneity. Regarding LA studies, 4 series reported VAS data and the pooled mean reduction was of 2.61 points with significant heterogeneity. The analysis of LA data about cosmetic concerns was not performed due to data paucity. Importantly, heterogeneities were not explained by meta-regression analyses using several covariates (i.e., baseline TN volume, follow-up duration, volume reduction rate). This systematic review showed that clinical data about TN TA efficacy are sparse and affected by high unexplained inconsistency. International societies should give indication about how we should clinically select and evaluate patients undergoing TN TA.

Long-term efficacy and safety of percutaneous ethanol injection (PEI) in cystic thyroid nodules: A systematic review and meta-analysis.

BACKGROUND: Percutaneous ethanol injection (PEI) is used for the treatment of benign cystic thyroid nodules. This systematic review and meta-analysis aimed to obtain strong evidence of its long-term efficacy and safety. METHODS: PubMed, CENTRAL, Scopus and Web of Science databases were searched until November 2020 for studies reporting data on volume reduction rate (VRR), compressive symptoms and cosmetic concerns. Associated complications were assessed. A random-effects model was designed to pool the data. RESULTS: Out of 385 papers, nine studies evaluating 1667 nodules were finally included. Overall, VRR at 6, 12, 24, 36, 60 and 120 months was 77%, 81%, 72%, 68%, 74% and 69%, respectively. Significant reductions in the compressive symptoms and cosmetic concerns were observed. No permanent complications were observed. CONCLUSIONS: The present meta-analysis showed that PEI could significantly reduce the volume of benign cystic thyroid nodules. This reduction was already effective at 6 months post-treatment, and the effect was stable over time.

Hobnail variant of papillary thyroid carcinoma showing goiter-like presentation and rapid growth.

SUMMARY: We present the case of a 47-year-old Caucasian previously healthy woman with a voluminous thyroid nodule occupying almost the entire anterior neck region. The lesion had progressively increased in size during the previous 3 months and the patient presented intermittent symptoms of dysphagia and odynophagia with a slight change in voice. Fine needle aspiration showed papillary carcinoma. Based on imaging and cytological findings, the patient underwent total thyroidectomy. The surgical sample revealed a totally enlarged thyroid gland (weight: 208 g) with the presence of a poly-lobulated lesion centrally located and involving the isthmus and both lobes. Hobnail features were present in more than 30% of the neoplastic cells in agreement with the criteria for this subtype. Psammoma bodies and focal necrosis were also present. The extra-thyroidal extension included strap muscles and peri-esophageal glands. Immunohistochemistry using VE1 antibody for detecting BRAF-V600E mutation resulted positive. The final diagnosis was papillary thyroid carcinoma (PTC) hobnail variant (HVPTC)-pT4a. The HVPTC is a rare entity and, in most cases, appears like a unifocal lesion with a maximum tumor size of 8 cm reported so far. To our knowledge, this represents the largest tumor ever described (14 cm), showing rapid growth and with multinodular goiter-like aspect. LEARNING POINTS: HVPTC is an aggressive variant of PTC, usually associated with radioactive iodine refractoriness, and a higher mortality rate compared to classic PTC. However, there is a marked individual variability in this association. HVPTC usually appears as small unifocal lesion but a multinodular goiter presentation may occur. The present case highlights that despite of the histology, our patient achieved a high ablation success rate after radioactive iodine therapy.

Regression of Papillary Thyroid Cancer during Nivolumab for Renal Cell Cancer.

Immune checkpoint inhibitors have been recently approved for cancer treatment. Nivolumab is a monoclonal antibody specific for programmed cell death-1 (PD-1) that modulates T-cell response. It was initially used for the treatment of malignant melanoma and then approved in other cancers, such as non-small cell lung cancer and clear cell renal cell carcinoma (ccRCC). So far, the activity of nivolumab in patients with thyroid malignancies has been reported in a single case of anaplastic thyroid cancer. Here, we report the case of a patient with ccRCC who developed a papillary thyroid carcinoma (PTC) under first-line sunitinib treatment. During nivolumab, the second-line treatment for ccRCC, we unexpectedly observed a complete regression of PTC.

Changes in Skeletal Microstructure Through Four Continuous Years of rhPTH(1-84) Therapy in Hypoparathyroidism.

Bone remodeling is reduced in hypoparathyroidism, resulting in increased areal bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) and abnormal skeletal indices by transiliac bone biopsy. We have now studied skeletal microstructure by high-resolution peripheral quantitative computed tomography (HR-pQCT) through 4 years of treatment with recombinant human PTH(1-84) (rhPTH[1-84]) in 33 patients with hypoparathyroidism (19 with postsurgical disease, 14 idiopathic). We calculated Z-scores for our cohort compared with previously published normative values. We report results at baseline and 1, 2, and 4 years of continuous therapy with rhPTH(1-84). The majority of patients (62%) took rhPTH(1-84) 100 µg every other day for the majority of the 4 years. At 48 months, areal bone density increased at the lumbar spine (+4.9% ± 0.9%) and femoral neck (+2.4% ± 0.9%), with declines at the total hip (-2.3% ± 0.8%) and ultradistal radius (-2.1% ± 0.7%) (p < .05 for all). By HR-pQCT, at the radius site, very similar to the ultradistal DXA site, total volumetric BMD declined from baseline but remained above normative values at 48 months (Z-score + 0.56). Cortical volumetric BMD was lower than normative controls at baseline at the radius and tibia (Z-scores -1.28 and - 1.69, respectively) and further declined at 48 months (-2.13 and - 2.56, respectively). Cortical porosity was higher than normative controls at baseline at the tibia (Z-score + 0.72) and increased through 48 months of therapy at both sites (Z-scores +1.80 and + 1.40, respectively). Failure load declined from baseline at both the radius and tibia, although remained higher than normative controls at 48 months (Z-scores +1.71 and + 1.17, respectively). This is the first report of noninvasive high-resolution imaging in a cohort of hypoparathyroid patients treated with any PTH therapy for this length of time. The results give insights into the effects of long-term rhPTH(1-84) in hypoparathyroidism. © 2020 American Society for Bone and Mineral Research.

Metabolic profile of human parathyroid adenoma.

PURPOSE: Recently, it has been demonstrated that Raman spectroscopy is able to differentiate between healthy parathyroid tissues and parathyroid adenoma based on the basis of a specific molecular fingerprint. However, to our knowledge, no previous studies have been performed to evaluate the metabolic profile of parathyroid adenoma. Therefore, we designed a proof of concept study aimed to investigate the glucose/fatty acid metabolisms, in addition to the mitochondrial changes, in solitary parathyroid adenoma and in healthy parathyroid glands. METHODS: Nine females with primary hyperparathyroidism due to a solitary parathyroid adenoma and formal surgical indication for parathyroidectomy have been enrolled. At the time of surgery, the removed specimens were immediately submitted unfixed and a tissue slice of about 0.5 cm in diameter was obtained from the nodular lesion. The expression of selected metabolic enzymes and proteins has been evaluated by western blot analysis, using human parathyroid whole tissue lysates as control. RESULTS: Data obtained highlighted an increase, compared with the healthy group, of: (i) the glucose uptake by the GLUT-1 receptor and its phosphorylation by hexokinase II (HXKII); (ii) the expression of 3-phosphoglycerate dehydrogenase (3-PGDH) and glucose-6-phosphate dehydrogenase (G6PD); (iii) lipids biosynthesis; and (iv) cytochrome c expression. CONCLUSIONS: Our findings highlight for the first time the parathyroid adenoma metabolic hallmarks that could represent potential molecular targets usable for the development of new pharmacological treatments, allowing to reduce surgical parathyroidectomy.

Calcium citrate: from biochemistry and physiology to clinical applications.

Adequate daily calcium intake should normally be achieved by dietary sources. Since low calcium diets are quite common in subjects that do not reach the recommended intake and particularly those at risk of fractures, calcium supplements may become necessary. Different forms of calcium salts are available, but products containing calcium citrate and calcium carbonate complexes are the most frequently used. Although only limited evidence on the efficacy and long-term safety of calcium citrate is available, these supplements may represent a valuable product for the management of different chronic pathological conditions. The aim of this review was to evaluate the current and potential clinical applications of calcium citrate. In particular, we focused on the use of calcium citrate supplementation in subjects with osteoporosis or in bariatric patients. Other pathological conditions that could benefit calcium citrate supplementation may include achloridria, chronic hypoparathyroidism and hypocitraturic subjects with moderate/high risk of nephrolithiasis. Indeed, citrate salts are widely used in the treatment of nephrolithiasis, since they have shown an inhibitory effect on kidney stone formation and recurrence.

Diagnostic Performance of 4D CT and Sestamibi SPECT/CT in Localizing Parathyroid Adenomas in Primary Hyperparathyroidism.

Background There currently is no consensus on the optimal localization procedure and imaging protocol for parathyroid adenoma. Parathyroid four-dimensional (4D) CT has emerged as a promising method for preoperative localization. Purpose To evaluate the diagnostic performance of parathyroid 4D CT and technetium 99m-sestamibi (hereafter, referred to as sestamibi) SPECT/CT in preoperative localization in patients with primary hyperparathyroidism. Materials and Methods This was a single-institution retrospective study of patients with primary hyperparathyroidism who underwent a combined imaging protocol of sestamibi SPECT/CT and 4D CT (noncontrast, contrast agent-enhanced, arterial, and delayed venous phases) acquired in a single setting from February 2013 to May 2016, with subsequent parathyroidectomy within 6 months. Reference standard for correct localization was on the basis of location denoted on operative reports, with pathologic confirmation of parathyroid adenoma or hyperplasia. By using a four-quadrant analysis, sensitivity, specificity, and area under the curve (AUC) for localization of the hyperfunctioning parathyroid gland or glands at sestamibi SPECT/CT and 4D CT were compared, per modality and in combination. Results Four hundred patients (319 women, 81 men; mean age, 61 years ± 14 [standard deviation]) were evaluated. Similar diagnostic performance was found in both combined 4D CT with sestamibi SPECT/CT and 4D CT alone (area under the curve [AUC], 0.88 [95% CI: 0.86, 0.90] and 0.87 [95% CI: 0.85, 0.90], respectively; P = .82). Both modalities outperformed sestamibi SPECT/CT (AUC, 0.78; 95% CI: 0.76, 0.81; P < .001). Four-dimensional CT showed higher sensitivity than did sestamibi SPECT/CT (sensitivity, 79.3% [414 of 522] vs 58.0% [303 of 522], respectively; P < .001). In a subset analysis, 4D CT had higher sensitivity than sestamibi SPECT/CT in patients with single-gland disease (sensitivity, 92.5% [297 of 321] vs 75.1% [241 of 321], respectively; P < .001) and with multigland disease (sensitivity, 58.2% [117 of 201] vs 30.8% [62 of 201], respectively; P < .001). Conclusion Four-dimensional CT provided superior preoperative localization compared with sestamibi SPECT/CT in patients with single and multigland disease. The combination of the two modalities did not improve diagnostic performance compared with four-dimensional CT alone. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Sinha and Oates in this issue.

Osteoanabolic and dual action drugs.

Teriparatide (TPTD) and abaloparatide (ABL) are the only osteoanabolic drugs available, at this time, for treatment of osteoporosis. TPTD is a 34-amino acid fragment that is identical in its primary sequence to the 34 amino acids of full-length human parathyroid hormone [hPTH(1-84)]. ABL is identical to parathyroid hormone-related peptide (PTHrP) through the first 22 residues with significantly different amino acids inserted thereafter, between residues 22 and 34. The osteoanabolic actions of PTH are due directly to its effects on cells of the osteoblast lineage and indirectly by stimulating IGF-I synthesis and suppressing sclerostin and associated enhancement of Wnt signalling. Both TPTD and ABL are ligands that bind to and activate the PTH receptor type 1 (PTHR1) receptor but they appear to do so differently: ABL favours the transient, more anabolic configuration of the receptor. Both TPTD and ABL reduce the risk of vertebral fractures and non-vertebral fractures. Both drugs are administered for a maximum of 24 months, and should be followed by an antiresorptive agent to maintain gains in bone mineral density (BMD). Romosozumab, a monoclonal antibody that binds to and inhibits sclerostin, appears to have dual actions by stimulating bone formation and reducing bone resorption. In the pivotal clinical trial, romosozumab, administered as a 210 mg monthly subcutaneous dose, significantly reduced new vertebral fractures and in a subsequent study reduced both vertebral and non-vertebral fractures.

Raman Spectroscopy Applied to Parathyroid Tissues: A New Diagnostic Tool to Discriminate Normal Tissue from Adenoma.

Primary hyperparathyroidism is an endocrine disorder characterized by autonomous production of parathyroid hormone. Patients with the symptomatic disease should be referred for parathyroidectomy. However, the distinction between the pathological condition and the benign one is very challenging in the surgical setting; therefore, accurate recognition is important to ensure success during minimally invasive surgery. At present, all intraoperative techniques significantly increase surgical time and, consequently, cost. In this proof-of-concept study, Raman microscopy was used to differentiate between healthy parathyroid tissue and parathyroid adenoma from 18 patients. The data showed different spectroscopic features for the two main tissue types of healthy and adenoma. Moreover, the parathyroid adenoma subtypes (chief cells and oxyphil cells) were characterized by their own Raman spectra. The partial least-squares discriminant analysis (PLS-DA) model built to discriminate healthy from adenomatous parathyroid tissue was able to correctly classify all samples in the calibration and validation data sets, providing 100% prediction accuracy. The PLS-DA model built to discriminate chief cell adenoma from oxyphil cell adenoma allowed us to correctly classify >99% of the spectra during calibration and cross-validation and to correctly predict 100% of oxyphil and 99.8% of chief cells in the external validation data set. The results clearly demonstrate the great potential of Raman spectroscopy. The final goal would be development of a Raman portable fiber probe device for intraoperative optical biopsy, both to improve the surgical success rate and reduce surgical cost.

A Rare Complication following Thyroid Percutaneous Ethanol Injection: Plummer Adenoma.

Percutaneous ethanol injection (PEI) is a technique used only for benign thyroid nodules, cystic or mixed cystic-solid with a large fluid component. It is a quite low-cost, safe, and outpatient method of treatment. Rare and severe complications have been described after PEI: jugular vein thrombosis and severe ethanol toxic necrosis of the larynx combined with necrotic dermatitis. Moreover, only four thyrotoxicosis cases due to Graves' disease have been reported. We report a case of 58-year-old female with a voluminous thyroid cystic nodule, occupying almost the entire left thyroid lobe. Our patient had already performed surgical visit and intervention of thyroidectomy had been proposed to her, which she refused. At baseline, our patient has a normal thyroid function with negative autoantibodies. According to the nodular structure, intervention of PEI has been performed with a significant improvement of compressive symptoms and cosmetic disorders. About 30 days after treatment, there was a significant volume reduction, but patient developed an acclaimed symptomatic thyrotoxicosis. After ruling out several causes of hyperthyroidism and according to the thyroid scintigraphy findings, we made the diagnosis of Plummer adenoma. To our knowledge, our patient is the first case of Plummer adenoma following PEI treatment of nontoxic thyroid nodule.

PTH(1-34) for the Primary Prevention of Postthyroidectomy Hypocalcemia: The THYPOS Trial.

CONTEXT: There are no studies evaluating teriparatide for prevention of post-thyroidectomy hypocalcemia. OBJECTIVE: Our objective was to evaluate whether teriparatide can prevent postsurgical hypocalcemia and shorten the hospitalization in subjects at high risk of hypocalcemia following thyroid surgery. DESIGN: This was a prospective phase II randomized open-label trial. SETTING: This trial was set on a surgical ward. PATIENTS: Twenty-six subjects (six males, 20 females) with intact PTH lower than10 pg/ml 4 hours after thyroidectomy were included. INTERVENTION: Subjects were randomized (1:1) to receive SC administration of 20 mcg of teriparatide every 12 hours until the discharge (treatment group) or to follow standard clinical care (control group). MAIN OUTCOME MEASURE: Adjusted serum calcium, duration of hospitalization, and calcium/calcitriol supplementation were measured. RESULTS: Overall, the incidence of hypocalcemia was 3/13 in treatment group and 11/13 in the control group (P = .006). Treated patients had a lower risk of hypocalcemia than controls (relative risk, 0.26 [95% confidence interval, 0.09-0.723)]). The median duration of hospitalization was 3 days (interquartile range, 1) in control subjects and 2 days (interquartile range, 0) in treated subjects (P = .012). One month after discharge, 10/13 subjects in the treatment group had stopped calcium carbonate supplements, while only 5/13 in the control group had discontinued calcium. The ANOVA for repeated measures showed a significant difference in calcium supplements between groups at 1-month visit (P = .04) as well as a significant difference between discharge and 1-month visit in the treatment group (P for interaction time group = .04) Conclusions: Teriparatide may prevent postsurgical hypocalcemia, shorten the duration of hospitalization, and reduce the need for calcium and vitamin D supplementation after discharge in high risk subjects after thyroid surgery.