Autofluorescence-guided hemithyroidectomy in a low-volume thyroid institution with no experience in parathyroid surgery: randomized clinical trial.

BACKGROUND: Recent studies suggest that low-volume surgeons with no experience in parathyroid surgery are at increased risk of causing parathyroid gland damage during thyroid surgery. The aim of this RCT was to evaluate the impact of using autofluorescence in hemithyroidectomy on parathyroid gland identification and preservation in a low-volume institution with no experience in parathyroid surgery. METHODS: Patients referred for hemithyroidectomy were randomized 1 : 1 to either autofluorescence-guided hemithyroidectomy (the near-infrared autofluorescence group) or conventional hemithyroidectomy (the control group). The primary outcome was parathyroid gland identification rate. Secondary outcomes were the rate of parathyroid gland autotransplantation and the rate of inadvertent parathyroid gland excision. RESULTS: A total of 170 patients were randomized to either autofluorescence-guided hemithyroidectomy (84 patients) or conventional hemithyroidectomy (86 patients). In the near-infrared autofluorescence group, 81.0% of parathyroid glands were identified, compared with 57.0% in the control group (P < 0.001). Autofluorescence enabled parathyroid gland visualization before the naked eye in 46.3% of cases. Surgeons had lower confidence in the parathyroid gland identification process in the control group than in the near-infrared autofluorescence group (59.1% versus 87.5% respectively; P < 0.001). In the near-infrared autofluorescence group, the parathyroid gland autotransplantation rate was initially high, but declined over time. There was no difference in the rate of inadvertent parathyroid gland excision. CONCLUSION: Autofluorescence guidance significantly improved the parathyroid gland identification rate in hemithyroidectomy in a low-volume institution with no experience in parathyroid surgery and provided an increase in surgical confidence. The pattern of parathyroid gland autotransplantation in autofluorescence-guided surgery indicates the presence of a learning curve. REGISTRATION NUMBER: NCT05044351 (http://www.clinicaltrials.gov).

Damage to the parathyroid glands is common during thyroid surgery. The main reason for that is that they can be difficult to see during surgery. The aim of this study was to see if the use of a new near-infrared camera during thyroid surgery could make it easier to see the parathyroid glands. Patients, where removal of part of their thyroid gland was planned, were randomly assigned to one of two groups. In the first group, the near-infrared camera was used, whereas it was not used in the other group. When the near-infrared camera was used, more parathyroid glands were found and the surgeons felt more secure in their handling of parathyroid glands.

Hypoparathyroidism and mortality after total thyroidectomy: A nationwide matched cohort study.

OBJECTIVE: Total thyroidectomy (TT) carries a risk of hypoparathyroidism (hypoPT). Recently, hypoPT has been associated with higher overall mortality rates. We aimed to evaluate the frequency of hypoPT and mortality in patients undergoing TT in Denmark covering 20 years. DESIGN: Retrospective Cohort study. PATIENTS AND MEASUREMENTS: Using population-based registries, we identified all Danish individuals who had undergone TT between January 1998 and December 2017. We included a comparison cohort by randomly selecting 10 citizens for each patient, matched on sex and birth year. HypoPT was defined as treatment with active vitamin D after 12 months postoperatively. We used cumulative incidence to calculate risks and Cox regression to compare the rate of mortality between patients and the comparison cohort. We evaluated patients in different comorbidity groups using the Charlson Comorbidity Index and by different indications for surgery. RESULTS: 7912 patients underwent TT in the period. The prevalence of hypoPT in the study period was 16.6%, 12 months postoperatively. After adjusting for potential confounders the risk of death due to any causes (hazard ratio; 95% confidence intervals) following TT was significantly increased (1.34; 1.15-1.56) for patients who developed hypoPT. However, subgroup analysis revealed mortality was only increased in malignancy cases (2.48; 1.99-3.10) whereas mortality was not increased when surgery was due to benign indications such as goitre (0.88; 0.68-1.15) or thyrotoxicosis (0.86; 0.57-1.28). CONCLUSIONS: The use of active vitamin D for hypoPT was prevalent one year after TT. Patients with hypoPT did not have an increased risk of mortality following TT unless the indication was due to malignancy.

Hypoparathyroidism following total thyroidectomy: high rates at a low-volume, non-parathyroid institution.

Background: Hypoparathyroidism following total thyroidectomy is globally the most common complication to thyroid surgery. The reported complication rates vary widely and might be highly dependent on the surgical experience. In this study we aimed to evaluate the rate of hypoparathyroidism following primary total thyroidectomy at a low-volume institution that only performs thyroid surgery and does not have any experience with parathyroid surgery. Methods: Retrospective cohort study. All patients undergoing primary total thyroidectomy at the ENT-Department, Goedstrup Hospital, Denmark, over a 5-year period (2016-2020) were identified through the procedure codes for total thyroidectomy. Medical records, pathology reports, biochemical and medical histories were fully assessed for each patient. The primary endpoint was the rate of hypoparathyroidism- both immediate and permanent. Secondary outcomes were parathyroid gland identification rates, rates of parathyroid gland autotransplantation, and rates of inadvertent parathyroid gland excision. Results: A total of 89 patients were included in the final analysis. A total of 33 patients (37.1%) experienced immediate hypoparathyroidism following surgery, while 30 patients (33.7%) still were on active vitamin D two months postoperatively. One year following surgery, 28 patients (31.5%) were still on active vitamin D and were considered as having permanent hypoparathyroidism. Sixty-one percent of the parathyroid glands were identified intraoperatively, and 19% of the patients experienced parathyroid autotransplantation. Inadvertent parathyroid gland excision occurred for 21% of the patients and was associated with a significantly increased risk of permanent hypoparathyroidism (RR = 2.99; 95% CI: 1.36 - 6.62, p = 0.005). Conclusion: Both transient and permanent hypoparathyroidism following total thyroidectomy at a low-volume, non-parathyroid institution occurred with much higher frequencies than previously reported. The elevated rates were most likely due to the low-volume, non-parathyroid nature of the surgeons which in part was mirrored in low parathyroid gland identifications rates, and high rates of autotransplantation and inadvertent parathyroid gland excision.

Ectopic Cushing's syndrome from a corticotropin-releasing hormone-secreting medullary thyroid carcinoma: a rare pitfall of inferior petrosal sinus sampling.

Summary: This case report describes a rare presentation of ectopic Cushing's syndrome (CS) due to ectopic corticotropin-releasing hormone (CRH) production from a medullary thyroid carcinoma (MTC). The patient, a 69-year-old man, presented with symptoms of muscle weakness, facial plethora, and easy bruising. An inferior petrosal sinus sampling test (IPSS) demonstrated pituitary adrenocorticotrophic hormone (ACTH) secretion, but a whole-body somatostatin receptor scintigraphy (68Ga-DOTATOC PET/CT) revealed enhanced uptake in the right thyroid lobe which, in addition to a grossly elevated serum calcitonin level, was indicative of an MTC. A 18F-DOPA PET/CT scan supported the diagnosis, and histology confirmed the presence of MTC with perinodal growth and regional lymph node metastasis. On immunohistochemical analysis, the tumor cell stained positively for calcitonin and CRH but negatively for ACTH. Distinctly elevated plasma CRH levels were documented. The patient therefore underwent thyroidectomy and bilateral adrenalectomy. This case shows that CS caused by ectopic CRH secretion may masquerade as CS due to a false positive IPSS test. It also highlights the importance of considering rare causes of CS when diagnostic test results are ambiguous. Learning points: Medullary thyroid carcinoma may secrete CRH and cause ectopic CS. Ectopic CRH secretion entails a rare pitfall of inferior petrosal sinus sampling yielding a false positive test. Plasma CRH measurements can be useful in selected cases.

Total thyroidectomy: reduction in postoperative hypoparathyroidism.

Objective: Total thyroidectomy is associated with a high risk of postoperative hypoparathyroidism, mainly due to the unintended surgical damage to the parathyroid glands or their blood supply. It is possible that surgeons who also perform parathyroid surgery see lower rates of postoperative hypoparathyroidism. In a single institution, we investigated the effects of restricting total thyroidectomy operations for Graves' disease to two surgeons who performed both thyroid and parathyroid surgeries. We aimed to evaluate the rates of postoperative hypoparathyroidism in a 10-year period with primary attention toward patients with Graves' disease. Design: Retrospective cohort study from a single institution. Methods: We defined the rate of permanent hypoparathyroidism after total thyroidectomy as the need for active vitamin D 6 months postoperatively. Between 2012 and 2016, seven surgeons performed all thyroidectomies. From January 2017, only surgeons also performing parathyroid surgery carried out thyroidectomies for Graves' disease. Results: We performed total thyroidectomy in 543 patients. The rate of permanent hypoparathyroidism decreased from 28% in 2012-2014 to 6% in 2020-2021. For patients with Graves' disease, the rate of permanent hypoparathyroidism decreased from 36% (13 out of 36) in 2015-2016 to 2% (1 out of 56) in 2020-2021. In cancer patients, the rate of permanent hypoparathyroidism decreased from 30% (14 out of 46) in 2012-2014 to 10% (10 out of 51) in 2020-2021. Conclusion: Restricting thyroidectomy to surgeons who also performed parathyroid operations reduced postoperative hypoparathyroidism markedly. Accordingly, we recommend centralisation of the most difficult thyroid operations to centres and surgeons with extensive experience in parathyroid surgery. Significance statement: Thyroid surgery is performed by many different surgeons with marked differences in outcome. Indeed, the risk of postoperative permanent hypoparathyroidism may be very high in low-volume centres. This serious condition affects the quality of life and increases long-term morbidity and the patients develop a life-long dependency of medical treatments. We encountered a high risk of hypoparathyroidism after the operation for Graves' disease and restricted the number of surgeons to two for these operations. Further, these surgeons were experienced in both thyroid and parathyroid surgeries. We show a dramatic reduction in postoperative hypoparathyroidism after this change. Accordingly, we recommend centralisation of total thyroidectomy to surgeons with experience in both thyroid and parathyroid procedures.

Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A in Denmark 1930­2021: A Nationwide Population-Based Retrospective Study

Studies of primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia type 2A (MEN 2A) shows divergence in frequency, disease definition, reporting of clinical characteristics and traces of selection bias. This is a nationwide population-based retrospective study of PHPT in MEN 2A, suggesting a representative frequency, with complete reporting and a strict PHPT definition. The Danish MEN 2A cohort 1930-2021 was used. Of 204 MEN 2A cases, 16 had PHPT, resulting in a frequency of 8% (CI, 5-12). Age-related penetrance at 50 years was 8% (CI, 4-15). PHPT was seen in the American Thyroid Association moderate (ATA-MOD) and high (ATA-H) risk groups in 62% and 38% of carriers, respectively. Median age at PHPT diagnosis was 45 years (range, 21-79). A total of 75% were asymptomatic and 25% were symptomatic. Thirteen underwent parathyroid surgery, resulting in a cure of 69%, persistence in 8% and recurrence in 23%. In this first study with a clear PHPT definition and no selection bias, we found a lower frequency of PHPT and age-related penetrance, but a higher age at PHPT diagnosis than often cited. This might be affected by the Danish RET p.Cys611Tyr founder effect. Our study corroborates that PHPT in MEN 2A is often mild, asymptomatic and is associated with both ATA-MOD and ATA-H variants. Likelihood of cure is high, but recurrence is not infrequent and can occur decades after surgery.

Evaluating the Rising Incidence of Thyroid Cancer and Thyroid Nodule Detection Modes: A Multinational, Multi-institutional Analysis.

Importance: There is epidemiologic evidence that the increasing incidence of thyroid cancer is associated with subclinical disease detection. Evidence for a true increase in thyroid cancer incidence has also been identified. However, a true increase in disease would likely be heralded by an increased incidence of thyroid-referable symptoms in patients presenting with disease. Objectives: To evaluate whether modes of detection (MODs) used to identify thyroid nodules for surgical removal have changed compared with historic data and to determine if MODs vary by geographic location. Design, Setting, and Participants: This was a retrospective analysis of pathology and medical records of 1328 patients who underwent thyroid-directed surgery in 16 centers in 4 countries: 4 centers in Canada, 1 in Denmark, 1 in South Africa, and 12 in the US. The participants were the first 100 patients (or the largest number available) at each center who had thyroid surgery in 2019. The MOD of the thyroid finding that required surgery was classified using an updated version of a previously validated tool as endocrine condition, symptomatic thyroid, surveillance, or without thyroid-referable symptoms (asymptomatic). If asymptomatic, the MOD was further classified as clinician screening examination, patient-requested screening, radiologic serendipity, or diagnostic cascade. Main Outcomes and Measures: The MOD of thyroid nodules that were surgically removed, by geographic variation; and the proportion and size of thyroid cancers discovered in patients without thyroid-referable symptoms compared with symptomatic detection. Data analyses were performed from April 2021 to February 2022. Results: Of the 1328 patients (mean [SD] age, 52 [15] years; 993 [75%] women; race/ethnicity data were not collected) who underwent thyroid surgery that met inclusion criteria, 34% (448) of the surgeries were for patients with thyroid-related symptoms, 41% (542) for thyroid findings discovered without thyroid-referable symptoms, 14% (184) for endocrine conditions, and 12% (154) for nodules with original MOD unknown (under surveillance). Cancer was detected in 613 (46%) patients; of these, 30% (183 patients) were symptomatic and 51% (310 patients) had no thyroid-referable symptoms. The mean (SD) size of the cancers identified in the symptomatic group was 3.2 (2.1) cm (median [range] cm, 2.6 [0.2-10.5]; 95% CI, 2.91-3.52) and in the asymptomatic group, 2.1 (1.4) cm (median [range] cm, 1.7 [0.05-8.8]; 95% CI, 1.92-2.23). The MOD patterns were significantly different among all participating countries. Conclusions and Relevance: This retrospective analysis found that most thyroid cancers were discovered in patients who had no thyroid-referable symptoms; on average, these cancers were smaller than symptomatic thyroid cancers. Still, some asymptomatic cancers were large, consistent with historic data. The substantial difference in MOD patterns among the 4 countries suggests extensive variations in practice.

Outcome and prognosis after adrenal metastasectomy: nationwide study.

BACKGROUND: Data regarding adrenal metastasectomy are limited. Here, clinical outcomes, safety, and prognostic factors in patients undergoing adrenal metastasectomy were evaluated in a large nationwide study. METHODS: Patients undergoing adrenal metastasectomy between 2000 and 2018 were identified in the Danish National Pathology Registry. Medical records were reviewed to confirm eligibility and to collect clinical data. The primary outcome was overall survival (OS). Cox multivariable regression analyses were? adjusted for baseline factors. RESULTS: In total, 435 patients underwent adrenal metastasectomy; the primary cancer origins were renal (n = 195, 45 per cent), lung (n = 121, 28 per cent), colorectal (n = 50, 11 per cent), and other (n = 69, 16 per cent). The median (interquartile range; i.q.r.) age was 66 (59-71) years, and 280 (64 per cent) were men. The 5-year OS was 31 per cent. The 30-day mortality was 1.8 per cent. Complications were more frequent and severe in patients who underwent open surgery compared with laparoscopic surgery (Clavien-Dindo III-V, 31.5 per cent versus 11.8 per cent respectively, P < 0.001). Factors associated with poor survival included non-radical pR2 resection (hazard ratio (HR) 3.57, 95 per cent c.i. 1.96 to 6.48), tumour size more than 50 mm (HR 1.79, 95 per cent c.i. 1.26 to 2.52), lung cancer origin (HR 1.77, 95 per cent c.i. 1.31 to 2.40), open surgical approach (HR 1.33, 95 per cent c.i. 1.04 to 1.71), presence of extra-adrenal metastases (HR 1.31, 95 per cent c.i. 1.01 to 1.71), and increasing Charlson co-morbidity index factors (HR 1.14 per one-point increase, 95 per cent c.i. 1.03 to 1.27). CONCLUSION: Adrenal metastasectomy is safe and may result in long-term survival in a subset of patients. Non-radical resection, large tumour size, lung cancer origin, open approach, presence of extra-adrenal metastases, and co-morbidity were associated with inferior outcomes.

The effect of parathyroidectomy compared to non-surgical surveillance on kidney function in primary hyperparathyroidism: a nationwide historic cohort study.

BACKGROUND: Patients with primary hyperparathyroidism (pHPT) and impaired kidney function (estimated glomerular filtration rate (eGFR) < 60 mL/min) are offered parathyroidectomy (PTX) to protect them from further complications. Surprisingly, two recent uncontrolled cohort studies have suggested a further decrease in kidney function following PTX. We aimed to examine the effects of PTX compared to non-surgical surveillance on kidney function in pHPT patients. METHODS: Historic cohort study. From the Danish National Patient Registry (NPR) and major medical biochemistry laboratories in Denmark, we identified 3585 patients with biochemically confirmed pHPT among whom n = 1977 (55%) were treated with PTX (PTX-group) whereas n = 1608 (45%) were followed without surgery (non-PTX group). Baseline was defined as time of diagnosis and kidney function was re-assessed 9-15 months after PTX (PTX group) or 9-15 months after diagnosis (non-PTX group). RESULTS: At follow-up, eGFR had decreased significantly in the PTX- compared to the non-PTX-group (median - 4% vs. - 1%, p < 0.01). Stratification by baseline eGFR showed that the decrease was significant for those with a baseline eGFR value of 80-89 and > 90 mL/min, but not for those with lower eGFR values. Findings did not differ between patients with mild compared to moderate/severe hypercalcemia. However, after mutual adjustments, we identified baseline levels of calcium, PTH, and eGFR as well as age and treatment (PTX vs. no-PTX) as independent predictors for changes in kidney function. CONCLUSION: Compared to non-surgical surveillance, PTX is associated with a small but significant decrease in kidney function in pHPT patients with an initial normal kidney function.

Effect of Daily Vitamin D3 Supplementation on Muscle Health: An Individual Participant Meta-analysis.

BACKGROUND: The role of vitamin D on muscle health is debated. METHODS: An individual participant metanalysis of 4 randomized placebo-controlled trials, investigating short-term (3-9months) effects of vitamin D3 in moderate (2800 IU) to high (7000 IU) daily oral doses on muscle health and quality of life (QoL). Inclusion criteria were either obesity (n = 52), newly diagnosed primary hyperparathyroidism (n = 41), Graves' disease (n = 86), or secondary hyperparathyroidism (n = 81). RESULTS: Overall (n = 260) as well as in a subgroup analysis including only vitamin D insufficient [25(OH)D < 50 nmol/L] individuals (n = 176), vitamin D supplementation did not affect measures of muscle health (isometric muscle strength, Timed Up and Go test, chair rising test, body composition, and balance) or QoL. However, a beneficial effect was present on QoL (physical component score) in vitamin D deficient [25(OH)D < 25 nmol/L] individuals (n = 34). Overall, relative changes in 25(OH)D inversely affected maximum muscle strength in a dose-response manner. Stratified into body mass index 30 kg/m2, vitamin D supplementation had divergent effects on isometric muscle strength, with beneficial effects in obese individuals (n = 93) at knee flexion 90° (P = 0.04), and adverse effects in nonobese individuals (n = 167) at handgrip (P = 0.02), knee extension 60° (P = 0.03) and knee flexion 60° (P < 0.01). CONCLUSION: Overall, short-term treatment with moderate to high daily doses of vitamin D did not affect muscle health or QoL. A potential beneficial effect was present on muscle strength in severely obese individuals and on QoL in vitamin D deficient individuals. Subgroup analyses, however, suggested negative effects of large relative increases in p-25(OH)D.

Trends in Diagnosis of Noninvasive Follicular Thyroid Neoplasm With Papillarylike Nuclear Features and Total Thyroidectomies for Patients With Papillary Thyroid Neoplasms.

Importance: Increasing detection of early-stage papillary thyroid neoplasms without improvements in mortality has prompted development of strategies to prevent or mitigate overtreatment. Objective: To determine adoption rates of 2 recent strategies developed to limit overtreatment of low-risk thyroid cancers: (1) a new classification, noninvasive follicular thyroid neoplasm with papillarylike nuclear features (NIFTP), and (2) hemithyroidectomy for selected papillary thyroid carcinomas (PTCs) up to 4 cm in size. Design, Setting, and Participants: This is a cross-sectional analysis of 3368 pathology records of 2 cohorts of patients from 18 hospitals in 6 countries during 2 time periods (2015 and 2019). Participating hospitals were included from the US (n = 12), Canada (n = 2), Denmark (n = 1), South Korea (n = 1), South Africa (n = 1), and India (n = 1). The records of the first 100 patients per institution for each year who underwent thyroid-directed surgery (hemithyroidectomy, total thyroidectomy, or completion thyroidectomy) were reviewed. Main Outcomes and Measures: Frequency of diagnosis of NIFTP, PTCs, and thyroidectomies during the study period. Results: Of the 790 papillary thyroid neoplasms captured in the 2019 cohort, 38 (4.8%) were diagnosed as NIFTP. Diagnosis of NIFTP was observed in the US, South Africa, and India. There was minimal difference in the total proportion of PTCs in the 2015 cohort compared with the 2019 cohort (778 [47.1%] vs 752 [44.5%]; difference, 2.6% [95% CI, -16.9% to 22.1%]). The proportion of PTCs eligible for hemithyroidectomy but treated with total thyroidectomy in the 2 cohorts demonstrated a decreasing trend from 2015 to 2019 (341 of 453 [75.3%] vs 253 of 434 [58.3%]; difference, 17.0% [95% CI, -1.2% to 35.2%]). Conclusions and Relevance: Results of this cohort study showed that the 2 mitigation strategies for preventing overtreatment of early-stage thyroid cancer have had mixed success. The diagnosis of NIFTP has only been applied to a small proportion of thyroid neoplasms compared with expected rates. However, more patients eligible for hemithyroidectomy received it in 2019 compared with 2015, showing some success with this deescalation strategy.

C-11 methionine positron emission tomography scans improve the preoperative localization of pathologic parathyroid glands in primary hyperparathyroidism.

BACKGROUND AND OBJECTIVE: Preoperative localization of pathologic parathyroid glands is essential in the preparation of a parathyroidectomy. We evaluated the use of a C-11 methionine positron emission tomography/computed tomography scan in a 7-year period in selected patients with primary hyperparathyroidism. The indications to perform a C-11 methionine positron emission tomography/computed tomography were either persistent primary hyperparathyroidism after parathyroidectomy or inconclusive preoperative localization on ultrasound and sestaMIBI. METHODS: A group of 36 patients was referred for a C-11 methionine positron emission tomography/computed tomography. Biochemical data, pathology, and results of sestaMIBI were collected retrospectively. The primary hyperparathyroidism patients were divided into two groups. In group 1 (N = 17), the C-11 methionine positron emission tomography/computed tomography was performed before parathyroidectomy. In group 2 (N = 19), the C-11 methionine positron emission tomography/computed tomography was performed after unsuccessful parathyroidectomy and before a reoperation. RESULTS: Overall, in 30 of the 36 patients (83%), C-11 methionine positron emission tomography/computed tomography identified a true-positive pathologic parathyroid gland confirmed by an experienced pathologist, consistent with a positive predictive value of 91%. In group 1, 94% of the patients (N = 16) had pathologic parathyroid tissue identified by C-11 methionine positron emission tomography/computed tomography. This resulted in a clinical benefit in 13 patients (76%). In group 2, the benefit was slightly lower, as 74% of the patients (N = 14) had a true-positive C-11 methionine positron emission tomography/computed tomography scan resulting in a clinical benefit in nine patients (47%). CONCLUSIONS: In two selected groups of patients planned for an initial operation or reoperation of primary hyperparathyroidism and inconclusive conventional imaging, we found C-11 methionine positron emission tomography/computed tomography to give parathyroid surgeons a clinical benefit in the majority of cases, electing the patients for unilateral surgery.

Primary hyperparathyroidism and recurrent ventricular tachyarrhythmia in a patient with novel RyR2 variant but without structural heart disease.

It is important to consider calcium and parathyroid hormone levels in patients with recurrent VT/VF without any obvious cause of arrhythmia. In similar cases to gain rhythm control using isoprenaline and do comprehensive molecular-genetic. Diagnosis and surgery in case of parathyroid adenoma may be needed to obtain definite arrhythmia control.

Coordination of Fusion and Trafficking of Pre-osteoclasts at the Marrow-Bone Interface.

Fusion is the final osteoclast differentiation step leading to bone resorption. In healthy trabecular bone, osteoclast fusion is restricted to bone surfaces undergoing resorption, and necessarily requires site-specific recruitment of mononucleated pre-osteoclasts originating from the bone marrow. However, the spatiotemporal mechanism coordinating recruitment and fusion is poorly investigated. Herein we identify a collagen/vascular network as a likely structure supporting this mechanism. We therefore used multiplex immunohistochemistry and electron microscopy on human iliac crest bone samples, in combination with functional assays performed in vitro with osteoclasts generated from healthy blood donors. First, we found that putative pre-osteoclasts are in close vicinity of a network of collagen fibers associated with vessels and bone remodeling compartment canopies. Based on 3D-reconstructions of serial sections, we propose that this network may serve as roads leading pre-osteoclasts to resorption sites, as reported for cell migration in other tissues. Importantly, almost all these bone marrow pre-osteoclasts, but only some osteoclasts, express the collagen receptor OSCAR, which is reported to induce fusion competence. Furthermore, differentiating osteoclasts cultured on collagen compared to mineral show higher fusion rates, higher expression of fusogenic cytokines, and a CD47 plasma membrane distribution pattern reported to be typical of a pre-fusion state-thus collectively supporting collagen-induced fusion competence. Finally, these in vitro assays show that collagen induces high cell mobility. The present data lead to a model where collagen fibers/vasculature support the coordination between traffic and fusion of pre-osteoclasts, by serving as a physical road and inducing fusion competence as well as cell mobility.

Effect of Parathyroidectomy on Cardiovascular Risk Factors in Primary Hyperparathyroidism: A Randomized Clinical Trial.

CONTEXT: It remains unclear whether risk of cardiovascular diseases is increased in patients with mild (<1.45 mmol/L) to moderate (≥1.45 to 1.60 mmol/L) primary hyperparathyroidism (PHPT). OBJECTIVE: We aimed to determine the short-term effect of parathyroidectomy (PTX) on arterial stiffness, cholesterol levels, and blood pressure (BP). DESIGN: This study was a clinical trial randomly allocating patients to either PTX or a control group (no surgery). Follow-up was performed 3 months after surgery in the PTX group and 3 months after baseline in the control group. SETTING: University hospital. PARTICIPANTS: We recruited 79 patients with PHPT; 69 participants completed the study. MAIN OUTCOMES: Office and ambulatory 24-hour BP, pulse wave velocity (PWV), augmentation index, and fasting plasma cholesterol levels. RESULTS: At baseline, participants had a median level of ionized calcium of 1.41 mmol/L (range, 1.33 to 1.60 mmol/L) and PTH of 10.4 pmol/L (4.5 to 30.4 pmol/L). Median age was 64 years (range, 18 to 81) and 72% were females. Following PTX, plasma total cholesterol levels decreased significantly compared with the controls (P = 0.04). Changes in PWV, augmentation index, and ambulatory 24-hour BP did not differ between groups, except for an increase in ambulatory diastolic BP following PTX. However, in patients with baseline levels of ionized calcium ≥1.45 mmol/L, PWV decreased significantly in response to PTX compared with the control group (P = 0.03). CONCLUSION: PTX may decrease risk of cardiovascular diseases in PHPT by lowering total cholesterol levels, although ambulatory diastolic BP increases in response to surgery. Patients with moderate to severe hypercalcemia may benefit from PTX by a decrease in PWV.

Innervation is higher above Bone Remodeling Surfaces and in Cortical Pores in Human Bone: Lessons from patients with primary hyperparathyroidism.

Mounting evidence from animal studies suggests a role of the nervous system in bone physiology. However, little is known about the nerve fiber localization to human bone compartments and bone surface events. This study reveals the density and distribution of nerves in human bone and the association of nerve profiles to bone remodeling events and vascular structures in iliac crest biopsies isolated from patients diagnosed with primary hyperparathyroidism (PHPT). Bone sections were sequentially double-immunostained for tyrosine hydroxylase (TH), a marker for sympathetic nerves, followed by protein gene product 9.5 (PGP9.5), a pan-neuronal marker, or double-immunostained for either PGP9.5 or TH in combination with CD34, an endothelial marker. In the bone marrow, the nerve profile density was significantly higher above remodeling surfaces as compared to quiescent bone surfaces. Ninety-five percentages of all nerve profiles were associated with vascular structures with the highest association to capillaries and arterioles. Moreover, vasculature with innervation was denser above bone remodeling surfaces. Finally, the nerve profiles density was 5-fold higher in the intracortical pores compared to bone marrow and periosteum. In conclusion, the study shows an anatomical link between innervation and bone remodeling in human bone.

Huge variations in definition and reported incidence of postsurgical hypoparathyroidism: a systematic review.

PURPOSE: The reported incidence of post surgical hypoparathyroidism (HypoPT) varies greatly. Previous research suggests that the definition of HypoPT is not consistent in the literature. We therefore conducted a systematic review to investigate how HypoPT is defined and whether this definition, as well as the selected threshold for hypocalcemia affects the incidence. METHODS: Using a predefined search string we identified all articles in PubMed reporting on the incidence of postsurgical HypoPT from 1st January 2010 to January 2017. RESULTS: We identified 89 articles that employed 20 different definition of HypoPT. The incidence of HypoPT varied from 0.0% to 20.2%. The definitions were not associated with incidence of HypoPT. Use of prophylactic post-operative calcium supplements, however decreased the risk of HypoPT (p = 0.03), and there was a trend towards a lower risk of HypoPT when using a definition of hypocalcemia below lower limit of the reference range (p = 0.09). CONCLUSION: The large number of definitions of HypoPT, as well as the huge variation in incidence point to a problem suggests that the awareness of HypoPT should be raised. Use of prophylactic post-operative calcium supplements may decrease risk of HypoPT. This, however, may be due to reverse causality as awareness of the risk of HypoPT may promote the use of calcium supplementation.

Bone Microstructure in Response to Vitamin D3 Supplementation: A Randomized Placebo-Controlled Trial.

Vitamin D supplementation is often used in the prevention and treatment of osteoporosis, but the role of vitamin D has lately been questioned. We aimed to investigate the effect of 3 months of daily vitamin D3 supplementation (70 µg [2800 IU] vs. placebo) initiated in winter months on bone health. This study is a double-blinded placebo-controlled randomized trial. Bone health was assessed by bone turnover markers, DXA, HRpQCT, and QCT scans. The participants were 81 healthy postmenopausal women with low 25(OH)D (< 50 nmol/l) and high PTH levels (> 6.9 pmol/l) at screening. Vitamin D3 supplementation significantly increased levels of 25(OH)D and 1,25(OH)2D by 59 nmol/l and 19 pmol/l, respectively, whereas PTH was reduced by 0.7 pmol/l (all p < 0.0001). Compared with placebo, vitamin D3 did not affect bone turnover markers, aBMD by DXA or trabecular bone score. Vitamin D3 increased trabecular vBMD (QCT scans) in the trochanter region (0.4 vs. - 0.7 g/cm3) and the femoral neck (2.1 vs. - 1.8 g/cm3) pall < 0.05. HRpQCT scans of the distal tibia showed reduced trabecular number (- 0.03 vs. 0.05 mm-1) and increased trabecular thickness (0.001 vs. - 0.005 mm), as well as an improved estimated bone strength as assessed by failure load (0.1 vs. - 0.1 kN), and stiffness (2.3 vs. - 3.1 kN/mm pall ≤ 0.01). Changes in 25(OH)D correlated significantly with changes in trabecular thickness, stiffness, and failure load. Three months of vitamin D3 supplementation improved bone strength and trabecular thickness in tibia, vBMD in the trochanter and femoral neck, but did not affect aBMD.

Health-related quality of life improves 1 year after parathyroidectomy in primary hyperparathyroidism: A prospective cohort study.

OBJECTIVE: Impaired quality of life (QoL) in primary hyperparathyroidism (PHPT) is commonly present. Patients may complain about nonspecific neurocognitive symptoms which can be difficult to quantify. Two different disease-specific questionnaires have been developed, that is, the parathyroid assessment of symptoms score (PAS) and the primary hyperparathyroidism quality of life (PHPQoL). Using these two questionnaires, we assessed relationship between QoL and biochemical indices in PHPT and effects of parathyroidectomy (PTX). DESIGN: A prospective cohort study. METHODS: Patients with PHPT diagnosed from 2015 to 2017 were asked to answer the questionnaires before and 12 months after PTX. Biochemistry was obtained on both occasions. RESULTS: A total of 104 PHPT patients answered PAS and PHPQoL questionnaires at baseline, with a median age of 64 years (73% females). PHPQoL score correlated inversely with ionized calcium and PTH at baseline (P Ë‚ 0.04). Total PAS and PHPQoL score did not differ between those with and without osteoporosis, renal calcifications and impaired renal function. Based on levels of ionized calcium, PHPQoL differed significantly between patients with mild- and moderate-severe hypercalcemia (P = 0.01). Fifty-three patients answered PAS and PHPQoL 12 months after PTX showing an improved QoL at follow-up (Pall  Ë‚ 0.02). Stratifying patients into groups based on levels of ionized calcium showed a significantly improved PHPQoL score in patients with mild (˂1.45 mmol/L) as well as moderate-severe hypercalcemia (≥1.45 mmol/L) at follow-up (Pall  Ë‚ 0.03). CONCLUSION: Quality of life improved 12 months after PTX in PHPT patients. Impaired QoL seems to be associated with the degree of hypercalcemia rather than organ manifestations attributable to PHPT.

The effect of vitamin D3 supplementation on markers of cardiovascular health in hyperparathyroid, vitamin D insufficient women: a randomized placebo-controlled trial.

PURPOSE: Emerging data supports an association between parathyroid hormone (PTH) and aldosterone. It has been speculated, that potential adverse cardiovascular effects of vitamin D insufficiency may partly be caused by the development of secondary hyperparathyroidism with increased activity of the renin-angiotensin-aldosterone system (RAAS). We aimed to investigate the effect of normalizing vitamin D status and/or reducing PTH levels on RAAS activity and other markers of cardiovascular health. METHODS: In a double-blinded study during wintertime, we randomized 81 healthy postmenopausal women with secondary hyperparathyroidism (PTH > 6.9 pmol/l) and 25-hydroxy-vitamin D (25(OH)D) levels < 50 nmol/l to 12 weeks of treatment with vitamin D3 70 µg/day (2800 IU/day) or identical placebo. Markers of cardiovascular health were defined as changes in the plasma RAAS, glycated hemoglobin, lipids, and lipoproteins, blood pressure, vascular stiffness, heart rate, and cardiac conductivity. RESULTS: Compared to placebo, vitamin D3 treatment significantly increased plasma levels of 25(OH)D and 1,25(OH)2D by 230% (95% CI: 189-272%) and 58% (190-271%), respectively. Vitamin D3 treatment reduced PTH by 17% (11-23%), but did not reduce RAAS activity. Compared to placebo, vitamin D3 treatment increased plasma levels of high-density lipoproteins (HDL) by 4.6% (0.12-9.12%), but did not affect other measured indices. CONCLUSIONS: Vitamin D3 supplementation normalized vitamin D levels and reduced PTH. The supplement increased levels of HDL, but had no effects on RAAS activity or other indices of cardiovascular health.