Management of Primary Hyperparathyroidism.

Since the last international guidelines were published in 2014 on the evaluation and management of primary hyperparathyroidism (PHPT), new information has become available with regard to evaluation, diagnosis, epidemiology, genetics, classical and nonclassical manifestations, surgical and nonsurgical approaches, and natural history. To provide the most current summary of these developments, an international group, consisting of over 50 experts in these various aspects of PHPT, was convened. This paper provides the results of the task force that was assigned to review the information on the management of PHPT. For this task force on the management of PHPT, two questions were the subject of systematic reviews using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology. The full report addressing surgical and nonsurgical management of PHPT, utilizing the GRADE methodology, is published separately in this series. In this report, we summarize the results of that methodological review and expand them to encompass a much larger body of new knowledge that did not specifically fit the criteria of the GRADE methodology. Together, both the systematic and narrative reviews of the literature, summarized in this paper, give the most complete information available to date. A panel of experts then considered the last set of international guidelines in light of the newer data and assessed the need for their revision. This report provides the evidentiary background to the guidelines report. In that report, evidence from all task forces is synthesized into a summary statement and revised guidelines for the evaluation and management of PHPT. © 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).

The evaluation and treatment of Paget's disease of bone.

Paget's disease of bone is a localized skeletal disorder, which is more common in England and in countries to which the English migrated. In recent decades, the prevalence in most countries has decreased. A family history of the disorder is present in approximately 15% of patients. Patients may be asymptomatic and may be diagnosed accidently as a consequence of an elevated serum alkaline phosphatase level or a finding on an x-ray or nuclear bone scan. The diagnosis is made by x-ray but nuclear bone scans define the extent of the disease. Salmon calcitonin and bisphosphonate drugs have proven effective, but by far, the most effective therapy is a single 5 mg intravenous infusion of zoledronic acid. This can normalize alkaline phosphatase levels for up to 6.5 years. A variety of gene mutations may predispose individuals to develop the disease but environmental factors such as measles virus likely play an important role.

Recent advances in the understanding and management of primary hyperparathyroidism.

Primary hyperparathyroidism is a hormonal disorder whose prevalence is approximately 1-2% in the United States of America. The disease has become more recognizable to clinicians in an earlier phase and, at present, patients can be diagnosed with "classic", "normocalcemic", "normohormonal", or "mild, asymptomatic" primary hyperparathyroidism. Surgery, with a focused parathyroidectomy when possible, or a four-gland exploration, is the only way to cure the disease. Cure is determined by use of intra-operative parathyroid hormone monitoring with long-term cure rates ranging from 90-95%. Newer adjuncts to surgery include CT or PET imaging and near-infrared immunofluorescence. This article highlights updates in parathyroid disease and advances in parathyroid surgery; it does not provide a comprehensive summary of the disease process or a review of surgical indications, which can be found in the AAES guidelines or NIH Symposium on primary hyperparathyroidism.

Recurrent primary hyperparathyroidism due to Type 1 parathyromatosis.

Parathyromatosis is a rare condition consisting of multiple nodules of benign hyperfunctioning parathyroid tissue scattered throughout the neck and superior mediastinum. As a potential cause of recurrent or persistent hyperparathyroidism, parathyromatosis is a challenging condition to diagnose and treat. The optimal evaluation and management of patients with parathyromatosis is not well established. The reported case involves a patient who was initially diagnosed with primary hyperparathyroidism. The diagnosis of Type 1 parathyromatosis was made after the patient developed recurrent hyperparathyroidism with hypercalcemia and osteoporosis 17 years after the initial operation and underwent two additional operations. The majority of parathyromatosis cases are diagnosed in the setting of secondary hyperparathyroidism. Consensus regarding the preoperative diagnosis and evaluation is lacking due to the paucity of cases of this rare clinical entity. Management involves complete surgical extirpation of all identifiable rests of parathyroid tissue. Intra-operative parathyroid hormone level monitoring and frozen section examination are excellent tools that could increase the rates of initial operative success. Despite this, long-term disease remission is rare, and medical therapy, including calcimimetics and bisphosphonates, may be required for postoperative or non-operative management.

Bone Quality in Paget's Disease of Bone.

Paget's disease of bone is produced by a localized increase in osteoclastic and osteoblastic activity which can progress slowly to involve an entire bone if untreated. A common feature is enlarged bones which are deformed, particularly in weight-bearing regions of the skeleton such as the lower extremity. Pathologic fractures may be a consequence, and nonunion of femoral fractures is not uncommon. Analyses of bone biopsies from patients with Paget's disease indicate that there is a lower, heterogeneous degree of bone mineralization and a younger tissue age than that found in control bone. Pagetic bone also has less resistance to plastic deformation and a straighter crack path than control bone.

Paget's disease of bone-genetic and environmental factors.

Paget's disease of bone is generally diagnosed in individuals aged >50 years, usually manifests in one or several bones and is initiated by osteoclast-induced osteolytic lesions. Subsequently, over a period of many years, osteoblastic activity can result in sclerosis and deformation of bone. The prevalence of Paget's disease is highest in the UK and in countries where a large number of residents have ancestors from the UK. Currently, in many countries, the prevalence of the disorder has decreased. A considerable number of affected patients have a family history of Paget's disease and the disorder has an autosomal dominant pattern of inheritance but with incomplete penetrance. A large number of mutations in SQSTM1 (which encodes sequestosome-1; also known as ubiquitin-binding protein p62) seem to account for the susceptibility to develop Paget's disease in some families; the involvement of other genes is currently under investigation. In addition to a genetic cause, environmental factors have been proposed to have a role in the pathogenesis of Paget's disease. Although most evidence has been presented for measles virus as an aetiologic factor, some studies have not confirmed its involvement. The decreasing incidence of Paget's disease, which could be attributed to measles vaccination along with the measles virus nucleocapsid protein induction of Paget's disease lesions in transgenic mice, supports an aetiologic role of the virus.

Paget's disease of bone: an endocrine society clinical practice guideline.

OBJECTIVE: The aim of this guideline was to formulate practice guidelines for the diagnosis and treatment of Paget's disease of the bone. PARTICIPANTS: The guideline was developed by an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize supporting evidence. CONCLUSIONS: We recommend that plain radiographs be obtained of the pertinent regions of the skeleton in patients with suspected Paget's disease. If the diagnosis is confirmed, we suggest that a radionucleotide bone scan be done to determine the extent of the disease. After diagnosis of Paget's disease, we recommend measurement of serum total alkaline phosphatase or, when warranted, a more specific marker of bone formation or bone resorption to assess the response to treatment or evolution of the disease in untreated patients. We suggest treatment with a bisphosphonate for most patients with active Paget's disease who are at risk for future complications. We suggest a single 5-mg dose of iv zoledronate as the treatment of choice in patients who have no contraindication. In patients with monostotic disease who have a normal serum total alkaline phosphatase, we suggest that a specific marker of bone formation and bone resorption be measured, although these may still be normal. Serial radionuclide bone scans may determine the response to treatment if the markers are normal. We suggest that bisphosphonate treatment may be effective in preventing or slowing the progress of hearing loss and osteoarthritis in joints adjacent to Paget's disease and may reverse paraplegia associated with spinal Paget's disease. We suggest treatment with a bisphosphonate before surgery on pagetic bone.

Characterization and management of testicular pathology in McCune-Albright syndrome.

CONTEXT: The testicular phenotype in McCune-Albright syndrome (MAS) has not been well characterized. Boys present with a relatively low incidence of precocious puberty in comparison with girls. Radiographic and histological studies are limited to small series and case reports, which report testicular microlithiasis and Sertoli cell hyperplasia. OBJECTIVE: Our objective was to characterize the biochemical, radiological, and histological spectrum and clinical management of testicular pathology in males with MAS. PATIENTS, DESIGN, AND SETTING: Fifty-four males with MAS participated in this prospective cohort study at a clinical research center. INTERVENTION: Evaluation included testicular exam, pubertal staging, testicular ultrasound, measurement of LH, FSH, and testosterone. Orchiectomies were performed when considered clinically indicated. MAIN OUTCOME MEASURE: Prevalence and characterization of ultrasound lesions with correlation to histology were evaluated. RESULTS: Of 54 males, 44 (81%) presented with ultrasound abnormalities including hyperechoic lesions (49%), hypoechoic lesions (30%), microlithiasis (30%), heterogeneity (47%), and focal calcifications (11%). Eight subjects underwent orchiectomy revealing large foci of Leydig cell hyperplasia, which could not be definitively distinguished from Leydig cell tumor. After no subjects developed clinical malignancy, a conservative approach was instituted, and subsequent subjects were followed with serial imaging. Testosterone and gonadotropins were normal in subjects without precocious puberty or pituitary disease. Eleven (21%) presented with precocious puberty, and a combination of aromatase inhibitors, androgen receptor blockers, and leuprolide resulted in improved predicted adult height. In addition, the first cases of testicular adrenal rest and bilateral germ cell tumors in association with MAS are presented. CONCLUSIONS: Contrary to prevailing thinking, the incidence of gonadal pathology in MAS is equal in males and females. The predominant histopathological finding was Leydig cell hyperplasia, which carries a low risk of malignant transformation and can be managed conservatively.

McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia.

Fibrous dysplasia (FD) is sometimes accompanied by extraskeletal manifestations that can include any combination of café-au-lait macules, hyperfunctioning endocrinopathies, such as gonadotropin-independent precocious puberty, hyperthyroidism, growth hormone excess, FGF23-mediated renal phosphate wasting, and/or Cushing syndrome, as well as other less common features. The combination of any of these findings, with or without FD, is known as McCune-Albright syndrome (MAS). The broad spectrum of involved tissues and the unpredictable combination of findings owe to the fact that molecular defect is due to dominant activating mutations in the widely expressed signaling protein, Gsα, and the fact these mutations arises sporadically, often times early in development, prior to gastrulation, and can distribute across many or few tissues.The complexity can be mastered by a systematic screening of potentially involved tissues and cognizance that the pattern of involved tissues is established, to some degree, in utero. Thorough testing allows the clinician to establish, often times at presentation, the full extent of the disease, and importantly as well what tissues are unaffected. Treatment and follow-up can then be focused on affected systems and a meaningful prognosis can be offered to the patient and family. The authors outline screening and treatment strategies that allow for effective management of the extraskeletal manifestations of FD.

The etiology of Paget's disease of bone: viral and genetic interactions.

Studies of the etiology of Paget's disease have focused separately on the viral and genetic components of the disease. In this issue of Cell Metabolism, Kurihara et al. (2011) join these components, reporting that sequestosome 1 mutation in patients and mice activates osteoclasts, while measles virus induces the phenotype of Paget's disease.

Metabolic bone disease: atypical femoral fractures.

Since 2005 reports have been published describing unusual femoral shaft fractures primarily in postmenopausal women treated for prolonged periods with a bisphosphonate drug for osteoporosis. In some patients pain develops in the femur prior to a completed fracture. Bilateral fractures have occurred in some patients. It is unclear whether oversuppression of bone cell activity is a major factor in the pathogenesis of the fractures, or whether these are a rare manifestation of the underlying bone disease. Such fractures do occur in other metabolic bone disorders in which there are marked abnormalities of bone structure.

Sentinel lymph node biopsy for papillary thyroid cancer: 12 years of experience at a single institution.

BACKGROUND: The purpose of this study was to report our experience with sentinel lymph node dissection (SLND) for papillary thyroid carcinoma, to evaluate the feasibility and safety of the procedure, and to examine its potential utility as a guide for central neck dissection. MATERIALS AND METHODS: A retrospective chart review of patients undergoing total thyroidectomy from January 1998 thru January 2010 was conducted. Intratumoral injection of blue dye was used to identify the SLN. Central neck dissection (CND) was performed if the SLN was positive on frozen section. Locally advanced disease, previous thyroid surgery, or lymphadenopathy on preoperative imaging or intraoperative palpation were exclusion criteria. RESULTS: A total of 211 patients underwent SLN mapping. Of these, 165 patients (78%) were female and 46 (22%) were male. Also, 75 (36%) were ≤45 years of age, and 136 (64%) were older than 45. Tumors were ≤2.0 cm (T1) in 142 patients (67%), 2-4 cm (T2) in 35 patients (17%), >4 cm with minimal invasion (T3) in 32 patients (15%), and locally invasive (T4) in 2 patients (1%). At least 1 blue node was found in 192 patients (91%). Also, 47 patients had a positive SLN on frozen section, with an additional 24 node-positive patients on permanent section, for a total of 71 (37%). There were 43 patients (91%) who underwent central neck dissection; 26 (60%) had additional metastases. CONCLUSIONS: Sentinel lymphadenectomy for papillary thyroid carcinoma is feasible, safe, and can identify patients who may benefit from central neck dissection.

Skeletal and hormonal effects of magnesium deficiency.

Magnesium (Mg) is the second most abundant intracellular cation where it plays an important role in enzyme function and trans-membrane ion transport. Mg deficiency has been associated with a number of clinical disorders including osteoporosis. Osteoporosis is common problem accounting for 2 million fractures per year in the United States at a cost of over $17 billion dollars. The average dietary Mg intake in women is 68% of the RDA, indicating that a large proportion of our population has substantial dietary Mg deficits. The objective of this paper is to review the evidence for Mg deficiency-induced osteoporosis and potential reasons why this occurs, including a cumulative review of work in our laboratories and well as a review of other published studies linking Mg deficiency to osteoporosis. Epidemiological studies have linked dietary Mg deficiency to osteoporosis. As diets deficient in Mg are also deficient in other nutrients that may affect bone, studies have been carried out with select dietary Mg depletion in animal models. Severe Mg deficiency in the rat (Mg at <0.0002% of total diet; normal = 0.05%) causes impaired bone growth, osteopenia and skeletal fragility. This degree of Mg deficiency probably does not commonly exist in the human population. We have therefore induced dietary Mg deprivation in the rat at 10%, 25% and 50% of recommended nutrient requirement. We observed bone loss, decrease in osteoblasts, and an increase in osteoclasts by histomorphometry. Such reduced Mg intake levels are present in our population. We also investigated potential mechanisms for bone loss in Mg deficiency. Studies in humans and and our rat model demonstrated low serum parathyroid hormone (PTH) and 1,25(OH)(2)-vitamin D levels, which may contribute to reduced bone formation. It is known that cytokines can increase osteoclastic bone resorption. Mg deficiency in the rat and/or mouse results in increased skeletal substance P, which in turn stimulates production of cytokines. With the use of immunohistocytochemistry, we found that Mg deficiency resulted in an increase in substance P, TNFalpha and IL1beta. Additional studies assessing the relative presence of receptor activator of nuclear factor kB ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG), found a decrease in OPG and an increase in RANKL favoring an increase in bone resorption. These data support the notion at dietary Mg intake at levels not uncommon in humans may perturb bone and mineral metabolism and be a risk factor for osteoporosis.

Paget disease: when to treat and when not to treat.

Paget disease of bone is a focal disorder of the skeleton that can affect one or more bones. Many patients are discovered accidentally because of elevated serum alkaline phosphatase activity or an abnormal skeletal radiograph intended to evaluate an unrelated condition. Patients are often asymptomatic, but a subset experience considerable morbidity that can include bone pain and skeletal deformity, as well as a variety of regional complications, such as hearing loss associated with cranial involvement, degenerative arthritis of the hip or knee, fractures of the lower extremities and, rarely, sarcoma or giant cell tumors. Bisphosphonates have proven to be effective in controlling disease activity because they inhibit osteoclast function. Administration of these agents can relieve bone pain, decrease biochemical markers of bone resorption and bone formation, and retard or reverse the early osteolytic phase of the disease. Future studies are needed to determine whether these drugs, if used in an early stage of the disease, can prevent complications in asymptomatic patients.

Multimarker circulating DNA assay for assessing blood of prostate cancer patients.

BACKGROUND: Prostate cancer (PCa) detection using serum-based prostate specific antigen (PSA) is limited by frequent false-positive and -negative results. Genetic aberrations such as allelic imbalance (AI) and epigenetic changes such as promoter hypermethylation have been detected in circulating DNA of cancer patients. We hypothesized that circulating multimarker DNA assays detecting both genetic and epigenetic markers in serum would be useful in assessing PCa patients. METHODS: We assayed blood from healthy male donors (n = 40) and 83 patients with American Joint Cancer Committee (AJCC) stage I-IV PCa. DNA was assayed for AI of 6 genome microsatellites. We assessed methylation of RASSF1, RARB2, and GSTP1 using a methylation-specific PCR assay and analyzed the sensitivity of each assay for the detection of genetic or epigenetic changes in circulating DNA. The relation between circulating tumor-related DNA detection and prognostic factors was investigated. RESULTS: The proportion of patients demonstrating AI for > or =1 marker was 47% (38 of 81 patients). Methylation biomarkers were detected in 24 of 83 patients (28%). By combining 2 DNA assays, the number of PCa patients positive for > or =1 methylated or LOH marker increased (52 of 83; 63%). The combined assays detected PCa in 15 of 24 patients (63%) with normal PSA concentrations. The combination of the DNA assays detected the presence of PCa regardless of AJCC stage or PSA concentration. Combination of the DNA and PSA assays gave 89% sensitivity. CONCLUSIONS: This pilot study demonstrates that the combined circulating DNA multimarker assay identifies patients with PCa and may yield information independent of AJCC stage or PSA concentration.