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Glucocorticoid-induced osteoporosis is the most common cause of secondary osteoporosis; nonetheless, it remains an undertreated condition. Transplantation-induced osteoporosis encompasses a broad range of unique pathogenetic features with distinct characteristics dependent on the transplanted organ. Understanding the pathogenesis of bone loss is key to recommending osteoporosis therapy in these patients. This review summarizes recent advances and addresses current issues in these fields.

Introduction: Denosumab represents a realistic treatment option to increase bone mineral density in kidney transplant recipients (KTRs). It is still unknown how and at what extent posttransplantation bone disease and graft function influence the effects of denosumab on mineral metabolism indexes. In this study, we analyze risk factors of hypocalcemia and parathyroid hormone (PTH) increase after denosumab administration in eighteen de novo KTRs and its management before and after this treatment. Methods: We conducted a monocentric, observational, prospective study on de novo KTRs. All KTRs enrolled received a single 60 mg subcutaneous dose of denosumab every 6 months. Before kidney transplantation, no patients were treated with calcio-mimetic. After kidney transplantation and before antiresorptive therapy, no patients were treated with calcio-mimetic drugs and/or vitamin D receptor agonists, while all patients received nutritional vitamin D supplementation (from 1,000 IU to 1,500 IU daily). Results: Hypocalcemia was related to the degree of lumbar osteoporosis (p = 0.047); the increase in the PTH level was correlated to baseline bone turnover markers (bone alkaline phosphatase, serum osteocalcin, and β-C-terminal telopeptide), the 25 OH status, and eGFR. The introduction of calcitriol, after the PTH increase, in addition to cholecalciferol was necessary to ensure an adequate control of serum calcium and PTH during a follow-up of 15 months. Following the treatment with denosumab, it was observed an improvement of areal bone mineral density both at lumbar and femoral sites with a mean percentual increase of 1.74% and 0.25%, respectively. Conclusions: Denosumab is an effective treatment for bone disease in KTRs. In our study, the increase in PTH is not a transient event but prolonged throughout the follow-up period and requires continuous supplementation therapy with calcitriol.

Background: Hypoparathyroidism and pseudohypoparathyroidism are rare disorders of mineral metabolism which may be associated with soft tissue calcification in the basal ganglia in the brain, and occasionally the skin and other tissues. The basal ganglia are the most common sites of calcification in the central nervous system in these disorders, and were first associated with this manifestation in a report from the Mayo Clinic in 1939. The reasons why the basal ganglia are a common site of soft tissue calcification in these rare disorders has been a matter of investigation for many years. Findings: Due to recent increased understanding of phosphate transport and new insights gained from mRNA expression in the basal ganglia, the pathophysiology of basal ganglia calcification (BGC) is now clearer. There is evidence that the absence of parathyroid hormone in hypoparathyroidism may play a direct role, but this is clearly not the case in pseudohypoparathyroidism, which is associated with increased parathyroid hormone levels. Maintaining the calcium/phosphorus ratio as close to normal as possible, and maintaining normal serum phosphate levels, may help mitigate the progression of BGC. There is no evidence of regression of BGC with conventional treatment, and long-term data with adjunctive or replacement therapy with parathyroid hormone or its analogues are not yet available. Purpose of the review: This review will focus on the pathophysiology of BGC in hypoparathyroidism and pseudohypoparathyroidism, and review the proposed pathophysiologic mechanisms, as well as the clinical implications of BGC on patient quality of life.

The finding of an indeterminate adrenal mass at radiological investigations is a challenge for physicians. Complex diagnostic work-up, periodic follow-up, or surgical intervention are therefore needed to rule out malignant lesions. Tertiary care hospitals are provided with F-18-fludeoxyglucose (F-18-FDG) positron emission tomography (PET) and F-18-dihydroxyphenylalanine (F-18-DOPA) PET, which aid in the characterization of indeterminate adrenal masses. Nevertheless, the histopathological examination may be required to exclude malignancy or rare etiologies. A 54-year-old woman presented to our clinic 6 months after a cerebral hemorrhage. She was hypertensive and had recently discovered a left adrenal mass of 15 mm during an abdominal ultrasound. Contrast-enhanced CT, following adrenal protocol, revealed a 14-mm adrenal mass without characteristics suggestive of an adrenal adenoma. Tumor markers were negative. Functional tests excluded hormone hypersecretion. An F-18-DOPA PET was negative. An F-18-FDG PET showed mild uptake of both the adrenal glands, with a more circumscribed pattern in the left one (maximum standardized uptake value 5 4). As the clinical diagnosis was still indeterminate, we performed laparoscopic left adrenalectomy. The histopathological examination described a sclerosing angiomatoid nodular transformation (SANT) of the adrenal gland, a benign lesion already described as a rare occurrence only in the spleen. IgG4 levels were reduced. In conclusion, this is a report of a SANT of the adrenal gland, a novel entity that should be taken into consideration in the differential diagnosis of indeterminate adrenal masses at CT scan. Copyright (C) 2019 Endocrine Society

Objective: Patients with primary aldosteronism (PA) can present with high PTH levels and negative calcium balance, with some studies speculating that aldosterone could directly stimulate PTH secretion. Either adrenalectomy or mineralocorticoid receptor blockers could reduce PTH levels in patients with PA. The aim of this study was to assess the relationship between aldosterone levels and parathyroid hormone (PTH)-vitamin D-calcium axis in a cohort of patients with PA, compared with patients with nonsecreting adrenocortical tumors in conditions of vitamin D sufficiency. Methods: We enrolled a series of 243 patients retrospectively, of whom 66 had PA and 177 had nonsecreting adrenal tumors, and selected those with full mineral metabolism evaluation and 25(OH) vitamin D levels >20 ng/mL at the time of initial endocrine screening. The final cohort was composed of 26 patients with PA and 39 patients, used as controls, with nonsecreting adrenal tumors. The relationships between aldosterone, PTH levels, and biochemistries of mineral metabolism were assessed. Results: Aldosterone was positively associated with PTH levels (r = 0.260, P < .05) in the whole cohort and in the PA cohort alone (r = 0.450; P = .02). In the multivariate analysis, both aldosterone concentrations and urinary calcium excretion were significantly related to PTH levels, with no effect of 25(OH) vitamin D or other parameters of bone metabolism. Conclusion: PTH level is associated with aldosterone, probably independent of 25(OH) vitamin D levels and urinary calcium. Whether aldosterone interacts directly with the parathyroid glands remains to be established.

The first adjunctive hormone therapy for chronic hypoparathyroidism, recombinant human parathyroid hormone (1–84) (rhPTH(1–84)) was approved by the FDA in January 2015. Since the approval of rhPTH(1–84), growing interest has developed in other agents to treat this disorder in both the scientific community and among pharmaceutical companies. For several reasons, conventional therapy with calcium and activated vitamin D supplementation, magnesium supplementation as needed, and occasionally thiazide-type diuretic therapy remains the mainstay of treatment, while endocrinologists and patients are constantly challenged by limitations of conventional treatment. Serum calcium fluctuations, increased urinary calcium, hyperphosphatemia, and a constellation of symptoms that limit mental and physical functioning are frequently associated with conventional therapy. Understanding how conventional treatment and hormone therapy work in terms of pharmacokinetics and pharmacodynamics is key to effectively managing chronic hypoparathyroidism. Multiple questions remain regarding the effectiveness of PTH adjunctive therapy in preventing or slowing the onset and progression of the classical complications of hypoparathyroidism, such as chronic kidney disease, calcium-containing kidney stones, cataracts, or basal ganglia calcification. Several studies point toward an improvement in the quality of life during replacement therapy. This review will discuss current clinical and research challenges posed by treatment of chronic hypoparathyroidism. Key points: Conventional therapy with calcium and activated forms of vitamin D are currently the mainstays of treatment for most patients with chronic hypoparathyroidism. Hormone therapy can be administered through FDA-approved once-daily rhPTH(1–84), or off-label multiple-daily injections of teriparatide. The former is the only FDA-approved drug, with safety and efficacy supported by a randomized placebo-controlled trial and open-label long-term extension trial data. Twice-daily teriparatide has been used in children safely for up to 10 years. New pharmacological options that replace the deficient hormone wi ll likely be available within the next few years.

Since normocalcemic primary hyperparathyroidism (NHPT) was first defined at the Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism in 2008, many papers have been published describing its prevalence and possible complications. Guidelines for the management of this condition are still lacking, and making the diagnosis requires fulfillment of strict criteria. Recent studies have shown that intermittent oscillations of serum calcium just below and slightly above the normal limits are very frequent, therefore challenging the assumption that serum calcium must be consistently normal to make the diagnosis. There is debate if these variations in serum calcium outside the normal range should be included under the rubric of NHPT or, rather, a milder form of classical primary hyperparathyroidism. Innovative approaches to define NHPT have been proposed that still need to be validated in prospective studies. Non-classical complications, especially cardiovascular complications, have been associated with NHPT, indicating that hyperparathyroidism may be a cardiovascular risk factor. New associations between parathyroid hormone (PTH) and several other comorbidities have also been reported from observational studies, suggesting that excessive PTH secretion might cause tissue dysfunction independent of serum calcium. Heterogeneous studies using different definitions of NHPT, however, make it difficult to draw definitive conclusions regarding the role of PTH excess when complications other than osteoporosis or kidney stones are described. This review will focus on clinical aspects and suggest an approach to NHPT.

The advent of new insights into phosphate metabolism must urge the endocrinologist to rethink the pathophysiology of widespread disorders, such as primary hyperparathyroidism, and also of rarer endocrine metabolic bone diseases, such as hypoparathyroidism and tumor-induced hypophosphatemia. These rare diseases of mineral metabolism have been and will be a precious source of new information about phosphate and other minerals in the coming years. The parathyroid glands, the kidneys, and the intestine are the main organs affecting phosphate levels in the blood and urine. Parathyroid disorders, renal tubule defects, or phosphatonin-producing tumors might be unveiled from alterations of such a simple and inexpensive mineral as serum phosphate. This review will present all these disorders from a ‘phosphate perspective’.

Several classes of medications may accelerate bone loss, thereby increasing the risk of low-trauma fractures in older or younger patients with normal bone density, osteopenia, or osteoporosis. Clinicians should be aware of these possible pharmacologic causes of bone loss in order to prevent fractures, especially in patients considered to be at very high risk due to recent fractures, propensity to falls, and/or comorbidities. Glucocorticoids, aromatase inhibitors, and many other drugs administered for a variety of chronic diseases are often noted to be taken during medical visits, in both inpatient and outpatient encounters. Medical personnel should always review the reconciled medications to safeguard the bone health of patients. This chapter focuses on the most common medications that cause osteoporosis, with attention to clinical aspects and management strategies in these situations.

Context Hypoparathyroidism is characterized by low serum calcium, increased serum phosphorus, and inappropriately low or decreased serum parathyroid hormone, which may be associated with soft tissue calcification in the basal ganglia of the brain. Objective To assess the prevalence and factors involved in the pathophysiology of basal ganglia calcification (BGC) in the brain in chronic hypoparathyroidism and to evaluate proposed pathophysiologic mechanisms. Design Case-control study with retrospective review of medical records over 20 years. Setting Single academic medical center. Patients 142 patients with chronic hypoparathyroidism and computed tomography (CT) head scans followed between January 1, 2000 and July 9, 2020, and 426 age- and sex-matched controls with CT head scans over the same interval. Interventions None. Main Outcome Measures Demographic, biochemical, and CT head imaging findings, with semiquantitative assessment of volumetric BGC. Results The study found that 25.4% of 142 patients followed for a median of 17 years after diagnosis of chronic hypoparathyroidism had BGC, which developed at a younger age than in controls. BGC was 5.1-fold more common in nonsurgical patients and less common in postsurgical patients. Low serum calcium and low calcium/phosphate ratio correlated with BGC. Neither serum phosphorus nor calcium × phosphate product predicted BGC. Lower serum calcium was associated with greater volume of BGC. The extent of BGC varied widely, with nonsurgical patients generally having a greater volume and distribution of calcification. Conclusions BGC is associated with low serum calcium and low serum calcium/phosphate ratio, which may be related to severity of the disease, its etiology, or duration of treatment.

Background: Basal ganglia calcification (BGC) is a well-known complication of hypoparathyroidism. It is currently thought that increased serum phosphate or calcium x phosphate product may be major risk factors. However, the pathophysiology of BGC is still unclear, since the literature is largely based on limited case series or case reports. Methods: We identified a large cohort of patients with hypoparathyroidism diagnosed between 2000 and 2020 and evaluated those with head CT scans performed over this interval. Etiology and date of onset of hypoparathyroidism were determined by medical records review. All head CT scan images were reviewed to confirm radiology reports reporting BGC. We retrieved laboratory data within 10 years before the first head CT that showed incident BGC. Three age- and sex- matched controls with head CT scans were selected for each patient, and compared to the patients with hypoparathyroidism. Results: Of 1014 unique patients with a verified diagnosis of hypoparathyroidism, 142 had a head CT scan performed between 2000 and 2020. Head CT scans were performed for reasons unrelated to hypoparathyroidism in 96.5% of patients. In this cohort, 80.3% of patients (n=114) had post-surgical hypoparathyroidism. Age at which the first head CT in patients was done was 62±20.6 (range 11–97), and duration of hypoparathyroidism at the time of first head CT was 11.0±14.4 years (0–71). Prevalence of BGC in patients with hypoparathyroidism was 25.4% (n=36), as compared with 7.3% in the control group (31/426) (P

Normocalcemic primary hyperparathyroidism (NHPT) was first described over 10 years ago, but uncertainties still remain about its definition, prevalence, and rates of complications. As a result, consensus management guidelines for this condition have not yet been published. Several hypotheses have been proposed for the pathophysiology of NHPT, but it may be a heterogeneous disorder with multiple causes, rather than a single etiology that explains this biochemical phenotype. A common clinical concern is whether NHPT should be treated surgically when complications are already present at first recognition of the disorder, rather than following patients clinically over time. The literature on NHPT is based mostly on larger studies of population‐based cohorts and smaller studies from referral centers. Lack of rigorous diagnostic criteria and selection bias inherent in populations seen at tertiary referral centers may explain the heterogeneity of reported rates of bone and renal complications in relation to consistently mild laboratory alterations. Unresolved questions remain about the significance of NHPT when it is diagnosed biochemically without evident bone or kidney complications. Moreover, its natural history remains to be elucidated because a proportion of what is classified as NHPT may revert to normal spontaneously, thus revealing previously unrecognized secondary hyperparathyroidism. These issues indicate that caution should be used in recommending surgery for NHPT. This review will focus on recent issues regarding the pathophysiology, evaluation, and management of NHPT. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Background: Adrenal lipid-poor adenomas (LPA) are defined by high unenhanced density (≥ 10 HU), and absolute and relative contrast medium washout > 60% and > 40%, respectively, at computerized tomography (CT). To date, no thorough histopathological characterization has been performed in those frequent lesions (one-third of adrenal adenomas). Our aim was to analyze the histopathological characteristics of adrenal LPA. Methods: Patients with LPA (n = 57) were selected among consecutive subjects referred for an adrenal incidentaloma or ACTH-independent Cushing syndrome. FluoroDeoxyGlucose-Positron Emission Tomography (FDG-PET) was performed in 37 patients. In patients treated by adrenalectomy (n = 17), Weiss score and Lin–Weiss–Bisceglia score (in tumors composed entirely or predominantly of oncocytes) were calculated. Results: Radiological parameters did not differ among patients with ACTH-independent Cushing syndrome (n = 6) and those with adrenal incidentalomas associated with primary aldosteronism (n = 2), autonomous cortisol secretion (n = 14), or non-functioning (n = 35). Patients treated by adrenalectomy had larger tumors (28.9 ± 11.2 vs 17.3 ± 8.4mm, P < 0.001), higher CT unenhanced density (29.1 ± 11.0 vs 23.1 ± 9.0 HU, P = 0.043), and FDG-PET adrenal uptake (9.0 ± 6.4 vs 4.4 ± 2.3 SUV, P = 0.003) than non-operated ones. Oncocytic features > 75% of the tumor were detected in 12/17 cases (70.6%). Five of those showed borderline-malignant histopathological characteristics by Lin–Weiss–Bisceglia score. Among remaining non-oncocytic tumors, 1/5 had a Weiss score ≥ 3. Overall, 6/17 tumors (35.3%) had borderline-malignant potential. Radiological parameters were similar between patients with benign and borderline-malignant tumors. Conclusions: Adrenal LPA are a heterogeneous group of tumors, mostly composed of oncocytomas. Up to 1/3 of those tumors may have a borderline-malignant potential at histopathology.

Introduction: Post-radiation fractures of the femur (PRF) are difficult to treat and are associated with a high risk of delayed union and non-union. We report a series of patients affected by soft tissue sarcoma (STS) of the thigh, treated with limb-sparing surgery and perioperative radiotherapy (RT), to analyse post-radiotherapy femur fracture (FF) rate and its management. Material and methods: 547 patients treated with surgery and RT for a deep primary STS of the thigh were included. “Periosteal stripping” and “bone tangential resection” were performed in case of tumor invasion. In the case of complete bone involvement, the patient received its complete resection and econstruction. Results: Twenty-three (4.3%) patients underwent surgical procedures involving periosteum and cortical bone. In 11 (2.0%) patients a bone resection was required because of massive bone involvement. Six out of these 11 (54.5%) patients developed major complications (infection and aseptic loosening). At the time of STS excision, 11 patients (2.0%) underwent prophylactic intramedullary nailing (PIN). PRF occurred in 15 patients (3.0%) at a median follow up of 52months (range 3–151). Among patients who developed PRF, three were treated with a prosthesis (no complications) and eight nailing (7/8, 87.5% did not heal and developed a non-union). Conclusions: Given the potentially devastating complication of a PRF, PIN should be considered. We suggest prophylactic IM nail in patients at higher risk the time of STS excision. In other cases, IM nail can be postponed in the following years considering the prognosis.

Context Steroid profiling by mass spectrometry has shown implications for diagnosis and subtyping of adrenal tumors. Objectives To investigate steroid profiles and their cardiovascular correlates in a large cohort of patients with nonsecreting (NS) adrenal incidentalomas and autonomous cortisol secretion (ACS). Design Cohort study. Setting University hospital. Patients Patients (n = 302) with incidentally discovered adrenal masses, divided into unilateral adenoma and hyperplasia with ACS (n = 46 and n = 52, respectively) and NS (n = 120 and n = 84, respectively). Post–dexamethasone suppression test (DST) cortisol 50 nmol/L defined NS and ACS, respectively. Intervention Analysis of 10-steroid panel by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and clinical data (mean follow-up 39 months). Main Outcome Measures Difference in baseline and post-DST steroid profiles between groups. Correlation with cardiovascular profile. Results Patients with unilateral adenomas and ACS showed higher cortisol, 11-deoxycortisol, and corticosterone and lower dehydroepiandrosterone than those with NS adenomas. Patients with ACS hyperplasia showed higher cortisol and lower androgens in women than those with NS. Patients with ACS had reduced suppression of post-DST cortisol, 11-deoxycortisol, and corticosterone, irrespective of adrenal morphology. Post-DST cortisol and corticosterone were associated with higher prevalence of severe/resistant hypertension. Patients with ACS unilateral adenomas showed higher incidence of worsening of hypertensive disease and novel cardiovascular events than those with NS, with post-DST cortisol [hazard ratio (HR) 1.02; 95% CI, 1.01 to 1.03; P < 0.001] and baseline corticosterone (HR 1.06; 95% CI, 1.01 to 1.12; P = 0.031) among the main predictors. Conclusions Patients with adrenal incidentalomas showed different steroid profiles, depending on functional status and adrenal morphology, with implications for their cardiovascular status.

Objective: Primary aldosteronism is associated with higher cardiovascular morbidity as compared with essential hypertension. Vascular complications encompass myocardial infarction and cerebrovascular events. Aortic damage in primary aldosteronism has never been explored, although a few cases of ascending aorta aneurisms have been reported. Design and methods: We consecutively enrolled patients affected by primary aldosteronism (n = 45) and compared them with patients affected by essential hypertension (n = 47), on an outpatient setting. Echocardiographic data of patients with primary aldosteronism were collected during a mean follow-up of 3 years, in subjects who underwent adrenal surgery (n = 12) and those on mineralocorticoid receptor antagonists (n = 33). Results and conclusion: We found that patients with primary aldosteronism had larger ascending aorta diameters than those with essential hypertension before starting any specific treatment. Patients with primary aldosteronism did not show significant changes in the size of ascending aorta during a mean of 3 years of follow-up, irrespective of the type of treatment (medical vs. surgical treatment). A longer follow-up will better clarify if worsening of the aortic damage may be better prevented by surgery rather than by mineralocorticoid receptor antagonists.

Primary hyperaldosteronism (PA) has recently been demonstrated to be strictly associated to metabolic syndrome as compared with essential hypertension (EH). Besides, the characteristics of metabolic syndrome are different in PA compared to EH, as high fasting glucose is more frequent in the former condition. The adverse effect of excess aldosterone on insulin metabolic signaling has generated increasing interest in the role of hyperaldosteronism in the pathogenesis of insulin resistance and resistant hypertension. Moreover, aldosterone receptor antagonist therapy in diabetic and cardiopathic patients improved coronary flow. The aim of this review is to present recent knowledge about the relationship between aldosterone, insulin resistance and diabetes.

Epidemiological studies have shown that overweight and cancer are closely related, even though obesity alone does not apparently heighten cancer risk by the same amount. Given the low overall risk of all cancers with obesity, it is unlikely that obesity alone causes cancer, but should instead be considered as a tumor promoter. There are three main hypotheses that could explain how obesity might contribute to cancer development and growth: the inflammatory cytokines from adipose tissue hypothesis, the insulin resistance and hyperinsulinemia hypothesis, and the unopposed estrogen cancer hypothesis. The link between obesity and cancer is that adipocytes constitute a major component of the tumor microenvironment for breast and abdominally metastasizing cancers, promoting tumor growth. This review will mainly focus attention on the relationship between adipose tissue, estrogens, and cancer risk.