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Normocalcemic hyperparathyroidism (NHPT) is variably defined, and information regarding complications and natural history are scarce. We aimed to describe the phenotype of NHPT in relation to hypercalcemic hyperparathyroidism (PHPT) and controls, to determine risk of progression, and to develop a predictive model for progression to PHPT. This is a retrospective chart review of 232 patients at a tertiary medical center, comparing 75 controls, 73 patients with NHPT, and 84 with PHPT. NHPT was intermediate in biochemical profile between controls and PHPT with respect to cCa, iPTH, intraindividual coefficient of variant of cCa, phosphorus, and 25(OH)D. NHPT patients had an increased adjusted risk of urolithiasis (OR 5.34, 95%CI, 2.41-12.71, P  < .001) and fragility fractures (OR 4.53, 95%CI, 1.63-14.84, P  = .006) versus controls, after adjustment for age, sex, and BMI. Fewer NHPT compared with PHPTH patients achieved cure with parathyroidectomy (P  = .001). NHPT more often had nonlocalizing imaging or polyglandular disease (P  = .005). Parathyroidectomy improved biochemical but not BMD parameters in NHPT. Over a median follow-up of 4.23 (IQR 1.76-5.31) years, NHPT patients managed expectantly experienced no change in iPTH, and progression to PHPT occurred in 9%. An XGBoost model combining 6 factors for progression (mean index 2 iPTH, mean index 2 cCa, 24-h urinary calcium, age, 25(OH)D, and presence of urolithiasis) had an area under the curve 1.00 (95%CI, 1.00-1.00, P  < .001) for predicting combined progression. NHPT is a mild variant of PHPT at intermediate risk of urolithiasis and fragility fractures. Cure was less often achieved with parathyroidectomy, which did not improve BMD parameters. Progression was infrequent with conservative management. Because only a minority progressed to PHPT, in addition to lower surgical success rates, we suggest conservative management for the majority of NHPT unless risk factors for progression are identified. [ABSTRACT FROM AUTHOR]

Author(s): Joshua N Farr [1]; Ming Xu [1]; Megan M Weivoda [1]; David G Monroe [1]; Daniel G Fraser [1]; Jennifer L Onken [1]; Brittany A Negley [1]; Jad G [...]

Osteoporosis affects one in every five women over the age of 50 worldwide. With a rapidly ageing population, the prevalence of fragility fractures, considered a largely preventable consequence of osteoporosis, is expected to increase. Age is also a major risk for cardiovascular disease and mortality, thus highlighting the importance of cardiovascular profiling of osteoporosis interventions. Although calcium and vitamin D are essential for a healthy bone metabolism, excessive supplementation may be associated with increased risk. Conversely, early pre-clinical data have suggested a possible cardiovascular benefit from bisphosphonate therapy. This review evaluates the evidence behind the cardiovascular benefits and risks that may be associated with osteoporosis therapy. [ABSTRACT FROM AUTHOR]

Chronic hypoparathyroidism is characterized by low serum calcium, increased serum phosphorus, and inappropriately low or decreased serum parathyroid hormone. This rare disorder is associated with a variety of complications. The prevalence, incidence, mortality, financial burden, and epidemiology of complications of this disorder are not well understood. This narrative review summarizes current information on the epidemiology and complications of chronic hypoparathyroidism. The reported prevalence of chronic hypoparathyroidism ranges from 6.4–37/100,000, and the incidence is reported to be 0.8–2.3/100,000/year. Mortality is not increased in studies from Denmark or South Korea but was increased in studies from Scotland and Sweden. The financial burden of this disorder is substantial because of increased health care resource utilization in two studies but not well quantitated. Recognized complications include hypercalciuria, nephrocalcinosis, kidney stones, and chronic kidney disease; low bone turnover and possibly upper extremity fractures; cardiac and vascular calcifications; basal ganglia calcifications, cataracts, infections, neuropsychiatric complications, and difficulties with pregnancy. This review concludes that chronic hypoparathyroidism is a rare disorder associated with significant morbidity that may not increase overall mortality but is associated with a substantial financial burden. © 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). [ABSTRACT FROM AUTHOR]

Tumor- induced osteomalacia is a rare and often misdiagnosed condition that presents with progressively worsening unexplained chronic pain and proximal muscle weakness. The osteomalacia leads to multiple stress fractures which do not heal properly, leading to progressive disability. It is caused by chronic hypophosphatemia due to inappropriate urinary phosphate wasting. This is due to a typically benign mesenchymal tumor that over-secretes a phospaturic hormone. Neurologists need to appreciate the relevance of chronic hypophosphatemia in people with chronic unexplained pain, as timely diagnosis and treatment of tumour- induced osteomalacia can be curative. [ABSTRACT FROM AUTHOR]

With an increasingly older population, the proportion of patients 85 years or older seeking interventions to protect their musculoskeletal health is growing. Osteoporosis in the geriatric population presents unique diagnostic and therapeutic challenges. Multimorbidity, frailty, falls, polypharmacy, and other neurobehavioral factors influence our approach to fracture prevention in this population. The vast majority of the evidence from clinical trials establish pharmacologic fracture efficacy in postmenopausal women. The evidence is scarce for the oldest old men and women, a population also at risk for adverse events and mortality. Most studies show continued efficacy of pharmacologic interventions in this age group, although they are largely limited by small sample sizes. We herein review the available evidence of pharmacologic interventions for fracture risk reduction in this population and explore the emerging senotherapeutic interventions in the pipeline. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Context: The diagnosis of osteoporosis and assessment of fracture risk prior to a sentinel fracture was transformed by the widespread clinical use of dual-energy X-ray absorptiometry (DXA) for the assessment of bone mineral density (BMD).Evidence Acquisition: This review is based on a collection of primary and review literature gathered from a PubMed search of "dual energy X-ray absorptiometry," "trabecular bone score," and "atypical femur fracture" among other keywords. PubMed searches were supplemented by the authors' prior knowledge of the subject.Evidence Synthesis: While uncertainty exists for some aspects of osteoporosis care, patient and clinician familiarity with BMD assessment for screening and monitoring is firmly established. Beyond BMD, lateral spine images obtained with DXA can diagnose osteoporosis and refine fracture risk through the detection of unrecognized vertebral fractures. In addition, analysis of DXA lumbar spine images can reflect changes in trabecular bone microarchitecture, a component of bone "quality" that predicts risk of fracture independent of BMD. Finally, monitoring of bone health by DXA may be extended to include assessment of the femoral cortices for rare but serious adverse effects associated with antiresorptive therapies.Conclusions: Increasing technologic sophistication requires additional consideration for how DXA imaging is performed, interpreted and applied to patient care. As with any test, clinicians must be familiar with DXA performance, pitfalls in analysis, and interpretation within each clinical context in which DXA is applied. With this perspective, care providers will be well positioned to contribute to continuous improvement of DXA performance and, in turn, quality of osteoporosis care. [ABSTRACT FROM AUTHOR]

Context: Reduced bone material strength index (BMSi) and increased cortical porosity (CtPo) have emerged as potentially contributing to fracture risk in type 2 diabetes mellitus (T2DM) patients.Objective: To determine whether BMSi or CtPo are related to other diabetic complications.Design: Cross-sectional observational study.Setting: Subjects recruited from a random sample of southeast Minnesota residents.Participants: A total of 171 T2DM patients (mean age, 68.8 years) and 108 age-matched nondiabetic controls (mean age, 67.3 years).Main Measures: Bone material strength index was measured using microindentation, skin advanced glycation end-products (AGEs) measured using autofluorescence, high-resolution peripheral quantitative computed tomography at the distal radius and tibia, assessment of diabetic microvascular complications including urine microalbuminuria, retinopathy, neuropathy, and vascular disease (ankle brachial index and transcutaneous oxygen tension [TcPO2]). All analyses were adjusted for age, sex, and body mass index.Results: Skin AGEs were negatively correlated with the BMSi in both T2DM (r = -0.30, P < 0.001) and control (r = -0.23, P = 0.020) subjects. In relating diabetic complications to CtPo, we found that T2DM patients with clinically significant peripheral vascular disease (TcPO2 ≤ 40 mm Hg) had higher (+21.0%, P = 0.031) CtPo at the distal tibia as compared to controls; in these subjects, CtPo was negatively correlated with TcPO2 at both the distal tibia (r = -0.39, P = 0.041) and radius (r = -0.41, P = 0.029).Conclusions: Our findings demonstrate that bone material properties are related to AGE accumulation regardless of diabetes status, while CtPo in T2DM patients is linked to TcPO2, a measure of microvascular blood flow. [ABSTRACT FROM AUTHOR]

Author(s): Joshua N Farr; Ming Xu; Megan M Weivoda; David G Monroe; Daniel G Fraser; Jennifer L Onken; Brittany A Negley; Jad G Sfeir; Mikolaj B Ogrodnik; Christine M Hachfeld; [...]

Background: The objective of this study was to determine whether patients infected with extended-spectrum beta-lactamase (ESBL)-producing organisms are colonized at multiple body sites. Methods: This was a prospective cohort study at a tertiary care center in Beirut, Lebanon. Hospitalized patients with infections caused by ESBL-producing organisms were included. Cultures were obtained from the primary site of infection as well as from other sites (skin, nasopharynx, urine, rectum). Molecular analysis was performed on isolates to determine clonal relatedness. Results: One hundred patients were included in the study. Only 22 patients had positive cultures from sites other than the primary site of infection. The most common ESBL gene was CTX-M-15 followed by TEM-1. In 11 of 22 patients, isolates collected from the same patient were 100% genetically related, while in the remaining patients, genomic relatedness ranged from 42.9% to 97.1%. Conclusions: Colonization at sites other than the primary site of infection was not common among our patient population infected with ESBL-producing organisms. The dynamics of transmission of these bacterial strains should be studied in further prospective studies to determine the value of routine active surveillance and the need for expanded precautions in infected and colonized patients. [ABSTRACT FROM AUTHOR]

ABSTRACT Necrobiotic xanthogranuloma (NXG) is a rare systemic and progressive granulomatous disease first described in 1980. Given no established first-line therapy, treatment focuses on the control of skin lesions and associated complications. Despite it being a granulomatous disease, NXG has not been associated with hypercalcemia. About 140 cases of NXG have been reported to date but, to our knowledge, this is the first case to be complicated by hypercalcemia. Our case confirms a granulomatous disease-mediated production of 1α-hydroxylase leading to increased synthesis of 1,25-dihydroxyvitamin D and subsequent hypercalcemia. Based on this pathophysiology, we elected to start systemic glucocorticoids, titrated to clinical and metabolic response. Steroid-sparing agents need to be considered to avoid long-term complications but continue controlling this granulomatous disease. © 2017 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Hypocalcemia secondary to hypoparathyroidism is a rare cause of congestive heart failure. However, its early recognition and treatment lead to significant improvement in cardiac function. We report a middle-aged woman presenting with symptoms of heart failure with a serum calcium level of 3.7 mg/dl and a serum inorganic phosphate level of 17.6 mg/dl 22 years after subtotal thyroidectomy. Besides calcium and calcitriol supplementation, she was the first patient with severe hypocalcemic cardiomyopathy to be given off-label recombinant human parathyroid hormone (PTH) because of an elevated serum calcium-phosphate product. We discuss the management and outcome of the patient and then present a brief review of similar previously reported cases. We also describe the pivotal role of calcium ion and the potential role of PTH in maintaining myocardial contractility, effective natriuresis, and possible pathogenic mechanisms contributing to heart failure secondary to hypocalcemia and hypoparathyroidism. [ABSTRACT FROM AUTHOR]

Question In adults with type 1 diabetes mellitus treated with insulin, does canaglifozin add-on treatment increase the risk for diabetic ketoacidosis (DKA)? Methods Design Randomized placebo-controlled trial. ClinicalTrials.gov NCT02139943. Allocation Unclear allocation concealment.* Blinding Blinded* {study sites and sponsor}†. Follow-up period 18 weeks. Setting Not reported. Patients 351 patients 25 to 65 years of age {mean age 42 y, 56% men}† who had type 1 diabetes for ≥1 year, hemoglobin (Hb) A1c level 7.0% to 9.0% (53 to 75 mmol/mol), body mass index 21 to 35 kg/m², and were receiving a stable insulin regimen (multiple daily injections or continuous subcutaneous infusion) for ≥8 weeks. Exclusion criteria included history of type 2 diabetes mellitus; DKA or severe hypoglycemic event in the past 6 months; myocardial infarction, unstable angina, coronary revascularization, or cerebrovascular accident in the past 12 weeks; history of New York Heart Association class III to IV cardiac disease; uncontrolled hypertension; estimated glomerular filtration rate >70 mL/min/1.73 m²; or treatment with an antihyperglycemic other than insulin in the past 12 weeks. Intervention Canagliflozin, 100 mg (n=117), canagliflozin, 300 mg (n=117), or placebo (n=117) once/d before the first meal. Outcomes Safety outcomes included ketone-related adverse events (i.e., acidosis, blood ketone body increased, blood ketone body present, DKA, diabetic ketoacidotic hyperglycemic coma, ketoacidosis, ketonemia, ketonuria, ketosis, metabolic acidosis, or urine ketone body present) and serious DKA. Patient follow-up 93%† (modified intention-to-treat analysis). Main results Risks for any ketone-related adverse events and for serious DKA events requiring hospitalization were increased with canagliflozin compared with placebo (Table). Conclusion In patients with insulin-treated type 1 diabetes mellitus, canagliflozin increased diabetic ketoacidosis. [ABSTRACT FROM AUTHOR]

Objective: We aimed to describe the clinical characteristics of a large cohort of patients diagnosed with tumor-induced osteomalacia (TIO), with a focus on patients with non-localizing and malignant TIO., Methods: This is a retrospective cohort of TIO patients in an academic medical center, diagnosed between January 1998 to May 2023. We described their demographics, biochemistries, tumor features, localization, treatment and complications., Results: Of 68 patients diagnosed with TIO, 49 (72%) were localizing and 5 (7.4%) were malignant. Of 50 patients who attempted localizing procedures, 29 (58%) achieved cure. 20 (40%) had persistent disease due to wrong tumor targeted, or refractory or recurrent tumors, despite up to 6 procedural attempts. There was no difference in demographics, phosphorus or baseline fibroblast growth factor-23 (FGF23) levels between localizing versus non-localizing groups, and malignant versus non-malignant groups. Lower extremity was the commonest site of localization (37%), with 47% in bone and 53% in soft tissue. 60% of malignant cases were located in the trunk. Tumor size correlated with peak FGF23 (R=0.566, p<0.001) but was not associated with malignancy risk (p=0.479). A cut-off FGF23 of >20 times upper limit of normal in the presence of normal renal function (p=0.025), and recurrence after initial cure (p=0.013) were factors significantly associated with malignancy. The non-localizing group had lower survival than localizing group (p=0.0097)., Conclusions: TIO is a condition with significant morbidity. Very high FGF23 level and disease recurrence are associated with malignant disease. Reasons behind the observation of higher mortality in non-localizing TIO should be further explored., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In addition to reducing fracture risk, zoledronic acid has been found in some studies to decrease mortality in humans and extend lifespan and healthspan in animals. Because senescent cells accumulate with aging and contribute to multiple co-morbidities, the non-skeletal actions of zoledronic acid could be due to senolytic (killing of senescent cells) or senomorphic (inhibition of the secretion of the senescence-associated secretory phenotype [SASP]) actions. To test this, we first performed in vitro senescence assays using human lung fibroblasts and DNA repair-deficient mouse embryonic fibroblasts, which demonstrated that zoledronic acid killed senescent cells with minimal effects on non-senescent cells. Next, in aged mice treated with zoledronic acid or vehicle for 8 weeks, zoledronic acid significantly reduced circulating SASP factors, including CCL7, IL-1β, TNFRSF1A, and TGFβ1 and improved grip strength. Analysis of publicly available RNAseq data from CD115+ (CSF1R/c-fms+) pre-osteoclastic cells isolated from mice treated with zoledronic acid demonstrated a significant downregulation of senescence/SASP genes (SenMayo). To establish that these cells are potential senolytic/senomorphic targets of zoledronic acid, we used single cell proteomic analysis (cytometry by time of flight [CyTOF]) and demonstrated that zoledronic acid significantly reduced the number of pre-osteoclastic (CD115+/CD3e-/Ly6G-/CD45R-) cells and decreased protein levels of p16, p21, and SASP markers in these cells without affecting other immune cell populations. Collectively, our findings demonstrate that zoledronic acid has senolytic effects in vitro and modulates senescence/SASP biomarkers in vivo . These data point to the need for additional studies testing zoledronic acid and/or other bisphosphonate derivatives for senotherapeutic efficacy.

Background: The importance of exercise in skeletal health is increasingly recognized by both patients and providers. However, the safety of prescribed or recreational exercise in at-risk populations remains under-reported and under-publicized. Yoga has gained widespread popularity due to its physical and psychological benefits. When practiced in a population at increased fracture risk, however, some yoga poses may increase fracture risk, particularly at the spine, rather than increasing BMD as noted in recent popular press reports., Case Report: Nine subjects (8 women) with a median age of 66 years (range 53-87), developed vertebral compression fracture (VCF) one month to six years after initiating yoga-associated spinal flexion exercises (SFE). VCF presented with back pain and occurred in the thoracicspine (N.=6), lumbar-spine (N.=4) and cervical-spine (N.=1). Four patients had osteoporosis by BMD criteria prior to VCF and 2 had osteopenia (median T-score -2.35; range -3.3 to +2.0). Interestingly, all patients had their lowest T-scores at the spine. Three patients had a history of fragility fracture prior to the index VCF. While one patient had primary hyperparathyroidism and another was treated with high dose prednisone, no other risk factors for bone loss including medications or secondary osteoporosis causes were identified in the other patients., Clinical Rehabilitation Impact: This study identified patients in whom increased torsional and compressive mechanical loading pressures occurring during yoga SFE resulted in de novo VCF. Despite the need for selectivity in yoga poses in populations at increased fracture risk, both scientific and media reports continue to advertise yoga as a bone protective activity. Accordingly, yoga is misconceived as a 'onesize-fits-all' prescription. Instead, the appropriate selection of patients likely to benefit from yoga must be a cornerstone of fracture prevention.

Background: Limited guidance exists for selecting a laboratory method for diagnosing GH deficiency (GHD) when it occurs as a late effect of radiotherapy in childhood cancer survivors (CCSs)., Methods: We searched Medline, Embase, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus for studies evaluating GHD that used IGF-1 or IGF-binding protein 3 (IGFBP-3) measurements compared with GH dynamic testing., Results: We included 15 studies [IGF-1 (8 studies) and IGFBP-3 (7 studies)] enrolling 477 patients. Comparator tests varied widely. Overall, both IGF-1 and IGFBP-3 had suboptimal diagnostic accuracy but were strongly correlated. The use of both tests simultaneously in the same cohort did not improve the diagnostic accuracy. Despite high variability in the testing protocols, dynamic tests remained the most accurate for appropriately identifying patients with GHD. The insulin tolerance test (ITT) appears to be the most accepted reference test when used alone or in combination with arginine; however, standardized testing strategies among practice groups are absent. GHRH and arginine stimulation performed almost similarly to the ITT; however, in one study GHRH with arginine stimulation had 66% sensitivity and 88% specificity compared with the ITT. Insufficient data were available to assess the accuracy of serial GH testing (nocturnal or over 24 hours)., Conclusion: The diagnostic accuracy of various dynamic tests for GHD in CCSs appears to follow the same patterns as those in non-CCSs. Interpreting GHRH stimulation is a challenge given the primarily hypothalamic dysfunction in CCSs. IGF-1 and IGFBP-3 perform poorly in this population.

Background: GH deficiency (GHD) is common among childhood cancer survivors (CCSs) with history of tumors, surgery, and/or radiotherapy involving the hypothalamus-pituitary region. We aimed to evaluate the effects of GH therapy (GHT) in CCSs on adult height, risk of diabetes mellitus, abnormal lipids, metabolic syndrome, quality of life, secondary tumors, and disease recurrence., Methods: We searched multiple databases for randomized and observational studies. Pairs of reviewers independently selected studies and collected data. Random effects meta-analysis was used to pool outcomes across the studies., Results: We included 29 observational studies at moderate to high risk of bias. Sixteen studies compared CCSs on GHT with those not on GHT (512 patients, GH dose: 0.3 to 0.9 IU/kg/week). GHT was significantly associated with height gain [standard deviation score, 0.61; 95% CI, 0.08 to 1.13] and was not significantly associated with the occurrence of secondary tumors [odds ratio (OR), 1.10; 95% CI, 0.72 to 1.67] or tumor recurrence (OR, 0.57; 95% CI, 0.31 to 1.02). Thirteen studies compared CCSs on GHT with normal age- or sex-matched controls or controls with idiopathic GHD or short stature. GHT was associated with either improved or unchanged risk of diabetes, lipid profiles, and metabolic syndrome. GHT was associated with improvements in quality of life., Conclusion: CCSs treated with GHT gain height compared with the untreated controls. GHT may improve lipid profiles and quality of life and does not appear to increase the risk of diabetes or the development of secondary tumors, although close monitoring for such complications remains warranted due to uncertainty in the current evidence.

Objective: To introduce the use of qualitative assessment in energy expenditure (EE) equation research to improve the understanding of performance of the equations in the clinical setting., Patients and Methods: Hospitalized individuals who had an indirect calorimetry (IC) measurement during their hospital stay from 2010 to 2012 were included in the study (n = 59). An additional 1000 patients hospitalized during this time were used to limit the IC cohort to a more "clinically relevant" BMI range (n = 46). The following estimation equations were assessed: Harris-Benedict, 25 kcal/kg using actual body weight, Mifflin St. Jeor, Ireton-Jones, Penn State, and Owen. Bland-Altman plots with Loess curves were generated to compare estimated basal caloric needs between EE equations and IC values., Results: This study found a large amount of variability with all EE equations. As the mean calorie level increased, the Harris Benedict, Mifflin St. Jeor, Penn State, and Owen equations all tended to increasingly under-predict caloric need., Conclusion: In a research setting a qualitative assessment of EE equations can provide a more comprehensive understanding of equation performance by complementing traditional quantitative methods. The addition of a Loess curve to the Bland-Altman plot further enhances qualitative assessment., (Copyright © 2018 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)