Osteoporosis treatment guidelines recommend assessment for potential causes of secondary osteoporosis, however, there are limited data evaluating the yield of laboratory tests recommended for routine screening. The purpose of this study was to quantify the frequency of abnormal laboratory results indicative of secondary osteoporosis in patients referred to a Metabolic Bone Clinic with a diagnosis of low bone density or fracture. A retrospective chart review was conducted on 890 consecutive patients at a tertiary academic medical center from October 2018 to December 2021. Upon referral, patients were asked to complete a standardized set of laboratory tests, including comprehensive metabolic panel, 25OHD, PTH, thyroid testing, complete blood count, phosphorus, tissue transglutaminase antibodies, and 24-h urine calcium with creatinine. Among 890 patients, 67% of subjects had at least one laboratory abnormality. The most common abnormalities were of 25OHD and PTH with 22.4% and 19.1% of each test respectively showing abnormal results. Over 99% of serologic testing was completed; however, urine calcium testing was completed in only 34% of subjects. Among individuals who completed 24-h urine calcium testing (n = 304), 26.5% had hypocalciuria (<100 mg/24 h), and 25.2% had hypercalciuria (>250 mg/24 h). Subjects with a Z-score <-2.0 were more likely to have abnormal laboratory results. This study demonstrates that laboratory abnormalities indicating secondary osteoporosis are very common among patients with low bone density and fracture. Systematic laboratory testing with a circumspect number of tests is appropriate in all patients with skeletal fragility.

Background/Objective:Weight loss in individuals with obesity offers metabolic benefits but may increase fracture risk, potentially influenced by the modality of weight loss. This study aimed to compare fracture risk in patients with obesity treated with semaglutide or sleeve gastrectomy (SG) using a large, real-world electronic health record dataset. Methods:We conducted a retrospective cohort analysis from 2016 to 2023, using the Atropos Eos electronic health record dataset, representing over 161 million patients seen in community hospitals and large practices in the U.S. Fracture outcomes were compared between adults with obesity treated with semaglutide or SG, using high-dimensional propensity scoring to reduce confounding and enhance group comparability. Results:We identified 92 405 individuals treated with semaglutide and 16 082 with SG. After high-dimensional propensity score matching, there were 2887 individuals in each group. The mean age was 45 years. Most participants were female (78.5% semaglutide, 77.7% SG) and White (50.3% vs 48.9%, respectively). The Charlson Comorbidity Index was 1.9 for both groups. Over a mean follow-up of 3 years, the semaglutide group experienced 86 fractures (2.98%) compared to 128 (4.43%) in the SG group (hazard ratio 0.74, 95% confidence interval: 0.56-0.98; E-value: 1.2). Conclusion:Our results indicate a 26% lower fracture risk for the semaglutide group vs SG, suggesting it may help offset the increased fracture risk typically associated with intentional weight loss. However, further research is needed.

Hypercalcemia during pregnancy is a risk for adverse maternal and fetal consequences. Although primary hyperparathyroidism is by far the most common etiology of hypercalcemia in pregnancy, an array of other etiologies of hypercalcemia associated with pregnancy and lactation have been described. Parathyroidectomy continues to be the preferred treatment for primary hyperparathyroidism. Medical management options are limited.

Real-world osteoporosis screening and treatment rates remain low despite guideline recommendations. Crystal Bone is a novel artificial intelligence/machine learning algorithm developed using a large Optum de-identified electronic health record (EHR) dataset to identify patients likely experiencing a fracture within 2 years. This analysis tested the generalizability of Crystal Bone in three US EHR datasets. Patients ≥50 years old with ≥2 EHR International Classification of Diseases (ICD) codes, ≥2 years of consecutive EHR history, and ≥4 years of database time since their first EHR ICD code in Optum Care Reliant Medical Group dataset (December 2014 – November 2020), Stanford Health Care dataset (January 2010 – August 2021), and Intermountain Health dataset (January 2012 – May 2022) were included. The primary outcome was area under the receiver operating characteristic (AUROC) for fracture prediction. Eligible patients (n=106,328) in Reliant and a random test subset in Stanford (n=25,668) and Intermountain Health (n=43,000) were scored by Crystal Bone. AUROC ranged from 0.74 to 0.77 across datasets. As a pre-screening tool providing adjunctive information if further patient review/follow-up is needed, Crystal Bone, at fracture risk threshold of ~0.15 was associated with positive predictive value across datasets of 18%–26%, at which the burden of screening/follow-up versus fracture offset seemed reasonable; negative predictive value (96%–98%) and specificity (97%–99%) were high. Sensitivity (16%–21%) was similar to other fracture prediction models. Among 3,715 patients with Crystal Bone scores above 0.15 in all datasets, 38%–62% had no prior osteoporosis intervention and 8%–23% had no fracture history. Applying Crystal Bone to EHR data successfully identified patients at risk of fracture within 2 years, including those not detected previously. Automated fracture risk prediction by Crystal Bone demonstrated consistent accuracy and precision across three different US healthcare systems, supporting the generalizability of the algorithm.

Vitamin D toxicity is a rare cause of hypercalcemia, but must be considered in cases of hypercalcemia where parathyroid hormone is low. The clinical manifestations of vitamin D toxicity are due to hypercalcemia, which can be caused by excessive ingestion or unregulated endogenous production of 25-hydroxyvitamin D or the more active metabolite 1,25-dihydroxyvitamin D. A growing number of rare disorders capable of producing 1,25-dihydroxyvitamin D have been described. This chapter reviews the various forms of vitamin D toxicity, mechanisms of hypercalcemia due to vitamin D toxicity, clinical manifestations, diagnosis, and management.

Germline and somatic pathogenic variants in the CDC73 gene, encoding the nuclear protein parafibromin, increase the risk for parathyroid carcinoma and cause hereditary primary hyperparathyroidism (PHPT) syndromes known as familial isolated hyperparathyroidism (FIHP) and hyperparathyroidism-jaw tumor syndrome (HPT-JT). The identification of pathogenic germline variants in PHPT-susceptibility genes can influence surgical planning for parathyroidectomy, guide screening for potential syndromic manifestations, and identify/exonerate at-risk family members. Numerous types of pathogenic germline variants have been described for CDC73-related conditions, including deletion, truncating, missense, and splice site mutations. Here, we report identification of a non-coding germline CDC73 variant (CDC73 c.1155-3A > G), previously categorized as a variant of uncertain significance (VUS), in a family with HPT-JT. This variant, found in two family members with PHPT, altered CDC73 splicing in peripheral blood cells and disrupted parafibromin immunostaining in associated parathyroid adenomas, strongly evidencing its pathogenicity. Sestamibi scintigraphy yielded nondiagnostic localization results for both patients' parathyroid adenomas, consistent with prior studies suggesting lower sensitivity for small or cystic lesions. Our findings demonstrate key aspects of CDC73-related disorders, highlight the diagnostic value of RNA testing, and exemplify the importance of obtaining a thorough, three-generational family history.

Awareness of the causes of hypercalcemia is essential for timely diagnosis of calcium disorders and optimal treatment. Citrate is commonly used as an anticoagulant during continuous renal replacement therapy (CRRT). Accumulation of citrate in the systemic circulation during CRRT may induce several metabolic disturbances, including total hypercalcemia and ionized hypocalcemia. The aim of the present study is to increase awareness of citrate accumulation and toxicity as a cause of hypercalcemia by relating three cases and reviewing the pathophysiology and clinical implications. We utilized electronic health records to examine the clinical cases and outlined key studies to review the consequences of citrate toxicity and general approaches to management. Citrate toxicity is associated with high mortality. A safe threshold for tolerating hypercalcemia during citrate anticoagulation is not clearly defined, and whether citrate toxicity independently increases mortality has not been resolved. Greater attention to citrate toxicity as a cause of hypercalcemia may lead to earlier detection, help to optimize the management of systemic calcium levels, and foster interest in future clinical studies.

Abstract Disclosure: N. Shah: None. H. Galitzer: None. D. Sellmeyer: None. Data on the prevalence of laboratory abnormalities in individuals with osteoporosis is limited. The purpose of this study was to quantify the frequency of test results indicative of secondary osteoporosis in patients referred for skeletal fragility. A retrospective chart review was conducted on 653 consecutive patients referred for low bone density or fracture at Stanford Medical Center from October 2018 to December 2021. Patients were asked to complete a standardized set of laboratory tests including comprehensive metabolic panel, 25-hydroxyvitamin D (25OHD), parathyroid hormone (PTH), thyroid testing, complete blood count, phosphorus, celiac screening, and 24 hour urine calcium. Demographics, bone density, and laboratory results were extracted from the medical record; statistical analysis was performed using STATA. Subjects were 65 +/- 14 (mean+SD) years old. The majority were White (59%) or Asian (24%). Most (81%) were postmenopausal women, 10% were men >50 years old, 9% were men under 50 and premenopausal women. Of men over 50/postmenopausal women, 32% had osteopenia and 67% had osteoporosis. Among premenopausal women/men under age 50, 67% had Z-scores of −2 or less. Over 99% of serologic testing was completed; however urine calcium testing was completed in 46% of subjects. Overall, 66% of subjects had at least one lab abnormality. The most common abnormalities were of PTH and 25OHD with 20% of each test showing abnormal results. Anemia was present in 16% of subjects, alkaline phosphatase and TSH each were abnormal in approximately 11% of subjects; serum phosphorus and calcium each were abnormal in 5% and celiac testing was positive in 1.2% of subjects. Of 299 subjects who completed urine collections, 27% had hypocalciuria (<100 mg), 24% had hypercalciuria (>250 mg). There was no difference in the prevalence of laboratory abnormalities among individuals with Z-scores <=−2, p=0.14. CKD stage 3 or lower was present in 15% of subjects; this was not counted in the overall rates of lab abnormalities as it was anticipated this was known. The prevalence of any lab abnormality was higher (77% vs 64%) among subjects with eGFR<60, p=0.01. PTH was significantly higher in individuals with 25 OH vitamin D levels <30, p=0.006. This study reveals a high prevalence of laboratory abnormalities while screening for secondary osteoporosis. While urine collection can be cumbersome, the high prevalence (52%) of abnormal results demonstrates the importance of this test. The rate of celiac disease is low, however, these patients were asymptomatic other than low bone density and otherwise would be undiagnosed. Low Z-score did not predict lab abnormalities. Current guidelines do not provide consensus on laboratory testing for secondary etiologies of osteoporosis due to the paucity of data. This study highlights the importance of screening patients with metabolic bone disease to identify secondary contributors. Presentation: Thursday, June 15, 2023

Calcinosis cutis is defined as abnormal deposition of calcium salts in the skin and subcutaneous tissues. Dystrophic calcification, the most common form of calcinosis cutis, is associated with autoimmune connective tissue diseases. This condition is associated with severe pain and can affect the patient's quality of life and lead to long-term disability. Treatment is often challenging, and there is a very limited evidence base for potential treatments of calcinosis cutis associated with systemic sclerosis and dermatomyositis. Inkless tattoo is very similar to microneedling, a minimally invasive procedure stimulating the wound-healing cascade contributing to elastin and collagen formation as well as neovascularization. This technique has not been reported as a potential therapeutic option for calcinosis cutis. Here, we present a patient with calcinosis cutis in the setting of dermatomyositis that responded dramatically to inkless tattoo application. Our results support the need for future studies of microneedling in patients with this disorder.

CONTEXT:The adverse skeletal effects of Roux-en-Y gastric bypass (RYGB) are partly caused by intestinal calcium absorption decline. Prebiotics, such as soluble corn fiber (SCF), augment colonic calcium absorption in healthy individuals. OBJECTIVE:We tested the effects of SCF on fractional calcium absorption (FCA), biochemical parameters, and the fecal microbiome in a post-RYGB population. METHODS:Randomized, double-blind, placebo-controlled trial of 20 postmenopausal women with history of RYGB a mean 5 years prior; a 2-month course of 20 g/day SCF or maltodextrin placebo was taken orally. The main outcome measure was between-group difference in absolute change in FCA (primary outcome) and was measured with a gold standard dual stable isotope method. Other measures included tolerability, adherence, serum calciotropic hormones and bone turnover markers, and fecal microbial composition via 16S rRNA gene sequencing. RESULTS:Mean FCA ± SD at baseline was low at 5.5 ± 5.1%. Comparing SCF to placebo, there was no between-group difference in mean (95% CI) change in FCA (+3.4 [-6.7, +13.6]%), nor in calciotropic hormones or bone turnover markers. The SCF group had a wider variation in FCA change than placebo (SD 13.4% vs 7.0%). Those with greater change in microbial composition following SCF treatment had greater increase in FCA (r2 = 0.72, P = 0.05). SCF adherence was high, and gastrointestinal symptoms were similar between groups. CONCLUSION:No between-group differences were observed in changes in FCA or calciotropic hormones, but wide CIs suggest a variable impact of SCF that may be due to the degree of gut microbiome alteration. Daily SCF consumption was well tolerated. Larger and longer-term studies are warranted.

CONTEXT:Primary hyperparathyroidism and malignancy are the etiologies in 90% of cases of hypercalcemia. When these entities are not the etiology of hypercalcemia, uncommon conditions need to be considered. In 2005, Jacobs and Bilezikian published a clinical review of rare causes of hypercalcemia, focusing on mechanisms and pathophysiology. This review is an updated synopsis of rare causes of hypercalcemia, extending the observations of the original article.EVIDENCE ACQUISITION:Articles reporting rare associations between hypercalcemia and unusual conditions were identified through a comprehensive extensive PubMed-based search using the search terms "hypercalcemia" and "etiology," as well as examining the references in the identified case reports. We categorized the reports by adults vs pediatric and further categorized the adult reports based on etiology. Some included reports lacked definitive assessment of etiology and are reported as unknown mechanism with discussion of likely etiology.EVIDENCE SYNTHESIS:There is a growing understanding of the breadth of unusual causes of hypercalcemia. When the cause of hypercalcemia is elusive, a focus on mechanism and review of prior reported cases is key to successful determination of the etiology.CONCLUSIONS:The ever-expanding reports of patients with rare and even unknown mechanisms of hypercalcemia illustrate the need for continued investigation into the complexities of human calcium metabolism.

Hypercalcemia occurs in up to 30% of patients with malignancies and can be due to osteolysis by metastases, parathyroid hormone-related protein (PTHrP), excess 1,25-dihydroxyvitamin D (1,25(OH)(2)D) production or, rarely, ectopic parathyroid hormone (PTH) secretion. Hypercalcemia in non-Hodgkin's lymphoma has been described with elevations in PTHrP or, more commonly, excess 1,25(OH)(2)D production. We present the first case of a patient with new diagnosis of non-Hodgkin's lymphoma and severe hypercalcemia who was found to have concurrently elevated PTHrP and 1,25(OH)(2)D. In human studies, PTHrP has shown limited ability to stimulate 1,25(OH)(2)D production. To demonstrate that both PTHrP and 1,25(OH)(2)D were of tumor origin in our patient, tissue from her tumor underwent histochemical staining, demonstrating expression of both PTHrP and CYP27B1, indicating the presence of 1,25(OH)(2)D production in the tumor tissue. Our case illustrates the complexity of hypercalcemia in patients with underlying malignancy and highlights the importance of a thorough diagnostic workup for achievement of a successful therapeutic approach. In our patient, definitive chemotherapeutic treatment resulted in achievement and maintenance of normal calcium, PTHrP and 1,25(OH)(2)D levels 18 months after initial diagnosis. Hypercalcemia occurs in up to 30% of malignancies and can be due to several mechanisms. We present the first case of cosecretion of parathyroid hormone related peptide (PTHrP) and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) in a patient with non-Hodgkin's lymphoma and demonstrate that both PTHrP and 1,25(OH)(2)D were of tumor origin by immunohistochemical staining.