Celiac disease and bone.

Celiac disease (CD) is an autoimmune disorder characterized by small intestinal inflammation triggered by gluten ingestion in genetically-predisposed individuals. A frequent extra-intestinal manifestation of CD is metabolic bone disease which contributes to an increased risk of fracture. The mechanisms underlying bone disease in CD remain incompletely understood, but multiple processes have been proposed including (1) malabsorption of calcium and vitamin D leading to secondary hyperparathyroidism and increased skeletal resorption, (2) pro-inflammatory cytokines altering the osteoprotegerin and receptor activator of nuclear kappa-B ligand ratio favoring osteoclastogenesis, (3) hypogonadism, and (4) low weight and malnutrition. Most studies show reduced bone mineral density in patients with CD. Bone microarchitecture is also deteriorated leading to reduced whole bone stiffness. Many, but not all investigations, have shown an increased risk of fracture associated with CD. The main stay of therapy for CD is maintaining a gluten-free diet. Improvement in bone mineral density with adherence to a gluten-free diet has been well-established. Bone mineral density remains lower, however, compared to controls and increased fracture risk can persist. There is no consensus on the timing of dual-energy x-ray absorptiometry for bone mineral density assessment in patients with CD. Routine screening for CD in patients with osteoporosis is not recommended. Little data are available on the use or efficacy of prescription osteoporosis therapeutics in patients with CD. Studies are needed to develop standardized guidelines for screening and treatment of metabolic bone disease in patients with CD to identify those who may need early intervention with prescription osteoporosis therapy.

Hypercalcemia: A Review.

Importance: Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma. Observations: Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival. Conclusions and Relevance: Mild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.

Celiac disease and bone

Abstract Celiac disease (CD) is an autoimmune disorder characterized by small intestinal inflammation triggered by gluten ingestion in genetically-predisposed individuals. A frequent extra-intestinal manifestation of CD is metabolic bone disease which contributes to an increased risk of fracture. The mechanisms underlying bone disease in CD remain incompletely understood, but multiple processes have been proposed including (1) malabsorption of calcium and vitamin D leading to secondary hyperparathyroidism and increased skeletal resorption, (2) pro-inflammatory cytokines altering the osteoprotegerin and receptor activator of nuclear kappa-B ligand ratio favoring osteoclastogenesis, (3) hypogonadism, and (4) low weight and malnutrition. Most studies show reduced bone mineral density in patients with CD. Bone microarchitecture is also deteriorated leading to reduced whole bone stiffness. Many, but not all investigations, have shown an increased risk of fracture associated with CD. The main stay of therapy for CD is maintaining a gluten-free diet. Improvement in bone mineral density with adherence to a gluten-free diet has been well-established. Bone mineral density remains lower, however, compared to controls and increased fracture risk can persist. There is no consensus on the timing of dual-energy x-ray absorptiometry for bone mineral density assessment in patients with CD. Routine screening for CD in patients with osteoporosis is not recommended. Little data are available on the use or efficacy of prescription osteoporosis therapeutics in patients with CD. Studies are needed to develop standardized guidelines for screening and treatment of metabolic bone disease in patients with CD to identify those who may need early intervention with prescription osteoporosis therapy. Arch Endocrinol Metab. 2022;66(5):756-64

Parathyroid Hormone and Cardiac Electrophysiology: A Review.

Calcium has long been known to be essential to cardiac electrical activity. Parathyroid hormone (PTH) is the main regulator of serum calcium and is central to calcium homeostasis. Although there are significant data linking parathyroid disease states with changes in cardiac electrophysiology, most data have focused on how PTH modulates serum calcium to produce these effects. Close scrutiny of early literature demonstrates that the relationship between PTH and electrocardiographic changes is not straightforward, and numerous studies have linked PTH to arrhythmia. Basic science research has demonstrated that there is a basis for a direct role of PTH on cardiac electrophysiology outside of its effect on serum calcium. Later studies in secondary hyperparathyroidism indicate that PTH disturbances could have important implications for broad categories of patients with cardiovascular disease. The current review summarizes the existing literature on PTH and electrophysiology based on clinical and basic science studies of various parathyroid states, providing directions for future study.

Risk of atrial fibrillation with use of oral and intravenous bisphosphonates.

Clinical studies suggest an association between bisphosphonate use and new-onset atrial fibrillation (AF). Intravenous bisphosphonates more potently increase the release of inflammatory cytokines than do oral bisphosphonates; thus, the risk of developing AF may be greater with intravenous preparations. We have evaluated incidence of new-onset AF with use of oral and intravenous bisphosphonates through a systematic review and meta-analysis of the literature. We searched PubMed, CINAHL, Cochrane Central Register of Controlled Trials, Scopus, and EMBASE databases for observational studies and randomized controlled trials (RCTs) published from 1966 to April 2013 that reported the number of patients developing AF with use of oral or intravenous bisphosphonates. The random-effects Mantel-Haenszel test was used to evaluate the relative risk of AF with use of oral and intravenous bisphosphonates. Nine studies (5 RCTs and 4 observational studies) were included in the final analysis. Pooled data from RCTs and observational studies (n = 135,347) showed a statistically significantly increased risk of new-onset AF with both intravenous (relative risk 1.40, 95% confidence interval 1.32 to 1.49) and oral (relative risk 1.22, 95% confidence interval 1.14 to 1.31) bisphosphonates. The z statistic, which assesses the difference between the 2 risk ratios, indicated higher risk of AF with intravenous bisphosphonates versus oral bisphosphonates (p = 0.03). In conclusion, pooled data from RCTs and observational studies suggest that risk of AF is increased by use of oral or intravenous bisphosphonates but further suggest that risk is relatively greater with intravenous preparations.

Nontraditional manifestations of primary hyperparathyroidism.

Classical primary hyperparathyroidism (PHPT) was previously a multisystemic symptomatic disorder not only with overt skeletal and renal complications but also with neuropsychological, cardiovascular, gastrointestinal, and rheumatic effects. The presentation of PHPT has evolved, and today most patients are asymptomatic. Osteitis fibrosa cystica is rarely seen today, and nephrolithiasis is less common. Gastrointestinal and rheumatic symptoms are not part of the clinical spectrum of modern PHPT. It remains unclear whether neuropsychological symptoms and cardiovascular disease, neither of which are currently indications for recommending parathyroidectomy (PTX), are part of the modern phenotype of PHPT. A number of observational studies suggest that mild PHPT is associated with depression, decreased quality of life, and changes in cognition, but limited data from randomized controlled trials (RCTs) have not indicated consistent benefits after surgery. The increased cardiovascular morbidity and mortality in severe PHPT has not been definitively demonstrated in mild disease, although there is some evidence for more subtle cardiovascular abnormalities, such as increased vascular stiffness, among others. Results from observational studies that have assessed the effect of PTX on cardiovascular health have been conflicting. The single RCT in this area did not demonstrate that PTX was beneficial. Despite recent progress in these areas, more data from rigorously designed studies are needed to better inform the clinical management of patients with asymptomatic PHPT.

Aortic valve calcification in mild primary hyperparathyroidism.

CONTEXT: It is unclear whether cardiovascular disease is present in primary hyperparathyroidism (PHPT). OBJECTIVE: Aortic valve structure and function were compared in PHPT patients and population-based controls. DESIGN: This is a case-control study. SETTING: The study was conducted in a university hospital metabolic bone disease unit. PARTICIPANTS: We studied 51 patients with PHPT and 49 controls. OUTCOME MEASURES: We measured the aortic valve calcification area and the transaortic pressure gradient. RESULTS: Aortic valve calcification area was significantly higher in PHPT (0.24 ± 0.02 vs. 0.17 ± 0.02 cm(2), p<0.01), although there was no difference in the peak transaortic pressure gradient, a functional measure of valvular calcification (5.6 ± 0.3 vs. 6.0 ± 0.3 mm Hg, P = 0.39). Aortic valve calcification area was positively associated with PTH (r = 0.34; P < 0.05) but not with serum calcium, phosphorus, or 25-hydroxyvitamin D levels or with calcium-phosphate product. Serum PTH level remained an independent predictor of aortic valve calcification area after adjustment for age, sex, body mass index, smoking status, history of hypercholesterolemia and hypertension, and estimated glomerular filtration rate. CONCLUSIONS: Mild PHPT is associated with subclinical aortic valve calcification. PTH, but not serum calcium concentration, predicted aortic valve calcification. PTH was a more important predictor of aortic valve calcification than well-accepted cardiovascular risk factors.