PTH and adiposity.

Although PTH is best known for its role as a regulator of skeletal remodelling and calcium homeostasis, more recent evidence supports a role for it in energy metabolism and other non-classical targets. In this report, we summarize evidence for an effect of PTH on adipocytes. This review is based upon all peer-reviewed papers, published in the English language with PubMed as the primary search engine. Recent preclinical studies have documented an effect of PTH to stimulate lipolysis in both adipocytes and liver cells and to cause browning of adipocytes. PTH also reduces bone marrow adiposity and hepatic steatosis. Although clinical studies are limited, disease models of PTH excess and PTH deficiency lend support to these preclinical findings. This review supports the concept of PTH as a polyfunctional hormone that influences energy metabolism as well as bone metabolism.

Parathyroid hormone controls skeletal and circulating calcium levels. Its secretion by the 4 parathyroid glands is regulated primarily by the concentration of the ionized calcium level. The other major target organ for parathyroid hormone is the kidney where it conserves filtered calcium by effects on the renal tubules. While bone and the kidney are indisputably the main target organs for PTH, recent studies are pointing to systems and organs that can be shown also to respond to PTH. One of these systems that PTH appears to target is fat cells, an important storehouse for energy. This review summarizes what is known about PTH's effects to stimulate the production of energy from fat cells when present in excess or to reduce the production of energy when deficient.

Validity of the short-form five-item Problem Area in Diabetes questionnaire as a depression screening tool in type 2 diabetes mellitus patients.

AIMS/INTRODUCTION: Depression is prevalent in diabetes patients and associated with poor outcomes, but is currently underdiagnosed, with no firm consensus on screening methods. We evaluated the validity of the short-form five-item Problem Areas in Diabetes (PAID-5) questionnaire as a screening tool for depression, comparing it with the Beck Depression Inventory-II (BDI-II) and nine-item Patient Health Questionnaire (PHQ-9). MATERIALS AND METHODS: A total of 208 English-speaking adults with type 2 diabetes, recruited from outpatient clinics, completed the BDI-II, PHQ-9 and PAID-5 questionnaires in English. Cronbach's α was used for internal reliability. Convergent validity was examined with BDI-II and PHQ-9. Receiver operating characteristics analyses were used to identify optimal PAID-5 cut-offs for the diagnosis of depression. RESULTS: All three screening tools were highly reliable, with BDI-II, PHQ-9 and PAID-5 having a Cronbach's α of 0.910, 0.870 and 0.940, respectively. There was a good correlation between BDI-II and PHQ-9, with a correlation co-efficient (r) of 0.73; and a moderate correlation between PAID-5 and PHQ-9, and PAID-5 and BDI-II, with r of 0.55 and 0.55 respectively (P values <0.01). An optimal PAID-5 cut-off ≥9 corresponded to both a BDI-II cut-off >14 (sensitivity 72%, specificity 784%, area under the curve 0.809) and a PHQ-9 cut-off >10 (sensitivity 84%, specificity 74%, area under the curve 0.806). Using a PAID-5 cut-off ≥9, the prevalence of depressive symptoms was 36.1%. CONCLUSIONS: Depressive symptoms are prevalent in people with type 2 diabetes, with the degree of distress significantly related to the severity of depressive symptoms. PAID-5 is a valid and reliable screening tool, and a score ≥9 could prompt further confirmation for depression.

Discontinuing Denosumab: Can It Be Done Safely? A Review of the Literature.

Denosumab, which has been approved for the treatment of osteoporosis since 2010, is a fully humanised monoclonal antibody against a cytokine, receptor activator of nuclear factor kappa B ligand (RANKL), involved in bone resorption. Continued use of denosumab results in a potent and sustained decrease in bone turnover, an increase in bone mineral density (BMD), and a reduction in vertebral and hip fractures. The anti-resorptive effects of denosumab are reversible upon cessation, and this reversal is accompanied by a transient marked increase in bone turnover that is associated with bone loss, and of concern, an increased risk of multiple vertebral fractures. In this review, we outline the effects of denosumab withdrawal on bone turnover markers, BMD, histomorphometry, and fracture risk. We provide an update on recent clinical trials that sought to answer how clinicians can transition away from denosumab safely with follow-on therapy to mitigate bone loss and summarise the recommendations of various international guidelines.

Tolerability and Efficacy of Long-Term Medical Therapy in Primary Aldosteronism.

INTRODUCTION: Patients with primary aldosteronism (PA) have increased cardiovascular risk, and there are concerns about the efficacy of medical therapy. OBJECTIVE: We aimed to assess long-term tolerability and efficacy of medical therapy in PA patients. METHODS: We conducted a retrospective study on 201 PA patients treated with medical therapy (spironolactone, eplerenone, or amiloride) from 2000 to 2020 at 2 tertiary centers. Clinical and biochemical control and side effects were assessed. RESULTS: Among 155 patients on long-term medications, 57.4% achieved blood pressure (BP) <140/90 mmHg, 90.1% achieved normokalemia (48.0% potassium ≥4.3 mmol/L), and 63.2% achieved renin >1 ng/mL/h. Concordance of biochemical control using potassium and renin levels was 49.1%. Side effects were experienced by 52.3% of patients, with 10.3% switching, 22.6% decreasing dose, and 11.0% stopping medications. Risk factors for side effects were spironolactone use, dose ≥ 50 mg, treatment duration ≥1 year, male gender, and unilateral PA. Patients with unilateral PA used higher spironolactone doses vs bilateral (57 vs 50 mg, P < 0.001) and had more side effects (63.2% vs 41.8%, P = 0.008). Forty-six unilateral PA patients who underwent surgery after initial medical therapy experienced improved BP (systolic from 141 to 135 mmHg, P = 0.045; diastolic from 85 to 79 mmHg, P = 0.002). CONCLUSION: Dose-dependent side effects limit efficacy of medical therapy in PA. Future prospective studies should assess the best monitoring strategy for biochemical control during long-term medical therapy. For unilateral PA, surgery remains preferable, yielding better control with less long-term side effects.

Re-evaluating absent clinical success after adrenalectomy in unilateral primary aldosteronism.

BACKGROUND: Adrenalectomy cures unilateral primary aldosteronism, and it improves or cures hypertension. However, a significant proportion of patients are classified with absent clinical success postsurgery, suggesting that surgery was ineffective. METHODS: We assessed all patients 6 to 12 months post-surgery for clinical outcomes using Primary Aldosteronism Surgical Outcomes (PASO), AVIS-2, and CONNsortium criteria. We estimated blood pressure changes after adjustment for changes in defined daily dosages of antihypertensive medications. We also reassessed all patients using PASO at their recent clinical visit. RESULTS: A total of 104 patients with unilateral primary aldosteronism underwent adrenalectomy at 2 tertiary centers from 2000 to 2019; 24 (23%), 31 (30%), and 54 (52%) patients were classified with absent clinical success using PASO, AVIS-2, and CONNsortium criteria, respectively. Among 24 patients with absent clinical success using PASO criteria, 10 had complete biochemical cure, 3 partial, 2 absent, and 9 had resolution of hypokalemia. On multivariable analysis, absent clinical success was associated with presence of hyperlipidemia, diabetes mellitus, and lower defined daily dosages at baseline. After adjustment for changes in defined daily dosages, 7 of 24 patients showed blood pressure improvement ≥20/10 mm Hg post-surgery. After a follow-up of mean 5.6 years, 12 of 24 patients showed partial or complete clinical success when reassessed using PASO criteria. Only 6 of 104 (5.8%) patients failed to show clinical improvement post-surgery using any of the 3 mentioned criteria or using PASO criteria at their recent clinical visit. CONCLUSION: Although some patients may be classified with absent clinical success post-surgery, the assessment of clinical outcomes remains subject to many variables. In patients with unilateral primary aldosteronism, evidenced by lateralization on AVS, unilateral adrenalectomy should remain the recommended treatment.

Preoperative Localization for Primary Hyperparathyroidism: A Clinical Review.

With increasing use of minimally invasive parathyroidectomy (PTx) over traditional bilateral neck exploration in patients with primary hyperparathyroidism (PHPT), accurate preoperative localization has become more important to enable a successful surgical outcome. Traditional imaging techniques such as ultrasound (US) and sestamibi scintigraphy (MIBI) and newer techniques such as parathyroid four-dimension computed tomography (4D-CT), positron emission tomography (PET), and magnetic resonance imaging (MRI) are available for the clinician to detect the diseased gland(s) in the preoperative workup. Invasive parathyroid venous sampling may be useful in certain circumstances such as persistent or recurrent PHPT. We review the diagnostic performance of these imaging modalities in preoperative localization and discuss the advantages and weaknesses of these techniques. US and MIBI are established techniques commonly utilized as first-line modalities. 4D-CT has excellent diagnostic performance and is increasingly performed in first-line setting and as an adjunct to US and MIBI. PET and MRI are emerging adjunct modalities when localization has been equivocal or failed. Since no evidence-based guidelines are yet available for the optimal imaging strategy, clinicians should be familiar with the range and advancement of these techniques. Choice of imaging modality should be individualized to the patient with consideration for efficacy, expertise, and availability of such techniques in clinical practice.

Outcomes in unilateral primary aldosteronism after surgical or medical therapy.

CONTEXT: Studies find surgery superior to medications in the treatment of primary aldosteronism (PA). It would be ideal to compare surgical and medical therapy in patients with unilateral PA only, who have the option between these treatment modalities. However, this is challenging as most patients with unilateral PA on adrenal vein sampling (AVS) undergo surgery. OBJECTIVE: To compare outcomes of surgery and medications in patients with confirmed or likely unilateral PA. DESIGN: Retrospective cohort study of 274 patients with PA managed at two referral centres from 2000 to 2019. PATIENTS: 154 patients identified with unilateral PA using AVS and a validated clinical prediction model were treated with surgical (n = 86) or medical (n = 68) therapy. MEASUREMENTS: Primary outcome was a composite incident cardiovascular event comprising acute myocardial infarction, coronary revascularization, stroke, atrial fibrillation or congestive cardiac failure. Secondary outcomes were clinical and biochemical control. RESULTS: Cardiovascular outcomes were comparable, with the surgery group having an adjusted hazard ratio of 0.93 (95% CI: 0.32-2.67), p = .89. Both treatments improved clinical and biochemical control, but surgery resulted in better systolic blood pressure, 133.0 ± 11.7 mmHg versus 137.9 ± 14.6 mmHg, p = .02, and lower defined daily dosages of antihypertensive medications, 1.0 (IQR 0.0-2.0) versus 2.6 (IQR 0.8-4.3), p < .001. In addition, 12 of 86 patients in the surgery group failed medical therapy before opting for surgery. CONCLUSION: In patients with unilateral PA who can tolerate medications, medical therapy improves clinical and biochemical control, and may offer similar cardiovascular protection. However, surgery reduces pill burden, may cure hypertension and is recommended for unilateral PA.

Comparison of the Osteoporosis Self-Assessment Tool for Asians and the fracture risk assessment tool - FRAX to identify densitometric defined osteoporosis: A discriminatory value analysis in a multi-ethnic female population in Southeast Asia.

OBJECTIVES: The accuracy of FRAX® as a screening tool to identify osteoporosis and how it compares with tools such as Osteoporosis Self-Assessment Tool for Asians (OSTA), in Southeast Asian women has so far been unexplored. We aimed to determine the FRAX® thresholds that accurately identify densitometric osteoporosis and to compare its performance with that of OSTA for this purpose. METHODS: Singaporean postmenopausal women (n = 1056) were evaluated. FRAX® Major Osteoporotic Fracture Probability (MOFP), Hip Fracture Probability (HFP) scores, and OSTA indices were calculated. Receiver operating characteristic (ROC) curves were constructed and via the Youden index, the optimal cut-off points of balanced sensitivity and specificity for dual energy X-ray absorptiometry (DXA)-defined osteoporosis were identified and the performance characteristics were compared. RESULTS: A FRAX® MOFP threshold of ≥3.7% had sensitivity, specificity, positive predictive value and negative predictive value of 0.78 (0.73-0.83), 0.63 (0.59-0.66), 0.4 (0.36-0.44), and 0.9 (0.87-0.92), respectively in identifying osteoporosis. The corresponding values for a HFP threshold of ≥0.6% were 0.85 (0.80-0.89), 0.58 (0.55-0.62), 0.39 (0.35-0.43), and 0.92 (0.9-0.94) and that for an OSTA index cut-off of ≤ -1.2 were 0.76 (0.70-0.81), 0.74 (0.71-0.77), 0.48 (0.43-0.54), and 0.91 (0.88-0.93). The area under the ROC curves were 82.8% (79.9%-85.6%), 77.6% (74.2%-81%), and 79.6% (76.5%-82.8%) for OSTA, MOFP, and HFP thresholds respectively. CONCLUSIONS: FRAX® and OSTA perform comparably in identifying osteoporosis in our population. OSTA has only 2 parameters and may be simpler to use. However, FRAX® may also have a role in primary screening to identify the postmenopausal woman to be referred for DXA scanning and may help facilitate fracture risk reduction discussions with the patient.

Changes in Skeletal Microstructure Through Four Continuous Years of rhPTH(1-84) Therapy in Hypoparathyroidism.

Bone remodeling is reduced in hypoparathyroidism, resulting in increased areal bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) and abnormal skeletal indices by transiliac bone biopsy. We have now studied skeletal microstructure by high-resolution peripheral quantitative computed tomography (HR-pQCT) through 4 years of treatment with recombinant human PTH(1-84) (rhPTH[1-84]) in 33 patients with hypoparathyroidism (19 with postsurgical disease, 14 idiopathic). We calculated Z-scores for our cohort compared with previously published normative values. We report results at baseline and 1, 2, and 4 years of continuous therapy with rhPTH(1-84). The majority of patients (62%) took rhPTH(1-84) 100 µg every other day for the majority of the 4 years. At 48 months, areal bone density increased at the lumbar spine (+4.9% ± 0.9%) and femoral neck (+2.4% ± 0.9%), with declines at the total hip (-2.3% ± 0.8%) and ultradistal radius (-2.1% ± 0.7%) (p < .05 for all). By HR-pQCT, at the radius site, very similar to the ultradistal DXA site, total volumetric BMD declined from baseline but remained above normative values at 48 months (Z-score + 0.56). Cortical volumetric BMD was lower than normative controls at baseline at the radius and tibia (Z-scores -1.28 and - 1.69, respectively) and further declined at 48 months (-2.13 and - 2.56, respectively). Cortical porosity was higher than normative controls at baseline at the tibia (Z-score + 0.72) and increased through 48 months of therapy at both sites (Z-scores +1.80 and + 1.40, respectively). Failure load declined from baseline at both the radius and tibia, although remained higher than normative controls at 48 months (Z-scores +1.71 and + 1.17, respectively). This is the first report of noninvasive high-resolution imaging in a cohort of hypoparathyroid patients treated with any PTH therapy for this length of time. The results give insights into the effects of long-term rhPTH(1-84) in hypoparathyroidism. © 2020 American Society for Bone and Mineral Research.

Aldosterone-potassium ratio predicts primary aldosteronism subtype.

OBJECTIVE: Prediction models have been developed to predict either unilateral or bilateral primary aldosteronism, and these have not been validated externally. We aimed to develop a simplified score to predict both subtypes and validate this externally. METHODS: Our development cohort was taken from 165 patients who underwent adrenal vein sampling (AVS) in two Asian tertiary centres. Unilateral disease was determined using both AVS and postoperative outcome. Multivariable analysis was used to construct prediction models. We validated our tool in a European cohort of 97 patients enrolled in the SPARTACUS trial who underwent AVS. Previously published prediction models were also tested in our cohorts. RESULTS: Backward stepwise logistic regression analysis yielded a final tool using baseline aldosterone-to-lowest-potassium ratio (APR, ng/dl/mmol/l), with an area under receiver-operating characteristic curve of 0.80 (95% CI 0.70-0.89). In the Asian development cohort, probability of bilateral disease was 90.0% (with APR <5) and probability of unilateral disease was 91.4% (with APR >15). Similar results were seen in the European validation cohort. Combining both cohorts, probability of bilateral disease was 76.7% (with APR <5), and probability for unilateral was 91.7% (with APR >15). Other models had similar predictive ability but required more variables, and were less sensitive for identifying bilateral PA. CONCLUSION: The novel aldosterone-to-lowest-potassium ratio is a convenient score to guide clinicians and patients of various ethnicities on the probability of primary aldosteronism subtype. Using APR to identify patients more likely to benefit from AVS may be a cost-effective strategy to manage this common condition.

Supplemental calcium intake in the aging individual: implications on skeletal and cardiovascular health.

Adequate calcium intake during childhood is necessary to achieve optimal peak bone mass and this has the potential by increasing bone reserves, to modulate the rate of age-associated bone loss. However, data regarding the efficacy of calcium obtained either through the diet or in the form of medicinal supplementation, for prevention of bone loss and osteoporotic fractures in the elderly is conflicting. Calcium alone is unlikely to be of benefit for this purpose though the co-administration of calcium and vitamin D may have modest fracture risk benefits. Supplemental calcium with or without vitamin D has recently come into the spotlight after the publication of the findings from a controversial randomized controlled trial that associated calcium supplementation with an increased risk of myocardial infarction. Since then, multiple studies have explored this potential link. The data remains conflicting and the potential mechanistic link if any exists, remains elusive. This review examines the relationship between supplemental calcium intake and skeletal and cardiovascular health in the aging individual through an appraisal of studies done on the subject in the last three decades. It also briefly details some of the studies evaluating fractional absorption of calcium in the elderly and the rationale behind the current recommended dietary allowances of calcium.

Optimal dosing and delivery of parathyroid hormone and its analogues for osteoporosis and hypoparathyroidism - translating the pharmacology.

In primary hyperparathyroidism (PHPT), bone loss results from the resorptive effects of excess parathyroid hormone (PTH). Under physiological conditions, PTH has actions that are more targeted to homeostasis and to bone accrual. The predominant action of PTH, either catabolic, anabolic or homeostatic, can be understood in molecular and pharmacokinetic terms. When administered intermittently, PTH increases bone mass, but when present continuously and in excess (e.g. PHPT), bone loss ensues. This dual effect of PTH depends not only on the dosing regimen, continuous or intermittent, but also on how the PTH molecule interacts with various states of its receptor (PTH/PTHrP receptor) influencing downstream signalling pathways differentially. Altering the amino-terminal end of PTH or PTHrP could emphasize the state of the receptor that is linked to an osteoanabolic outcome. This concept led to the development of a PTHrP analogue that interacts preferentially with the transiently linked state of the receptor, emphasizing an osteoanabolic effect. However, designing PTH or PTHrP analogues with prolonged state of binding to the receptor would be expected to be linked to a homeostatic action associated with the tonic secretory state of the parathyroid glands that is advantageous in treating hypoparathyroidism. Ideally, further development of a drug delivery system that mimics the physiological tonic, circadian, and pulsatile profile of PTH would be optimal. This review discusses basic, translational and clinical studies that may well lead to newer approaches to the treatment of osteoporosis as well as to different PTH molecules that could become more advantageous in treating hypoparathyroidism.

AXIAL BMD IN DIABETIC AND NONDIABETIC SOUTHEAST ASIANS WITH HIP FRACTURES: DO RACE AND BODY MASS INDEX MATTER?

OBJECTIVE: Obesity is less prevalent in Asian subjects with type 2 diabetes mellitus (T2DM) in contrast to Caucasians. Whether higher axial bone mineral density (BMD) often reported in T2DM is independent of body mass index (BMI) has not been clearly shown. BMD characterization in T2DM patients with hip fractures has also not been performed. We compared the BMD of Asian diabetic and nondiabetic patients with new hip fractures and explored how BMD was influenced by BMI. METHODS: We included 255 diabetic and 148 nondiabetic patients. BMD adjusted for age; BMI; race; sex; renal function; and use of statins, proton pump inhibitors, steroids, anticonvulsants, and calcium and/or vitamin D supplements were compared between the groups. We were particularly interested in the BMD comparison between underweight diabetics and nondiabetics with hip fractures. RESULTS: The presence of T2DM was associated with higher BMD (g/cm(2)) at the femoral neck (0.527 ± 0.103 vs. 0.491 ± 0.102, P<.01) and lumbar spine [LS] (0.798 ± 0.147 vs. 0.723 ± 0.156, P<.01). This association persisted after adjustment for multiple confounding variables including BMI. The age-, BMI-, and sex-adjusted LS BMD was higher in underweight (BMI <18.5 kg/m(2)) diabetics compared to similar weight nondiabetics (0.733 ± 0.126 vs. 0.649 ± 0.131 g/cm(2), P = .014). CONCLUSION: T2DM is independently associated with higher axial BMD in patients with new hip fractures. The finding of higher BMD even in underweight diabetics with hip fractures compared to their nondiabetic counterparts suggests that higher BMD in subjects with T2DM is not due to higher BMI. ABBREVIATIONS: BMD = bone mineral density BMI = body mass index CV = coefficient of variation DXA = dual-energy X-ray absorptiometry HbA1c = glycated hemoglobin IGF-1 = insulin growth factor-1 LS = lumbar spine 25(OH)D = 25-hydroxyvitamin D T2DM = type 2 diabetes mellitus.