Features of patients and fracture risk in hypoparathyroidism; a single center study.

PURPOSE: Patients with hypoparathyroidism (hypoPT) have low bone turnover and high bone mineral density (BMD). However, data on fracture risk are conflicting. The objectives of this study were: 1. To describe clinical/biochemical characteristics of hypoPT patients followed at a single medical center. 2. To identify postsurgical hypoPT patients and investigate their fracture rate compared with gender/age-matched post-surgical normocalcemic patients. METHODS: Retrospective analysis of patient's medical records treated at the tertiary medical center in 2010-2021 identified by computerized medical database search. RESULTS: The cohort included 133 patients (91% women, mean age 64 ± 13 years) of whom 105 (79%) had post-thyroidectomy hypoparathyroidism and the remainder had an autoimmune/idiopathic/other etiology. Mean follow-up time was 21 ± 12 and 27 ± 12 years, respectively. The control group included 142 post-thyroidectomy patients without hypoparathyroidism. Patients in the postsurgical hypoparathyroidism group were older and had higher calcium and PTH levels at diagnosis than the non-surgical hypoPT patients. Comparing the postsurgical hypoPT and postsurgical normocalcemic control patients revealed a significantly higher BMD in the hypoPT group. Yet, fracture rates were 31% in the postsurgical hypoparathyroidism group and 21% in the control group (P = 0.1) over a similar median follow-up period (17 and 18.4 years, respectively). In both groups the most common fracture site was the spine (50% and 70%, respectively; p = 0.33), mainly nonclinical morphometric fractures. Higher phosphorus blood level was associated with increased fracture risk. CONCLUSIONS: The relatively high BMD in patients with postsurgical hypoparathyroidism is not associated with lower fracture risk. Silent morphometric fractures are quite common in this group of patients.

Denosumab is not associated with risk of malignancy: systematic review and meta-analysis of randomized controlled trials.

The immunomodulatory effects of denosumab have raised concerns for risk of malignancy. This meta-analysis of 25 randomized controlled trials (21,523 patients) shows similar risk of malignancy between denosumab (60 mg every 6 months, up to 48 months) and any comparator. Post-marketing surveillance may detect rare or late-occurring drug effects. Possible increased risk of malignancy in patients treated with denosumab has been concerned due to inhibition of the immune modulator receptor activator of nuclear factor κ-Β ligand (RANKL). We aimed to assess the risk of malignancy associated with denosumab treatment. PubMed and Cochrane Central Register of Controlled Trials were searched up to May 27, 2019 to include all randomized controlled trials of denosumab (60 mg every 6 months) versus any comparator. Trials using higher drug doses for prevention of skeletal-related events were excluded. Data were independently extracted by two reviewers and analyzed using a fixed-effect model to pool risk ratios (RRs) with 95% confidence intervals (CI). Twenty-five trials (21,523 patients) were included. The risk of malignancy was similar between denosumab and other comparators (absolute risk difference 0%, RR 1.08 [95% CI, 0.93-1.24], I2 = 0%). Sensitivity analysis based on adequate allocation concealment showed similar results. The risk of malignancy did not differ between groups in any of the subgroup analyses, including stratification by race, individual comparators, indications for treatment, and longer drug exposure (≥ 24 months, 9 studies). The risk ratio of malignancy-related death was similar between groups. Early concerns about a potential increased risk of malignancy resulting from an immunomodulatory effect of denosumab are not supported by evidence from this meta-analysis of 25 RCTs with drug exposure of up to 48 months. Since RCTs with longer observation for safety outcomes are not expected, post-marketing surveillance will be the main means for detection of rare or late-occurring events.

Denosumab-induced hypocalcemia in patients with osteoporosis: can you know who will get low?

Hypocalcemia was reported at low rates (0.05-1.7%) in denosumab-treated postmenopausal women with osteoporosis. This real-life study shows a 7.4% rate of denosumab-induced hypocalcemia in community-dwelling osteoporotic men and women. Pretreatment serum calcium and creatinine levels are major predictors for this complication. Serum-calcium monitoring may help to identify and prevent severe hypocalcemia. PURPOSE: RCTs have reported a 0.05-1.7% rate of hypocalcemia in denosumab-treated postmenopausal women with osteoporosis, but long-term real-life data are lacking. We assessed the rate of hypocalcemia in osteoporotic community-dwelling patients treated with denosumab. METHODS: A retrospective analysis was conducted based on medical records (2010-2018) from a large HMO. An albumin-adjusted serum calcium concentration lower than 8.5 mg/dL was defined as hypocalcemia. RESULTS: We included 2005 patients (93% women, mean age 76 ± 9 years). Hypocalcemia developed during treatment in 149 patients (7.4%; 1% less than 8 mg/dL): in 66 after 0.5-1 years; 48 after 1-2 years; 35 after > 2 years. On comparison of the hypocalcemic and normocalcemic patients, the strongest predictors of hypocalcemia were pretreatment levels of albumin-adjusted serum calcium (9.1 ± 0.4 vs. 9.4 ± 0.5 mg/dL, respectively; p < 0.05) and creatinine (0.9 ± 0.5 vs. 0.8 ± 0.3 mg/dL, respectively; p < 0.05). The hypocalcemia rate increased in parallel to a decrease in eGFR (p = 0.032 for the difference between eGFR ranges). Baseline calcium level ≤ 9.31 mg/dL predicted hypocalcemia with a sensitivity of 77% and specificity of 56%. A model of (- 2)*calcium + creatinine predicted hypocalcemia (3.7% when lower and 17.1% when higher than - 17.4). Gender, age, 25-hydroxyvitamin-D, parathyroid hormone, alkaline phosphatase, and whether denosumab was given as first or advanced line of osteoporotic therapy had no predictive value. CONCLUSION: Real-life rates of denosumab-induced hypocalcemia are higher than previously reported. Hypocalcemia might develop after each dose of denosumab in ongoing treatment. Adequate calcium and vitamin D supplementation are needed. Serum calcium monitoring is advised in high-risk patients for early detection of severe hypocalcemia.

Clinically silent chromaffin-cell tumors: Tumor characteristics and long-term prognosis in patients with incidentally discovered pheochromocytomas.

BACKGROUND: Chromaffin-cell tumors (CCT), a rare group of catecholamine producing endocrine neoplasms, are traditionally suspected and diagnosed in patients presenting with episodic hypertension, together with the classic triad of headache, sweating, and tachycardia. Asymptomatic CCT are increasingly diagnosed, frequently as "incidentalomas". We have conducted a multicenter retrospective study, to assess the characteristics of a group of patients with clinically silent CCT, compared with a group of patients with typical CCT. METHODS: Forty-three consecutive patients with CCT (24 with silent and 19 with typical tumors) have been retrospectively studied for a period of up to 20 yr (between 1989 and 2009); clinical picture, biochemical tests, as well as topographic and functional assessment were analyzed at diagnosis and periodically following treatment. Surgical samples were reviewed for neuroendocrine markers and for signs of invasiveness. RESULTS: Patients with clinically silent CCT were significantly older than the typical ones (56.3±3.4 vs 48.0±4.8 yr; p<0.05); 15 of them (63%) were completely asymptomatic, and 9 patients (37%) complained of non-specific abdominal symptoms. Hypertension was present in only 6 silent CCT patients (25%), it was well controlled [mean blood pressure (BP) 134/84 mmHg], and persisted after surgery in only 2 patients. Fourteen out of twenty-four silent CCT patients (58%) were managed pre-operatively with prophylactic combination of α and ß blockade, despite normal BP values. Clinically silent CCT were larger than typical CCT (mean diameter of 5.2±2.3 cm vs 4.6±1.5 cm, p<0.05) and secreted higher a mounts of normeta neph rines. All clinically silent CCT patients were defined as "cured" after surgery. CONCLUSION: Clinically silent CCT are more prevalent than previously reported. With an adequate pre-surgical diagnosis and patient preparation, the prognosis of silent tumors is usually excellent.

Subacute thyroiditis: clinical characteristics and treatment outcome in fifty-six consecutive patients diagnosed between 1999 and 2005.

OBJECTIVE: To identify predictive factors of clinical outcome of subacute thyroiditis. DESIGN: Retrospective case series of 56 consecutive patients treated in 3 outpatient clinics between 1999 and 2005. Medical records were reviewed for demographic data, seasonal disease distribution, laboratory and clinical course, treatment, and short-term outcome. MAIN OUTCOME: Mean age was 48.6+/-12 yr; 70% were females. Twenty-five percent had antithyroid antibodies and 9% had recurrent disease. Differences in occurrence by season were not significant (p=0.28). Ultrasound, performed in 35 patients, revealed thyroid nodules in 25 (median size, 17 mm). Ten patients received no treatment, and 43 received either non-steroidal anti-inflammatory drugs (NSAID) (no.=25) or glucocorticoids (no.=18); data for 3 patients were missing. Median disease duration was 77 days; mean peak free T4 (FT4) level was 43.7+/-25.3 pmol/l. A hypothyroid phase was documented in 31 patients, and remained permanent in 6. Peak FT4 level, but not erythrocyte sedimentation rate or clinical score, was positively correlated with the highest TSH level and with disease duration. Untreated patients had less severe clinical disease than treated patients, but a similar outcome. Patients given glucocorticoids had a shorter overall disease duration (p=0.03), with no differences in duration of hyperthyroidism, peak FT4 or highest TSH levels, compared with patients given NSAID. CONCLUSION: Subacute thyroiditis follows an unpredictable clinical course that is hardly affected by its clinical features or treatment.

Adrenal incidentaloma: clinical characteristics and comparison between patients with and without extraadrenal malignancy.

UNLABELLED: Adrenal incidentaloma (AI) is frequently found in patients with a history of malignancy and, as such, is not always considered a true incidental finding. OBJECTIVE: To compare the short-term clinical and biochemical behavior of adrenal incidentalomas between oncology and non-oncology patients. DESIGN: Retrospective comparative case series of 100 consecutive patients with adrenal incidentaloma, followed from 1995 to 2005 in the endocrinology clinic of a tertiary university medical center. MAIN OUTCOME: A history of malignancy was present in 32 patients. Median follow-up was 24 months. Mean tumor size was 24+/-10 mm. Endocrine evaluation yielded functional abnormalities in 12.2% (subclinical Cushing's 7.4%, Cushing's syndrome 1.1%, hyperaldosteronism 1.3%, pheochromocytoma 3.6%). During follow-up, adrenal function remained unchanged in all patients, but tumor growth was seen in 12.5%. Compared to the non-oncology patients, the oncology group had a higher mean age (67.5+/-9.6 vs 59.4+/-1.3 yr, p=0.001) and greater tumor growth (23.3% vs 7%, p=0.035), with no significant differences for tumor size, functional abnormalities, and extent of change in tumor size. Surgery was performed in 9 patients (3 oncologic) and revealed metastasis in one. None of the other patients had clinical or radiological findings suggesting adrenal malignancy. CONCLUSION: Our study suggests a similar clinical behavior of adrenal incidentaloma in oncology and non-oncology patients. More studies are needed to assist clinicians in selecting oncology patients with AI for whom a more conservative approach can be recommended.