Neuropsychiatric Comorbidity in Primary Hyperparathyroidism Before and After Parathyroidectomy: A Population Study.

BACKGROUND: Primary hyperparathyroidism (PHPT) is often accompanied by neuropsychiatric symptoms. This study aimed to map out psychiatric comorbidity as reflected by medical treatment for psychiatric symptoms. METHODS: A retrospective case-control analysis and a prospective cohort analysis of psychotropic drug utilization before and after PTX. A total of 8279 PHPT patients treated with parathyroidectomy in Sweden between July 1, 2008 and December 31, 2017 compared to a matched control cohort from the total population (n = 82,790). Information on filled prescriptions was collected from the Swedish Prescribed Drug Register (SDR). Socioeconomic data and diagnoses were added by linkage to national patient and population registers. Regression analyses were used to calculate relative drug utilization (OR) within 3 years prior to PTX and relative incidence of drug treatment (RR) within 3 years postoperatively. RESULTS: Utilization of antidepressant, anxiolytic and sleep medication was more comprehensive in PHPT patients compared with the controls prior to PTX. The most common were benzodiazepines [OR 1.40 (95% CI: 1.31-1.50)] and selective serotonin reuptake inhibitors [SSRI; OR 1.38 (95% CI: 1.30-1.47)]. Postoperatively, the excess prescription rate for anxiolytic benzodiazepines decreased within three years from a 30 to 19% excess and for benzodiazepines for sleep from 31 to 14%. No corresponding decrease in excess prescription rate was observed for SSRI. CONCLUSION: PHPT is associated with increased utilization of antidepressive medications and benzodiazepines before PTX. This study implies that psychiatric symptoms should be considered in PHPT patients and continuous medication should be reevaluated after PTX.

Prediction of cognitive response to surgery in elderly patients with primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (pHPT) can be associated with potentially reversible cognitive impairment, which is occasionally mistaken for natural ageing and dementia. The aim was to evaluate short-term medical normalization of hypercalcaemia in surgical decision-making for elderly patients with mild cognitive deficiency. METHODS: Patients with pHPT were included in a prospective observational study. A test panel including the Montreal Cognitive Assessment (MoCA) and validated tools for estimation of psychological status (Hospital Anxiety and Depression Scale, HADS), and muscle strength (timed-stands test, TST) was applied at baseline, after 4 weeks of calcimimetic treatment, and after parathyroidectomy. Mild cognitive impairment was defined by a MoCA score below 26. A longitudinal increase in MoCA score of at least 2 points 6 months after surgery was considered clinically meaningful. RESULTS: Of 110 patients who underwent testing, 35 aged 50 years or more were identified to have mild cognitive dysfunction, including 19 who were aged at least 70 years (median MoCA score 23, i.q.r. 21-24). Calcimimetic treatment resulted in normalization of calcium levels, and improvements in MoCA and HADS scores, and TST time. Normal MoCA scores (at least 26) were reached in 17 patients by 6 months after surgery, of whom 10 were aged 70 years or older. Long-term increase in MoCA score correlated with the decrease in ionized calcium concentration (r = -0.536, P = 0.022). Baseline calcium concentration and improvement in MoCA with calcimimetic treatment were identified as independent predictors of favourable outcome after parathyroidectomy. CONCLUSION: Medical normalization of hypercalcaemia can aid in predicting outcome after parathyroidectomy.

Short-term medical treatment of hypercalcaemia in primary hyperparathyroidism predicts symptomatic response after parathyroidectomy.

BACKGROUND: Primary hyperparathyroidism is often associated with non-disease-specific symptoms. The aim of this study was to evaluate whether normalization of hypercalcaemia with short-term medical treatment can be used to predict the effects of parathyroidectomy and guide in surgical decision-making. METHODS: This observational study included patients who received calcimimetic treatment for 4 weeks before parathyroidectomy (30-60 mg daily). A panel of tests was used to assess various aspects of quality of life (European Organisation and Treatment of Cancer QLQ-C30 core questionnaire, Hospital Anxiety and Depression Scale and Positive State of Mind questionnaire), cognitive function (Montreal Cognitive Assessment) and muscle strength (timed-stands test). The tests were carried out at baseline, after 4 weeks of calcimimetic treatment, and at 6 weeks and 6 months after parathyroidectomy. The predictive values of changes during calcimimetic treatment were determined for each test. RESULTS: The study included 110 patients of median age 62 years (91 women). Calcimimetic treatment resulted in normalization of calcium levels and improvements in quality-of-life parameters. The time spent on the timed-stands test was significantly shortened. Eleven of 38 participants with a baseline Montreal Cognitive Assessment score below 26, indicating mild cognitive impairment, reached scores of at least 26 during treatment with calcimimetic. Improvements during treatment with calcimimetic correlated well with postoperative outcomes (positive predictive values 74-96 per cent). CONCLUSION: The method described in this study may be used to aid surgical decision-making for patients with primary hyperparathyroidism and non-disease-specific symptoms by predicting the effects of normalization of hypercalcaemia.

ANTECEDENTES: El hiperparatiroidismo primario (pHPT) a menudo se asocia con síntomas no específicos de la enfermedad. El objetivo de este estudio fue evaluar si la normalización de la hipercalcemia a corto plazo con tratamiento médico se podría usar para predecir los efectos de la paratiroidectomía y guiar la toma de decisiones quirúrgicas. MÉTODOS: Estudio observacional (ClinicalTrials.gov, registro NCT02227264) que incluyó 110 pacientes programados para paratiroidectomía (mediana de edad 62 años; 91 mujeres). Intervención: tratamiento calcimimético, cuatro semanas, 30-60 mg al día. Medidas de resultado: Un panel de pruebas para evaluar los aspectos de la calidad de vida (cuestionario de calidad de vida core 30, QLQ-C30; escala hospitalaria de ansiedad y depresión (HAD) y estado mental positivo (PSOM); función cognitiva (evaluación cognitiva de Montreal, MoCa) y fuerza muscular (Timed-Stands Test, TST). Las pruebas se realizaron cuatro veces: al inicio del estudio (basal), después de cuatro semanas de tratamiento calcimimético, a las seis semanas y seis meses después de la paratiroidectomía. Para cada prueba se determinaron los valores predictivos de los cambios durante el tratamiento calcimimético. RESULTADOS: El tratamiento con fármacos calcimiméticos determinó una normalización en los niveles de calcio y una mejoría en los parámetros de calidad de vida. El tiempo del TST se redujo significativamente. Once de los 38 participantes con una puntuación MoCa basal < 26, definida como deterioro cognitivo leve, alcanzaron puntuaciones ≥ 26 durante el uso de la medicación. Las mejoras observadas durante el tratamiento mostraron una buena correlación con el resultado postoperatorio (valores predictivos positivos 74-96%). CONCLUSIÓN: Este estudio presenta un método basado en la predicción de los efectos de la normalización de la hipercalcemia para ayudar en la toma de decisiones quirúrgicas en pacientes con pHPT y síntomas no específicos de la enfermedad.

Amino acid profiles in adults with growth hormone (GH) deficiency before and during GH replacement therapy.

OBJECTIVE: GH replacement to growth hormone deficient (GHD) adults improves body composition. In a subset however, lean body mass (LBM) fails to increase despite normalization of IGF-I and amino acid availability could be of importance. We analyzed amino acid (AA) profiles in plasma and erythrocytes (RBC) and associations with LBM, serum IGF-I and IGFBP-1 before and during GH replacement. DESIGN AND METHODS: Examinations were performed in 15 GHD patients (six women), aged 34-61 yrs before and after 12 months of GH therapy and in a control group of 20 healthy males aged 31-68 yrs. LBM was measured by dual energy X-ray absorptiometry (DXA), free AAs in plasma and RBC by high performance liquid chromatography and serum IGF-I and IGFBP-1 by in-house RIAs. SETTING: Tertiary care referral centre. RESULTS: At baseline, female GHD patients tended to have lower concentrations of the essential branched - chain AAs isoleucine and leucine, total essential AAs, and of the non-essential AA glutamine than the male patients. Male GHD patients tended to have higher plasma and RBC glutamate than controls. At 12 months, IGF-I had normalized in all but one patient and mean LBM gain was 1.9+/-0.4 kg. AA levels were unchanged. The change in LBM at 12 months was positively correlated to the ratio between the sum of isoleucine, leucine and valine and baseline LBM kg/m(2) (r=0.76, p=0.001, n=15). CONCLUSION: Our results suggest that the essential branched-chain amino acids in plasma are important for the LBM response to GH substitution. Our finding has to be confirmed in larger groups of GHD adults before making a proper selection of AAs to be measured in plasma and added as dietary supplement during GH therapy. GH administration did not change AA levels and measurements are not useful for monitoring of GH therapy at the time being.

Osteoblast dysfunction in male idiopathic osteoporosis.

The etiology of primary osteoporosis in young and middle-aged men is unknown. We have studied osteoblast function in cells derived from men with idiopathic osteoporosis and in control cells from age-matched men with osteoarthrosis. Osteoblasts were isolated from transiliac bone biopsies. Osteoblast function was measured as vitamin D-stimulated osteocalcin production and production of cytokines and factors involved in osteoclast activation and bone formation. Cell proliferation was measured as (3)H-thymidine incorporation. Parathyroid hormone-related peptide (PTHrP) mRNA was measured using reverse-transcriptase polymerase chain reaction. In osteoporotic men, bone mineral density at the femoral neck was correlated to in vitro production of osteocalcin. Osteoblasts from osteoporotic men produced significantly less osteocalcin after vitamin D stimulation but had increased production of macrophage colony-stimulating factor (M-CSF) compared to controls. The osteocalcin response was negatively correlated to production of M-CSF, interleukin-6, and C-terminal propeptide of type I collagen. Basal (3)H-thymidine incorporation was similar in cells from osteoporotic patients and controls. PTHrP (10(-9 )M) significantly increased cell proliferation in control cells but not in osteoporotic cells. Basal PTHrP mRNA levels were significantly higher in osteoporotic cells than in cells from controls. The results are in agreement with previous histomorphologic studies indicating that men with idiopathic osteoporosis have an osteoblast dysfunction with decreased osteocalcin production and increased production of factors stimulating osteoclast activation. This indicates a catabolic cellular metabolic balance leading to negative bone turnover, resulting in osteoporosis. The cause of such cellular dysfunction needs further evaluation.

The effects of arg-vasopressin on osteoblast-like cells in endothelial nitric oxide synthase-knockout mice and their wild type counterparts.

In the present study, we investigated whether nitric oxide (NO) could be involved in the effects of arg-vasopressin (AVP) on osteoblast-like cells. Cells derived from endothelial nitric oxide synthase (eNOS)-knockout mice and their wild type (WT) counterparts, and an osteosarcoma cell line (SaOS-2) were used. AVP (10-100 pmol/l) increased proliferation of osteoblast-like cells from WT mice. The effect was abolished by an AVP V1-receptor antagonist. AVP increased proliferation of cells from eNOSKO mice only when a NO donor, SNAP, was added. A nitric oxide synthase-inhibitor, L-NAME, antagonized the increase in cell proliferation in response to AVP in SaOS-2 cells. In conclusion, this study indicates that NO is involved in the effects of AVP on cell proliferation in osteoblast-like cells.

Inhibited anabolic effect of insulin-like growth factor-I on stromal bone marrow cells in endothelial nitric oxide synthase-knockout mice.

AIMS: Insulin-like growth factor-I (IGF-I), parathyroid hormone (PTH) and PTH-related protein (PTHrP) are hormones that have anabolic effects on bone formation. The aim of this study was to investigate whether production of nitric oxide (NO) is involved in the effect of IGF-I and PTH/PTHrP on osteoblast-like cells. METHODS: Bone marrow stromal cells from adult endothelial nitric oxide synthase (eNOS)-knockout (eNOSKO) mice and wild type (WT) counterparts were cultivated with osteogenic substances. The cells showed an osteoblastic phenotype measured as osteocalcin production and alkaline phosphatase activity. DNA synthesis was measured as [3H] thymidine incorporation in the bone marrow cells and in a human osteosarcoma cell-line (SaOS-2). RESULTS: The stimulatory effect of IGF-I on thymidine incorporation seen in WT animals was absent in eNOSKO mice. Addition of a NO donor to eNOSKO cells recovered the effect of IGF-I on thymidine incorporation. PTH/PTHrP stimulated cell proliferation in both WT and eNOSKO mice. In SaOS-2 cells, incubation with IGF-I together with a NOS inhibitor resulted in an inhibition of the anabolic effect of IGF-I on cell proliferation. CONCLUSIONS: The stimulatory effect of IGF-I on WT cell proliferation was abolished in eNOSKO cells, recovered by an NO donor and inhibited in osteosarcoma cells by a NOS inhibitor. The results indicate that the effect of IGF-I is dependent on NO production. The impaired IGF-I response may contribute to the bone defect formation seen in eNOSKO animals.

Calcitonin-suppressed expression of parathyroid hormone-related protein in breast cancer cells.

Parathyroid hormone-related protein (PTHrP) is a key factor behind humoral hypercalcemia of malignancy (HHM). It is produced in most breast tumors and may be an important local mediator of skeletal metastases due to breast cancer. PTHrP may mediate local bone destruction in the absence of increased circulating PTHrP. Calcitonin (CT) is used for treatment of HHM, but there are data showing that CT can increase PTHrP expression and secretion in vitro. We have therefore studied the effect of CT on PTHrP gene expression and secretion in MCF-7 breast cancer cells. PTHrP mRNA decreased significantly after 4, 8, and 16 h incubation with 10 nM salmon calcitonin (sCT) when compared with the respective controls. PTHrP mRNA also decreased significantly and dose-dependently after incubation with sCT at 0.1 to 10 nM for 16 h. The PTHrP levels in the conditioned medium also decreased in a similar dose-dependent manner. The adenylate cyclase agonist forskolin lowered the PTHrP mRNA dose-dependently. In cells exposed to varying concentrations of sCT for 15 min, the cAMP levels increased dose-dependently. In conclusion, sCT can suppress PTHrP gene expression in MCF-7 breast cancer cells. The suppressive effect is probably exerted mainly via the cAMP-protein kinase A pathways.

Parathyroid hormone-related protein in patients with primary breast cancer and eucalcemia.

Parathyroid hormone-related protein (PTHrP) is a causative factor of humoral hypercalcemia in breast cancer and other malignancies. We studied circulating PTHrP levels with three different immunoassays directed against different parts of the PTHrP molecule in 48 patients with breast cancer and eucalcemia. The methods used were: (a) a RIA with antibodies directed toward the midregion (63-78); (b) an immunofluorometric assay with two antibodies against 1-34 and 38-67; and (c) an immunoradiometric assay with antibodies against 1-40 and 1-72. Although most patients had PTHrP levels indistinguishable from normal when measured by all three methods, four patients had increased serum levels in the IFMA. PTHrP was detected by immunohistochemistry in tumors from nearly all patients. One patient with elevated PTHrP in plasma measured by IFMA showed intense staining of tumor by immunohistochemistry; the tumor was histologically graded as III (severe) and was the largest of all tumors in this patient group. The IFMA can identify increased serum PTHrP in some patients with breast cancer who are not hypercalcemic. This assay may be especially useful in screening patients for this tumor during a relative early phase of the disease.

Quantification of parathyroid hormone-related protein mRNA by competitive PCR and time-resolved lanthanide fluorometry.

Using dissociation and enhancement time-resolved lanthanide fluorometry, we have developed a quantitative competitive (QC)-PCR for measuring parathyroid hormone-related protein (PTHrP) mRNA after reverse transcription. A cloned PTHrP cDNA target was also modified by deletion of 10 bp and insertion of 21 bp in the midregion of the fragment and cloned for use as a competitor (i.e., internal standard). Two primers spanning 362 bp of target and 373 bp of competitor were designed and one of the primers was biotinylated. Two oligonucleotide probes, one recognizing the target and the other hybridizing to the competitor, were labeled with Eu chelate. Two equal aliquots of PCR products were assayed with each probe separately in streptavidin-coated wells. After 35 PCR cycles, the competitor signal decreased exponentially (y = e(3.74 - 0.624x); r2 = 0.965) and the target signal increased exponentially (y = e(1.14 + 0.497x); r2 = 0.984) when 1000 copies/tube of the competitor and 0-100,000 copies/tube of the target DNA were added. Log-transformed data for the ratio of target to competitor signals (y) and the copies of the target DNA added (x) were used for plotting the linear calibration curve (y = 2.79 + 2.76x; r2 = 0.976). This QC-PCR enables analysis of multiple samples simultaneously and can be used to study PTHrP gene expression in malignancy and physiology.

Short-term starvation increases calcidiol-24-hydroxylase activity and mRNA level in rat kidney.

The renal mitochondrial calcidiol-24-hydroxylase activity and the corresponding cytochrome P-450 mRNA level were measured in rats subjected to short-term starvation alone or in combination with calcitriol treatment. Short-term starvation of 24 and 48 h increased the mRNA level by five- and six-fold, respectively. The 24-hydroxylase activity increased by five- and threefold, respectively. Treatment with calcitriol markedly increased the enzyme activity about 20-fold and the mRNA level about six-fold. In rats subjected to calcitriol treatment combined with 24 h of starvation, a significant further increase in enzyme activity was observed. The mRNA levels increased but the difference was not significant statistically. The results indicate that the mechanism by which starvation stimulates the enzymes is different, at least in part, from that behind the stimulatory effect of calcitriol.

The short and long-term effects of octreotide on calcium homeostasis in patients with acromegaly.

OBJECTIVE: The somatostatin analogue octreotide (Sandostatin, Sandoz) is effective in reducing growth hormone levels in patients with acromegaly. Early and transient gastrointestinal side-effects are frequent. The aim was to evaluate whether gastrointestinal side-effects during the initial phase of octreotide treatment affect calcium homeostasis, and whether effects on calcium homeostasis are seen during long-term treatment with octreotide in patients with optimal effect on GH and subjectively normal gastrointestinal function. DESIGN: We first studied short-term treatment with octreotide during 14 days. From day 15 of the study medication was withdrawn, and on day 20 follow-up measurements were made. We then observed the effects of long-term treatment with octreotide. Mean duration of treatment until the day of blood sampling was 32 months (range 9-48 months). PATIENTS: Sixteen patients with acromegaly were studied, ten in the short-term study and ten in the long-term study; four were included in both. MEASUREMENTS: Serum levels of calcium, phosphate, PTH, alkaline phosphatase, 1,25(OH)2 Vit D, vitamin D-binding protein and sex hormone-binding globulin (SHBG) were measured before treatment (day 0) and on days 4, 6, 8, 14 and 20 during the short-term study and, except SHBG, before treatment and during therapy in the long-term study. RESULTS: During the short-term treatment mean (+/- SEM) serum calcium decreased significantly (on days 6 and 8, 2.21 +/- 0.08 and 2.15 +/- 0.09 mmol/l, respectively vs basal level, 2.38 +/- 0.08 mmol/l), whereas significant increments were seen in mean serum PTH (on day 14, 36 +/- 4 vs basal, 24 +/- 3 ng/l; ng/l divided by 9.425 = pmol/l), mean serum 1,25(OH)2 Vit D (on day 8, 112 +/- 7 vs basal 96 +/- 8 pmol/l), and 'free 1,25(OH)2 Vit D-index', i.e. molar ratio of 1,25(OH)2 Vit D and vitamin D-binding protein (on days 8 and 14, 1.72 +/- 0.09 x 10(-5) and 1.66 +/- 0.11 x 10(-5), respectively vs basal, 1.33 +/- 0.09 x 10(-5)). The changes were within the normal range. No changes were seen in serum phosphate, alkaline phosphatase, or vitamin D-binding protein. During the long-term study mean serum calcium and phosphate decreased significantly, 2.32 +/- 0.04 vs basal 2.42 +/- 0.04 mmol/l and 1.24 +/- 0.07 vs basal 1.40 +/- 0.09 mmol/l, respectively, whereas mean serum PTH increased significantly, 40 +/- 8 vs basal 21 +/- 5 ng/l. The changes were within the normal range. No changes were seen in serum alkaline phosphatase, 1,25(OH)2 Vit D, free 1,25(OH)2 Vit D-index, or vitamin D-binding protein. CONCLUSION: Altered calcium homeostasis during octreotide treatment in acromegaly is not only initial and temporary, but can also be seen after several years of treatment. The clinical relevance of these long-standing effects needs to be further investigated.