Clinical value of 11C-methionine positron emission tomography in persistent primary hyperparathyroidism-A case report with a mediastinal parathyroid adenoma.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is a common endocrine disorder caused by pathologic growth of one or more of the parathyroid glands. Parathyroidectomies (PTX) in patients with PHPT are procedures with low morbidity, few complications, and a high cure rate. However, the parathyroid glands may be found at various anatomical locations and occasionally they are intrathoracic. CASE PRESENTATION: We present a 57-year-old patient with PHPT. Before the first and second operation, the preoperative imaging indicated pathologic parathyroid tissue in the neck. Due to postoperative persistent hypercalcemia we performed a 11C-methionine positron emission tomography (11C-MET-PET/CT). The scan showed a focus with increased activity in the mediastinum. Due to persistent disease, an ectopic parathyroid gland in the mediastinum was suspected. At a third operation, the parathyroid adenoma was resected through an anterolateral thoracotomy. Biochemical values normalized and bone mineral density improved postoperatively. Hence, an ectopic localization of a parathyroid gland should be considered during the preoperative planning of a PTX, especially in the re-operative setting. A multidisciplinary effort is necessary to address an intrathoracic adenoma. CONCLUSION: Ectopic parathyroid glands should be suspected when positive sestaMIBI uptake is seen in the mediastinum and other types of imaging (e.g. contrast enhanced CT scan or PET-CT) may confirm the finding of an ectopic parathyroid adenoma. From the present case and previous studies we found 11C-MET-PET/CT valuable in difficult PHPT cases.

Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus.

The purpose of this review is to assess the most recent evidence in the management of primary hyperparathyroidism (PHPT) and provide updated recommendations for its evaluation, diagnosis and treatment. A Medline search of "Hyperparathyroidism. Primary" was conducted and the literature with the highest levels of evidence were reviewed and used to formulate recommendations. PHPT is a common endocrine disorder usually discovered by routine biochemical screening. PHPT is defined as hypercalcemia with increased or inappropriately normal plasma parathyroid hormone (PTH). It is most commonly seen after the age of 50 years, with women predominating by three to fourfold. In countries with routine multichannel screening, PHPT is identified earlier and may be asymptomatic. Where biochemical testing is not routine, PHPT is more likely to present with skeletal complications, or nephrolithiasis. Parathyroidectomy (PTx) is indicated for those with symptomatic disease. For asymptomatic patients, recent guidelines have recommended criteria for surgery, however PTx can also be considered in those who do not meet criteria, and prefer surgery. Non-surgical therapies are available when surgery is not appropriate. This review presents the current state of the art in the diagnosis and management of PHPT and updates the Canadian Position paper on PHPT. An overview of the impact of PHPT on the skeleton and other target organs is presented with international consensus. Differences in the international presentation of this condition are also summarized.

A functional amino acid substitution in the glucose-dependent insulinotropic polypeptide receptor (GIPR) gene is associated with lower bone mineral density and increased fracture risk.

CONTEXT: Food ingestion decreases bone resorption, and glucose-dependent insulinotropic polypeptide (GIP) may mediate this effect. Mice overexpressing GIP have increased osteoblast activity and are rescued from age-related bone loss, whereas GIPR knockout mice have decreased cortical bone mass and compromised bone quality. Carriers of the functional variant GIPR Glu354Gln (rs1800437) have higher plasma glucose 2 hours after glucose ingestion, suggesting that the variant encoding GIPR 354Gln decreases the effect of GIP. OBJECTIVE: The objective of the study was to investigate the effect of GIPR Glu354Gln on bone mineral density (BMD) and fracture risk. DESIGN: This was a prospective, comprehensive, cohort study (number NCT00252408). PARTICIPANTS: A total of 1686 perimenopausal women were included. MAIN OUTCOME MEASURES: Dual-energy X-ray absorptiometry was performed at baseline and after 10 years. Incident fractures were recorded during the follow-up and were obtained from the Danish National Patient Registry, giving a total follow-up time of a minimum 16 years. RESULTS: After 10 years, women with the minor frequency C allele of rs1800437 (354Gln) had significantly lower BMD at the femoral neck compared with carriers of the major G-allele (CC: 0.755 ± 0.015 g/cm(2) vs CG: 747 ± 0.005 g/cm(2); GG: 0.766 ± 0.004 g/cm(2), P < .001). Correspondingly, total hip BMD was significantly lower among C allele carriers (CC: 0.881 ± 0.016 g/cm(2); CG: 0.884 ± 0.005 g/cm(2); and GG: 0.906 ± 0.004 g/cm(2), P < .001). Finally, women homozygous for the variant C allele had an increased risk (hazard ratio 1.6, confidence interval 1.0-2.6, P < .05) of nonvertebral fractures. CONCLUSION: This study demonstrates an association between a functional GIPR polymorphism Glu354Gln (rs1800437) and BMD and fracture risk. These findings further establish GIP to be involved in the regulation of bone density.

Investigations of the anti-inflammatory effects of vitamin D in adipose tissue: results from an in vitro study and a randomized controlled trial.

Inflammation is a key feature of obesity and type 2 diabetes. The active vitamin D metabolite, 1,25-dihydroxyvitamin D [1,25(OH)2D], modulates the inflammation in vitro. We studied whether inflammation in adipose tissue (AT) cultures could be reduced by incubation with 1,25(OH)2D in vitro, or by oral treatment with vitamin D in vivo in obese subjects with low plasma levels of 25-hydroxyvitamin D. Samples of subcutaneous AT were stimulated with IL-1ß to induce inflammation. In the in vitro study, samples were concomitantly incubated with or without 1,25(OH)2D, and analyzed for mRNA and protein levels of inflammatory markers IL-6, IL-8, and MCP-1. In the in vivo study, samples of subcutaneous AT from obese subjects obtained before and after treatment with 7,000 IU of vitamin D daily or placebo in a randomized controlled trial were stimulated with IL-1ß. The samples were analyzed for AT gene expression and compared with plasma markers of inflammation. In the in vitro study, concomitant incubation with 1,25(OH)2D reduced mRNA levels of MCP-1 by 45% (p=0.01), of IL-6 by 32% (p=0.002), and of IL-8 by 34% (p=0.03), and reduced secretion of IL-8 protein by 18% (p=0.005). In vivo treatment with vitamin D did not reduce AT expression or circulating levels of MCP-1, IL-6, or IL-8. 1,25(OH)2D has significant anti-inflammatory effects in AT in vitro. However, a similar reduction in AT and systemic inflammation cannot be obtained by oral treatment with vitamin D in obese subjects.

Changes in calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum: a controlled cohort study.

UNLABELLED: Pregnancy and lactation cause major changes in calcium homeostasis and bone metabolism. This population-based cohort study presents the physiological changes in biochemical indices of calcium homeostasis and bone metabolism during pregnancy and lactation INTRODUCTION: We describe physiological changes in calcium homeostasis, calcitropic hormones and bone metabolism during pregnancy and lactation. METHODS: We studied 153 women planning pregnancy (n=92 conceived) and 52 non-pregnant, age-matched female controls. Samples were collected prior to pregnancy, once each trimester and 2, 16 and 36 weeks postpartum. The controls were followed in parallel. RESULTS: P-estradiol (E2), prolactin and 1,25-dihydroxyvitamin D (1,25(OH)2D) increased (p<0.001) during pregnancy, whereas plasma levels of parathyroid hormone (P-PTH) and calcitonin decreased (p<0.01). Insulin-like growth factor I (IGF-I) was suppressed (p<0.05) in early pregnancy but peaked in the third trimester. Postpartum, E2 was low (p<0.05); prolactin decreased according to lactation status (p<0.05). 1,25(OH)2D was normal and IGF-I was again reduced (p<0.05). P-PTH and calcitonin increased postpartum. From early pregnancy, markers of bone resorption and formation rose and fall, respectively (p<0.001). From the third trimester, bone formation markers increased in association with IGF-I changes (p<0.01). Postpartum increases in bone turnover markers were associated with lactation status (p<0.001). During lactation, plasma phosphate was increased, whereas calcium levels tended to be decreased which may stimulate PTH levels during and after prolonged lactation. CONCLUSION: The increased calcium requirements in early pregnancy are not completely offset by increased intestinal calcium absorption caused by high 1,25(OH)2D since changes in bone markers indicated a negative bone balance. The rise in bone formation in late pregnancy may be initiated by a spike in IGF-I levels. The high bone turnover in lactating women may be related to high prolactin and PTH levels, low E2 levels and perhaps increased parathyroid hormone-related protein levels.

Risk of fractures associated with treatment for benign prostate hyperplasia in men.

UNLABELLED: Treatment of benign prostate hyperplasia with α-blockers may affect blood pressure while treatment with 5-α-reductase inhibitors may affect conversion of testosterone potentially leading to osteoporosis. In our study, neither 5-α-reductase inhibitors nor α-blockers were associated with negative effects on fractures, α-blockers perhaps being associated with a limited decrease in fractures. INTRODUCTION: The objective is to study fracture risk associated with drugs for benign prostate hyperplasia. The hypotheses were that (1) α-blockers may elevate fracture risk by causing presyncope/falls and (2) 5-α-reductase inhibitors may elevate fracture risk by lowering dihydrotestosterone. METHODS: This is a nationwide case-control study using all 9,719 male fracture patients aged ≥60 years in the year 2000 as cases and drawing 29,156 age- and gender-matched controls. The main exposure was the use of the drugs mentioned above for benign prostate hyperplasia. Confounder control included social variables, contacts to hospitals and general practitioners, alcoholism and other variables. RESULTS: For the 5-α-reductase inhibitors, no change in overall risk of fractures was seen. No change in risk of hip, spine and forearm fractures was present. For the α-blockers, a decrease in overall risk of fractures was seen, as well as a decrease in the risk of hip and spine fractures, but only at average doses >0.5 defined daily doses per day. No decrease was seen for forearm fractures. A decreasing risk of any fracture, hip fractures and spine fractures were seen with increasing dose of α-blockers, while no such association was seen for the forearm fractures. CONCLUSION: Neither the 5-α-reductase inhibitors nor α-blockers were associated with negative effects on fracture risk. A small trend towards a decrease in fracture risk may be present for the α-blockers. However, more research is needed to confirm if this trend is real.

Methotrexate, azathioprine, cyclosporine, and risk of fracture.

We studied the fracture risk associated with use of methotrexate, azathioprine, and cyclosporine. The study was designed as a case-control study. All patients with a fracture (n = 124,655) in the year 2000 in Denmark served as cases. Information on fractures and confounders was retrieved from the National Hospital Discharge Register and a number of other national registers. For each case, three age- and gender-matched controls were randomly drawn from the general population (n = 373,962). Exposure was use of the drugs and a number of covariates including other immunosuppressive drugs, corticosteroids, any cancer, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, liver and kidney disease, prior fracture, and alcoholism. Azathioprine was associated with an increase in overall fracture risk, but besides this, none of the drugs was significantly associated with overall fracture risk or risk of hip, spine, or forearm fracture. Liver [odds ratio (OR) = 1.55, 95% confidence interval (CI) 1.42-1.69] and kidney (OR = 1.26, 95% CI 1.16-1.37) diseases were significantly associated with increased risk of fractures. Azathioprine was associated with an increase in overall fracture risk but not in the risk of spine, hip, or forearm fractures. Methotrexate and cyclosporine were not associated with fracture risk. It thus seems that the underlying disease for which the treatment is administered may be responsible for much of the increase in fracture risk rather than the drugs used to treat the disorder in question.

Vitamin D and its binding protein Gc: long-term variability in peri- and postmenopausal women with and without hormone replacement therapy.

OBJECTIVE: Measurement of plasma 25-hydroxyvitamin D (25OHD) level is often used to evaluate a patient's vitamin D status. The purpose of this study was to investigate the variability in individual plasma 25OHD- and vitamin D-binding protein- (Gc) levels over a 5-year period in postmenopausal women with and without hormone replacement therapy (HRT). MATERIAL AND METHODS: A total of 187 women were followed-up for 5 years. At baseline, 89 women were allocated to treatment with HRT, given orally. Measurements were performed at baseline and after 1, 2 and 5 years of follow-up. RESULTS: At baseline, 25OHD levels were positively associated with sunbathing and use of vitamin D supplements, and inversely associated with smoking. HRT therapy increased plasma levels of Gc (+8 %) but did not affect 25OHD levels or the free 25OHD index (molar ratio of 25OHD- to Gc levels). Among those classified in the lowest 25OHD tertile at baseline, 40 % remained in the lowest tertile during all subsequent measurement time-points. Similarly, 32 % of those classified in the highest baseline tertile remained in the highest tertile during all subsequent measurements. Use of the free 25OHD index showed similar results. No independent predictors of changes in vitamin D tertiles during follow-up were identified, which suggests that the observed variation was caused by the intra-individual variation in measured parameters. For all participants, the within-patient variability in 25OHD measurements was between 13 % and 19 %. CONCLUSIONS: In healthy postmenopausal women, HRT increases Gc levels. Owing to the high intra-individual variation in plasma 25OHD, it seems questionable to use a single estimate as a predictor of individual vitamin D status.

Influence of hyper- and hypothyroidism, and the effects of treatment with antithyroid drugs and levothyroxine on fracture risk.

The purpose of this study was to assess alterations in fracture risk in patients with hyper- and hypothyroidism, and the effects of antithyroid drugs and levothyroxine on fracture risk. The study was designed as a case-control study. All patients with a fracture (n = 124,655) in the year 2000 in Denmark served as cases. For each case, three age- and gender-matched controls were randomly drawn from the general population (n = 373,962). Exposure variables were a diagnosis of hyperthyroidism, hypothyroidism, ever use of antithyroid drugs, and ever use of levothyroxine. Adjustments were made for time since diagnosis, surgery for hyperthyroidism, thyroid cancer, prior fracture, alcoholism, and corticosteroid use. There was an increase in the risk of any fracture within the first 5 years after a diagnosis of hyperthyroidism, and the first 10 years after a diagnosis of hypothyroidism. Use of antithyroid drugs was associated with a significantly reduced fracture risk independently of the dose used (odds ratio [OR] 0.79-0.84, 2P < 0.05). No effect of levothyroxine on fracture risk was present. Thyroid surgery for hyperthyroidism and thyroid cancer were not associated with fracture risk. A prior fracture, alcoholism, and corticosteroid use were significant risk factors for fractures. Fracture risk is increased at the time of diagnosis of both hyper- and hypothyroidism, and this increase seems reversible. Low-dose levothyroxine was not associated with fracture risk. The effect of antithyroid drugs may be caused by the reduction in thyroid hormone levels.

Response rates to oestrogen treatment in perimenopausal women: 5-year data from the Danish Osteoporosis Prevention Study (DOPS).

OBJECTIVE: To characterise women with no response or with a good response to hormone replacement therapy (HRT), evaluated by change in bone mineral density (BMD). DESIGN: Nested case-control study within a comprehensive cohort study. SUBJECTS AND METHODS: In the Danish Osteoporosis Prevention Study (DOPS), perimenopausal women were allocated to either HRT or no HRT. In the present study, we included 466 women who had been treated with HRT for 5 years and 466 untreated women from the same cohort. Non-responders were women in the treatment group, who decreased in BMD more than the mean decrease observed in the untreated group. Good responders were women with a larger increase in BMD than the upper 95% percentile of untreated women. Baseline characteristics were evaluated as predictors of response to HRT. RESULTS: 8.4 and 5.6% were classified as non-responders, whereas 25 and 57% were good responders according to changes in BMD of the femoral neck and lumbar spine, respectively. Combining measuring sites, 2.6% were non-responders and 20% were good responders. Non-responders at the femoral neck were more often smokers and had a lower spine BMD. Good responders were older, had a higher body weight, and higher alcohol consumption. In addition, good responders at both measurements sites had a lower BMD at the total hip. CONCLUSION: A favourable BMD response to HRT can be expected in most post-menopausal women especially if they are non-smokers with a moderate--as opposed to low--alcohol intake, a high body mass and a low initial hip BMD.

Biological variation of soluble CD163.

A soluble plasma form of CD163 (sCD163) was recently identified. The protein has anti-inflammatory effects in vitro and is elevated in patients with myelo-monocytic leukaemia and infection. For rational use and evaluation of this potential new quantity it is important to have knowledge of its biological variability and to use a methodology that has a sufficiently analytical quality. The day-to-day and diurnal biological variabilities of sCD163 were studied in 12 healthy people using a sandwich ELISA. The within-run-, between run- and total analytical coefficients of variation were estimated to 3.6%, 4.8% and 6.0%, respectively. The day-to-day within-subject biological variation was estimated to 9.0%, and the between-subject biological variation to 35.9%. A diurnal variation in sCD163 concentrations with 14% lower values in the night (supine position) was observed. The ratio between total analytical variation and within-subject biological variation was 0.67. The index of individuality, calculated as the ratio between within-subject biological variation and between-subject biological variation, was low and similar to complement factors and immunoglobulins. A low index of individuality is important in a monitoring situation where small changes from the set point of the individual can be detected in serial measurements. For this purpose, the critical difference for a series of results in the same patient (significant at p < 0.05) was calculated to 30% for samples taken on different days and measured in separate runs.

Statins decrease bone turnover in postmenopausal women: a cross-sectional study.

BACKGROUND: Statins have been suggested as potential agents in the management of osteoporosis. Reviews of medical records have shown an increased bone mass and some studies have shown a reduced occurrence of fractures in subjects on long-term treatment with statins. We studied the effects of treatment with statins on calcium homeostasis, bone turnover and bone mineral density. DESIGN: In a cross-sectional design, plasma levels of parathyroid hormone (PTH) and biochemical markers of bone turnover, bone mineral density (BMD) and body composition (fat- and lean tissue-mass) were measured in 140 postmenopausal women who had been treated with a statin for more than 2 years (median 4 years) and compared to 140 age- and gender-matched, population-based controls. RESULTS: Plasma levels of bone turnover markers were lower in the statin-treated subjects than in the controls: osteocalcin (-9%, P = 0.03), bone-specific alkaline phosphatase (-14%, P < 0.01), and C-terminal telopeptide of type I collagen (-11%, P < 0.01). On the other hand, plasma PTH levels were 16% higher in the statin-treated subjects than in the controls (P < 0.01). However, body composition and BMD at the lumbar spine, hip, forearm and whole body did not differ between the two groups. No correlation could be demonstrated between changes in biochemical quantities and dose or duration of statin use. CONCLUSION: Our data show that statins affect the function of bone cells. Most likely, the effect is antiresorptive.

Soluble CD163: a marker molecule for monocyte/macrophage activity in disease.

By immunoprecipitation we have identified a soluble plasma form of CD163 (sCD163), the IL-6 inducible macrophage-receptor for clearing haptoglobin-haemoglobin complexes. A sandwich ELISA for measuring sCD163 was established and used to determine the sCD163 levels in normal subjects and patients with inflammatory and myeloproliferative diseases. In normal subjects, the concentration of sCD163 was high (median 1.9 mg/l) with low intra-individual variation. Highly increased levels were seen in patients with sepsis, myeloid leukaemia and in patients with Gaucher disease characterized by accumulation of tissue macrophages. Although the physiological role of sCD163 remains unknown, our present data suggest that sCD163 might prove to be a valuable marker molecule in infectious and myeloproliferative diseases.

Loop diuretics alter the diurnal rhythm of endogenous parathyroid hormone secretion. A randomized-controlled study on the effects of loop- and thiazide-diuretics on the diurnal rhythms of calcitropic hormones and biochemical bone markers in postmenopausal women.

BACKGROUND: Thiazide diuretics (TD) reduce urinary calcium, bone loss and fracture risk. Loop diuretics (LD) may have opposite effects. These effects could depend on induced rhythmic changes in bone and calcium homeostasis. DESIGN: After a run-in period of 7 days, we studied (in a factorial design) the diurnal rhythms of plasma levels of calcium, phosphate, parathyroid hormone (PTH), 1,25-dihydroxyvitamin D and osteocalcin, as well as renal excretions rates of calcium, phosphate, and cross-linked N-terminal telopeptide of type 1 collagen (NTx) in 50 postmenopausal women randomized to treatment with either a thiazide diuretic (TD; bendroflumethiazide, n = 14), a loop diuretic (LD; bumetanide, n = 13), LD plus TD (bendroflumethiazide plus bumetanide, n = 11), or placebo (n = 12). RESULTS: In all four groups, all measured quantities showed a diurnal variation. LD caused a steep increase, with a subsequent decrease, in urinary calcium and plasma PTH. The mean 24 h plasma PTH concentration was increased (8.5 +/- 0.9 mmol L-1) compared with placebo (4.4 +/- 0.4 mmol L-1), whereas net 24 h renal calcium excretion did not differ from that of the placebo group due to a rebound hypocalciuria. Compared with placebo, diurnal rhythms of plasma phosphate and osteocalcin were changed with an increase during daytime and a decrease during the night. TD did not alter the diurnal rhythm of any of the measured quantities. However, the 24-h renal calcium excretion decreased, whereas the mean 24-h plasma calcium concentration increased without PTH suppression. LD plus TD caused changes similar to those observed with LD alone. CONCLUSION: One daily dose of LD increases parathyroid activity with alterations in the diurnal pattern of osteocalcin. This could indicate a potential anabolic effect of LD.

Fracture risk is increased in Crohn's disease, but not in ulcerative colitis.

AIMS: To study fracture rates and risk factors for fractures in patients with Crohn's disease and ulcerative colitis. METHODS: 998 self administered questionnaires were issued to members of the Danish Colitis/Crohn Association, and 1000 questionnaires were issued to randomly selected control subjects. 845 patients (84.5%) and 645 controls (65.4%) returned the questionnaire (p<0.01). 817 patients and 635 controls could be analysed. RESULTS: Analysis was performed on 383 patients with Crohn's disease (median age 39, range 8-82 years; median age at diagnosis 26, range 1-75 years), 434 patients with ulcerative colitis (median age 39, range 11-86 years; median age at diagnosis 29, range 10-78 years), and 635 controls (median age 43, range 19-93 years, p<0.01). The fracture risk was increased in female patients with Crohn's disease (relative risk (RR) = 2.5, 95% confidence interval (CI) 1.7-3.6), but not in male patients with Crohn's disease (RR = 0.6, 95% CI 0.3-1.3) or in patients with ulcerative colitis (RR = 1.1, 95% CI 0.8-1.6). An increased proportion of low energy fractures was observed in patients with Crohn's disease (15.7% versus 1.4 % in controls, 2p<0. 01), but not in patients with ulcerative colitis (5.4%, 2p=0.30). The increased fracture frequency in Crohn's disease was present for fractures of the spine, feet, and toes and fractures of the ribs and pelvis. Fracture risk increased with increasing duration of systemic corticosteroid use in Crohn's disease (2p=0.028), but not in ulcerative colitis (2p=0.50). CONCLUSIONS: An increased risk of low energy fractures was observed in female patients with Crohn's disease, but not in male patients with Crohn's disease or in patients with ulcerative colitis.