All-cause and cardiovascular mortality risk after surgery versus radioiodine treatment for hyperthyroidism.

BACKGROUND: Little is known about the long-term side-effects of different treatments for hyperthyroidism. The few studies previously published on the subject either included only women or focused mainly on cancer outcomes. This register study compared the impact of surgery versus radioiodine on all-cause and cause-specific mortality in a cohort of men and women. METHODS: Healthcare registers were used to find hyperthyroid patients over 35 years of age who were treated with radioiodine or surgery between 1976 and 2000. Comparisons between treatments were made to assess all-cause and cause-specific deaths to 2013. Three different statistical methods were applied: Cox regression, propensity score matching and inverse probability weighting. RESULTS: Of the 10 992 patients included, 10 250 had been treated with radioiodine (mean age 65·1 years; 8668 women, 84·6 per cent) and 742 had been treated surgically (mean age 44·1 years; 633 women, 85·3 per cent). Mean duration of follow-up varied between 16·3 and 22·3 years, depending on the statistical method used. All-cause mortality was significantly lower among surgically treated patients, with a hazard ratio of 0·82 in the regression analysis, 0·80 in propensity score matching and 0·85 in inverse probability weighting. This was due mainly to lower cardiovascular mortality in the surgical group. Men in particular seemed to benefit from surgery compared with radioiodine treatment. CONCLUSION: Compared with treatment with radioiodine, surgery for hyperthyroidism is associated with a lower risk of all-cause and cardiovascular mortality in the long term. This finding was more evident among men.

Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years.

UNLABELLED: Limited data exist on the efficacy of long-term therapies for osteoporosis. In osteoporotic postmenopausal women receiving denosumab for 7 years, nonvertebral fracture rates significantly decreased in years 4-7 versus years 1-3. This is the first demonstration of a further benefit on fracture outcomes with long-term therapy for osteoporosis. INTRODUCTION: This study aimed to evaluate whether denosumab treatment continued beyond 3 years is associated with a further reduction in nonvertebral fracture rates. METHODS: Participants who completed the 3-year placebo-controlled Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were invited to participate in an open-label extension. The present analysis includes 4,074 postmenopausal women with osteoporosis (n = 2,343 long-term; n = 1,731 cross-over) who enrolled in the extension, missed ≤1 dose during their first 3 years of denosumab treatment, and continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1-3 of denosumab with that of the fourth year and with the rate during years 4-7 was evaluated. RESULTS: For the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab treatment (referent) and 1.36 in the fourth year (rate ratio [RR] = 0.64; 95 % confidence interval (CI) = 0.48 to 0.85, p = 0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1-3 were compared to years 4-7 in the long-term group (RR = 0.79; 95 % CI = 0.62 to 1.00, p = 0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip bone mineral density (BMD). CONCLUSIONS: Denosumab treatment beyond 3 years was associated with a further reduction in nonvertebral fracture rate that persisted through 7 years of continuous denosumab administration. The degree to which denosumab further reduces nonvertebral fracture risk appears influenced by the hip bone density achieved with initial therapy.

Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk.

CONTEXT: The FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial showed denosumab significantly reduced the risk of fractures in postmenopausal women with osteoporosis. OBJECTIVE: We evaluated the effect of denosumab on the incidence of new vertebral and hip fractures in subgroups of women at higher risk for these fractures. DESIGN: FREEDOM was a 3-yr, randomized, double-blind, placebo-controlled, phase 3 trial. PARTICIPANTS AND SETTING: Postmenopausal women (N = 7808) with osteoporosis were enrolled at 213 study sites worldwide. INTERVENTIONS: Subjects received s.c. denosumab (60 mg) or placebo every 6 months and daily supplements of calcium (≥1000 mg) and vitamin D (≥400 IU). MAIN OUTCOME MEASURES: This post hoc analysis evaluated fracture incidence in women with known risk factors for fractures including multiple and/or moderate or severe prevalent vertebral fractures, aged 75 yr or older, and/or femoral neck bone mineral density T-score of -2.5 or less. RESULTS: Compared with placebo, denosumab significantly reduced the risk of new vertebral fractures in women with multiple and/or severe prevalent vertebral fractures (16.6% placebo vs. 7.5% denosumab; P < 0.001). Similarly, denosumab significantly reduced the risk of hip fractures in subjects aged 75 yr or older (2.3% placebo vs. 0.9% denosumab; P < 0.01) or with a baseline femoral neck bone mineral density T-score of -2.5 or less (2.8% placebo vs. 1.4% denosumab; P = 0.02). These risk reductions in higher-risk individuals were consistent with those seen in patients at lower risk of fracture. CONCLUSIONS: Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at higher risk for fracture. These results highlight the consistent antifracture efficacy of denosumab in patients with varying degrees of fracture risk.

The role of adrenal scintigraphy in the preoperative management of primary aldosteronism.

BACKGROUND AND AIMS: Differentiation between the two major subgroups of primary aldosteronism, bilateral hyperplasia and aldosterone producing adenoma is essential since therapy in the former is medical and in the latter surgical. The aim of the present study was to evaluate the clinical utility of adrenocortical scintigraphy in the management of primary aldosteronism. MATERIAL AND METHODS: [131I] norcholesterol (NP-59) scintigraphy with dexamethasone suppression for subclassification and lateralization of primary aldosteronism was evaluated in 49 patients with long-term follow-up after diagnosis and treatment. RESULTS: Thirty-three patients with the diagnosis of aldosterone producing adenoma were operated with adrenalectomy. Preoperative scintigraphy showed lateralized isotope uptake in 27/33 patients while 6 showed no uptake. Twenty-two were cured and three significantly improved. Thus, in 25/33 (76%), scintigraphy showed the correct side as the patients benefited of surgery. Two patients did not improve. Fourteen patients with a probable diagnosis of bilateral hyperplasia had normal scintigraphies. CONCLUSIONS: In the present retrospective study we found limited sensitivity of NP-59 scintigraphy. However, when a lateralized scintigraphic uptake is achieved it has a high accuracy. Scintigraphy may be used as an adjunct in cases where adrenal venous sampling is inconclusive.

Calcium and vitamin D3 supplements in calcium and vitamin D3 sufficient early postmenopausal healthy women.

OBJECTIVE: To study the calcium homeostasis in healthy, calcium and vitamin D replete early postmenopausal women during oral supplementation with calcium and vitamin D3. DESIGN: A prospective, placebo-controlled, randomised, double-single-blind, 3-week study. SETTING: Outpatient clinic at Copenhagen University Hospital, Denmark. SUBJECTS: In all, 17 started, one was excluded. Totally, 16 healthy women, 45-61 y of age (mean 57.3 y) who were at least 4 y after menopause (mean 6.7 y) completed. INTERVENTIONS: All underwent three consecutive 7-day study periods. Each began with 4 days of normal diet followed by 3 days treatment of either C: one tablet of 1.250 mg calcium carbonate (ie 500 mg Ca2+ per tablet) twice daily (breakfast and dinner), or CD3: as in C but plus 400 IU vitamin D3 b.i.d., or P (only) placebo tablets b.i.d. RESULTS: At baseline plasma 25-hydroxycholecalciferol was normal (66+/-22 nmol/l) and the calcium intake without supplements 850 mg/day. In group C, the 24-h urinary calcium increased by 35% (6.9+/-2.0 mmol), vs the placebo group P (5.1+/-1.6 mmol) (P < 0.05). Addition of 800 IU vitamin D3 daily (CD3) did not increase calcium excretion further (6.6+/-2.1 mmol) but decreased plasma 1,25-(OH)2-vitamin D3 by 21% (P < 0.05). CONCLUSIONS: In this carefully controlled study calcium plus vitamin D3 supplements only had minor influences of uncertain significance on the calcium balance in healthy, calcium and vitamin D sufficient early postmenopausal women.

Extracellular calcium increases free cytoplasmic calcium and DNA synthesis in human osteoblasts.

A high concentration of extracellular calcium (8 mM) induced an increase in free cytoplasmic calcium, a lower cyclic AMP level and increased DNA synthesis in primary cultures of human osteoblast-like cells. Inhibition of protein kinase C with bisindolylmaleimide I inhibited the stimulatory effect of extracellular calcium on DNA synthesis in human osteoblast-like cells, whereas inhibition of protein kinase A with Rp-cAMPs had no effect on DNA synthesis. This indicates that protein kinase C, possibly via increased free cytoplasmic calcium, mediates the effect of extracellular calcium on DNA synthesis in osteoblast-like cells rather than a relative decrease in cyclic AMP and protein kinase A activity. Furthermore, a low concentration (0.5 mM) of extracellular calcium decreased DNA synthesis. In conclusion, these data suggest that a high extracellular calcium level may be a coupling factor that recruits osteoblasts in the bone remodeling process, and that a low level of extracellular calcium may also regulate osteoblast function.

Weak evidence of thyrotropin receptors in primary cultures of human osteoblast-like cells.

Extra-thyroidal thyrotropin (TSH) receptors (TSHRs) have been demonstrated in several tissues and cells, including human and rat osteosarcoma cell lines. We have explored whether human TSHR (hTSHRs) also are present in primary cultures of human osteoblast-like (hOB) cells. [(125) I]TSH binding was limited in hOB cells, but somewhat higher in UMR 106-01 cells and considerably higher in hTSHR-transfected CHO cells. In hOB cells, the basal intracellular cAMP levels increased 282% after stimulation with 10 U/L TSH. In the hTSHR-transfected CHO cells, the cAMP increase was 3030% in response to 10 U/L TSH and 1240% after 1 U/L TSH. Free cytoplasmic calcium did not change in response to TSH in hOB cells. HTSHR mRNA was detected in hOB cells from 3/4 bone by reverse transcriptase polymerase chain reaction RT-PCR and nucleotide sequencing HTSHR mRNA, but could not be demonstrated with the RNase protection technique in hOB cells from 5 different donors. In conclusion, even after the use of several methods, we have found only weak evidence for expression and presence of functionally active hTSHR in hOB cells. Given the low level of expression, specific binding and cAMP signaling, we suggest that it is unlikely that circulating TSH plays a physiological role for bone metabolism mediated through osteoblasts.

Rapid suppression of S-PTH by oral calcitriol and calcium in healthy premenopausal women.

The influence of oral calcium +/- cholecalciferol or calcitriol on S-PTH and whole blood ionized calcium (B-Ca++) in the very short term has not been elucidated. B-Ca++ and S-PTH were measured after overnight fast every 5 or 15 min for 4-h in 7 healthy premenopausal women (30-45 years) in a crossover design where the subjects were studied on 4 different days. Study 1: (control), 125-ml tap water (also given in studies 2-4); study 2: 1000 mg calcium, as calcium carbonate; study 3: 1000 mg calcium and 400 IU (5 microg) cholecalciferol; and study 4: 0.5 microg calcitriol plus 1000 mg calcium. Calcium plus 1,25(OH)2 vitamin D3 induced a rapid and significant fall in S-PTH compared to the control period (p < 0.02). Calcium alone or calcium plus cholecalciferol did not change the PTH levels significantly compared to control (water). B-Ca++ increased significantly after calcium plus 1,25(OH)2 vitamin D3 (p<0.01) and calcium plus cholecalciferol (p<0.05) compared to the control period. The B-Ca++ elevation was significantly higher after calcium plus 1,25 vitamin D3 than after calcium plus cholecalciferol (p<0.05). In conclusion, oral calcitriol plus calcium causes a rapid elevation in B-Ca++ and suppression of the PTH secretion also in the short term (hours).

[Osteoporosis among the elderly is a "silent epidemics". Insufficient prophylaxis and underdiagnosing are big problems]. / Osteoporos hos äldre en "tyst epidemi". Bristfällig profylax och underdiagnostik ett stort problem.

The increasing number of fractures due to osteoporosis continues to put economical and practical burdens on the national health service. Despite the fact that knowledge of the disease and its consequences has increased tremendously and new, effective drugs have been developed only a minority of the patients are diagnosed and appropriately treated. Resources should be made available to improve methods of measuring bone mineral density as well as establishing outpatient osteoporosis clinics at all hospitals in the country. Age ought not to be a limiting factor to initiate treatment or prevention of fractures. The present situation for the osteoporosis patient, the clinical syndromes with special reference to age-related and secondary osteoporosis, their causes, diagnosis and treatment are briefly reviewed.

Interleukin-1beta upregulates PTHrP-mRNA expression and protein production and decreases TGF-beta in normal human osteoblast-like cells.

Osteoblasts are regulated by complex interactions among systemic hormones, cytokines, and local growth factors. Bone resorption, at the level of the basic multicellular unit, is initiated by stimulation of osteoblast activity. The stimulatory effect of interleukin-1beta (IL-1beta) on bone resorption has not been fully clarified. We have therefore studied the influence of IL-1beta on the local production and secretion of parathyroid hormone-related protein (PTHrP) and transforming growth factor-beta (TGF-beta) from normal human osteoblast-like cells (hOB cells). Using a quantitative PCR-assay following reverse transcription of RNA, in situ hybridization, and a two-site immunofluorometric assay for PTHrP, we demonstrate that IL-1beta in a dose- and time-dependent manner increases PTHrP-mRNA expression and PTHrP-protein secretion. In addition, IL-1beta decreased the TGF-beta protein concentration in conditioned medium. Our results suggest that the actions of IL-1beta on bone may be mediated by novel mechanisms involving both local increase of PTHrP, a potent stimulator of bone resorption, and a decrease of TGF-beta, an important anabolic and coupling factor for bone turnover.

Quality of life aspects and costs in treatment of Graves' hyperthyroidism with antithyroid drugs, surgery, or radioiodine: results from a prospective, randomized study.

The patients' views and costs of three different forms of treatment for Graves' hyperthyroidism were investigated. The study comprises 174 patients with Graves' hyperthyroidism who were stratified into two age groups: 20 to 34 years and 35 to 55 years. The younger group was randomly assigned to treatment with antithyroid drug plus thyroxine for 18 months or subtotal thyroidectomy, and in the older group iodine-131 was added as a third alternative. The patients' views of their therapy were based on a questionnaire formulated to identify possible differences between the three treatment forms. The costs were assessed by analyzing the official hospital reimbursement system for both outpatient and inpatient costs for a period of 2 years from the day of randomization. The results show that no significant differences in opinion were found between the five treatment groups with regard to any of the questions. Furthermore, only 10% of the patients expressed slight and 3% major hesitation to recommend the treatment form received to a friend with similar disease. Twenty percent of the patients with endocrine ophthalmopathy reported the eye problems to be much more troublesome and 14% somewhat more troublesome than the thyroid problems. The cost proportion between the medical and surgical treatment in the young group was 1:2.5 (1 = 1126 United States dollars [USD]) before and 1:1.3 (1 = 2284 USD) after inclusion of the relapse costs. The proportion between the medical, surgical, and iodine-131 treatment in the older group was 1:2.5:1.6 (1 = 1164 USD) before and 1:1.6:1.4 (1 = 1972 USD) after inclusion of the relapse costs.

Parathyroid hormone-related protein (1-37) induces cAMP response in human osteoblast-like cells.

During recent years parathyroid hormone-related protein (PTHrP) research has been focused on the physiological functions of different fragments of the PTHrP molecule. Here we demonstrate that PTHrP (1-37) induced cyclic adenosine monophosphate (cAMP) response in primary human osteoblast-like cells, which were well characterized by the presence of alkaline phosphatase activity and osteocalcin production after stimulation with 1,25-dihydroxyvitamin D3. However, there was no cAMP response to PTHrP (58-77). Furthermore, the response to PTHrP (1-37) was dose dependent, with a significant increase at 1 nM. The presence of PTHrP (1-37)-induced cAMP response in human osteoblast-like cells implies that aminoterminal PTHrP fragments may exert important functions in the bone.

Effect of acute endurance and strength exercise on circulating calcium-regulating hormones and bone markers in young healthy males.

Physical activity plays a role in the maintenance of the skeleton but the mechanical, metabolic and hormonal mechanisms involved are largely unknown. The influence of acute endurance and strength exercise on circulating levels of calcitonin, parathyroid hormone (PTH), PTH-related peptide (PTHrP), osteocalcin, carboxyterminal cross-linked telopeptide of type I collagen (ICTP) and ionized calcium (Ca2+) was therefore evaluated. Eight healthy young males performed three exercise bouts on separate occasions: endurance exercise, i.e. cycling on a cycle ergometer for 45 min at 55% of Vo2max (E55%) and 15 min at 85% of Vo2max (E85%) and strength exercise at 85% of three repetitions maximum using a leg-press device (STR). Control experiments included the same subjects with the same time schedule but without exercise. Blood samples were taken before, immediately after exercise and during the recovery period. Hormones and bone markers were measured by use of various immunoassays. There was no obvious influence on calcitonin and PTHrP levels, whereas PTH was increased after strength exercise. ICTP and osteocalcin levels correlated positively at all times and showed regular variations. In comparison with the controls, ICTP levels showed a more pronounced decrease following physical activity whereas osteocalcin followed the same pattern as the controls except for after prolonged endurance exercise when a decrease was abolished. In conclusion, an increase in PTH after strength exercise and a pronounced decrease in ICTP after all exercise together with a relative increase in osteocalcin after prolonged endurance exercise might reflect some mechanisms involved in the positive effect of physical activity on bone mass.

Graves' hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine--a prospective, randomized study. Thyroid Study Group.

To analyze the benefits and risks of three common treatments, we randomly assigned 179 patients with Graves' hyperthyroidism as follows: 60 patients, 20-34 yr of age (young adults), received antithyroid drugs for 18 months (medical) or subtotal thyroidectomy (surgical), and 119 patients, 35-55 yr of age (old adults), received medical, surgical, or radioiodine (iodine-131) treatment. The follow-up time was at least 48 months. Antithyroid drugs, surgery, or iodine-131 treatment normalized the mean serum hormone levels within 6 weeks. The risk of relapse was highest in the medically treated young and old adults (42% vs. 34%), followed by that in those treated with iodine-131 (21%) and that in the surgically treated young and old adults (3% vs 8%), respectively. Elevated TSH receptor antibodies at the end of medical therapy or increasing TSH receptor antibodies values after medical or surgical treatment increased the probability of relapse. Development or worsening of ophthalmopathy was not associated with relapse per se. Ninety percent of the subjects in all groups were satisfied with the treatment they received. No significant difference in sick-leave due to Graves' or other diseases was seen during the first 2 yr after initiation of therapy. The increased risk of ophthalmopathy in patients with high serum T3 levels, especially when treated with iodine-131, and the relatively high frequency of relapse after treatment with antithyroid drugs are important factors to consider when selecting therapy for Graves' disease.

International comparison of hip fracture rates in 1988-89.

A comparison of hip fracture rates among nine countries (Canada, Chile, Finland, Hong Kong, Scotland, Sweden, Switzerland, the United States and Venezuela) was made using national hospital discharge data for the same time interval. The rates increased by age and were higher for females than males in all nine countries. When based on overall discharge rates, the incidence of hip fracture appeared high in three European countries (Finland, Scotland and Sweden) relative to the other countries. However, when transfer cases were removed and adjustments made for differences in case definition, the risk of hip fracture for both men and women was much similar among the four European and two North American countries, but higher than in Hong Kong. Rates of fracture were lowest in Venezuela and Chile, varying from three to 11 times less than for residents of the other seven countries. Although there are limitations in using hospital discharge data as a measure of incidence, the wide variation in the risk of hip fracture across the nine countries appears real but differences between North American and north European countries may not be as great as previously reported. Such cross-national comparisons may help clarify different etiologic hypotheses.

Circulating monomer-like calcitonin in osteoporotic patients.

Physiological concentrations of monomeric calcitonin can inhibit osteoclastic bone resorption in vitro. We therefore investigated the circulating molecular forms, including monomer-like calcitonin, and their concentrations in 9 men and 9 women with established osteoporosis. Calcitonin was immunoextracted from serum by the use of rabbit calcitonin antibodies coupled to Sepharose 4B. The lyophilized extracts were incubated with 6 M urea overnight and gel chromatographed in a fast protein liquid chromatography (FPLC) system; calcitonin was measured by radioimmunoassay in the fractions. FPLC disclosed immunoreactive calcitonin of three different molecular sizes in the patients. The two largest forms were approximately 30 and 10 kDa and one eluted at the same position as monomeric calcitonin (3.4 kDa). After extraction and FPLC we found slightly higher calcitonin concentrations in osteoporotic women than previously reported levels in age-matched healthy women. Male patients had higher levels than female patients. None of the osteoporotic patients lacked monomer-like calcitonin. There was no significant correlation between the extracted total or monomer-like calcitonin and bone mineral density of the femoral neck. It is concluded that the circulating calcitonin in both male and female patients comprises three different molecular forms and that there is no deficiency of the monomer-like form. The calcitonin levels in the female patients were slightly higher than in a previous control group.

Midmolecular parathyroid hormone-related peptide in serum during pregnancy, lactation and in umbilical cord blood.

Indications of an important physiological role of parathyroid hormone-related peptide (PTHrP) for fetal calcium homeostasis, maternal-fetal calcium transport and reproduction have accumulated over recent years. The PTHrP concentrations were measured by an earlier developed midregion radio-immunoassay in serum from lactating healthy females and umbilical cord blood and compared with levels in age-matched non-pregnant or lactating females. The PTHrP concentrations could be measured in all samples after silica cartridge C18 extraction of 10-12 ml of serum. The concentrations were significantly higher during lactation (mean +/- SD: 0.72 +/- 0.14 pmol/l, N = 22) and in umbilical cord blood (0.85 +/- 0.18 pmol/l, N = 12) compared with healthy age-matched women (0.48 +/- 0.09 pmol/l, N = 10, p < 0.001). The molecular forms of PTHrP were also studied in an age-matched control group, in pregnant women and in umbilical cord blood by gel chromatography in a fast protein liquid chromatography system of Sep-Pak-extracted pooled serum. In all three groups we found heterogeneity of the molecular forms with two predominant peaks. The smallest fragment had a molecular weight of 4-6 kD while the largest form appeared as a high-molecular-weight molecule. In conclusion, the concentrations of midmolecule PTHrP fragments in serum are elevated during lactation and in umbilical cord blood. Because the midregion of PTHrP has unique actions, our results indicate that PTHrP may play an important physiological role for the mother and for the maternal-fetal calcium transport.