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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.

To examine vitamin D status and parathyroid function in normal Danish women postpartum.Three cross-sectional measures during follow-up of 89 women postpartum.We assessed vitamin D status by measuring plasma 25-hydroxyvitamin D (P-25OHD) and the degree of secondary hyperparathyroidism by measuring plasma parathyroid hormone (P-PTH) in 89 Caucasian women at three consecutive visits: (mean (range)) 23 (10-37) days (spring), 117 (95-140) days (late summer) and 274 (254-323) days (winter) postpartum.P-25OHD showed seasonal variations with higher values in late summer than in the other periods (P0.001). At the first visit, 65% received vitamin D supplements. At the following visits, almost 50% were supplemented. Vitamin D insufficiency (P-25OHD50 nmol/l) occurred more often during winter (28%) than in spring (14%) (Fisher's exact test, P = 0.02) or late summer (7%) (P = 0.0001). Irrespective of season, vitamin D insufficiency occurred most frequent in women who did not take vitamin D supplements (Fisher's exact test, P0.02). Frank vitamin D deficiency (P-25OHD25 nmol/l) was observed during winter in 6%. At all three periods, P-25OHD correlated inversely with P-PTH indicating secondary hyperparathyroidism at deficient vitamin D status. During spring, late summer and winter three, one and four females, respectively, had elevated plasma PTH.Vitamin D insufficiency with secondary hyperparathyroidism is a frequent finding in healthy Danish women postpartum and especially during winter. Vitamin D supplements reduced the risk of vitamin D insufficiency, especially during winter. Our results support the importance of increased alertness regarding information of pregnant and lactating women about vitamin D supplements. Furthermore, it has to be studied whether the present recommendations of an intake of 5-10 microg vitamin D/day are sufficient, especially during winter months.

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).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.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 %.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.

The objective of this study was to assess the effect on calcium homeostasis of changing PTH replacement therapy (PTH-RT) from intact PTH (PTH(1-84)) to teriparatide (PTH(1-34)). This study is a consecutive case series. All patients with postoperative hypoparathyroidism who changed medication from PTH(1-84) (100 µg) to PTH(1-34) (20 µg) were included. Plasma ionized calcium, daily dose of 1α-hydroxylated-vitamin D metabolites alfacalcidol, calcium, TSH and PTH was collected. Eight patients (women = 88%) with a mean age of 54 ± 12 years and a duration of hypoPT of 13 ± 6 years were included. Before initiation of PTH(1-84), the mean daily dose of alfacalcidol was 1.9 ± 1.1 µg/d and calcium supplements were 1,550 ± 705 mg. Alfacalcidol dose was reduced with 88 ± 29% (p < 0.01) after 6 months of PTH(1-84) treatment and terminated in six patients. Calcium levels were reduced with 78 ± 36% (p = 0.02) to 273 ± 353 mg/d and stopped in five patients. Six patients received 100 µg PTH(1-84) daily, the seventh 2 out of 3 days and the last every second day. When changing from PTH(1-84) to PTH(1-34), plasma ionized calcium initially dropped and the demand for supplements increased. Alfacalcidol was resumed in five patients; mean daily dose increased to 1.50 ± 1.56 µg/d, (p = 0.02) and calcium increased to 329 ± 368 mg/d, (p = 0.72). Five patients received 20 µg PTH(1-34) a day, two patients twice-a-day and one 20/40 µg/d alternately. Compared with PTH(1-34), PTH(1-84) has a longer plasma half-life and a higher calcemic response. We have shown a need for higher doses of alfacalcidol and calcium supplements to maintain normal serum calcium when treated with PTH(1-34) compared to PTH(1-84) and in some a need for more than one daily PTH(1-34) dose.

UNLABELLED: To study effects of loop diuretics on bone, 87 women were randomized to 1 year of treatment with bumetanide or placebo. Compared with placebo, bumetanide decreased BMD by 2% at the total hip and by 1.4% at the whole body. Levels of biochemical bone markers were lower in the placebo than in the bumetanide group. Thus, treatment with loop diuretics affects bone metabolism. INTRODUCTION: Loop diuretics may affect bone because they increase the renal calcium excretion and alters the diurnal rhythm of plasma PTH levels. We studied the effects of 1 year of treatment with the loop diuretic bumetanide on bone metabolism. MATERIALS AND METHODS: In a double-blinded design, 87 healthy postmenopausal women with osteopenia were randomized to 1-year bumetanide treatment 2 mg/day or placebo. BMD, plasma levels of calcitropic hormones, and biochemical bone markers were measured at baseline, after 1 year of treatment (week 52), and 6 months after withdrawal of treatment (week 78). Calcium (800 mg/day) and vitamin D (10 microg/day) were administered to all participants during the entire 1.5-year study period. RESULTS: Compared with placebo, urinary calcium (+17%) and plasma PTH levels (+9%) increased significantly in response to bumetanide. After 1 year of treatment, BMD in the bumetanide compared with the placebo group was significantly decreased by 2% at the total hip and ultradistal forearm and by 1.4% at the whole body. In addition, levels of biochemical markers of bone turnover differed significantly (approximately 20%) between groups, with lower levels in the placebo than in the bumetanide group. Six months after the end of treatment, the effects of bumetanide were weakening. CONCLUSIONS: Treatment with loop diuretics affects bone turnover and decreases BMD. Further studies may reveal whether loop diuretics should be considered as a risk factor for fracture.

Objectives. To study the fracture risk associated with the use of corticosteroids in any formulation and administration. Design. Case–control study. Setting. Community-based study in Denmark. Subjects. Cases were all subjects with any fracture sustained during the year 2000 (n = 124 655). For each case, three controls (n = 373 962) matched on age and gender were randomly drawn from the background population. Adjustments were made for concurrent diseases (lung diseases, rheumatic disorders), use of other drugs (inhaled bronchodilators), contacts to hospitals and general practitioners, and social variables. Results. An increased risk of any fracture, hip, spine, and forearm fractures was present with use of more than 2.5 mg of prednisolone or equivalent orally per day. For inhaled corticosteroids a limited increase in the risk of any fracture was present in users of more than 7.5 mg prednisolone equivalents per day (equivalent to 1875 μg of budesonide per day). However, no increase in the risk of hip, spine or forearm fractures was present in users of inhaled corticosteroids. For other topical corticosteroids (dermal, rectal, nasal, local application in the mouth, the eyes or the ears) no increase in fracture risk could be demonstrated even at high doses after adjustment for confounders. Conclusions. Ingestion of more than 2.5 mg of oral prednisolone equivalents per day is associated with an increase in fracture risk. No increase is associated with inhaled corticosteroids except at daily dosages above 7.5 mg of prednisolone equivalents. No increase in fracture risk is associated with other forms of topical corticosteroids.

Summary: Purpose: To assess fracture risk associated with different antiepileptic drugs (AEDs). An increased fracture risk has been reported in patients with epilepsy. Classical AEDs have been associated with decreased bone mineral density. The effects of newer AEDs are unknown. Methods: We undertook a population-based pharmacoepidemiologic case–control study with any fracture as outcome and use of AEDs as exposure variables (124,655 fracture cases and 373,962 controls). Results: All AEDs were associated with an increased fracture risk in an unadjusted analysis. After adjustment for prior fracture, use (ever) of corticosteroids, comorbidity, social variables, and diagnosis of epilepsy, carbamazepine [CBZ; odds ratio (OR), 1.18; 95% confidence interval (CI), 1.10–1.26], [and oxcarbazepine (OXC; 1.14, 1.03–1.26)], clonazepam (CZP; 1.27, 1.15–1.41), phenobarbital (PB; 1.79, 1.64–1.95), and valproate (VPA; 1.15, 1.05–1.26) were statistically significantly associated with risk of any fracture. Ethosuximide (0.75, 0.37–1.52), lamotrigine (1.04, 0.91–1.19), phenytoin (1.20, 1.00–1.43), primidone (1.18, 0.95–1.48), tiagabine (0.75, 0.40–1.41), topiramate (1.39, 0.99–1.96), and vigabatrin (0.93, 0.70–1.22) were not statistically significantly associated with fracture risk after adjustment for confounders. The relative increase was modest and in the same range for the significant and nonsignificant results. CBZ, PB, OXC, and VPA displayed a dose–response relation. Fracture risk was more increased by liver-inducing AEDs (OR, 1.38; 95% CI, 1.31–1.45) than by noninducing AEDs (1.19; 95% CI, 1.11–1.27). Conclusions: A very limited increased fracture risk is present in users of CBZ, CZP, OXC, PB, and VPA. A limited significant increase cannot be excluded for the other AEDs because of the statistical power.

Aim: To compare the number of patients diagnosed with osteoporosis and osteoporotic fractures in Denmark, with the number of subjects expected to have osteoporosis. Subjects and methods: From the National Hospital Discharge Register, records for all patients diagnosed with osteoporosis and/or with osteoporotic fractures between 1995 and 1999 were retrieved. Based on normal Danish values for BMD, the expected number of subjects aged 50 years or more with osteoporosis according to the WHO definition was calculated. Results: The estimated prevalence of osteoporosis was 40.8% of women aged ≥50 years and 17.7% among men. The expected annual incidence was 58,658/million inhabitants in women ≥50 years of age and 23,648/million in men ≥50 years. However, the observed incidence was only 4,823 and 862/million per year, respectively (8.2% and 3.6% of the expected). In 1999, a total of 34,691 hip, spine, and forearm fractures were reported in subjects ≥50 years, and of these, 18,566 were potentially attributable to osteoporosis (14,240 fractures in women and 4,326 in men equaling 14,976 and 5,297/million per year). Only 0.3% of men ≥50 years were receiving a bisphosphonate, while 2.2% of women received a bisphosphonate or raloxifene. Among women ≥50 years, 27.7% received hormone replacement therapy. Conclusions: Osteoporotic fractures of the hip, spine, and forearm are rather frequent in Denmark, but the diagnosis of osteoporosis is rarely used. It seems that osteoporosis is markedly underdiagnosed and undertreated in Denmark as probably also elsewhere. This may have significant implications for the prevention of osteoporotic fractures.

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 p0.05) was calculated to 30% for samples taken on different days and measured in separate runs.

Background Thiazide diuretics (TDs) reduce whereas loop diuretics (LDs) increase urinary calcium. We studied the effects of different doses of a TD and LD on electrolytes, calcitropic hormones and biochemical bone markers. Subjects and methods In a five-period crossover study, comparing four active doses with placebo, 40 postmenopausal women with osteopenia were treated with different doses of LD bumetanide (n = 20, 0·5–2·0 mg per day) or TD bendroflumethiazide (n = 20, 2·5–10 mg per day). Each treatment period lasted 1 week. Results Urinary calcium decreased dose-dependently in response to the bendroflumethiazide. The best hypocalciuric effect was achieved by 5 mg day−1 of bendroflumethiazide. Total plasma calcium levels increased, whereas ionised calcium at ambient pH-values decreased because of increased pH-values in response to the bendroflumethiazide. Plasma PTH levels did not change, whereas a slight dose-dependent increase occurred in plasma 1,25(OH)2D levels. As a marker of bone formation, plasma osteocalcin levels increased. Conversely, bumetanide dose-dependently increased renal calcium losses with a concomitant increase in plasma PTH and 1,25(OH)2D levels. Plasma osteocalcin levels increased and bone-specific alkaline phosphatase levels decreased dose-dependently. Conclusion Whether a LD or TD is chosen as diuretic therapy affects calcium homeostasis. The effects of LDs are potentially harmful to bone. Further studies are needed to evaluate whether long-term treatment with LDs causes osteoporosis. Until then, we suggest using, if possible, a TD rather than a LD as diuretic therapy in order not to risk deleterious effects on bone metabolism.

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

Summary objective The pituitary secretes many hormones of significance to bone turnover and thus skeletal integrity. The aim of this study was to examine fracture risk in patients with pituitary disorders with special reference to GH deficiency and hyperprolactinaemia. design Case-control study. measurements Fracture occurrence. patients A self-administered questionnaire was issued to 537 consecutive patients with pituitary disorders excluding Cushing’s disease. A total of 426 (79%) returned the questionnaire and 422 of these could be analysed. Each respondent was compared to three age- and gender-matched control respondents to the same questionnaire drawn randomly from the background population. results The patients had a mean age of 51·4 ± 14·8 years. One hundred and eight patients had acromegaly, 86 had prolactinomas, 136 had non-functioning pituitary adenomas (NFPA), 23 had craniopharyngiomas, and 73 had other types of pituitary disorders. For the total group the fracture risk was not elevated either before or after confirmed diagnosis compared to controls. However, among the patients with prolactinomas, the fracture risk was significantly increased before (relative risk, RR = 1·6, 95% CI: 1·1–2·3) but not after diagnosis. In patients with NFPA, fracture risk was borderline significantly elevated following diagnosis (RR = 1·6, 95% CI: 1·0–2·6). Patients with subnormal stimulated peak GH values suggestive of GH deficiency had a significantly higher risk of fractures after diagnosis than patients who had normal stimulated peak GH values (odds ratio, OR = 4·90, 95% CI: 1·10–21·88). conclusions Untreated prolactinomas were associated with a significant increase in fracture risk. Growth hormone deficiency was also associated with a higher fracture risk.

L’hyperparathyroidie primitive (PHPT) est une maladie frequente, curable (chirurgie), compliquee d’atteintes renales et osseuses. L’hypercalcemie familiale benigne (FHH) est une maladie genetique rare, non curable dont la presentation biologique est proche de celle de la PHPT : une hypercalcemie associee a une concentration d’hormone parathyroidienne (PTH) inadaptee. La mesure de l’excretion fractionnelle de calcium (FE Ca ) est recommandee pour distinguer ces 2 affections. Methodes D’une premiere cohorte, 146 adultes (63 avec FHH genetiquement prouvee, 83 avec PHPT chirurgicalement prouvee) ont ete etudies. Tous avaient une hypercalcemie ([calcium ionise] a jeun ≥ 1,32 mM) et une PTH normale. Les donnees disponibles ont ete comparees en analyse multivariee afin de developper une equation de risque (Pro-FHH) pour distinguer les patients avec FHH de ceux avec PHPT. Apres une validation interne ( boot-strap ), une cohorte independante, incluant 38 adultes avec FHH et 55 avec PHPT, a permis de tester la validation externe. Resultats Les patients avec FHH et ceux avec PHPT avaient des valeurs de calcemie, PTH, osteocalcine et FE Ca differentes. Pro-FHH a ete developpee grâce a ces 4 valeurs. L’aire sous la courbe ROC etait plus elevee pour Pro-FHH que pour FE Ca (0,969 vs. 0,873, p Ca classait de facon erronee 24 patients, pro-FHH les classait correctement. Ces resultats sont confirmes dans une cohorte independante. Discussion Pro-FHH a une meilleure capacite a discriminer la FHH et la PHPT que FE Ca. Une evaluation prospective de cet outil simple est necessaire.

OBJECTIVE: This report summarizes data on traditional and nontraditional manifestations of primary hyperparathyroidism (PHPT) that have been published since the last International Workshop on PHPT.PARTICIPANTS: This subgroup was constituted by the Steering Committee to address key questions related to the presentation of PHPT. Consensus was established at a closed meeting of the Expert Panel that followed.EVIDENCE: Data from the 5-year period between 2008 and 2013 were presented and discussed to determine whether they support changes in recommendations for surgery or nonsurgical follow-up.CONSENSUS PROCESS: Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was undertaken. After extensive review and discussion, the subgroup came to agreement on what changes in the recommendations for surgery or nonsurgical follow-up of asymptomatic PHPT should be made to the Expert Panel.CONCLUSIONS: 1) There are limited new data available on the natural history of asymptomatic PHPT. Although recognition of normocalcemic PHPT (normal serum calcium with elevated PTH concentrations; no secondary cause for hyperparathyroidism) is increasing, data on the clinical presentation and natural history of this phenotype are limited. 2) Although there are geographic differences in the predominant phenotypes of PHPT (symptomatic, asymptomatic, normocalcemic), they do not justify geography-specific management guidelines. 3) Recent data using newer, higher resolution imaging and analytic methods have revealed that in asymptomatic PHPT, both trabecular bone and cortical bone are affected. 4) Clinically silent nephrolithiasis and nephrocalcinosis can be detected by renal imaging and should be listed as a new criterion for surgery. 5) Current data do not support a cardiovascular evaluation or surgery for the purpose of improving cardiovascular markers, anatomical or functional abnormalities. 6) Some patients with mild PHPT have neuropsychological complaints and cognitive abnormalities, and some of these patients may benefit from surgical intervention. However, it is not possible at this time to predict which patients with neuropsychological complaints or cognitive issues will improve after successful parathyroid surgery.

Familial Hypocalciuric Hypercalcaemia (FHH) Type 1 is caused by an inactivating mutation in the calcium-sensing receptor (CASR) gene resulting in elevated plasma calcium levels. We investigated whether FHH is associated with change in bone density and structure. We compared 50 FHH patients with age- and gender-matched population-based controls (mean age 56 years, 69 % females). We assessed areal BMD (aBMD) by DXA-scans and total, cortical, and trabecular volumetric BMD (vBMD) as well as bone geometry by quantitative computed tomography (QCT) and High-Resolution peripheral-QCT (HR-pQCT). Compared with controls, FHH females had a higher total and trabecular hip vBMD and a lower cortical vBMD and hip bone volume. Areal BMD and HRpQCT indices did not differ except an increased trabecular thickness and an increased vBMD at the transition zone between cancellous and cortical bone in of the tibia in FHH. Finite element analyses showed no differences in bone strength. Multiple regression analyses revealed correlations between vBMD and P-Ca(2+) levels but not with P-PTH. Overall, bone health does not seem to be impaired in patients with FHH. In FHH females, bone volume is decreased, with a lower trabecular volume but a higher vBMD, whereas cortical vBMD is decreased in the hip. This may be due to either an impaired endosteal resorption or corticalization of trabecular bone. The smaller total bone volume suggests an impaired periosteal accrual, but bone strength is not impaired. The findings of more pronounced changes in females may suggest an interaction between sex hormones and the activity of the CaSR on bone.

Parathyroid hormone (PTH) is produced and secreted by the parathyroid glands and has primary effects on kidney and bone. During the pathological growth of one or more parathyroid glands, the plasma level of PTH increases and causes primary hyperparathyroidism (PHPT). This disease is normally characterised by hyperparathyroid hypercalcaemia. In PHPT a continuously elevated PTH stimulates the kidney and bone causing a condition with high bone turnover, elevated plasma calcium and increased fracture risk. If bone resorption is not followed by a balanced formation of new bone, irreversible bone loss may occur in these patients. Medical treatment can help to minimise the loss of bone but the cure of PHPT is by parathyroidectomy. After operation, bone mineral density increases during the return to normal bone metabolism. Supplementation with calcium and vitamin D after operation may improve the normalisation to normal bone metabolism with a secondary reduction in fracture risk.

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.The objective of the study was to investigate the effect of GIPR Glu354Gln on bone mineral density (BMD) and fracture risk.This was a prospective, comprehensive, cohort study (number NCT00252408).A total of 1686 perimenopausal women were included.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.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.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.

Objectives Vitamin D insufficiency is common in subjects with type 2 diabetes. Observational studies suggest that vitamin D plays a role in the pathogenesis of type 2 diabetes. However, results of intervention studies have been inconsistent. We investigated the effects of improving vitamin D status on insulin sensitivity, insulin secretion, and inflammatory markers in patients with type 2 diabetes. Materials/methods A double blind, randomized, placebo controlled trial was conducted. Sixteen patients with type 2 diabetes and hypovitaminosis D were recruited. Eight patients received colecalciferol and (280 μg daily for 2 weeks, 140 μg daily for 10 weeks) and 8 patients received identical placebo tablets for 12 weeks. Before and after intervention, patients underwent IVGTT, hyperinsulinemic euglycemic clamp, assessment of baseline high-frequency insulin pulsatility, glucose-entrained insulin pulsatility, DXA scans, 24-hour-ambulatory blood pressure monitorings, and fasting blood samples. Results Serum-25(OH) vitamin D and serum-1,25(OH)2 vitamin D increased significantly after 12 weeks in the intervention group (p = 0.01, p = 0.004). Serum-25(OH) vitamin D was also significantly higher in the vitamin D group compared to the placebo group (p = 0.02) after intervention. Although no significant changes in insulin sensitivity, inflammation, blood pressure, lipid profile, or HbA1c were found, we observed borderline (p between 0.05 and 0.10) improvements of insulin secretion, in terms of c-peptide levels, first phase incremental AUC insulin and insulin secretory burst mass. Conclusions Improvement in vitamin D status does not improve insulin resistance, blood pressure, inflammation or HbA1c, but might increase insulin secretion in patients with established type 2 diabetes.

Low 25-hydroxyvitamin D levels are common in patients with primary hyperparathyroidism (PHPT) and associated with higher PTH levels and hungry bone syndrome after parathyroidectomy (PTX). However, concerns have been raised about the safety of vitamin D supplementation in PHPT.We aimed to assess safety and effects on calcium homeostasis and bone metabolism of supplementation with high doses of vitamin D in PHPT patients.This was an investigator-initiated double-blind, randomized, placebo-controlled, parallel-group trial from a single center.Forty-six PHPT patients were recruited, with a mean age of 58 (range 29-77) years, and 35 (76%) were women.Intervention included daily supplementation with 70 μg (2800 IU) cholecalciferol or identical placebo for 52 weeks. Treatment was administered 26 weeks before PTX and continued for 26 weeks after PTX.PTH, calcium homeostasis, and bone metabolism were evaluated.Preoperatively, 25-hydroxyvitamin D increased from 50 to 94 nmol/L in the treatment group and decreased from 57 to 52 nmol/L in the placebo group (P.001). Compared with placebo, vitamin D decreased PTH significantly by 17% before PTX (P = .01), increased lumbar spine bone mineral density by 2.5% (P = .01), and decreased C-terminal β-CrossLaps by 22% (P.005). The trabecular bone score did not change in response to treatment, but improved after PTX. Postoperatively, PTH remained lower in the cholecalciferol group compared with the placebo group (P = .04). Plasma creatinine and plasma and urinary calcium did not differ between groups.Daily supplementation with a high vitamin D dose safely improves vitamin D status and decreases PTH in PHPT patients. The vitamin D treatment is accompanied by reduced bone resorption and improved bone mineral density before operation.

Patients with “asymptomatic” primary hyperparathyroidism (PHPT) often describe improvement after surgery. We evaluated muscle and balance function, quality of life (QoL), and well-being in 58 PHPT patients and 58 population-based matched controls in a cross-sectional study. We tested whether patients considered “asymptomatic” according to international guidelines have functional impairment. Mean age of the patients and controls was 59 years, and 47 (81 %) were women. Patients had higher levels of plasma PTH and ionized calcium. Creatinine and 25-hydroxyvitamin D levels did not differ between groups. Altogether, 16 (28 %) patients were “asymptomatic.” Compared with controls, PHPT was associated with significantly lower QoL in all eight domains of the short form-36 questionnaire, lower well-being (WHO Five Well-Being Index; p

Low plasma 25-hydroxy-vitamin D (25OHD) is associated with obesity. Vitamin D (VD) may be implicated in obesity and its complications such as insulin resistance, hypertension, and low-grade inflammation. We investigated the effects of VD supplementation on fat distribution and on obesity complications in obese adults with low plasma levels of 25OHD.In a double-blind design 52 subjects aged 18 to 50years with BMI30kg/m(2) and plasma 25OHD50nmol/l were randomized to 26weeks of treatment with 7000IU of VD daily or placebo. Body composition was assessed by DXA and subcutaneous (SAT) and visceral adipose tissue (VAT), intrahepatic (IHL) and intramyocellular lipids (IMCL) were evaluated by magnetic resonance imaging and magnetic resonance spectroscopy. Insulin resistance (HOMA-IR), blood pressure, plasma lipids, and circulating inflammatory markers were also investigated.VD treatment increased mean plasma levels of 25OHD from 33nmol/l to 110nmol/l (P0.0001) and decreased median parathyroid hormone levels from 5.3 to 4.5pmol/l (P0.01) in the intervention group. Treatment did not change body fat, SAT, VAT, IHL, or IMCL compared with placebo. Neither did treatment affect HOMA, blood pressure, plasma lipids or any of several inflammatory markers investigated including hsCRP.Increasing 25OHD levels by VD treatment for 26weeks have no effects on obesity complications in obese adults with low baseline plasma 25OHD.

BACKGROUND/OBJECTIVES: The objective of this study was to assess vitamin D status and possible consequences of low plasma 25-hydroxyvitamin D (25OHD) levels in a population of healthy mothers and their infants.Subjects/methods:A total of 107 women aged 24-41 years gave birth to 108 infants. They were followed up three times during 9 months. RESULTS: Cord blood 25OHD level (43.3 ± 20.4 nmol/l) on average was 62 ± 16% of maternal levels (73.3 ± 30.7 nmol/l), measured 1-2 weeks postpartum. Cord blood 25OHD correlated positively with maternal 25OHD levels (r=0.83, P50 nmol/l. During follow-up, most of the children (>85%) had 25OHD levels >50 nmol/l, which most likely was attributable to the use of supplements, as more than 95% of the children were given daily vitamin D supplements of 10 μg of vitamin D.Cord blood parathyroid hormone levels were very low (median 0.21; interquartile range 0.11-0.33 pmol/l), with increasing levels (P CONCLUSIONS: Vitamin D deficiency is widespread in newborn. Maternal 25OHD levels above 50 nmol/l are needed to prevent vitamin D deficiency among newborn. The objective of this study was to assess vitamin D status and possible consequences of low plasma 25-hydroxyvitamin D (25OHD) levels in a population of healthy mothers and their infants.Subjects/methods:A total of 107 women aged 24-41 years gave birth to 108 infants. They were followed up three times during 9 months.

UNLABELLED: The effects of treatment with 100 μg parathyroid hormone (PTH) (1-84) or an identical placebo on muscle function and quality of life (QoL) was studied in hypoparathyroid patients. At baseline, we found reduced QoL but no myopathy in the patients. Six months of treatment did not improve QoL, and muscle strength decreased slightly.INTRODUCTION: A reduced quality of life (QoL) and myopathy that may be due to the absence of PTH have been reported in patients with hypoparathyroidism (hypoPT).METHODS: Sixty-two patients with chronic hypoPT were randomized to 6 months of treatment with either PTH(1-84) 100 μg/d s.c. or placebo, given as add-on therapy to conventional treatment. Muscle function and postural stability were investigated using a dynamometer chair, a stadiometer platform, the repeated chair stands test, the timed up and go test, and electromyography. QoL was assessed using the 36-item Short Form Health Survey and the WHO-5 Well-Being Index.RESULTS: The mean age of the patients was 52 ± 11 years, and 85 % were females. At baseline, QoL was significantly reduced in comparison with norm-based scores. Compared with placebo, PTH did not improve QoL or muscle function. Rather, max force production decreased significantly by 30 % at elbow flexion in the PTH group compared with the placebo group. Moreover, there was a nonsignificant trend for muscle strength to decrease in the upper extremities and on knee extension in response to PTH. Treatment did not affect postural stability. Electromyography showed a slight decrease in the duration of motor unit potentials in the PTH group, indicating a tendency toward myopathy, which, however was not symptomatic.CONCLUSIONS: Overall, our data do not support an immediate beneficial effect of PTH replacement therapy on muscle function or QoL. A high frequency of hypercalcemia among our patients may have compromised the potential beneficial effects of reversing the state of PTH insufficiency.

Background: Measurement of milk cobalamin is hampered by the high content of the cobalamin-binding protein haptocorrin, and limited data are available relating trustworthy measures of milk cobalamin to cobalamin status in healthy mothers and their children. Objectives: The objectives were to explore the concentration of cobalamin and haptocorrin in foremilk and hindmilk during the first 9 mo of lactation and to relate these results to biomarkers of an impaired cobalamin status of mother and child. Design: Milk samples from 25 mothers were collected at 2 wk, 4 mo, and 9 mo postpartum for the measurement of cobalamin and haptocorrin. Plasma samples from a larger cohort of lactating mothers (n = 107) and their infants (n = 108) were collected at the same time points for the measurement of cobalamin, holotranscobalamin, total transcobalamin, total haptocorrin, and methylmalonic acid. Results: Median (range) concentrations of cobalamin in hindmilk were 760 (210‐1880), 290 (140‐690), and 440 (160‐1940) pmol/L at 2 wk, 4 mo, and 9 mo, respectively; the respective haptocorrin concentrations were 25 (9‐102), 22 (4‐100), and 180 (30‐460) nmol/L. We found slightly lower values in foremilk. A decrease in milk cobalamin at 4 mo was associated with decreases in plasma cobalamin (P , 0.0001) and holotranscobalamin (P , 0.0001) in the infants. Strong positive associations in paired maternal-infant cobalamin concentrations were found at all time points. Conclusions: Foremilk and hindmilk contained comparable amounts of cobalamin and haptocorrin, but marked changes were observed during 9 mo of lactation. At 4 mo, low concentrations of milk cobalamin mirrored biochemical changes in infants, which suggests an impaired cobalamin status and indicates that nutrition from only mother’s milk may not be sufficient for the supply of cobalamin from this age. This trial was registered by the Danish Data Protection Agency at www.datatilsynet.dk/english as 200841-2185. Am J Clin Nutr doi: 10.3945/ajcn.113.058479.

BackgroundFamilial hypocalciuric hypercalcemia (FHH) is often due to inactivating variants in the calcium-sensing receptor (CASR) gene causing chronically elevated plasma calcium levels with inappropriately normal or elevated parathyroid hormone levels. In patients with primary hyperparathyroidism, the state of hyperparathyroid hypercalcemia is associated with reduced muscle strength and impaired quality of life (QoL).ObjectiveTo study whether FHH affects muscle function, postural stability, and QoL.DesignIn a cross-sectional study, we investigated muscle strength (handgrip, elbow flexion/extension, and knee flexion/extension), balance function, physical activity, and QoL in 50 patients with FHH and in a similar number of age- and gender-matched population-based healthy controls. All but one of the FHH cases had genetically verified inactivating variants in theCASRgene.ResultsStudied subjects (n=100, 68% females) had a mean age of 56.0 years. Muscle strength as assessed by measuring maximum force and maximum force production did not differ between the groups. Neither did groups differ in terms of QoL, physical activity, or postural stability, as assessed during normal standing with eyes open, normal standing with eyes closed, semi-tandem standing, or tandem standing. Adjustment for vitamin D status (plasma 25-hydroxyvitamin D levels) and BMI did not change results.ConclusionDespite a state of chronic hypercalcemia, muscle strength, balance function, and QoL are not impaired in patients with FHH. Our findings are reassuring for patients with FHH as they should not be considered as having a severe disease.

Hypoparathyroidism is characterized by hypocalcemia with inappropriately low parathyroid hormone (PTH) levels. Bone turnover is abnormally low and bone mineral density (BMD) is typically increased. Plasma calcium levels can be normalized by treatment with calcium supplements and vitamin D analogs, but bone turnover remains low and patients complain of a reduced quality of life (QoL). During recent years, a number of studies have shown that PTH replacement therapy (PTH-RT) may maintain calcium levels within the normal range, while the need for calcium and vitamin D supplements is reduced. In the initial response to subcutaneous PTH injections once or twice daily, bone turnover is overstimulated. BMD increases in cancellous bone, but decreases in cortical bone due to an increased porosity. Microcomputed tomography scans and histomorphometric studies on bone biopsies have shown changes similar to the well-known bone anabolic effects of PTH treatment in osteoporosis rather than a normalization of bone remodeling balancing the anabolic and catabolic effects of PTH. Most recently, continuous PTH delivery by pump was shown to increase the levels of bone markers into the normal range (without overstimulation of bone turnover) and with a normalization of renal calcium excretion. As PTH has a short plasma half-life, these findings indicate that exposure to PTH once or twice daily is not sufficient to reestablish a calcium homeostasis and bone metabolism that resembles normal physiology. Further studies should assess the effects of continuous PTH exposure by pump delivery (or multiple daily injections) on BMD and bone histology, as well as the effects of PTH-RT on indices of QoL.

We aimed to identify all patients with postsurgical hypoparathyroidism (HypoPT) and to evaluate their risks of renal complications and cardiovascular disease in relation to their disease and its treatment. We identified possible patients through the Danish National Patient Registry and a prescription database. Case status was adjudicated by review of individual patients' hospital records. For each patient with postsurgical HypoPT due to surgery for nonmalignant diseases between 1988 and 2012, three age-matched (± 2 years) and gender-matched controls were selected from the general background population. The prevalence of postsurgical HypoPT was 22 per 100,000 inhabitants. We identified 688 patients who had undergone neck surgery since 1988 with subsequent hypocalcaemia and inappropriate low parathyroid hormone (PTH) levels that necessitated treatment with calcium and/or vitamin D supplementation for more than 6 months. The average age at diagnosis was 49 years (range, 17-87 years), and 88% were women. Sixteen percent of all patients had had neck surgery prior to the operation causing HypoPT. Compared with controls, patients with HypoPT had an increased risk of renal complications (hazard ratio [HR], 3.67; 95% confidence interval [CI], 2.41-5.59) and hospitalization due to seizures (HR, 3.82; 95% CI, 2.15-6.79), whereas there was no increased risk of cardiac arrhythmias (HR, 1.11; 95% CI, 0.79-1.57) or cardiovascular disease or death (HR, 0.89; 95% CI, 0.73-1.09). In conclusion, although risk of seizures and renal complications is increased, mortality and risk of cardiovascular diseases or arrhythmias is not increased in patients with HypoPT. Further study should try to determine how to reduce the risk of seizures and renal complications in HypoPT.

The interaction between muscle and bone is complex. The aim of this study was to investigate if variations in the muscle genes myostatin (MSTN), its receptor (ACVR2B), myogenin (MYOG), and myoD1 (MYOD1) were associated with fracture risk, bone mineral density (BMD), bone mineral content (BMC), and lean body mass. We analyzed two independent cohorts: the Danish Osteoporosis Prevention Study (DOPS), comprising 2,016 perimenopausal women treated with hormone therapy or not and followed for 10 years, and the Odense Androgen Study (OAS), a cross-sectional, population-based study on 783 men aged 20-29 years. Nine tag SNPs in the four genes were investigated. In the DOPS, individuals homozygous for the variant allele of the MSTN SNP rs7570532 had an increased risk of any osteoporotic fracture, with an HR of 1.82 (95 % CI 1.15-2.90, p = 0.01), and of nonvertebral osteoporotic fracture, with an HR of 2.02 (95 % CI 1.20-3.41, p = 0.01). The same allele was associated with increased bone loss (BMC) at the total hip of 4.1 versus 0.5 % in individuals either heterozygous or homozygous for the common allele (p = 0.006), a reduced 10-year growth in bone area at the total hip of 0.4 versus 2.2 and 2.3 % in individuals heterozygous or homozygous for the common allele, respectively (p = 0.01), and a nonsignificantly increased 10-year loss of total-hip BMD of 4.4 versus 2.7 and 2.9 % in individuals heterozygous or homozygous for the common allele, respectively (p = 0.08). This study is the first to demonstrate an association between a variant in MSTN and fracture risk and bone loss. Further studies are needed to confirm the findings.

Vitamin D insufficiency is frequent in the general population. Meta-analyses of randomized controlled trials (RCTs) have shown a decreased risk of falls in elderly treated with vitamin D supplements, which may be due to an improved neuromuscular function in vitamin D-replete subjects. In most observational studies, vitamin D status correlates positively with muscle strength and postural stability. However, as physical activity is associated with vitamin D status as well as muscle strength, effects of vitamin D status on muscular health can only be assessed properly in RCTs. A systematic search was performed and 16 RCTs on the effects of treatment with vitamin D on muscle function were identified. All except one of the studies were performed in subjects above 50 years of age. Baseline 25-hydroxyvitmin D (25OHD) levels were below 50 nmol/l in 11 studies. Plasma 25OHD levels increased significantly in all studies. In seven studies, a beneficial effect of vitamin D treatment was documented on muscle strength of the lower legs, body sway, and/or physical performance. Identified studies were heterogeneous with regard to most aspects including indices measured. No obvious characteristics delineated studies showing beneficial effects from studies showing no effects. Only a few investigators reported the statistical power of measurements performed. In conclusion, evidence from RCTs do support an effect of vitamin D supplements on muscle strength and function in the elderly, but more studies showing a lack of an effect have been published than studies showing beneficial effects. There is a major lack of data on possible effects in younger subjects.

Low levels of 25-hydroxyvitamin D (25OHD) are associated with increased bone turnover and risk of fractures. Plasma 25OHD is inversely related to body mass index, and vitamin D deficiency is common in obesity. We aimed to determine whether vitamin D supplementation affects bone turnover and bone mineral density (BMD) in obese subjects. Fifty-two healthy obese men and women aged 18–50 years with plasma 25OHD levels below 50 nmol/L were randomized to 7,000 IU of cholecalciferol daily or placebo for 26 weeks. We measured plasma levels of 25OHD, parathyroid hormone (PTH), and markers of bone turnover, as well as BMD at the hip, spine, forearm, and whole body. Compared with placebo, treatment with cholecalciferol increased mean plasma 25OHD from 35 to 110 nmol/L (p

CONTEXT: The pathogenesis of primary hyperparathyroidism (PHPT) is largely unknown.OBJECTIVE: The objective of the study was to ascertain the plasma levels of calcium, PTH, and 25-hydroxyvitamin D (25OHD) as measured prior to a clinical diagnosis of PHPT.STUDY SUBJECTS: Within three population-based cohorts, we identified participants diagnosed with PHPT after their inclusion. Cases (n = 117) were compared with age, gender, and season-matched controls (n = 233).RESULTS: Time from inclusion until a diagnosis of PHPT was median 5.6 yr. Parathyroidectomy was performed in 97%. At the cohort inclusion, undiagnosed PHPT was present in 63% of the cases. Among those without PHPT at inclusion (n = 43), 55% had normocalcemic hyperparathyroidism (vs. 21% in the matched controls, P < 0.01), and 31% had normoparathyroid hypercalcemia. Overall, 25OHD levels were lower in the cases. Compared with their matched controls, 25OHD levels were lower in normocalcemic hyperparathyroidism but not in normoparathyroid hypercalcemia. An adenoma was removed from 78% of the cases with normocalcemic hyperparathyroidism, whereas 39% of the cases with normoparathyroid hypercalcemia had parathyroid hyperplasia (P = 0.02). Overlap performance showed a positive predictive value for later PHPT of 95% for plasma calcium levels greater than 2.52 mmol/liter. Excluding cases with vitamin D insufficiency, the positive predictive value for later PHPT was 83% for PTH levels greater than 5.0 pmol/liter.CONCLUSION: Years prior to a clinical diagnosis of PHPT, calcium homeostasis shows signs of perturbations. Latent PHPT may be characterized by either normocalcemic hyperparathyroidism or normoparathyroid hypercalcemia. Such patients should be offered long-term follow-up to ascertain whether their biochemical profile represents an early state of PHPT. The pathogenesis of primary hyperparathyroidism (PHPT) is largely unknown.

Background: The risk of type 1 diabetes (T1DM), infections, cancer, schizophrenia and multiple sclerosis (MS) has been associated with environmental factors including vitamin D status. Materials and Methods: Data were obtained from all children born in Denmark in 1940 (n = 72,839), 1977 (n = 89,570), and 1996 (n = 74,015). Information on contacts to hospitals (1977–2009) was obtained from the National Hospital Discharge Register. The main exposure variable was season of birth as a proxy variable for vitamin D status (summer: April–September and winter: October–March). Results: No associations between season of birth and risk of MS were seen in the 1940 cohort or the 1996 cohort. In the 1977 cohort, there was a borderline statistically significant decreased risk of MS in those born during wintertime compared with those born during summertime (HR = 0.70, 95% CI: 0.47–1.04, p = 0.07). There were no significant differences within the groups regarding season and risk of T1DM at any age, T1DM before 10 y, infection, any type of cancer, schizophrenia and myocardial infarction. In the 1977 cohort the risk of pneumonia was significantly lower among those born in the summer compared with the winter at any age (HR 0.91, 95% CI 0.85–0.97, p < 0.01) and at age < 10 y (HR 0.90, 95% CI 0.84–0.97, p < 0.01). Conclusion: MS and pneumonia in young subjects may be related to season of birth and thus maternal vitamin D exposure. Low sunlight exposure in the winter time leading to low vitamin D levels during pregnancy may be a potential explanation.

PURPOSE: This study aims to quantify bone mineral density (BMD) changes following surgery in patients with primary hyperparathyroidism (PHPT) and to assess their relationship with clinical and biochemical variables. METHODS: A historic cohort of 236 PHPT patients with DXA scans pre- and 1-year postoperatively, clinical data, and biochemical data was analyzed. RESULTS: The mean age was 60 years (range 19-86) and 81 % of the patients were women. A significant postoperative 2.6 % (95 % CI, 2.1; 3.1) increase in lumbar spine BMD was seen. The increase in BMD was positively associated with preoperative plasma PTH (p = 0.002), Ca(2+) (p CONCLUSIONS: We found significant postoperative BMD improvements both at the hip and the spine. BMD improvements were also significant in mild cases. At all scan sites, there were positive associations between preoperative plasma PTH levels and postoperative BMD increases. The measured BMD changes may mainly be due to a decrease in PTH-induced bone turnover with refilling of the remodeling space. This study aims to quantify bone mineral density (BMD) changes following surgery in patients with primary hyperparathyroidism (PHPT) and to assess their relationship with clinical and biochemical variables.

Introduction: Vitamin D may affect multiple health outcomes. If so, an effect on mortality is to be expected. Using pooled data from randomized controlled trials, we performed individual patient data (IPD) and trial level meta-analyses to assess mortality among participants randomized to either vitamin D alone or vitamin D with calcium.\ud \ud Subjects and Methods: Through a systematic literature search, we identified 24 randomized controlled trials reporting data on mortality in which vitamin D was given either alone or with calcium. From a total of 13 trials with more than 1000 participants each, eight trials were included in our IPD analysis. Using a stratified Cox regression model, we calculated risk of death during 3 yr of treatment in an intention-to-treat analysis. Also, we performed a trial level meta-analysis including data from all studies.\ud \ud Results: The IPD analysis yielded data on 70,528 randomized participants (86.8% females) with a median age of 70 (interquartile range, 62–77) yr. Vitamin D with or without calcium reduced mortality by 7% [hazard ratio, 0.93; 95% confidence interval (CI), 0.88–0.99]. However, vitamin D alone did not affect mortality, but risk of death was reduced if vitamin D was given with calcium (hazard ratio, 0.91; 95% CI, 0.84–0.98). The number needed to treat with vitamin D plus calcium for 3 yr to prevent one death was 151. Trial level meta-analysis (24 trials with 88,097 participants) showed similar results, i.e. mortality was reduced with vitamin D plus calcium (odds ratio, 0.94; 95% CI, 0.88–0.99), but not with vitamin D alone (odds ratio, 0.98; 95% CI, 0.91–1.06).\ud \ud Conclusion: Vitamin D with calcium reduces mortality in the elderly, whereas available data do not support an effect of vitamin D alone.

ObjectiveTo investigate the relationship between vitamin D status in healthy women and cardiovascular outcome.Design and methodsBetween 1990 and 1993, 2016 healthy, recently postmenopausal women were enrolled in the Danish Osteoporosis Prevention Study. Serum levels of 25-hydroxyvitamin D (25(OH)D, nmol/l) were measured at baseline. Participants were followed for 16 years. The primary end point was a combination of death, heart failure, myocardial infarction (MI) and stroke. Vitamin D deficiency was defined as serum 25(OH)DResultsAt baseline, mean age was 50 years and BMI 25. Women with vitamin D deficiency (n=788) had more cardiovascular risk factors than vitamin D-replete women (n=1225). Compared with vitamin D-replete women, women with low 25(OH)D levels had significantly higher BMI and triglycerides, lower HDL and hip–waist ratio and less education. More were smokers among the vitamin D deficient (47 vs 38%). A primary end point was experienced by 118 (15%) with vitamin D deficiency and by 125 (10%) of the vitamin D replete. Hazard ratio (HR) was 1.49 (95% confidence interval: 1.16–1.92;P=0.002) in the vitamin D deficient. Adjusted HR was 1.32 (1.02–1.71;P=0.03). In total, 135 women died; of these, 65 (8%) were of the vitamin D deficient and 70 (6%) in the vitamin D-replete group; unadjusted HR was 1.44 (1.02–2.01;P=0.04) for vitamin D deficiency.ConclusionHealthy women with vitamin D deficiency have increased risk of adverse cardiovascular outcome.

Hypoparathyroidism (hypoPT) is characterized by a state of low bone turnover and high bone mineral density (BMD) despite conventional treatment with calcium supplements and active vitamin D analogues. To assess effects of PTH substitution therapy on 3-dimensional bone structure, we randomized 62 patients with hypoPT into 24 weeks of treatment with either PTH(1-84) 100 µg/day subcutaneously or similar placebo as an add-on therapy. Micro-computed tomography was performed on 44 iliac crest bone biopsies (23 on PTH treatment) obtained after 24 weeks of treatment. Compared with placebo, PTH caused a 27% lower trabecular thickness (p

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 lactationWe describe physiological changes in calcium homeostasis, calcitropic hormones and bone metabolism during pregnancy and lactation.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.P-estradiol (E2), prolactin and 1,25-dihydroxyvitamin D (1,25(OH)2D) increased (p0.001) during pregnancy, whereas plasma levels of parathyroid hormone (P-PTH) and calcitonin decreased (p0.01). Insulin-like growth factor I (IGF-I) was suppressed (p0.05) in early pregnancy but peaked in the third trimester. Postpartum, E2 was low (p0.05); prolactin decreased according to lactation status (p0.05). 1,25(OH)2D was normal and IGF-I was again reduced (p0.05). P-PTH and calcitonin increased postpartum. From early pregnancy, markers of bone resorption and formation rose and fall, respectively (p0.001). From the third trimester, bone formation markers increased in association with IGF-I changes (p0.01). Postpartum increases in bone turnover markers were associated with lactation status (p0.001). During lactation, plasma phosphate was increased, whereas calcium levels tended to be decreased which may stimulate PTH levels during and after prolonged lactation.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.

Conventional treatment of hypoparathyroidism (hypoPT) with calcium supplements and active vitamin D analoges causes a high renal calcium excretion and over-mineralized bone.We studied 62 patients with known hypoPT randomised to 6 months of treatment with either PTH(1-84) 100 µg/d s.c. or similar placebo, administrated as an add-on therapy.Participants have had hypoPT for a mean of 12 (range: 1; 37) yrs. Only 4 subjects had idiopathic hypoPT whereas 58 had acquired hypoPT following surgery. Mean age of subjects was 52±11 yrs and 85% were females.PTH(1-84) maintained p-calcium and p-phosphate levels within the physiological range. Compared with placebo, participants randomised to PTH (1-84) reduced their daily dose of calcium supplements by 68 % (pWith the actual add on therapy there were no change in renal calcium excretion in response to treatment. Compared with placebo, bone mineral density (BMD) decreased significantly at the hip (-1.59 ± 0.57%), lumbar spine (-1.76 ± 1.03%) and whole body (-1.26 ± 0.49%), but not at the forearm. Bone turnover assessed by measurements of formative bone markers (serum levels of P1NP, osteocalcin, and bone-specific alkaline phosphatase (BSAP)) and resorptive bone markers (urinary-NTX, serum-CTX ) increased gradually during the 6 months of treatment. Compared with placebo, 6 months of treatment with PTH(1-84) increased plasma levels of BASP by 226 ± 36%, osteocalcin by 807 ±186%, P1NP by 1315 ± 330%, and CTX by 1209 ± 459%. Urinary NTX increased by 830 ± 165%. These changes could be explained by our findings of trabecular tunnelling with removal of old interstitial bone packets. In conclusion, PTH substitution therapy is capable of maintaining normal p-calcium levels with a significantly reduced need for calcium supplements and active vitamin D. In contrast to the effect of PTH(1-84) treatment in patients with osteoporosis, causing an increase in BMD, administration of PTH(1-84) to patients with hypoPT causes a decrease in BMD. This is explained by a marked increase in bone turnover, which is abnormally low in hypoPT during convention treatment. Accordingly, PTH substitution therapy counteracts the state of over-mineralized bone and may during long-term treatment cause a more physiological bone metabolism.Disclosure: Investigational drugs were provided free of charge by Nycomed, Denmark.

Bisphosphonates has for many years been the mainstay of antiresorptive treatment, acting predominantly by inducing apoptosis of mature osteoclasts. During recent years, an advanced understanding of the genetic and biological mechanism involved in bone resorption has revealed new therapeutic targets for antiresorptive treatments. Several of these new drugs act by targeting specific pathways within the osteoclastic cells and may reduce bone resorption without a concomitant decrease in bone formation. Such an uncoupling may result in a net bone formation, thereby causing a bone "anabolic" effect through an antiresorptive mechanism. Moreover, in contrast to e.g., bisphosphonates several of the new drugs are not deposited within bone and therefore their duration of action is related to their presence in plasma. Accordingly, their antiresorptive effect is quickly reversible, which may be of advantages if reversal of a suppressed bone turnover is warranted under certain clinical conditions such as osteonecrosis of the jaw. In this paper, we will review the pharmacological properties and clinical effects of drugs that recently have been (denosumab, bazedoxifene, lasofoxifene), or currently are being tested in large phase III clinical trials (Catepsin K inhibitor), as well as drugs that have shown potential beneficial effects in phase I or II trials and may be tested in upcoming phase III trials (integrin antagonists, c-Src kinase inhibitor, inhibitors of the acidification process within the resorption lacuna, and glucagon-like peptide).

Anabolic treatment that remodels bone tissue and restores bone biomechanical competence is essential in the treatment of osteoporosis. In addition, long term antiresorptive therapy may have limitations because of the reduced renewal of bone tissue. The only pure anabolic drugs available at present are intact PTH (1-84) (Preotact®) and the truncated PTH (1-34) (Teriparatide, Forteo®) while strontium ranelate may possess antiresorptive as well as anabolic properties. The marketed antiresorptive and anabolic antiosteoporotic drugs have limitations in their use due to adverse effects or to the occurrence of rare but severe late complications. Furthermore, indications may be restricted by co-existing diseases or treatment duration may be limited. However, new anabolic drugs are being developed mimicking the effect of PTH, or targeting the calcium sensing receptor (CaSR) or the Wnt/β-catenin signalling pathway. The PTH mimetics are truncated or altered PTH fragments, parathyroid hormone related peptide (PTHrP) and calcilytics stimulating endogenous PTH secretion. Calcimimetics (e.g. strontium) and calcilytics (e.g. lithium) may also affect bone cells directly through the CaSR. The Wnt pathway that stimulates osteoblastic proliferation, differentiation and function may be activated by neutralizing antibodies to secreted inhibitors of Wnt signalling (e.g. Sclerostin or Dickkopf) or by small molecules (e.g. lithium) that inhibits the glycogen synthase kinase 3β mediated degradation of β-catenin. Finally, blocking of activin A by soluble receptor fusion proteins has been shown to increase bone mass by a dual anabolic-antiresorptive action. The present paper summarises the physiological background and the present evidence for these effects.