Risk of fractures in primary hyperparathyroidism: a systematic review and meta-analysis.

An increased risk of fractures in primary hyperparathyroidism (PHPT) has been reported in a number of relatively small studies. Performing a systematic literature search, we identified available studies and calculated common estimates by pooling results from the individual studies in a meta-analysis. Searching EMBASE and PubMed, we identified published studies reporting the risk of fractures in PHPT compared to a control group. We calculated odds ratio (OR) with 95% confidence interval (CI). A total of 804 studies were identified of which 12 studies were included. Risk of any fracture was increased compared to controls (OR 2.01; 95% CI, 1.61-2.50; I2 46%, 5 studies). Analysis of fracture risk at specific sites showed an increased risk of fracture at the forearm (OR 2.36; 95% CI, 1.64-3.38; I2 0%, 4 studies) and spine (OR 3.00; 95% CI, 1.41, 6.37, I2 88%, 9 studies). Risk estimate for hip fractures was non-significantly increased (OR 1.27; 95% CI, 0.97-1.66; I2 0%, 3 studies). Risk of vertebral fractures (VFx) was also increased if analyses were restricted to only studies with a healthy control group (OR 5.76; 95% CI, 3.86-8.60; I2 29%, 6 studies), studies including patients with mild PHPT (OR 4.22; 95% CI, 2.20-8.12; I2 57%, 4 studies) or studies including postmenopausal women (OR 8.07; 95% CI, 4.79-13.59; I2 0%, 3 studies). PHPT is associated with an increased risk of fractures. Although a number of studies are limited-it seems that the risk is increased across different skeletal sites including patients with mild PHPT and postmenopausal women.

Bone metabolism, density, and geometry in postmenopausal women with vitamin D insufficiency: a cross-sectional comparison of the effects of elevated parathyroid levels.

Increased levels of parathyroid hormone (PTH) may have adverse effects on bone health. In a cross-sectional design, we investigated this hypothesis among 102 postmenopausal vitamin D insufficient women. Elevated PTH was associated with altered bone geometry, decreased bone mineral density in the spine, and increased bone turnover. INTRODUCTION: In vitamin D insufficiency, elevated parathyroid hormone (PTH) levels may contribute to adverse effect on bone. We assessed effects of PTH responses to vitamin D insufficiency on bone metabolism, density, and geometry. METHODS: Using a cross-sectional design, we investigated 102 healthy postmenopausal women with low 25-hydroxy-vitamin D (< 50 nmol/L) levels, who had either secondary hyperparathyroidism with elevated PTH levels (> 6.9 pmol/L, N = 51) or normal PTH levels (N = 51). Bone mineral density (BMD) and bone geometry were assessed by Dual-Energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT) and high-resolution peripheral QCT (HRpQCT) scans. Bone metabolism was assessed by biochemistry including bone turnover markers. RESULTS: Levels of 25(OH)D were 38 (IQR 31-45) nmol/L with no differences between groups. PTH levels were 8.5 (IQR 7.5-9.5) in women with SHPT and 5.2 (4.4-6.6) pmol/L in women with normal PTH (p < 0.001). BMI and eGFR did not differ between groups. SHPT was associated with lower total- and trabecular bone area, lower cortical perimeter, and increased cortical area in tibia and radius. SHPT was associated with a lower weight-adjusted BMD at the lumbar spine (p < 0.05). High compared to normal PTH levels were associated with significantly lower plasma levels of 1,25(OH)2D, phosphate, but higher levels of osteocalcin and borderline higher levels of CTx. PTH correlated to osteocalcin and CTx. CONCLUSIONS: High PTH levels are associated with altered bone geometry, increased bone turnover, and reduced BMD at the spine. Whether an increased cortical thickness with a lower trabecular volume is an effect of PTH or not needs further elucidations.

Benefits and safety of dietary protein for bone health-an expert consensus paper endorsed by the European Society for Clinical and Economical Aspects of Osteopororosis, Osteoarthritis, and Musculoskeletal Diseases and by the International Osteoporosis Foundation.

A summary of systematic reviews and meta-analyses addressing the benefits and risks of dietary protein intakes for bone health in adults suggests that dietary protein levels even above the current RDA may be beneficial in reducing bone loss and hip fracture risk, provided calcium intakes are adequate. Several systematic reviews and meta-analyses have addressed the benefits and risks of dietary protein intakes for bone health in adults. This narrative review of the literature summarizes and synthesizes recent systematic reviews and meta-analyses and highlights key messages. Adequate supplies of dietary protein are required for optimal bone growth and maintenance of healthy bone. Variation in protein intakes within the "normal" range accounts for 2-4% of BMD variance in adults. In older people with osteoporosis, higher protein intake (≥ 0.8-g/kg body weight/day, i.e., above the current RDA) is associated with higher BMD, a slower rate of bone loss, and reduced risk of hip fracture, provided that dietary calcium intakes are adequate. Intervention with dietary protein supplements attenuate age-related BMD decrease and reduce bone turnover marker levels, together with an increase in IGF-I and a decrease in PTH. There is no evidence that diet-derived acid load is deleterious for bone health. Thus, insufficient dietary protein intakes may be a more severe problem than protein excess in the elderly. Long-term, well-controlled randomized trials are required to further assess the influence of dietary protein intakes on fracture risk.

Health-related quality of life in patients with nonsurgical hypoparathyroidism and pseudohypoparathyroidism.

OBJECTIVE: Nonsurgical hypoparathyroidism (NS-HypoPT) and pseudohypoparathyroidism (PHP) are rare diseases, with a prevalence of 2/100.000 and 1/100.000, respectively. Only few studies on Quality of Life (QoL) among patients with Ns-HypoPT and PHP are available. We aimed to investigate the QoL among patients with Ns-HypoPT and PHP including information about education. DESIGN: A cohort study with patients identified from a previously epidemiological study. PATIENTS: Fifty seven patients with Ns-HypoPT and 30 patients with PHP. MEASUREMENTS: The well-validated questionnaires SF-36v2 and WHO-5 Well Being Index. Results compared to norm-based material, disease-specific norm-based material and patients with postsurgical HypoPT RESULTS: SF36v2 showed a significantly reduced score in all eight subdomains in patients with NS-HypoPT compared with a norm-based population. PHP patients scored lower in five subdomains. Females were more affected than males. Compared with postsurgical HypoPT, Ns-HypoPT and PHP are compatible at most domains. At the domains Physical Function, Social Function and Mental Health, Ns-HypoPT and PHP patients scored significantly lower (Pall  < .05). At the Mental Component Score, patients with Ns-HypoPT had a lower score compared with postsurgical HypoPT (P < .01). The overall WHO-5 Well Being Index score was comparable between groups (P = .45). No differences were seen comparing patients with postsurgical HypoPT and Ns-HypoPT (P = .68) or postsurgical HypoPT and PHP (P = .67). A WHO-5 score below 28 indicates depression (NS-HypoPT=7; PHP=3, P = .71), whereas a score between 28-50 suggesting poor emotional well-being (NS-HypoPT=19; PHP=5, P = .13). The remaining patients scored above 50 suggesting well-being. CONCLUSION: QoL is impaired equally among patients with Ns-HypoPT and PHP.

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.

Hypercalcemia after discontinuation of long-term denosumab treatment.

UNLABELLED: Denosumab is used for treatment of osteoporosis. We present a case report of hypoparathyroid hypercalcemia and increased bone turnover associated with discontinuation of treatment for 10 years with denosumab. There is a need for evidence-based guidelines on discontinuation of long-term denosumab treatment to avoid side effects and preserving anti-fracture efficacy. PURPOSE: Denosumab is commonly used as an anti-resorptive agent for the treatment of osteoporosis. After discontinuation of denosumab, however, bone resorption increases again, and the bone mass gained during therapy is rapidly declining. Thus, treatment with denosumab is considered to be reversible. METHODS: We present a case report of asymptomatic hypoparathyroid hypercalcemia in a patient who discontinued long-term treatment with denosumab. RESULTS: A 67-year-old woman with osteoporosis was treated with denosumab 60 mg subcutaneously every 6 months from 2004 to 2014. She received the last injection in May 2014. Routine biochemistry in November 2014 showed increased s-ionized calcium (I-Ca) 1.64 mmol/L (1.18-1.32 mmol/L) and suppressed p-parathyroid hormone (PTH) 1.6 pmol/L (1.6-6.9 pmol/L). The patient was extensively examined, but no underlying disease was found. In January 2015, the patient began treatment with alendronat 70 mg weekly. In April 2015, serum levels of type 1 collagen C-terminal cross-linked telopeptide, procollagen type 1 N-terminal propeptide and bone-specific alkaline phosphatase were still markedly elevated. From then on, I-Ca and PTH normalized and the bone turnover markers (BTM) decreased. CONCLUSION: In this case report, we describe increased BTMs and hypercalcemia associated with discontinuation of 10 years treatment with denosumab. The increase in BTMs is assumed to be temporary and normalization is expected. Since denosumab is commonly used, there is an urgent need for evidence-based guidelines on discontinuation of long-term treatment, avoiding side effects and preserving anti-fracture efficacy.

European Society of Endocrinology: European Society of Endocrinology Clinical Guideline: treatment of chronic hypoparathyroidism in adults

Hypoparathyroidism (HypoPT) is a rare (orphan) endocrine disease with low calcium and inappropriately low (insufficient) circulating parathyroid hormone levels, most often in adults secondary to thyroid surgery. Standard treatment is activated vitamin D analogues and calcium supplementation and not replacement of the lacking hormone, as in other hormonal deficiency states. The purpose of this guideline is to provide clinicians with guidance on the treatment and monitoring of chronic HypoPT in adults who do not have end-stage renal disease. We intend to draft a practical guideline, focusing on operationalized recommendations deemed to be useful in the daily management of patients. This guideline was developed and solely sponsored by The European Society of Endocrinology, supported by CBO (Dutch Institute for Health Care Improvement) and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles as a methodological base. The clinical question on which the systematic literature search was based and for which available evidence was synthesized was: what is the best treatment for adult patients with chronic HypoPT? This systematic search found 1100 articles, which was reduced to 312 based on title and abstract. The working group assessed these for eligibility in more detail, and 32 full-text articles were assessed. For the final recommendations, other literature was also taken into account. Little evidence is available on how best to treat HypoPT. Data on quality of life and the risk of complications have just started to emerge, and clinical trials on how to optimize therapy are essentially non-existent. Most studies are of limited sample size, hampering firm conclusions. No studies are available relating target calcium levels with clinically relevant endpoints. Hence it is not possible to formulate recommendations based on strict evidence. This guideline is therefore mainly based on how patients are managed in clinical practice, as reported in small case series and based on the experiences of the authors.(AU)

Unexplained high BMD in DXA-scanned patients is generalized throughout the skeleton and characterized by thicker cortical and trabecular bone.

Unexplained high bone mineral density (BMD) is a rare condition and the mechanisms responsible are yet to be described in detail. The aim of the study was to identify patients with unexplained high BMD from a local DXA database and compare their radiological phenotype with an age- and a gender-matched group of population-based controls. We defined high BMD as a DXA Z-score ≥ + 2.5 at the total hip and lumbar spine. We characterized the findings as "unexplained" if no osteodegenerative changes, bone metabolic disease, or arthritis at the hip or lumbar spine was observed. All participants were investigated with high-resolution peripheral quantitative computed tomography (HR-pQCT), QCT, DXA, fasting blood samples, a 24-h urine sample, and questionnaires. The DXA database contained data on 25,118 patients. Initially, 138 (0.55%) potential participants with high BMD were identified, and during the study ten additional cases were identified from new DXA scans. Sixty-seven patients accepted to participate in the study, and among these we identified 15 women and one man with unexplained high BMD. These 15 women had higher BMD throughout the skeleton relative to controls, similar area/volume at the hip and the distal extremities, a higher number of trabeculae, which was thicker than in the controls, and a higher finite element estimated bone strength. The 15 women were heavier and had a higher fat mass then controls. We conclude that patients with unexplained high BMD have a generalized high BMD phenotype throughout their skeleton, which is characterized with a denser microarchitecture.

Effects of PTH(1-84) therapy on muscle function and quality of life in hypoparathyroidism: results from a randomized controlled trial.

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.

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.

Maternal and infant vitamin D status during the first 9 months of infant life-a cohort study.

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, P<0.001). At birth, 23% of mothers and 61% of infants had 25OHD <50 nmol/l. Vitamin D deficiency (25OHD<25 nmol/l) was present in 66% of the children born by mothers with 25OHD levels below 50 nmol/l (P<0.01), whereas only one child was born with deficiency among mothers with 25OHD >50 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<0.01) reaching 3.08 (2.67-3.92 pmol/l) at the last visit. Vitamin D levels were not associated with anthropometric indices of the newborn infant or their growth during follow-up. CONCLUSIONS: Vitamin D deficiency is widespread in newborn. Maternal 25OHD levels above 50 nmol/l are needed to prevent vitamin D deficiency among newborn.

Melatonin and the skeleton.

Melatonin may affect bone metabolism through bone anabolic as well as antiresorptive effects. An age-related decrease in peak melatonin levels at nighttime is well documented, which may increase bone resorption and bone loss in the elderly. In vitro, melatonin reduces oxidative stress on bone cells by acting as an antioxidant. Furthermore, melatonin improves bone formation by promoting differentiation of human mesenchymal stem cell (hMSC) into the osteoblastic cell linage. Bone resorption is reduced by increased synthesis of osteoprogeterin (OPG), a decoy receptor that prevents receptor activator of NK-κB ligand (RANKL) in binding to its receptor. Moreover, melatonin is believed to reduce the synthesis of RANKL preventing further bone resorption. In ovariectomized as well as nonovariectomized rodents, melatonin has shown beneficial effects on bone as assessed by biochemical bone turnover markers, DXA, and µCT scans. Furthermore, in pinealectomized animals, bone mineral density (BMD) is significantly decreased compared to controls, supporting the importance of sufficient melatonin levels. In humans, dysfunction of the melatonin signaling pathway may be involved in idiopathic scoliosis, and the increased fracture risk in nighttime workers may be related to changes in the circadian rhythm of melatonin. In the so-far only randomized study on melatonin treatment, no effects were, however, found on bone turnover markers. In conclusion, melatonin may have beneficial effects on the skeleton, but more studies on humans are warranted in order to find out whether supplementation with melatonin at bedtime may preserve bone mass and improve bone biomechanical competence.

Effects of vitamin D supplementation on body fat accumulation, inflammation, and metabolic risk factors in obese adults with low vitamin D levels - results from a randomized trial.

BACKGROUND: 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. METHODS: In a double-blind design 52 subjects aged 18 to 50years with BMI>30kg/m(2) and plasma 25OHD <50nmol/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. RESULTS: VD treatment increased mean plasma levels of 25OHD from 33nmol/l to 110nmol/l (P<0.0001) and decreased median parathyroid hormone levels from 5.3 to 4.5pmol/l (P<0.01) 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. CONCLUSION: Increasing 25OHD levels by VD treatment for 26weeks have no effects on obesity complications in obese adults with low baseline plasma 25OHD.

Polymorphisms of muscle genes are associated with bone mass and incident osteoporotic fractures in Caucasians.

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.

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.

Expression of vitamin D-metabolizing enzymes in human adipose tissue -- the effect of obesity and diet-induced weight loss.

OBJECTIVE: Low vitamin D (VD) levels are common in obesity. We hypothesized that this may be due to metabolism of VD in adipose tissue (AT). Thus, we studied (1) whether the VD-metabolizing enzymes were expressed differently in AT of lean and obese individuals and in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), and (2) whether their expression was influenced by weight loss. METHODS: Samples of SAT and VAT were analyzed for expression of the vitamin-D-25-hydroxylases CYP2R1, CYP2J2, CYP27A1 and CYP3A4, the 25-vitamin-D-1α-hydroxylase CYP27B1, the catabolic vitamin-D-24-hydroxylase CYP24A1, and the vitamin D receptor, using reverse transcriptase-PCR. Moreover, plasma 25-hydroxy-vitamin D (25OHD) level was measured and related to the expression of these enzymes. Samples of SAT and VAT from 20 lean women and 20 obese women, and samples of SAT from 17 obese subjects before and after a 10% weight loss were analyzed. RESULTS: A plasma 25OHD level <50 nmol l(-1) was highly prevalent in both lean (45%) and obese (90%) women (P<0.01). Plasma 25OHD increased by 27% after weight loss in the obese individuals (P<0.05). Expression levels of the 25-hydroxylase CYP2J2 and the 1α-hydroxylase CYP27B1 were decreased by 71% (P<0.0001) and 49% (P<0.05), respectively, in SAT of the obese. CYP24A1 did not differ between lean and obese women, but the expression was increased by 79% (P<0.05) after weight loss. CONCLUSION: Obesity is characterized by a decreased expression of the 25-hydroxylase CYP2J2 and the 1α-hydroxylase CYP27B1 in SAT, whereas the catabolic CYP24A1 does not differ between lean and obese women. However, the expression of CYP24A1 is increased after weight loss. Accordingly, AT has the capacity to metabolize VD locally, and this can be dynamically altered during obesity and weight loss.

PTH replacement therapy of hypoparathyroidism.

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.

Effects of 25OHD concentrations on chances of pregnancy and pregnancy outcomes: a cohort study in healthy Danish women.

BACKGROUND/OBJECTIVES: Plasma 25-hydroxyvitamin D (P-25OHD) concentrations may affect pregnancy outcomes. To elucidate this further, we studied the effects of pre-conception P-25OHD concentrations on chances for pregnancy as well as the effects of P-25OHD during pregnancy on the risk of miscarriage, birth weight and length, Apgar score and head circumference. Moreover, we studied whether pregnancy and breastfeeding patterns affect maternal P-25OHD concentrations. SUBJECTS/METHODS: A total of 153 healthy Caucasian women with pregnancy plans were followed with measurements performed before pregnancy, at pregnancy weeks 11±2, 22±1 and 35±2 as well as 15±7, 129±12 and 280±15 days postpartum. Furthermore, 75 non-pregnant, age-matched women were followed in parallel as controls. RESULTS: The 203 women were aged 29 (25-35) years. At baseline, median P-25OHD was 59 nmol/l. Of these women, 31% had P-25OHD <50 nmol/l, whereas 12% had levels above 80 nmol/l. Within ∼6 months after inclusion, 63% conceived. P-25OHD was not associated with chances of conceiving or overall risk of miscarriage. However, women with a miscarriage in their second trimester (n=3) had lower P-25OHD concentrations at measurements performed in the first trimester compared with women without a miscarriage (P=0.03). P-25OHD before or during pregnancy was not associated with gestational length or infant parameters. Adjustments for possible confounders did not change the result. During pregnancy, P-25OHD changed significant over time, but similar changes occurred within the control group, indicating no effect of pregnancy per se (P=0.59). Overall, P-25OHD did not differ according to length of breastfeeding at 2 weeks, and 4 and 9 months postpartum, although women breastfeeding for >9 months had lower P-25OHD levels at the last visit compared with the controls. CONCLUSION: P-25OHD concentrations did not affect fertility or pregnancy outcomes, although low P-25OHD may be associated with an increased risk of late miscarriage.