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.

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.

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.

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.

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.

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.

Effects of paracetamol, non-steroidal anti-inflammatory drugs, acetylsalicylic acid, and opioids on bone mineral density and risk of fracture: results of the Danish Osteoporosis Prevention Study (DOPS).

UNLABELLED: Pain medication has been associated with fractures. We found higher weight in paracetamol and non-steroidal anti-inflammatory drugs (NSAID) users and lower vitamin D levels in opioid and acetylsalicylic acid users. None of the pain medications influenced bone mineral density or loss. NSAID were associated with an increased fracture risk. INTRODUCTION: To study the effects of use of paracetamol, non-steroidal anti-inflammatory drugs (NSAID), acetylsalicylic acid (ASA), and opioids on bone mineral density (BMD) and risk of fractures. METHODS: Two-thousand sixteen perimenopausal women followed for 10 years as part of a partly randomised comprehensive cohort study on hormone therapy (HT). BMD was measured at baseline and after 10 years by DXA (Hologic). RESULTS: Paracetamol users were heavier (70.4 ± 13.4 vs. 67.7 ± 11.9 kg, 2p < 0.01) than non-users. NSAID users were heavier (71.6 ± 15.6 vs. 67.8 ± 11.9 kg, 2p = 0.04) than non-users. ASA users had lower 25-hydroxy-vitamin D (25OHD) levels (21.9 ± 9.3 vs. 25.3 ± 12.4 ng/ml, 2p < 0.01) than non-users. Opioid users had lower 25OHD (21.4 ± 8.4 vs. 25.2 ± 12.3 ng/ml) and lower intake of vitamin D (2.2 ± 1.1 vs. 3.1 ± 3.0 µg/day, 2p < 0.01) than non-users. Despite these differences, no baseline differences were present in spine, hip, forearm or whole body BMD. Over 10 years, no differences were present in BMD alterations except a small trend towards a higher BMD gain in the spine in users of paracetamol, NSAID, ASA, and opioids compared to non-exposed. After adjustment, NSAID exposed sustained more fractures (HR = 1.44, 95% CI 1.07-1.93) than non-users. For users of paracetamol and opioids, a non-significant trend towards more fractures was present after adjustment. For ASA users, no excess risk of fractures was present. CONCLUSION: Significant differences exist between subjects exposed to pain medications and non-users. Despite an absence of an effect over time on BMD, users of NSAID experienced more fractures than expected. The reasons for this have to be explored in further studies.

Changes in bone mineral density and body composition during pregnancy and postpartum. A controlled cohort study.

UNLABELLED: In a controlled cohort study, bone mineral density (BMD) was measured in 153 women pre-pregnancy; during pregnancy; and 0.5, 4, 9, and 19 months postpartum. Seventy-five age-matched controls, without pregnancy plans, were followed in parallel. Pregnancy and breastfeeding cause a reversible bone loss, which, initially, is most pronounced at trabecular sites but also involves cortical sites during prolonged breastfeeding. INTRODUCTION: Conflicting results have been reported on effects of pregnancy and breastfeeding on BMD and body composition (BC). In a controlled cohort study, we elucidate changes in BMD and BC during and following a pregnancy. METHODS: We measured BMD and BC in 153 women planning pregnancy (n = 92 conceived), once in each trimester during pregnancy and 15, 129, and 280 days postpartum. Moreover, BMD was measured 19 months postpartum (n = 31). Seventy-five age-matched controls, without pregnancy plans, were followed in parallel. RESULTS: Compared with controls, BMD decreased significantly during pregnancy by 1.8 ± 0.5% at the lumbar spine, 3.2 ± 0.5% at the total hip, 2.4 ± 0.3% at the whole body, and 4.2 ± 0.7% at the ultra distal forearm. Postpartum, BMD decreased further with an effect of breastfeeding. At 9 months postpartum, women who had breastfed for <9 months had a BMD similar to that of the controls, whereas BMD at the lumbar spine and hip was decreased in women who were still breastfeeding. During prolonged breastfeeding, BMD at sites which consist of mostly trabecular bone started to be regained, whereas BMD at sites rich in cortical bone decreased further. At 19 months postpartum, BMD did not differ from baseline at any site. During pregnancy, fat- and lean-tissue mass increased by 19 ± 22% and 5 ± 6% (p < 0.001), respectively. Postpartum, changes in fat mass differed according to breastfeeding status with a slower decline in women who continued breastfeeding. Calcium and vitamin D intake was not associated with BMD changes. CONCLUSION: Pregnancy and breastfeeding cause a reversible bone loss. At 19 months postpartum, BMD has returned to pre-pregnancy level independently of breastfeeding length. Reversal of changes in fat mass depends on breastfeeding status.

Risk of femoral shaft and subtrochanteric fractures among users of bisphosphonates and raloxifene.

UNLABELLED: Prior studies have suggested an association between bisphosphonate use and subtrochanteric fractures. This cohort study showed an increased risk of subtrochanteric and femoral shaft fractures both before and after the start of drugs against osteoporosis including bisphosphonates. This may suggest an effect of the underlying disease rather than the drugs used. INTRODUCTION: The objective of this study is to determine the association between drugs against osteoporosis and the risk of femoral shaft and subtrochanteric fractures. No separation was made between atypical and typical fractures. METHODS: Nationwide cohort study from Denmark with all users of bisphosphonates and other drugs against osteoporosis between 1996 and 2006 (n = 103,562) as exposed group and three age- and gender-matched controls from the general population (n = 310,683). Adjustments were made for prior fracture, use of systemic hormone therapy, and use of systemic corticosteroids. RESULTS: After initiation of therapy, an increased risk of subtrochanteric fractures was seen for alendronate (hazard ratio (HR) = 2.41, 95% confidence interval (CI) 1.78-3.27), etidronate (HR = 1.96, 95% CI 1.62-2.36), and clodronate (HR = 20.0, 95% CI 1.94-205), but not for raloxifene (HR = 1.06, 95% CI 0.34-3.32). However, an increased risk of subtrochanteric fractures was also present before the start of alendronate (OR = 2.36, 95% CI 2.05-2.72), etidronate (OR = 3.05, 95% CI 2.59-3.58), clodronate (OR = 10.8, 95% CI 1.14-103), raloxifene (OR = 1.90, 95% CI 1.07-3.40), and strontium ranelate (OR = 2.97, 95% CI 1.07-8.27). Similar trends were seen for femoral shaft fractures and overall fracture risk. After the start of etidronate, no dose-response relationship was present (p for trend, 0.54). For alendronate, a decreasing risk was present with increasing average daily dose (p for trend, <0.01). CONCLUSIONS: Although an increased risk of femoral shaft and subtrochanteric fractures are seen with the use of several types of bisphosphonates, the increased risk before the start of the drugs may point at an effect of the underlying disease being treated. The increased risk may, thus, perhaps be due to confounding by indication.

Polymorphisms of the peroxisome proliferator-activated receptor γ (PPARγ) gene are associated with osteoporosis.

UNLABELLED: Stimulation of PPARγ turns mesenchymal stem cells into adipocytes instead of osteoblasts. We investigated the effect of polymorphisms in the PPARγ gene on BMD and fracture risk in two Danish cohorts and found opposing effects of certain SNPs and haplotypes in the two cohorts probably owing to environmental factors. INTRODUCTION: Stimulation of PPARγ causes development of mesenchymal stem cells to adipocytes instead of osteoblasts leading to decreased osteoblast number and BMD. The aim of this study was to examine the effect of PPARG polymorphisms on BMD and fracture risk in two Danish cohorts: AROS, a case-control population comprising 809 individuals and DOPS, a population comprising 1,716 perimenopausal women allocated to hormone therapy or not at baseline and followed for 10 years. On the basis of linkage disequilibrium between SNPs throughout the gene and previous studies we chose 10 polymorphisms for investigation. METHODS: In AROS, individuals heterozygous for the polymorphisms rs12497191, rs4135263, and rs1151999 had an increased risk of vertebral fractures (OR = 1.48-1.76, p = 0.005-0.04) compared with individuals homozygous for the common allele. In DOPS, individuals heterozygous for rs1151999 had an increased BMD at the hip sites (p ≤ 0.02). An interaction between rs1151999 and diet was found on BMD in both cohorts. RESULTS: For the polymorphism rs1152003 there was an interaction with body weight on BMD at all sites in both cohorts (p ≤ 0.07). Stratified analyses revealed that in the high weight group in AROS individuals homozygous for the variant allele had a decreased BMD (p ≤ 0.02), whereas the same pattern was found in the low weight group in DOPS (p ≤ 0.03). A number of haplotype associations were found as well, the direction of which was opposite in the two cohorts. CONCLUSION: Our study suggests an association SNPs in PPARG and haplotypes thereof and BMD and fracture risk. The effect however appears to be modifiable by environmental factors.

Polymorphisms in the ALOX12 gene and osteoporosis.

UNLABELLED: ALOX12 produces ligands for PPARγ thereby turning mesenchymal stem cells into adipocytes instead of osteoblasts. We investigated the effect of polymorphisms in the ALOX12 gene on BMD and fracture risk in two Danish cohorts and found four polymorphisms and a haplotype thereof to be associated with BMD and fracture risk. INTRODUCTION: Stimulation of the PPARγ with ligands produced by the ALOX enzymes drives mesenchymal stem cells in an adipocyte direction at the expense of osteoblasts leading to decreased osteoblast number and BMD. Previously, polymorphisms in the ALOX12 gene have been associated with osteoporosis. METHODS: We examined the effect of ALOX12 polymorphisms on BMD and the risk of fractures in two Danish cohorts: AROS, a case-control population comprising 809 individuals and DOPS, a population comprising 1,716 perimenopausal women allocated to hormone therapy or not at baseline and followed for up to 10 years. On the basis of linkage disequilibrium (LD) between SNPs throughout the gene and previous genetic association studies we chose ten polymorphisms for investigation. Genotyping was carried out using the Sequenom MassARRAY genotyping system and TaqMan assays. RESULTS: In AROS, individuals heterozygous for the polymorphisms rs3840880, rs9897850, rs2292350 and rs1126667 had a 3.0-4.7% decreased lumbar spine BMD (p = 0.02-0.06) and an increased risk of vertebral fractures (p < 0.05) compared with individuals homozygous for either allele. In DOPS, none of the individual SNPs were associated with BMD or incident fractures. In both cohorts, the above-mentioned SNPs comprised an LD-block (pairwise D´ = 1.0, r (2) = 0.45-0.97). A haplotype comprising all the common alleles (frequency 9%) was associated with decreased bone loss at the hip (p < 0.05) and decreased incidence of osteoporotic fractures (p < 0.05) in DOPS and increased femoral neck BMD in AROS (p < 0.05). CONCLUSION: Our study suggests that genetic variants in ALOX12 may influence BMD and fracture risk.

Bone mineral density in Klinefelter syndrome is reduced and primarily determined by muscle strength and resorptive markers, but not directly by testosterone.

SUMMARY: Klinefelter syndrome (KS) patients have lower bone mineral density (BMD) at the spine, hip and forearm compared to healthy subjects, but frank osteoporosis is not common. Muscle strength and bone markers predicted BMD but KS itself and serum testosterone did not. Low vitamin D and high PTH were frequent among KS. INTRODUCTION: The long-term consequence of KS on bone health is not well described. The objective of this study is to investigate the regional BMD and its determinants in KS. METHODS: This is a cross-sectional study. BMD at the spine, hip and forearm are measured by DXA and correlated to biochemical markers of bone turnover, vitamin D metabolites, PTH, sex hormones, growth factors as well as muscle strength and anthropometric measures. The setting is at a university clinical research centre. The study involves 70 adult KS patients and 71 age-matched healthy subjects. RESULTS: In KS, BMD was universally lowered in all regions. Markers of bone formation or bone resorption were not altered in KS, but 25-OH-Dvitamin was lower (55 vs. 82 nmol/L, p < 0.0001) than in healthy subjects. Significantly more KS patients had low BMD (Z-scores below -2) at the forearm (15 KS vs. two healthy subjects, p = 0.001) but not at the spine or hip. Muscle strength (bicep and quadriceps) was lower among KS patients. Multivariate analysis revealed that muscle strength, treatment with testosterone (ever/never), age at diagnosis, SHBG, bone-specific alkaline phosphatase and 1CTP were all independent predictors of BMD, but androgens was not. CONCLUSIONS: KS patients had lower BMD at the spine, hip and forearm compared to age-matched healthy subjects, but frank osteoporosis was not common. Muscle strength, previous history of testosterone treatment, age at diagnosis and bone markers were predictors of BMD, but testosterone was not. Signs of secondary hyperparathyroidism were present among KS. Dietary intake of vitamin D or sun exposure may be lower in KS patients.

Stroke in relation to use of raloxifene and other drugs against osteoporosis.

UNLABELLED: Prior studies have associated fatal stroke with raloxifene. In a cohort study, we found no excess risk of stroke with raloxifene; whereas, an excess risk of stroke and fatal stroke was seen with alendronate and etidronate. However, the excess risks were small. PURPOSE: We aim to study the association between use of raloxifene and other drugs against osteoporosis and risk of stroke. METHODS: This is a nationwide cohort study from Denmark. All users of bisphosphonates and other drugs against osteoporosis between 1996 and 2006 (n = 103,562) as exposed group and three age- and gender-matched controls from the general population (n = 310,683). RESULTS: Before the drugs were started, patients later initiating alendronate or raloxifene had fewer strokes than the controls. In contrast, patients who later did start clodronate have more strokes. Among the later users of other bisphosphonates, strontium ranelate or parathyroid hormone, no change in the risk of stroke was present. Patients who started raloxifene neither had an excess risk of strokes nor of fatal strokes. No dose-response relationship was present. Among users of alendronate, a decreasing overall risk of stroke was seen with increasing dose. However, for fatal strokes, the risk increased with increasing dose of alendronate. Among users of etidronate, no trend with dose was present for overall stroke risk; whereas for fatal strokes, an increasing risk was seen with increasing dose of etidronate. CONCLUSIONS: Raloxifene does not seem associated with an excess risk of strokes. The increase seen for alendronate did not seem to be causal as no classical dose-response relationship was present. The dose-response relationship for fatal strokes with alendronate and etidronate needs further examination. However, the excess risks were small and may be due to the underlying disease.

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

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

Use of bisphosphonates and raloxifene and risk of deep venous thromboembolism and pulmonary embolism.

SUMMARY: Prior studies have associated raloxifene and strontium ranelate with deep venous thromboembolism and pulmonary embolism. In a cohort study, we observed an increased risk also with the bisphosphonates. However, the increase was present already before the start of bisphosphonates pointing at an effect of the underlying condition. INTRODUCTION: We seek to study the association between use of drugs against osteoporosis and risk of deep venous thromboembolism (DVT) and pulmonary embolism (PE). METHODS: Nationwide register-based cohort study from Denmark with all users of bisphosphonates and other drugs against osteoporosis between 1996 and 2006 (n = 103,562) as cases and three age- and gender-matched controls from the general population (n = 310,683). RESULTS: Before start of a drug against osteoporosis, an increased risk of DVT/PE was present in the crude analysis for alendronate, etidronate, and risedronate. However, upon adjustment, this increase in risk disappeared. Before start of raloxifene, a decreased risk of DVT/PE was present (odds ratio (OR) = 0.53, 95% confidence interval (CI), 0.39-0.71). After start of a drug, alendronate (HR = 1.20, 95% CI, 1.00-1.43), clodronate (HR = 4.06, 95% CI, 1.47-11.2), and etidronate (HR = 1-37, 95% CI, 1.23-1.51) were all associated with an increased risk of DVT/PE, while raloxifene was only borderline, significantly associated with risk of DVT/PE (HR = 1.64, 95% CI, 0.97-2.77). No dose-response relationship was present except for alendronate, where the risk was inversely associated with dose, i.e., the risk of DVT/PE decreased with increasing average daily dose. The HR for DVT/PE was higher with clodronate and etidronate than with alendronate. Alendronate and raloxifene carried the same risk for DVT/PE. CONCLUSION: Bisphosphonates seem associated with an increased risk of DVT/PE. However, the association does not seem to be causal.

Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop.

OBJECTIVE: Asymptomatic primary hyperparathyroidism (PHPT) is a common clinical problem. The purpose of this report is to guide the use of diagnostic tests for this condition in clinical practice. PARTICIPANTS: Interested professional societies selected a representative for the consensus committee and provided funding for a one-day meeting. A subgroup of this committee set the program and developed key questions for review. Consensus was established at a closed meeting that followed. The conclusions were then circulated to the participating professional societies. EVIDENCE: Each question was addressed by a relevant literature search (on PubMed), and the data were presented for discussion at the group meeting. CONSENSUS PROCESS: Consensus was achieved by a group meeting. Statements were prepared by all authors, with comments relating to accuracy from the diagnosis subgroup and by representatives from the participating professional societies. CONCLUSIONS: We conclude that: 1) reference ranges should be established for serum PTH in vitamin D-replete healthy individuals; 2) second- and third-generation PTH assays are both helpful in the diagnosis of PHPT; 3) DNA sequence testing can be useful in familial hyperparathyroidism or hypercalcemia; 4) normocalcemic PHPT is a variant of the more common presentation of PHPT with hypercalcemia; 5) serum 25-hydroxyvitamin D levels should be measured and, if vitamin D insufficiency is present, it should be treated as part of any management course; and 6) the estimated glomerular filtration rate should be used to determine the level of kidney function in PHPT: an estimated glomerular filtration rate of less than 60 ml/min.1.73 m2 should be a benchmark for decisions about surgery in established asymptomatic PHPT.

Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: an ecologic meta-regression analysis.

UNLABELLED: We performed a meta-analysis of cross-sectional studies on serum 25(OH)D status globally. Serum 25(OH)D levels on average were 54 nmol/l, were higher in women than men, and higher in Caucasians than in non-Caucasians. There was no trend in serum 25(OH)D level with latitude. Vitamin D deficiency was widespread. INTRODUCTION: We studied vitamin D status (expressed as serum 25-hydroxy-vitamin D [25(OH)D]) in native subjects worldwide. METHODS: Meta-analysis and meta-regression of studies reporting on 25(OH)D in healthy subjects retrieved from Pubmed, Embase and Web of Science using the terms "serum", "25-hydroxy-vitamin D", "cholecalciferol", and "human". A total of 394 studies were included. RESULTS: The mean 25(OH)D level was 54 nmol/l (95% CI: 52-57 nmol/l). Women had borderline significantly higher 25(OH)D levels than men, and Caucasians had higher levels than non-Caucasians. 25(OH)D levels were higher in subjects aged >15 years than in younger subjects. Unadjusted there was no significant decrease in 25(OH)D with latitude (slope of curve -0.03 +/- 0.12 nmol/l per degree latitude north or south of equator, p = 0.8). There was a significant decline with latitude for Caucasians (-0.69 +/- 0.30 nmol/l per degree, p = 0.02), but not for non-Caucasians (0.03 +/- 0.39 nmol/l per degree, p = 0.14). After adjustment for age, gender, and ethnicity, no overall correlation was present between 25(OH)D and latitude (-0.29 +/- 0.24 nmol/l per degree, p = 0.23). CONCLUSION: There was no overall influence of latitude on 25(OH)D. However, in separate analyses 25(OH)D decreased with latitude in Caucasians but not in non-Caucasians. A widespread global vitamin D insufficiency was present compared with proposed threshold levels.