Pseudohypoparathyroidism - epidemiology, mortality and risk of complications.

OBJECTIVE: Pseudohypoparathyroidism (PHP) is caused by a mutation within the GNAS gene or upstream of the GNAS complex locus. It is characterized by target organ resistance to PTH, resulting in hypocalcaemia and hyperphosphataemia. Studies in patients with PHP are limited. We sought to identify all patients in Denmark with PHP and access their mortality data and risk of complications. DESIGN: Patients were identified through the Danish National Patient Registry and a prescription database, with subsequent validation by investigation of patient charts. METHODS: For each case, three age- (±2 years) and gender-matched controls were randomly selected from the general background population. We identified a total of 60 cases, equal to a prevalence of 1·1/100 000 inhabitants. The average age at diagnosis was 13 years (range 1-62 years), and 42 were women. Only 14 patients had an identified mutation in the GNAS1 gene. RESULTS: Compared with controls, patients with PHP had an increased risk of neuropsychiatric disorders (P < 0·01), infections (P < 0·01), seizures (P < 0·01) and cataract (P < 0·01), whereas their risk of renal, cardiovascular, malignant disorders and fractures was compatible with the general background population. The same tendencies were found in a subgroup analysis in cases with genetically verified PHP. CONCLUSION: Patients with PHP have an increased risk of neuropsychiatric disorders, infections, cataract and seizures, whereas mortality among PHP patients is compatible with that in the background population.

Reduced fat mass and increased lean mass in response to 1 year of melatonin treatment in postmenopausal women: A randomized placebo-controlled trial.

OBJECTIVE: Apart from regulating the circadian rhythm, melatonin exerts a variety of actions in the living organism. Among these functions, melatonin is believed to have a positive effect on body weight and energy metabolism. So far, the evidence for this relies mainly on animal models. In this study, we aimed to determine the effects of melatonin on body composition, lipid and glucose metabolism in humans. DESIGN/METHODS: In a double-blind, placebo-controlled study, we randomized 81 postmenopausal women to 1 year of treatment with melatonin (1 or 3 mg nightly) or placebo. Body composition was measured by DXA. Measures were obtained at baseline and after 1 year of treatment along with leptin, adiponectin and insulin. Markers of glucose homeostasis were measured at the end of the study. RESULTS: In response to treatment, fat mass decreased in the melatonin group by 6·9% (95% CI: 1·4%; 12·4%, P = 0·02) compared to placebo. A borderline significant increase in lean mass of 5·2% was found in the melatonin group compared to placebo (3·3%, (IQR:-1·7; 6·2) vs -1·9%, (IQR: -5·7; 5·8), P = 0·08). After adjusting for BMI, lean mass increased by 2·6% (95% CI: 0·1; 5·0, P = 0·04) in the melatonin group. Changes in body weight and BMI did not differ between groups. Adiponectin increased borderline significantly by 21% in the melatonin group compared to placebo (P = 0·08). No significant changes were observed for leptin, insulin or markers of glucose homeostasis. CONCLUSION: Our results suggest a possibly beneficial effect of melatonin on body composition and lipid metabolism as 1 year of treatment reduces fat mass, increases lean mass and is associated with a trend towards an increase in adiponectin.

Association between bone indices assessed by DXA, HR-pQCT and QCT scans in post-menopausal women.

Quantitative computed tomography (QCT), high-resolution peripheral QCT (HR-pQCT) and dual X-ray absorptiometry (DXA) scans are commonly used when assessing bone mass and structure in patients with osteoporosis. Depending on the imaging technique and measuring site, different information on bone quality is obtained. How well these techniques correlate when assessing central as well as distal skeletal sites has not been carefully assessed to date. One hundred and twenty-five post-menopausal women aged 56-82 (mean 63) years were studied using DXA scans (spine, hip, whole body and forearm), including trabecular bone score (TBS), QCT scans (spine and hip) and HR-pQCT scans (distal radius and tibia). Central site measurements of areal bone mineral density (aBMD) by DXA and volumetric BMD (vBMD) by QCT correlated significantly at the hip (r = 0.74, p < 0.01). Distal site measurements of density at the radius as assessed by DXA and HR-pQCT were also associated (r = 0.74, p < 0.01). Correlations between distal and central site measurements of the hip and of the tibia and radius showed weak to moderate correlation between vBMD by HR-pQCT and QCT (r = -0.27 to 0.54). TBS correlated with QCT at the lumbar spine (r = 0.35) and to trabecular indices of HR-pQCT at the radius and tibia (r = -0.16 to 0.31, p < 0.01). There was moderate to strong agreement between measuring techniques when assessing the same skeletal site. However, when assessing correlations between central and distal sites, the associations were only weak to moderate. Our data suggest that the various techniques measure different characteristics of the bone, and may therefore be used in addition to rather than as a replacment for imaging in clinical practice.

Inverse Correlation at the Hip Between Areal Bone Mineral Density Measured by Dual-Energy X-ray Absorptiometry and Cortical Volumetric Bone Mineral Density Measured by Quantitative Computed Tomography.

Quantitative computed tomography (QCT) is considered to measure true volumetric bone mineral density (vBMD; mg/cm3) and enables differentiation between cortical and trabecular bone. We aimed to determine the value of QCT by correlating areal BMD (aBMD) by dual-energy X-ray absorptiometry (DXA) with vBMD when using a fixed threshold to delineate cortical from trabecular bone. In a cross-sectional study, 98 postmenopausal women had their hip scanned by DXA and by QCT. At the total hip and the trabecular bone compartment, aBMD correlated significantly with vBMD (r=0.74 and r=0.63; p<0.01, respectively). A significant inverse correlation was found between aBMD and cortical vBMD (r=-0.57; p<0.01). Total hip volume by QCT did not change with aBMD. However, increased aBMD was associated with a decreased trabecular bone volume (r=-0.36; p<0.01) and an increased cortical volume (r=0.69; p<0.01). Changing the threshold used to delineate cortical from trabecular bone from default 350 mg/cm3 to either 300 or 400 mg/cm3 did not affect integral vBMD (p=89) but had marked effects on estimated vBMD at the cortical (p<0.001) and trabecular compartments (p<0.001). Furthermore, increasing the threshold decreased cortical thickness (p<0.001), whereas the strength parameter in terms of buckling ratio increased (p<0.001). Our results show good agreement between aBMD and integral vBMD. However, using a fixed threshold to differentiate cortical from trabecular bone causes an apparent increase in cortical volume with a decrease in cortical density as aBMD increases. This may be caused by the classification of a larger part of the transition zone as cortical bone with increased aBMD.

Effects of adding chymosin to milk on calcium homeostasis: a randomized, double-blind, cross-over study.

Calcium intake and absorption is important for bone health. In a randomized double-blind cross-over trial, we investigated effects of adding chymosin to milk on the intestinal calcium absorption as measured by renal calcium excretion and indices of calcium homeostasis. The primary outcome of the study was 24-h renal calcium excretion that is considered a proxy measure of the amount of calcium absorbed from the intestine. We studied 125 healthy men and women, aged 34 (25-45) years on two separate days. On each day, a light breakfast was served together with 500 ml of semi-skimmed milk to which either chymosin or similar placebo was added. Compared with placebo, chymosin did not affect 24-h urinary calcium, calcium/creatinine ratio, plasma parathyroid hormone, calcitonin or ionized calcium levels. However, during the first 4 h after intake of milk with chymosin, urinary calcium-creatinine ratio was significantly increased (17%) compared with placebo. Stratification by daily calcium intake showed effect of chymosin in participant with a habitual intake above the median (>1,050 mg/day) in whom both urinary calcium and calcium/creatinine ratio were significantly increased compared with placebo. Effects did not depend on plasma 25-hydroxyvitamin D levels. Chymosin added to milk increases renal calcium excretion in the hours following intake without affecting plasma levels of calcium or calciotropic hormones. The effect most likely represents enhanced intestinal calcium absorption shortly after intake. Further studies are warranted on whether intake of milk-added chymosin may cause beneficial effects on bone. www.ClinicalTrials.gov no. NCT01370941.

Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: a randomized controlled trial.

Melatonin is known for its regulation of circadian rhythm. Recently, studies have shown that melatonin may have a positive effect on the skeleton. By increasing age, the melatonin levels decrease, which may lead to a further imbalanced bone remodeling. We aimed to investigate whether treatment with melatonin could improve bone mass and integrity in humans. In a double-blind RCT, we randomized 81 postmenopausal osteopenic women to 1-yr nightly treatment with melatonin 1 mg (N = 20), 3 mg (N = 20), or placebo (N = 41). At baseline and after 1-yr treatment, we measured bone mineral density (BMD) by dual X-ray absorptiometry, quantitative computed tomography (QCT), and high-resolution peripheral QCT (HR-pQCT) and determined calciotropic hormones and bone markers. Mean age of the study subjects was 63 (range 56-73) yr. Compared to placebo, femoral neck BMD increased by 1.4% in response to melatonin (P < 0.05) in a dose-dependent manner (P < 0.01), as BMD increased by 0.5% in the 1 mg/day group (P = 0.55) and by 2.3% (P < 0.01) in the 3 mg/day group. In the melatonin group, trabecular thickness in tibia increased by 2.2% (P = 0.04), and volumetric bone mineral density (vBMD) in the spine, by 3.6% (P = 0.04) in the 3 mg/day. Treatment did not significantly affect BMD at other sites or levels of bone turnover markers; however, 24-hr urinary calcium was decreased in response to melatonin by 12.2% (P = 0.02). In conclusion, 1-yr treatment with melatonin increased BMD at femoral neck in a dose-dependent manner, while high-dose melatonin increased vBMD in the spine. Further studies are needed to assess the mechanisms of action and whether the positive effect of nighttime melatonin will protect against fractures.

The effect of melatonin treatment on postural stability, muscle strength, and quality of life and sleep in postmenopausal women: a randomized controlled trial.

BACKGROUND: Melatonin is often used as a sleeping aid in elderly adults. As previous studies suggest a protective role of melatonin against osteoporosis, it is important to document its safety. Treatment should not cause any hangover effect that could potentially lead to falls and fractures. We therefore aimed to evaluate the effect of melatonin on balance- and muscle function. METHODS AND PATIENTS: In a double-blind placebo-controlled study, we randomized 81 postmenopausal women with osteopenia to receive 1 or 3 mg melatonin, or placebo nightly for 12 months. Postural balance as well as muscle function was measured. In addition, we assessed quality of life and sleep at baseline and after 12 months treatment. RESULTS: Compared to placebo, one-year treatment with melatonin did not affect postural balance or risk of falls. Furthermore, no significant changes between groups were observed in muscle strength in neither upper- nor lower extremities. Treatment did not affect quality of life or sleep. However, in the subgroup of women with sleep disturbances at baseline, a trend towards an improved sleep quality was seen (p = 0.08). CONCLUSION: Treatment with melatonin is safe in postmenopausal women with osteopenia. There is no hangover effect affecting balance- and muscle function following the intake of melatonin. In women with a good quality of sleep, melatonin has no effect, however in poor quality of sleep, small doses of melatonin trended towards improving the quality. TRIAL REGISTRATION: (# NCT01690000).

Increased trabecular volumetric bone mass density in Familial Hypocalciuric Hypercalcemia (FHH) type 1: a cross-sectional study.

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.

Muscle function is impaired in patients with "asymptomatic" primary hyperparathyroidism.

BACKGROUND: Patients with "asymptomatic" primary hyperparathyroidism (PHPT) often describe improvement after surgery. METHODS: 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. RESULTS: 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 < 0.001), and impaired postural stability during normal standing with eyes open (p < 0.05) or closed (p < 0.001). Maximum isometric muscle strength was reduced in both upper (p < 0.01) and lower (p < 0.001) extremities. Physical performance was decreased during 10 repeated chair stands (p < 0.001) and time to walk 3 m forward and back (p < 0.05). Restricting analyses to "asymptomatic" patients showed significantly lower muscle strength at knee extension and flexion and impaired postural stability than in matched controls. CONCLUSIONS: PHPT is associated with deleterious effects on muscles and QoL. Impairments also apply to patients with mild disease, normally considered "asymptomatic." This may explain why "asymptomatic" patients report improvements following surgery. The impaired muscle function may contribute to increased fracture risk independent of bone mineral density.

Vitamin D status in Greenland is influenced by diet and ethnicity: a population-based survey in an Arctic society in transition.

Vitamin D status as measured by plasma 25-hydroxyvitamin D (25(OH)D) is important to human health. Circumpolar people rely on dietary sources and societal changes in the Arctic are having profound dietary effects. The objective of the present study was to determine plasma 25(OH)D status and factors important to plasma 25(OH)D in populations in Greenland. Inuit and non-Inuit aged 50-69 years in the capital in West Greenland (latitude 64°15'N) and in a major town and remote settlements in East Greenland (latitude 65°35'N) were surveyed. Supplement use and lifestyle factors were determined by questionnaires. Inuit food scores were computed from a FFQ of seven traditional Inuit and seven imported food items. 25(OH)D2 and 25(OH)D3 levels were measured in the plasma. We invited 1 % of the population of Greenland, and 95 % participated. 25(OH)D3 contributed 99·7 % of total plasma 25(OH)D. Non-Inuit had the lowest median plasma 25(OH)D of 41 (25th-75th percentile 23-53) nmol/l compared with 64 (25th-75th percentile 51-81) nmol/l in Inuit (P< 0·001). Plasma 25(OH)D was below 20 and 50 nmol/l in 13·8 and 60·1 % of participants, respectively, with Inuit food item scores below 40 % (P< 0·001), and in 0·2 and 25·0 % of participants, respectively, with higher scores (P< 0·001). The Inuit diet was an important determinant of plasma 25(OH)D (P< 0·001) and its effect was modified by ethnicity (P= 0·005). Seal (P= 0·005) and whale (P= 0·015) were major contributors to plasma 25(OH)D. In conclusion, a decrease in the intake of the traditional Inuit diet was associated with a decrease in plasma 25(OH)D levels, which may be influenced by ethnicity. The risk of plasma 25(OH)D deficiency in Arctic populations rises with the dietary transition of societies in Greenland. Vitamin D intake and plasma 25(OH)D status should be monitored.

BMD improvements after operation for primary hyperparathyroidism.

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 < 0.001), and alkaline phosphatase (p = 0.014). Hip BMD increased 1.5 % (1.1; 1.9). The increase in BMD was positively associated with preoperative plasma PTH (p = 0.005) and Ca(2+) (p < 0.001) and inversely associated with plasma creatinine (p = 0.004) and age (p = 0.018). Total forearm BMD did not change significantly (-0.2 % (-0.5; 0.1)). An increase in forearm BMD was seen in 38 % of all patients, and the changes were positively associated with plasma PTH (p < 0.001) and Ca(2+) (p = 0.009). In all 91 patients with mild PHPT (plasma Ca(2+) < 1.45 mmol/l), there was a significant postoperative increase in spine BMD (1.9 % (1.2; 2.7)) and in hip BMD (1.0 % (0.4; 1.6)), but not in the forearm BMD (-0.3 % (-0.7; 0.2)). The postoperative BMD gain was higher in the hip and forearm in patients operated for adenomas compared with patients treated for hyperplasia. 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.

Effects of increasing age, dosage, and duration of PTH treatment on BMD increase--a meta-analysis.

We studied the effects of increasing age, dosage, and duration of parathyroid hormone (PTH) treatment on changes in bone mineral density (BMD). Randomized placebo controlled trials on PTH treatment in men or women were retrieved from PubMed (1951 to present), Web of Science (1945 to present), or Embase (1974 to present). The search date was November 16, 2010. All studies comparing PTH treatment to either placebo or antiresorptive drugs--for example, bisphosphonates or hormone replacement therapy--were included. A total of 214 studies were identified in the initial search, and 15 of these trials were included. By metaregression analysis, we found that the increase in spine BMD (Z-score) after PTH treatment was blunted by increasing age (R(2) = 0.27; 2p = 0.01, slope -0.023 Z-scores per year, 11 studies). By increasing PTH dosage (µg/d), spine BMD increased significantly (2p = 0.002) with a slope of +0.011 Z-scores/µg/d of teriparatide. Furthermore, the duration of treatment was positively correlated to spine BMD (P < 0.001) with a slope of +0.043 Z-score for each extra month of treatment. We evaluated the BMD effect in hips and found no age dependency (R(2) = 0.04; P = 0.66; 8 studies). However, for the spine, we found a significant relation to daily dosage (P = 0.011), Z-score coefficient 0.0051 ± 0.0020 (2p < 0.01). The treatment duration also correlated positively by a Z-score coefficient of 0.0170 ± 0.0053, 2p < 0.01 per extra month of treatment. PTH treatment alone seems to be able to improve BMD significantly. However, the BMD increase was significantly lower with increasing age in the spine. No age dependency was observed in the hips. In general the effect of treatment was improved with increasing dosage and duration of treatment from 6 to 36 months.

Oral bisphosphonate use increases the risk for inflammatory jaw disease: a cohort study.

PURPOSE: The objective of this study was to address whether among people living in Denmark, those treated with medications to prevent osteoporosis have an increased risk for inflammatory jaw disease compared with those not treated. PATIENTS AND METHODS: A historical cohort study was designed to compare the rate of inflammatory jaw-related events, ie, osteomyelitis, osteitis, periostitis, or sequestrum, between Danish patients who had been prescribed oral bisphosphonates (BP) and other drugs for the treatment of osteoporosis between 1996 and 2006 (the exposed group), and a random sample of the Danish population drawn from a nationwide registry who had not been prescribed oral BPs or other medications to treat osteoporosis (the nonexposed group). The nonexposed subjects were age- and gender-matched to the exposed subjects and randomly drawn from the general population at a ratio of 3 non-BP subjects to 1 BP subject. The primary explanatory variable was oral BP exposure status. Associations between BP treatment and inflammatory jaw events were ascertained using hazard ratios (HR) Cox proportional hazards models. RESULTS: The study sample was composed of 103,562 index subjects and 310,683 control subjects. After adjusting for other factors, including diabetes and chemotherapy, alendronate (HR = 3.15, 95% confidence interval 1.44-6.87) and etidronate (HR = 2.23, 95% confidence interval 1.15-4.31) were associated with an increased risk for inflammatory jaw events. There was no association between oral BP dose and risk for inflammatory jaw events. CONCLUSION: The oral BPs alendronate and etidronate were associated with an increased risk for inflammatory jaw events.

Determinants of plasma PTH and their implication for defining a reference interval.

BACKGROUND: To improve the diagnostic sensitivity of PTH measurements, more data on the upper limit of the reference interval for PTH levels were requested at a recent international consensus conference. As PTH levels vary inversely with plasma 25-hydroxyvitamin D (25OHD) levels and as vitamin D insufficiency is widespread, particular attention should be given to the influence of low vitamin D levels on the PTH reference interval. AIM, DESIGN AND METHODS: In a cross-sectional design, including 2316 women aged 17-84, we determined 95% reference interval using a nonparametric approach and studied the effects of potential predictors on plasma PTH levels. RESULTS: PTH was a positive function of age, body weight and BMI and inversely associated with total daily calcium intake, smoking, plasma calcium levels and 25OHD levels, all of which explained 16% of the variability in plasma PTH levels. The threshold value for 25OHD levels below which PTH levels started to rise was 82 nmol/l. Plasma PTH levels varied inversely with the seasonal variations in 25OHD levels. Mean PTH level was 4·1 pmol/l with a reference interval equal to 2·0-8·6 pmol/l. Restricting the population in whom the reference interval was calculated to only women with 25OHD levels above 30 or 100 nmol/l lowered the upper limit of the reference interval to 8·4 and 7·1 pmol/l, respectively. Similar, stratification according to age, body mass index, smoking and calcium intake had only minor impact on the reference interval. CONCLUSION: Indices with known effects on plasma PTH levels have only a minor impact on the upper levels of the normative reference interval in women with intact renal function.

Vitamin D status, physical performance and body mass in patients surgically cured for primary hyperparathyroidism compared with healthy controls - a cross-sectional study.

OBJECTIVE: Low plasma 25-hydroxyvitaminD (25OHD) levels, reduced muscle strength and increased body mass index (BMI) are well-known characteristics of primary hyperparathyroidism (PHPT). Mechanisms for low 25OHD levels, increased BMI and potential changes after parathyroidectomy are unknown. Muscle strength is reported to increase following surgical cure, but whether the improvement corresponds to healthy controls' performances remains largely unknown. PATIENTS: We studied 51 patients with former PHPT [mean age 61(36-77) years] successfully treated by surgery [mean time since operation 7·4(5-15) years] and 51 sex- and age-matched controls. MEASUREMENTS: Physical performance include "repeated chair stand" (RCS), "timed up and go" (TUG), muscle strength [hand grip, elbow flexion/extension and knee flexion/extension (60°/90°)], postural stability, biochemistry and anthropometric indices. RESULTS: Forty-one cases had pathologically verified adenoma, three had hyperplasia and three had uncertain diagnosis whereas four had missing data. Dietary calcium intake, vitamin D supplementation and biochemistry including PTH and 25OHD levels did not differ between groups. Former patients had significantly higher BMI (28·8 ± 6·0 kg/m²) than controls (26·0 ± 4·7kg/m²). Muscle pain was more frequently reported by cases than controls, and cases performed RCS slower than controls (P = 0·02). Furthermore, female cases had lower muscle strength in knee flexion 60° (P = 0·02) and 90° (P = 0·05). Former patients no longer differed from controls after adjustment for BMI. CONCLUSION: Following cure, 25OHD levels are normalized suggesting 25OHD insufficiency is not a constitutional characteristics in patients with PHPT. Increased BMI seems to be sustained. Whether this is caused by decreased muscle strength or reduced muscular performance causes adiposity needs further investigations.

Are antiresorptive drugs effective against fractures in patients with diabetes?

We studied whether the reduction in bone turnover by use of antiresorptive drugs is detrimental in patients with diabetes who already have low bone turnover due to hyperglycemia in a nationwide cohort study from Denmark. All users of antiresorptive drugs against osteoporosis between 1996 and 2006 (n = 103,562) were the exposed group, with three age- and gender-matched controls from the general population (n = 310,683). Patients on bisphosphonates and raloxifene had a higher risk of hip, spine, and forearm fractures. However, no difference was observed in the antifracture efficacy between patients with diabetes and nondiabetic controls or between patients with type 1 and type 2 diabetes. Too few were users of strontium to allow analysis for this compound. The excess risk of fractures among patients treated with bisphosphonates or raloxifene compared to nonexposed controls was due to the higher a priori risk of fractures among patients treated for osteoporosis. Diabetes does not seem to affect the fracture-preventive potential of bisphosphonates or raloxifene. The low-turnover state of diabetes thus does not seem to be a hindrance to the effect of these drugs against osteoporosis. Therefore, patients with diabetes should receive treatment for osteoporosis in the same way as nondiabetic patients.

Increased fracture risk in normocalcemic postmenopausal women with high parathyroid hormone levels: a 16-year follow-up study.

High PTH levels increase bone turnover and decrease bone mineral density (BMD). Low plasma 25-hydroxyvitamin D (25OHD) levels cause secondary hyperparathyroidism, but the relative contribution of low 25OHD and high PTH levels on risk of fracture is largely unknown. Within the cohort of women (n = 2,016) included in the Danish Osteoporosis Prevention Study (DOPS), we studied risk of fracture according to parathyroid status. Analyses were performed on effects of high PTH levels (i.e., in the upper tertile, ≥4.5 pmol/L) on risk of incident fractures at different 25OHD levels during 16 years of follow-up. Incident fractures were assessed using a nationwide hospital discharge register. In addition, effects of high PTH levels on BMD and vertebral fractures were assessed by DXA scans and spinal X-ray examination after 10 years of follow-up. High PTH levels were associated with a decreased body mass index, adjusted BMD, and an increased risk of any fracture (HR = 1.41, 95% CI 1.11-1.79) as well as an increased risk of osteoporotic fractures (HR = 1.59, 95% CI 1.20-2.10). Plasma 25OHD levels per se did not affect fracture risk, but high PTH levels were associated with an increased fracture risk only at 25OHD levels <50 nmol/L and 50-80 nmol/L. High PTH levels did not increase risk of fracture at 25OHD levels >80 nmol/L. In conclusion, PTH levels in the upper part or above the upper level of the reference interval increase risk of fracture in the presence of low vitamin D levels.

Use of bisphosphonates and risk of breast cancer.

A decreased risk of breast cancer has been reported among patients given bisphosphonates. The present aims were to study potential associations between different antiosteoporosis drugs, including bisphosphonates, and the risk of breast cancer before and after start of treatment and to appraise possible dose-effect relationships. From national Danish registers, all female users of bisphosphonates aged ≥40 years and other drugs against osteoporosis between 1996 and 2006 were identified (n = 87,104). This cohort was compared with a control group, where each patient was matched on age with three nonexposed women from the general population (n = 261,322). Before start of most drugs against osteoporosis an increased risk of breast cancer was seen compared to controls (e.g., adjusted OR = 1.09, 95% CI 1.04-1.16 for alendronate). This excess risk was higher in younger women (e.g., OR = 4.48, 95% CI 2.98-6.75 for alendronate in women ≤50 years) and disappeared in women older than 70 years (e.g., OR = 0.95, 95% CI 0.88-1.01 for alendronate). In contrast, a decreased risk of breast cancer was seen after start of alendronate (HR = 0.53, 95% CI 0.38-0.73), etidronate (HR = 0.80, 95% CI 0.73-0.89), and raloxifene (HR = 0.53, 95% CI 0.38-0.73). No dose-response relationship was present for alendronate and etidronate, whereas a decreasing risk was seen with increasing daily dose of raloxifene. Bisphosphonate treatment in women was associated with a reduced risk of breast cancer. However, no causal relationship seemed to be present.

Forearm bone mineral density in familial hypocalciuric hypercalcemia and primary hyperparathyroidism: a comparative study.

Studies have shown that cancellous bone is relatively preserved in primary hyperparathyroidism (PHPT), whereas bone loss is seen in cortical bone. Familial hypocalciuric hypercalcemia (FHH) patients seem to preserve bone mineral in spite of hypercalcemia and often elevated plasma parathyroid hormone (PTH). The objective of this study was to compare total and regional forearm bone mineral density (BMD) in patients with PHPT and FHH and to examine if differences can be used to separate the two disorders. We included 63 FHH, and 121 PHPT patients in a cross-sectional study. We performed dual-energy X-ray absorptiometry scans of the forearm, hip and lumbar spine and measured a number of biochemical variables. PTH patients had significantly lower Z-scores in all parts of the forearm compared to FHH. This was also the case after adjustment for body mass index. When stratifying for age, gender and PTH, T-scores were still significantly lower in PHPT patients than in FHH patients at the total, the mid and the ultradistal forearm, but not at the proximal 1/3 forearm. In a multiple regression analysis BMD Z-score was lower in PHPT compared to FHH at the total forearm, the mid forearm and the ultradistal forearm but not the proximal forearm when adjusting for biochemical variables including PTH, 1,25(OH)(2)D and Ca(2+). These observations support that inactivating mutations in the CASR gene in bone cells in FHH may protect against forearm bone loss. Differences between the two groups in total or regional forearm BMD were inferior to the calcium/creatinine clearance ratio as a diagnostic tool to separate FHH from PHPT.

Multiplex ligation-dependent probe amplification (MLPA) screening for exon copy number variation in the calcium sensing receptor gene: no large rearrangements identified in patients with calcium metabolic disorders.

BACKGROUND: Mutation screening of the CASR by DNA sequencing is commonly used in the diagnosis of disorders of calcium metabolism, such as familial hypocalciuric hypercalcaemia (FHH). Exon copy number variation is not detected by currently used molecular genetic screening methods, and might be a genetic cause of inherited forms of hyper- or hypocalcaemia caused by the CASR. OBJECTIVE: We wanted to further evaluate possible genetic causes for disorders of calcium metabolism, by investigating the prevalence of exon copy number variations, such as large deletions or duplications of the CASR. PATIENTS AND METHODS: The study included 257 patient samples referred to our laboratory for molecular genetic analysis of the CASR gene. A total of 245 were patients suspected to have FHH, while the remaining 12 samples represent patients with a phenotype of idiopathic hypocalcaemia/hypoparathyroidism. All samples were previously found negative for CASR mutations. Multiplex ligation-dependent probe amplification was used to screen the patients for exon copy number variations. RESULTS: All exons were amplified with mean normalised ratios between 0.98 and 1.06. We did not identify any exon copy number variation in the CASR. Bioinformatic analyses revealed that the CASR gene contains 52% repeated elements, of which approximately 6% consist of Alu elements. CONCLUSIONS: The present study indicates that including CASR MLPA analysis as a routine part of the diagnostic setup is not necessary, but could still be of interest in cases with a clear family history and no evidence of missense mutations in the CASR gene.