Revisiting the endocrine and metabolic manifestations of COVID-19 two years into the pandemic.

An extraordinary effort of the universal endocrine community has led to important insights into endocrine and metabolic aspects of COVID-19. In this Editorial, we introduce a special issue of Reviews in Endocrine and Metabolic Disorders that calls attention, through the efforts of internationally recognized experts in the field, to features that are now widely recognized as endocrine and metabolic manifestations of COVID-19. These advances in our knowledge have seminal implications for how we can prevent and manage these aspects of COVID-19.

Consensus statement from 2nd International Conference on Controversies in Vitamin D.

The 2nd International Conference on Controversies in Vitamin D was held in Monteriggioni (Siena), Italy, September 11-14, 2018. The aim of this meeting was to address ongoing controversies and timely topics in vitamin D research, to review available data related to these topics and controversies, to promote discussion to help resolve lingering issues and ultimately to suggest a research agenda to clarify areas of uncertainty. Several issues from the first conference, held in 2017, were revisited, such as assays used to determine serum 25-hydroxyvitamin D [25(OH)D] concentration, which remains a critical and controversial issue for defining vitamin D status. Definitions of vitamin D nutritional status (i.e. sufficiency, insufficiency and deficiency) were also revisited. New areas were reviewed, including vitamin D threshold values and how they should be defined in the context of specific diseases, sources of vitamin D and risk factors associated with vitamin D deficiency. Non-skeletal aspects related to vitamin D were also discussed, including the reproductive system, neurology, chronic kidney disease and falls. The therapeutic role of vitamin D and findings from recent clinical trials were also addressed. The topics were considered by 3 focus groups and divided into three main areas: 1) "Laboratory": assays and threshold values to define vitamin D status; 2) "Clinical": sources of vitamin D and risk factors and role of vitamin D in non-skeletal disease and 3) "Therapeutics": controversial issues on observational studies and recent randomized controlled trials. In this report, we present a summary of our findings.

Hypercalciuria: its value as a predictive risk factor for nephrolithiasis in asymptomatic primary hyperparathyroidism?

CONTEXT: The latest guidelines of the 4th International Workshop on Asymptomatic Primary Hyperparathyroidism (aPHPT) reintroduced hypercalciuria (i.e. urinary calcium > 400 mg/day) as criterion for surgery. However, the value of hypercalciuria as a predictor of nephrolithiasis and the correct cut-off values still need to be confirmed. OBJECTIVE: To evaluate the prevalence of silent kidney stones in a large series of patients with aPHPT and the sensibility, specificity and predictive value of different cut-off values of hypercalciuria in identifying patients with nephrolithiasis. DESIGN: One hundred seventy-six consecutive patients with aPHPT were evaluated at our Institution by serum and urinary parameters and kidney ultrasound. RESULTS: Silent nephrolithiasis was found in 38 (21.6%) patients. In the univariate and multivariate model, hypercalciuria was a predictor of nephrolithiasis using the criterion of 400 mg/24 h [(OR 2.30, (1.11-4.82) P = 0.025], 4 mg/kg/bw [OR 2.65, (1.14-6.25) P = 0.023], gender criterion [OR 2.79, (1.15-6.79) P = 0.023] and the cut-off value derived from the ROC analysis [(> 231 mg/24 h) OR 5.02 (1.68-14.97) P = 0.004]. Despite these several predictive criteria, however, hypercalciuria had a low positive predictive value (PPV), ranging from 27.4 to 32.7%. CONCLUSIONS: Hypercalciuria is a predictor of nephrolithiasis, but its PPV is low.

Long-term denosumab treatment restores cortical bone loss and reduces fracture risk at the forearm and humerus: analyses from the FREEDOM Extension cross-over group.

Upper limb fractures (including wrist, forearm, and humerus) represent a significant burden among postmenopausal women with osteoporosis. Up to 7 years of treatment with denosumab resulted in an increase in bone mineral density and decrease in fractures in upper limb sites. INTRODUCTION: Upper limb (wrist, forearm, and humerus) fractures are a significant burden in osteoporosis, associated with significant morbidity and mortality. Denosumab, a monoclonal antibody against RANK ligand, increases bone mineral density (BMD) and decreases vertebral, nonvertebral, and hip fractures. Here, we evaluated the long-term effect of denosumab treatment on upper limb fracture risk and BMD. METHODS: In the FREEDOM trial, subjects were randomized 1:1 to receive every-6-month denosumab 60 mg or placebo subcutaneously for 3 years, after which all subjects could receive denosumab for up to 7 years (Extension). Among placebo subjects who completed FREEDOM and enrolled in the Extension, wrist, forearm, humerus, and upper limb fracture rates and rate ratios between different time periods (FREEDOM years 1-3, Extension years 1-3, and Extension years 4-7) were computed. BMD at the ultradistal radius, 1/3 radius, and total radius was analyzed in a subset of subjects in a BMD substudy. RESULTS: This analysis included 2207 subjects (116 in the BMD substudy). Fracture rates decreased over the 7-year Extension; fracture rate ratios between Extension years 4-7 (denosumab) and FREEDOM years 1-3 (placebo) reduced significantly for the wrist (0.57), forearm (0.57), humerus (0.42), and upper limb (0.52; p < 0.05 for all). Percentage increase in BMD from Extension baseline at the ultradistal radius, 1/3 radius, and total radius was significant by Extension year 7 (p < 0.05 for all). CONCLUSIONS: Long-term treatment with denosumab decreases upper limb fracture risk and increases forearm BMD, suggesting beneficial effects on both cortical and trabecular bone accruing over time.

Abaloparatide-SC improves trabecular microarchitecture as assessed by trabecular bone score (TBS): a 24-week randomized clinical trial.

In a phase 2 trial of 222 postmenopausal women with osteoporosis aged 55 to 85 years randomized to one of three different doses of abaloparatide-SC, subcutaneous teriparatide, or placebo for 24 weeks, abaloparatide-SC resulted in improvements in skeletal microarchitecture as measured by the trabecular bone score. INTRODUCTION: Subcutaneous abaloparatide (abaloparatide-SC) increases total hip and lumbar spine bone mineral density and reduces vertebral and non-vertebral fractures. In this study, we analyzed the extent to which abaloparatide-SC improves skeletal microarchitecture, assessed indirectly by trabecular bone score (TBS). METHODS: This is a post hoc analysis of a phase 2 trial of 222 postmenopausal women with osteoporosis aged 55 to 85 years randomized to abaloparatide-SC (20, 40, or 80 µg), subcutaneous teriparatide (20 µg), or placebo for 24 weeks. TBS was measured from lumbar spine dual X-ray absorptiometry (DXA) images in 138 women for whom the DXA device was TBS software compatible. Assessments were made at baseline, 12 and 24 weeks. Between-group differences were assessed by generalized estimating equations adjusted for relevant baseline characteristics, and a pre-determined least significant change analysis was performed. RESULTS: After 24 weeks, TBS increased significantly by 2.27, 3.14, and 4.21% versus baseline in participants on 20, 40, and 80 µg abaloparatide-SC daily, respectively, and by 2.21% in those on teriparatide (p < 0.05 for each). The TBS in the placebo group declined by 1.08%. The TBS increase in each treatment group was significantly higher than placebo at 24 weeks (p < 0.0001 for each) after adjustment for age, BMI, and baseline TBS. A dose-response was observed at 24 weeks across the three doses of abaloparatide-SC and placebo (p = 0.02). The increase in TBS in the abaloparatide-SC 80 µg group was significantly greater than TPTD (p < 0.03). CONCLUSIONS: These results are consistent with an effect of abaloparatide-SC to improve lumbar spine skeletal microarchitecture, as assessed by TBS.

Bone imaging in hypoparathyroidism.

Hypoparathyroidism (HypoPT) is an uncommon endocrine disorder characterized by chronic deficiency or absence of parathyroid hormone (PTH), which leads to a profound reduction in bone remodeling. Subjects with HypoPT typically have bone mineral densities (BMDs) by dual-energy X-ray absorptiometry (DXA) above average at all skeletal sites, with greatest scores observed at the lumbar spine. Trabecular bone score (TBS), an indirect measure of bone microarchitecture, also appears to be normal in HypoPT. By peripheral quantitative computed tomography (pQCT) of the radius, volumetric BMD at cancellous and cortical compartments, as well as cortical area and thickness, are greater in hypoparathyroid subjects than in controls. The use of high-resolution pQCT (HRpQCT) confirmed the increase in cortical volumetric BMD but demonstrated reduced cortical thickness, associated with lower cortical porosity in HypoPT. Trabeculae tend to be more numerous but thinner in hypoparathyroid subjects. It is not clear whether these structural and the dynamic skeletal abnormalities in HypoPT affect bone strength or fracture risk. Treatment of HypoPT with PTH leads to improvement in bone remodeling rate, variable changes in bone density, and a transient increase in estimated bone strength. The effect of PTH therapy on fracture risk remains unknown. This article reviews skeletal involvement and the effect of PTH treatment in patients with HypoPT, as assessed by DXA, TBS, QCT, and HRpQCT. Data on bone strength and fracture risk in HypoPT are also reviewed here.

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.

Low vitamin D levels have become less common in primary hyperparathyroidism.

UNLABELLED: We compared temporal trends in serum 25-hydroxyvitamin D and parathyroid hormone (PTH) in two primary hyperparathyroidism (PHPT) cohorts recruited 20 years apart. The prevalence of 25-hydroxyvitamin D levels <20 and <30 ng/mL declined by 30-50 %, respectively, and was accompanied by lower PTH. In the older cohort, higher PTH may be due to lower 25-hydroxyvitamin D. INTRODUCTION: Vitamin D deficiency may exacerbate PHPT. Whether there have been temporal trends in 25-hydroxyvitamin D (25OHD) levels in PHPT is unclear. The prevalence of low vitamin D levels (25OHD <20 and <30 ng/mL) and associated biochemical and bone mineral density (BMD) profiles were assessed in two PHPT cohorts recruited over 20 years apart. METHODS: This is a cross-sectional comparison of serum 25OHD levels, calciotropic hormones, and BMD between two PHPT cohorts recruited at the same hospital: the "old" (N = 103) and "new" (N = 100) cohorts were enrolled between 1984 and 1991 and between 2010 and 2014, respectively. RESULTS: Mean 25OHD levels were 26 % higher in the new cohort (23 ± 10 vs. 29 ± 10 ng/mL, p < 0.0001). Levels of 25OHD <20 and <30 ng/mL declined from 46 and 82 %, respectively, to 19 and 54 % (both p < 0.0001). Supplemental vitamin D use was common in the new (64 %) but not the old cohort (0 %). The new cohort demonstrated 33 % lower serum PTH levels (p < 0.0001). Neither serum nor urine calcium differed. BMD was higher in the new cohort at all skeletal sites (all p < 0.001). CONCLUSION: With the rise in vitamin D supplementation over the last two decades, low 25OHD levels are no longer common in PHPT patients in the New York area. Those with 25OHD <20 and <30 ng/mL have declined by over 50 and 30 %, respectively. The lower mean PTH levels in the new cohort are most likely accounted for by higher vitamin D intake. Whether improved vitamin D status also underlies the relatively higher BMD in the more vitamin D replete cohort of PHPT patients is unknown.

Taxonomy of rare genetic metabolic bone disorders.

UNLABELLED: This article reports a taxonomic classification of rare skeletal diseases based on metabolic phenotypes. It was prepared by The Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation (IOF) and includes 116 OMIM phenotypes with 86 affected genes. INTRODUCTION: Rare skeletal metabolic diseases comprise a group of diseases commonly associated with severe clinical consequences. In recent years, the description of the clinical phenotypes and radiographic features of several genetic bone disorders was paralleled by the discovery of key molecular pathways involved in the regulation of bone and mineral metabolism. Including this information in the description and classification of rare skeletal diseases may improve the recognition and management of affected patients. METHODS: IOF recognized this need and formed a Skeletal Rare Diseases Working Group (SRD-WG) of basic and clinical scientists who developed a taxonomy of rare skeletal diseases based on their metabolic pathogenesis. RESULTS: This taxonomy of rare genetic metabolic bone disorders (RGMBDs) comprises 116 OMIM phenotypes, with 86 affected genes related to bone and mineral homeostasis. The diseases were divided into four major groups, namely, disorders due to altered osteoclast, osteoblast, or osteocyte activity; disorders due to altered bone matrix proteins; disorders due to altered bone microenvironmental regulators; and disorders due to deranged calciotropic hormonal activity. CONCLUSIONS: This article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.

ß-Adrenergic receptor antagonists and fracture risk: a meta-analysis of selectivity, gender, and site-specific effects.

UNLABELLED: By meta-analysis, the risk of fracture was 15% lower in patients treated with ß-adrenergic blockers compared to controls independent of gender, fracture site, and dose. This might be attributable to ß1-selective blockers. INTRODUCTION: The aim of this study is to determine by meta-analysis whether ß-adrenergic blockers (BBs) reduce fracture risk and whether the effect, if demonstrable, is dependent upon selectivity, dose, gender, or fracture site. METHODS: A literature search was performed in electronic databases MEDLINE, EMBASE, and reference sections of relevant articles to identify eligible studies. Adjusted estimates of fracture risk effect size (ES) were pooled across studies using fixed or random-effects (RE) meta-analysis as appropriate. Dose-related effects were evaluated using meta-regression. To explore the relative efficacy of ß1-selective blockers in comparison to nonselective BBs, adjusted indirect comparison was performed. RESULTS: A total of 16 studies (7 cohort and 9 case-control studies), involving 1,644,570 subjects, were identified. The risk of any fracture was found to be significantly reduced in subjects receiving BBs as compared to control subjects (16 studies, RE pooled ES = 0.86, 95% CI 0.78-0.93; I(2) = 87 %). In a sensitivity analysis limited to those studies deemed to be most robust, the BB effect to reduce fracture risk was sustained (four studies, pooled ES = 0.79, 95% CI 0.67-0.94; I(2) = 96%). The risk of a hip fracture was lower in both women and men receiving BBs (women: pooled ES = 0.86, 95% CI 0.80-0.91; I(2) = 1% and men: pooled ES = 0.80, 95% CI 0.71-0.90; I(2) = 0%). Similar risk reductions were found for clinical vertebral and forearm fractures, although statistical significance was not reached. The reduction in risk did not appear to be dose-related (test for a linear trend p value 0.150). Using adjusted indirect comparisons, it was estimated that ß1-selective agents were significantly more effective than nonselective BBs in reducing the risk of any fracture (six studies, ß1-selective blockers vs. nonselective BBs: RE pooled ES = 0.82, 95% CI = 0.69-0.97). CONCLUSIONS: The findings suggest that the risk of fracture is approximately 15% lower in patients treated with BBs compared to controls independent of gender, fracture site, and dose. This risk reduction might be associated with the effects of ß1-selective blockers.

Comparison of two commercially available ELISAs for circulating sclerostin.

UNLABELLED: This study investigates the performance and correlation of sclerostin measurements by two commercially available sclerostin ELISAs from TECOmedical and Biomedica. We found that the correlation between the results of two sclerostin assays is strong. INTRODUCTION: Circulating sclerostin levels may provide insight into the pathophysiology of metabolic bone diseases such as osteoporosis. However, recent studies suggest that commercially available assays give different results. We compare the analytical performance of the two most used commercially available sclerostin ELISAs from TECOmedical and Biomedica. METHODS: Sclerostin levels were assessed in 20 paired serum, EDTA, and heparin plasma convenience samples from hospitalized patients. In addition, sclerostin was measured in serum samples from 34 patients with metabolic bone diseases and from 10 patients with chronic kidney disease (CKD). Samples from three healthy donors were used to determine stability and intra- and inter- assay precision. RESULTS: The average serum sclerostin concentration of all patients (n = 64) was 0.713 ± 0.58 ng/mL with the Biomedica assay and 0.734 ± 0.43 ng/mL with the TECO assay (p < 0.05). The results correlated strongly (r = 0.9; p < 0.0001), with Passing-Bablok regression showing a linear relationship but with a slight systematic and proportional difference between both assays. Sclerostin levels were about 30% higher in plasma than in serum for both assays, while no significant difference was seen between EDTA and heparin plasma. Intra- and inter- precision were <10% for TECO and <20% for Biomedica. Samples were stable for up to three freeze-thaw cycles with both assays. CONCLUSIONS: The two commercially available ELISAs for measuring circulating levels of sclerostin are comparable. However, given the small but statistically significant systematic and proportional differences between both assays, results and reference ranges will be assay-specific. Results will also be specific to serum or plasma.

A trabecular plate-like phenotype is overrepresented in Chinese-American versus Caucasian women.

UNLABELLED: This study used extreme phenotype selection to define two trabecular bone phenotypes in a cohort of Chinese-American and Caucasian women. A trabecular plate-predominant phenotype is more common in Chinese-Americans while the rod-predominant phenotype is more typical of Caucasians. The robustness of these phenotypic associations with respect to lifestyle factors suggests that this trait may have a genetic basis and that these phenotypes can be utilized in future genetic studies. INTRODUCTION: Compared to Caucasians, Chinese-Americans have more plate-like trabecular bone when measured by individual trabecula segmentation (ITS). These findings suggest a phenotypic difference between the races, which may be amenable to genetic analysis. We sought to identify a single ITS plate trait to pursue in genetic studies by conducting an extreme phenotype selection strategy to numerically define two distinct phenotypes-plate-like and rod-like-and determine whether the selected phenotypic associations were independent of lifestyle factors in order to conduct future genetic studies. METHODS: A previously described cohort of 146 Chinese-American and Caucasian women with high-resolution peripheral quantitative computed tomography imaging and ITS analyses were studied with logistic regression and receiver operator characteristic analyses. RESULTS: The tibial plate-to-rod (TPR) ratio was the best ITS discriminator of race. Using extreme phenotypic selection, two TPR ratio phenotypes were defined numerically: plate-like as a TPR ratio value in the highest quartile (≥1.336) and rod-like as a TPR ratio value in the lowest quartile (≤0.621). Women with a plate-like phenotype were 25.7 times more likely (95 % CI 7.3-90.1) to be Chinese-American than women with rod-like morphology. After controlling for constitutional and lifestyle covariates, women in the highest vs. lowest TPR ratio quartile were 85.0 times more likely (95 % CI 12.7-568.0) to be Chinese-American. CONCLUSION: Using extreme phenotype selection, we defined a plate- and rod-like trabecular bone phenotype for the TPR ratio trait. The former phenotype is more common in Chinese-American women, while the latter is more typical of Caucasian women. The robustness of these phenotypic associations after controlling for differences in constitution and lifestyle suggest that the TPR ratio may have a genetic basis and that the extreme phenotypes defined in this analysis can be utilized for future studies.

The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group.

UNLABELLED: Osteoporosis causes an elevated fracture risk. We propose the continued use of T-scores as one means for diagnosis but recommend that, alternatively, hip fracture; osteopenia-associated vertebral, proximal humerus, pelvis, or some wrist fractures; or FRAX scores with ≥3% (hip) or 20% (major) 10-year fracture risk also confer an osteoporosis diagnosis. INTRODUCTION: Osteoporosis is a common disorder of reduced bone strength that predisposes to an increased risk for fractures in older individuals. In the USA, the standard criterion for the diagnosis of osteoporosis in postmenopausal women and older men is a T-score of ≤ -2.5 at the lumbar spine, femur neck, or total hip by bone mineral density testing. METHODS: Under the direction of the National Bone Health Alliance, 17 clinicians and clinical scientists were appointed to a working group charged to determine the appropriate expansion of the criteria by which osteoporosis can be diagnosed. RESULTS: The group recommends that postmenopausal women and men aged 50 years should be diagnosed with osteoporosis if they have a demonstrable elevated risk for future fractures. This includes having a T-score of less than or equal to -2.5 at the spine or hip as one method for diagnosis but also permits a diagnosis for individuals in this population who have experienced a hip fracture with or without bone mineral density (BMD) testing and for those who have osteopenia by BMD who sustain a vertebral, proximal humeral, pelvic, or, in some cases, distal forearm fracture. Finally, the term osteoporosis should be used to diagnose individuals with an elevated fracture risk based on the World Health Organization Fracture Risk Algorithm, FRAX. CONCLUSIONS: As new ICD-10 codes become available, it is our hope that this new understanding of what osteoporosis represents will allow for an appropriate diagnosis when older individuals are recognized as being at an elevated risk for fracture.

Relationship of bone mineralization density distribution (BMDD) in cortical and cancellous bone within the iliac crest of healthy premenopausal women.

Bone mineralization density distribution (BMDD) is an important determinant of bone mechanical properties. The most available skeletal site for access to the BMDD is the iliac crest. Compared to cancellous bone much less information on BMDD is available for cortical bone. Hence, we analyzed complete transiliac crest bone biopsy samples from premenopausal women (n = 73) aged 25-48 years, clinically classified as healthy, by quantitative backscattered electron imaging for cortical (Ct.) and cancellous (Cn.) BMDD. The Ct.BMDD was characterized by the arithmetic mean of the BMDD of the cortical plates. We found correlations between Ct. and Cn. BMDD variables with correlation coefficients r between 0.42 and 0.73 (all p < 0.001). Additionally to this synchronous behavior of cortical and cancellous compartments, we found that the heterogeneity of mineralization densities (Ct.Ca(Width)), as well as the cortical porosity (Ct.Po) was larger for a lower average degree of mineralization (Ct.Ca(Mean)). Moreover, Ct.Po correlated negatively with the percentage of highly mineralized bone areas (Ct.Ca(High)) and positively with the percentage of lowly mineralized bone areas (Ct.Ca(Low)). In conclusion, the correlation of cortical with cancellous BMDD in the iliac crest of the study cohort suggests coordinated regulation of bone turnover between both bone compartments. Only in a few cases, there was a difference in the degree of mineralization of >1wt % between both cortices suggesting a possible modeling situation. This normative dataset of healthy premenopausal women will provide a reference standard by which disease- and treatment-specific effects can be assessed at the level of cortical bone BMDD.

Improved adherence with PTH(1-84) in an extension trial for 24 months results in enhanced BMD gains in the treatment of postmenopausal women with osteoporosis.

UNLABELLED: The purpose of this study is to examine the effect of PTH(1-84) treatment over 24 months followed by 12 months discontinuation on BMD, bone turnover markers, fractures and the impact of adherence on efficacy. INTRODUCTION: There is limited information about the effect of PTH(1-84) after 18 months and limited data about the impact of compliance on response to anabolic therapy. METHODS: Seven hundred and eighty-one subjects who received active PTH(1-84) in the Treatment of Osteoporosis with Parathyroid hormone trial for approximately 18 months were entered into a 6-month open-label extension. Thereafter, they were followed for 12 additional months after discontinuation of treatment. Endpoints examined included changes in BMD and biochemical markers. RESULTS: PTH(1-84) treatment over 24 months increased BMD at the lumbar spine by 6.8% above baseline (p<0.05).The total corresponding BMD increases at the hip and femoral neck were 1.1 and 2.2% above baseline. Larger increases in spine BMD were observed in participants with ≥80% adherence to daily injections of PTH(1-84) (8.3% in adherent vs 4.9% in poorly adherent patients). Total hip BMD gains were 1.7% in adherent vs 0.6% in poorly adherent participants. Markers of bone turnover (BSAP and NTx) peaked 6 months after starting PTH(1-84) treatment and declined slowly but remained above baseline at 24 months. After discontinuation of PTH(1-84) treatment (at 24 months), bone turnover markers returned to near baseline levels by 30 months. The adherent group sustained significantly fewer fractures than the poorly adherent group. CONCLUSIONS: PTH(1-84) treatment over 24 months results in continued increases in lumbar spine BMD. Adherence to treatment with PTH(1-84) for up to 24 months is also associated with greater efficacy.

Correlation between 25-hydroxyvitamin D levels and latitude in Brazilian postmenopausal women: from the Arzoxifene Generations Trial.

SUMMARY: We investigated vitamin D status in Brazilian cities located at different latitudes. Insufficiency (<50 nmol/L) was common (17 %), even in those living in a tropical climate. Vitamin D insufficiency increased as a function of latitude. Mean 25-hydroxyvitamin D (25(OH)D) levels in each site and latitude correlation were very high (r = -0.88; p=0.02). [corrected]. INTRODUCTION: Inadequate vitamin D, determined by low levels of 25(OH)D, has become very common despite the availability of sunlight at some latitudes. National data from a country that spans a wide range of latitudes would help to determine to what extent latitude or other factors are responsible for vitamin D deficiency. We investigated vitamin D status in cities located at different latitudes in Brazil, a large continental country. METHODS: The source is the Brazilian database from the Generations Trial (1,933 osteopenic or osteoporotic postmenopausal women (60 to 85 years old) with 25(OH)D measurements). 25(OH)D below 25 nmol/L (10 ng/mL) was an exclusion criterion. Baseline values were between fall and winter. The sites included Recife, Salvador, Rio de Janeiro, São Paulo, Curitiba, and Porto Alegre. Mean and standard deviation of 25(OH)D, age, spine and femoral neck T-score, calcium, creatinine, and alkaline phosphatase were calculated for each city. Pearson correlation was used for 25(OH)D and latitude. RESULTS: Insufficiency (<50 or <20 ng/mL) was common (329 subjects, 17 %). Vitamin D insufficiency increased as a function of latitude, reaching 24.5 % in the southernmost city, Porto Alegre. The correlation between mean 25(OH)D levels in each site and latitude was very high (r = -0.88, p < 0.0001). CONCLUSION: There is a high percentage of individuals with vitamin D insufficiency in Brazil, even in cities near the equator, and this percentage progressively increases with more southern latitudes.

Use of parathyroid hormone in hypoparathyroidism.

Hypoparathyroidism is a disorder characterized by hypocalcemia, deficient PTH, and abnormal bone remodeling. Standard treatment of hypoparathyroidism consists of oral calcium and vitamin D supplementation. However, maintaining serum calcium levels can be a challenge. In addition, concerns exist regarding hypercalciuria and ectopic calcifications that can be associated with such treatment. Hypoparathyroidism is the only classic endocrine deficiency disease for which the missing hormone, PTH, is not yet an approved treatment. This review focuses on the use of PTH in the treatment of hypoparathyroidism, in the form of teriparatide [PTH(1-34)] and the full-length molecule, PTH(1-84). Studies in hypoparathyroid subjects demonstrate that PTH(1-34) and PTH(1-84) lower or abolish supplemental calcium and vitamin D requirements as well as increase markers of bone turnover. Densitometric and histomorphometric studies in some subjects treated with PTH(1- 34) and PTH(1-84) show an improvement in bone-remodeling dynamics and return of bone metabolism toward normal levels. Given the chronic nature of hypoparathyroidism, and the expectation that PTH will be used for extended periods of time in hypoparathyroidism, further studies are needed to determine the long-term safety of PTH therapy in this population.

What's in a name? What constitutes the clinical diagnosis of osteoporosis?

Osteoporosis is a skeletal disorder in which reductions in bone strength predispose to an increased risk for fractures. Currently, the diagnosis is officially made based exclusively on bone mineral density T-scores that are ≤-2.5 at the spine or hip. Limiting the clinical diagnosis of osteoporosis solely to a T-score-based criterion, which is the official convention in the USA, creates uncertainty about the use of the term osteoporosis to diagnose older women and men who have T-scores >-2.5, but either have already sustained low-trauma fractures or are recognized as having high fracture risk based on absolute fracture risk calculations from FRAX or other algorithms. A failure to diagnose such patients as having osteoporosis may be one component of the well-documented underdiagnosis and undertreatment of this disease which limits our ability to reduce the burden of fractures worldwide. There is a need to expand the criteria for making a clinical diagnosis and to codify these changes in order to help patients, physicians, policy makers, and payers better understand who has this disease and the elevated risk for fracture that it represents.

Volumetric bone mineral density at the spine and hip in Chinese American and White women.

UNLABELLED: This study evaluated racial differences in bone size and volumetric density at the spine and hip in pre- and postmenopausal Chinese American and White women. Compared with White women, Chinese American women have greater cortical volumetric bone density (vBMD) at the hip, congruent with the results at the peripheral skeleton. INTRODUCTION: Chinese American women have lower rates of fracture than White women despite lower areal bone density. At the forearm and tibia, however, Chinese American women have higher cortical vBMD as well as greater trabecular and cortical thickness, but smaller bone area as measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) compared with White women. Since HR-pQCT data are obtained at peripheral sites, it is unclear whether these differences are relevant to the clinically important lumbar spine and hip. This study assesses racial differences in bone size and vBMD at the spine and hip in Chinese American and White women. METHODS: QCT of the spine and hip was measured to assess racial differences in bone size, structure, and vBMD in pre- (n = 83) and postmenopausal (n = 50) Chinese American and White women. Data were adjusted for weight, height, physical activity, total calcium intake, parathyroid hormone, and 25-hydroxyvitamin D levels. RESULTS: Among premenopausal women, lumbar spine trabecular vBMD was 5.8% greater in Chinese American versus White women (p = 0.01). At the hip, cortical vBMD was 3% greater at the femoral neck (p = 0.05) and 3.6% greater at the total hip (p = 0.01) in premenopausal Chinese American compared with White women. Among postmenopausal women, there was no difference in lumbar spine trabecular vBMD. Cortical vBMD was 4% greater at the total hip (p = 0.02) and tended to be greater at the femoral neck (p = 0.058) in Chinese American versus White women. CONCLUSIONS: Consistent with earlier findings in the peripheral skeleton, cortical vBMD is greater at the hip in Chinese American versus White women.

Treatment failure in osteoporosis.

UNLABELLED: Guidelines concerning the definition of failure of therapies used to reduce the risk of fracture are provided. INTRODUCTION: This study aims to provide guidelines concerning the definition of failure of therapies used to reduce the risk of fracture. METHODS: A working group of the Committee of Scientific Advisors of the International Osteoporosis Foundation was convened to define outcome variables that may assist clinicians in decision making. RESULTS: In the face of limited evidence, failure of treatment may be inferred when two or more incident fractures have occurred during treatment, when serial measurements of bone remodelling markers are not suppressed by anti-resorptive therapy and where bone mineral density continues to decrease. CONCLUSION: The provision of pragmatic criteria to define failure to respond to treatment provides an unmet clinical need and may stimulate research into an important issue.