Long-Term Safety and Efficacy of Recombinant Human Parathyroid Hormone (1-84) in Adults With Chronic Hypoparathyroidism.

Context: Chronic hypoparathyroidism is conventionally treated with oral calcium and active vitamin D to reach and maintain targeted serum calcium and phosphorus levels, but some patients remain inadequately controlled. Objective: To assess long-term safety and efficacy of recombinant human parathyroid hormone (1-84) (rhPTH(1-84)) treatment. Methods: This was an open-label extension study at 12 US centers. Adults (n = 49) with chronic hypoparathyroidism were included. The intervention was rhPTH(1-84) for 6 years. The main outcome measures were safety, biochemical measures, oral supplement doses, bone indices. Results: Thirty-eight patients (77.6%) completed the study. Throughout 72 months, mean albumin-adjusted serum calcium was within 2.00 to 2.25 mmol/L (8.0-9.0 mg/dL). At baseline, 65% of patients with measurements (n = 24/37) were hypercalciuric; of these, 54% (n = 13/24) were normocalciuric at month 72. Mean serum phosphorus declined from 1.6 ± 0.19 mmol/L at baseline (n = 49) to 1.3 ± 0.20 mmol/L at month 72 (n = 36). Mean estimated glomerular filtration rate was stable. rhPTH(1-84)-related adverse events were reported in 51.0% of patients (n = 25/49); all but 1 event were mild/moderate in severity. Mean oral calcium supplementation reduced by 45% ± 113.6% and calcitriol by 74% ± 39.3%. Bone turnover markers declined by month 32 to a plateau above pretreatment values; only aminoterminal propeptide of type 1 collagen remained outside the reference range. Mean bone mineral density z score fell at one-third radius and was stable at other sites. Conclusion: 6 years of rhPTH(1-84) treatment was associated with sustained improvements in biochemical parameters, a reduction in the percentage of patients with hypercalciuria, stable renal function, and decreased supplement requirements. rhPTH(1-84) was well tolerated; no new safety signals were identified.

The PARADIGHM (physicians advancing disease knowledge in hypoparathyroidism) registry for patients with chronic hypoparathyroidism: study protocol and interim baseline patient characteristics.

BACKGROUND: The PARADIGHM registry of adult and pediatric patients with chronic hypoparathyroidism evaluates the long-term safety and effectiveness of treatment with recombinant human parathyroid hormone, rhPTH(1-84), and describes the clinical disease course under conditions of routine clinical practice. In this first report, we detail the registry protocol and describe the baseline characteristics of two adult patient cohorts from an interim database analysis. One cohort after study entry were prescribed rhPTH(1-84), and the other cohort received conventional therapy of calcium and active vitamin D. METHODS: An observational study of patients with chronic hypoparathyroidism in North America and Europe, collecting data for ≥10 years per patient. Main outcome measures were baseline patient demographics, clinical characteristics, medications, and disease outcome variables of symptoms, biochemical parameters, and health assessments. Baseline is the enrollment assessment for all variables except biochemical measurements in patients treated with rhPTH(1-84); those measurements were the most recent value before the first rhPTH(1-84) dose. Exclusion criteria applied to the analysis of specified outcomes included pediatric patients, patients who initiated rhPTH(1-84) prior to enrollment, and those who received rhPTH(1-34). Clinically implausible biochemical outlier data were excluded. RESULTS: As of 30 June 2019, data of 737 patients were analyzed from 64 centers; 587 (80%) were women, mean ± SD age 49.1±16.45 years. At enrollment, symptoms reported for patients later prescribed rhPTH(1-84) (n=60) and those who received conventional therapy (n=571), respectively, included fatigue (51.7%, 40.1%), paresthesia (51.7%, 29.6%), muscle twitching (48.3%, 21.9%), and muscle cramping (41.7%, 33.8%). Mean serum total calcium, serum phosphate, creatinine, and estimated glomerular filtration rate were similar between cohorts. Health-related quality of life (HRQoL) 36-item Short Form Health Survey questionnaire scores for those later prescribed rhPTH(1-84) were generally lower than those for patients in the conventional therapy cohort. CONCLUSIONS: At enrollment, based on symptoms and HRQoL, a greater percentage of patients subsequently prescribed rhPTH(1-84) appeared to have an increased burden of disease than those who received conventional therapy despite having normal biochemistry measurements. PARADIGHM will provide valuable real-world insights on the clinical course of hypoparathyroidism in patients treated with rhPTH(1-84) or conventional therapy in routine clinical practice. TRIAL REGISTRATION: EUPAS16927, NCT01922440.

Association of Loneliness With Falls: A Study of Older US Adults Using the National Social Life, Health, and Aging Project.

Objectives: Falls represent a significant cause of morbidity and mortality in older adults, and are more common among those living alone. We aimed to determine if there is an association between loneliness and falls. Methods: Participants were surveyed in three waves separated by 5 years. We used the three-item UCLA Loneliness Scale to measure loneliness. Results: Data from 2337 respondents, with both loneliness and fall data in at least two consecutive waves, were included. Over three waves, 51% respondents reported a fall and 23% reported ≥ two falls. In multivariate analysis, the odds of having ≥ one fall 5 years later increased by a factor of 1.11 per one point increase on the loneliness scale (OR = 1.11, 95% CI 1.04, 1.19; p < .01). Discussion: Lonely older adults have increased odds of future falls. Strategies for combating loneliness in older adults may help reduce fall-related morbidity and mortality.

Safety and Efficacy of 5 Years of Treatment With Recombinant Human Parathyroid Hormone in Adults With Hypoparathyroidism.

CONTEXT: Conventional hypoparathyroidism treatment with oral calcium and active vitamin D is aimed at correcting hypocalcemia but does not address other physiologic defects caused by PTH deficiency. OBJECTIVE: To evaluate long-term safety and tolerability of recombinant human PTH (1-84) [rhPTH(1-84)]. DESIGN: Open-label extension study; 5-year interim analysis. SETTING: 12 US centers. PATIENTS: Adults (N = 49) with chronic hypoparathyroidism. INTERVENTION(S): rhPTH(1-84) 25 or 50 µg/d initially, with 25-µg adjustments permitted to a 100 µg/d maximum. MAIN OUTCOME MEASURE(S): Safety parameters; composite efficacy outcome was the proportion of patients with ≥50% reduction in oral calcium (or ≤500 mg/d) and calcitriol (or ≤0.25 µg/d) doses, and albumin-corrected serum calcium normalized or maintained compared with baseline, not exceeding upper limit of normal. RESULTS: Forty patients completed 60 months of treatment. Mean albumin-corrected serum calcium levels remained between 8.2 and 8.7 mg/dL. Between baseline and month 60, levels ± SD of urinary calcium, serum phosphorus, and calcium-phosphorus product decreased by 101.2 ± 236.24 mg/24 hours, 1.0 ± 0.78 mg/dL, and 8.5 ± 8.29 mg2/dL2, respectively. Serum creatinine level and estimated glomerular filtration rate were unchanged. Treatment-emergent adverse events (AEs) were reported in 48 patients (98.0%; hypocalcemia, 36.7%; muscle spasms, 32.7%; paresthesia, 30.6%; sinusitis, 30.6%; nausea, 30.6%) and serious AEs in 13 (26.5%). At month 60, 28 patients (70.0%) achieved the composite efficacy outcome. Bone turnover markers increased, peaked at ∼12 months, and then declined to values that remained above baseline. CONCLUSION: Treatment with rhPTH(1-84) for 5 years demonstrated a safety profile consistent with previous studies and improved key biochemical parameters.

Quality of Life in Hypoparathyroidism.

Patients with hypoparathyroidism have a multitude of physical, emotional, and cognitive complaints consistent with reduced quality of life (QOL). Impaired QOL in patients treated with conventional therapy with calcium and active vitamin D has been documented in epidemiologic (registry) studies, case-controlled studies, and surveys, and at baseline in clinical trials of parathyroid hormone (PTH). Treatment with PTH has been shown to improve QOL in some but not all studies.

Recombinant Human Parathyroid Hormone Effect on Health-Related Quality of Life in Adults With Chronic Hypoparathyroidism.

Context: Reduced health-related quality of life (HRQoL) is common in patients with hypoparathyroidism treated conventionally with calcium and active vitamin D supplements. Objective: To examine the effects of recombinant human parathyroid hormone [rhPTH(1-84)] on HRQoL as measured by the 36-Item Short-Form Health Survey (SF-36) during a multinational, randomized, placebo-controlled study. Patients: Adults (N = 122) with chronic hypoparathyroidism. Intervention(s): After an optimization period when calcium and/or active vitamin D supplements were adjusted to reach target serum calcium levels (8.0 to 9.0 mg/dL; 2.0 to 2.2 mmol/L), patients were randomly assigned to receive placebo (n = 39) or rhPTH(1-84) (n = 83) (starting dose, 50 µg/d, could be titrated up to 100 µg/d); supplement doses were adjusted to maintain target serum calcium levels. Main Outcome Measure(s): Change from baseline (postoptimization, at randomization) to week 24 in HRQoL as assessed by the SF-36. Results: Overall, the between-group differences were not statistically significant. However, in the rhPTH(1-84) group, there were significant improvements in the physical component summary score (P = 0.004), and in body pain (P < 0.05), general health (P < 0.05), and vitality (P < 0.001) domains as compared with baseline values. In the placebo group, there were no significant changes for any domains. The magnitude of change between 0 and 24 weeks in SF-36 scores was negatively correlated with baseline scores, such that patients with lower HRQoL at baseline were more likely to experience improvement in response to treatment. Conclusion: Treatment with rhPTH(1-84) may improve HRQoL in adults with hypoparathyroidism.

Hypoparathyroidism.

This corrects the article DOI: 10.1038/nrdp.2017.55.

Hypoparathyroidism.

Hypoparathyroidism is a disease characterized by inadequately low circulating concentrations of parathyroid hormone (PTH) resulting in low calcium levels and increased phosphate levels in the blood. Symptoms of the disease result from increased neuromuscular irritability caused by hypocalcaemia and include tingling, muscle cramps and seizures. The most common cause of the disease is inadvertent removal of, or injury to, the parathyroid glands during neck surgery, followed by genetic, idiopathic and autoimmune aetiologies. Conventional treatment includes activated vitamin D and/or calcium supplements, but this treatment does not fully replace the functions of PTH and can lead to short-term problems (such as hypocalcaemia, hypercalcaemia and increased urinary calcium excretion) and long-term complications (which include nephrocalcinosis, kidney stones and brain calcifications). PTH replacement has emerged as a new treatment option. Clinical trials using human PTH(1-34) and PTH(1-84) showed that this treatment was safe and effective in studies lasting up to 6 years. Recombinant human PTH(1-84) has been approved in the United States and Europe for the management of hypoparathyroidism; however, its effect on long-term complications is still being evaluated. Clinical practice guidelines, which describe the consensus of experts in the field, have been published and recognize the need for more research to optimize care. In this Primer, we summarize current knowledge of the prevalence, pathophysiology, clinical presentation and management of hypoparathyroidism.

Vertebral fracture assessment: Enhancing the diagnosis, prevention, and treatment of osteoporosis.

Osteoporosis is a highly prevalent condition, resulting in significant morbidity and mortality. Nevertheless, it is frequently untreated. Vertebral fractures often do not come to clinical attention, yet, their presence is diagnostic of osteoporosis, helps to predict the risk of future fractures, and may alter the choice of pharmacotherapy. The addition of lateral spine imaging technology to the densitometer, for vertebral fracture assessment (VFA), represented a major advancement in the ability to diagnose vertebral fractures and osteoporosis. VFA is an under-utilized and highly effective imaging tool to enhance osteoporosis detection and fracture prevention. Several factors make VFA an ideal technology to evaluate for vertebral fractures. These include: the ability to obtain the image at the same time the bone density is done, with significantly lower radiation exposure than with spine radiography, and at a lower cost. This review provides an overview of the clinical significance of identifying vertebral fractures, the origins of the VFA, its clinical indications, a review of the methods used to diagnose vertebral fracture, an overview on interpreting the VFA, and the strengths and limitations of this technique.

Ethnic Differences in Trabecular Bone Score.

Trabecular bone score (TBS), a noninvasive textural analysis of the lumbar spine dual-energy X-ray absorptiometry (DXA) image, has been shown to predict fractures in Caucasian (CA) populations but has not been thoroughly studied in African-American (AA) populations. The aim of this study was to compare the TBS in AAs and CAs and to assess whether TBS can be used to refine fracture risk stratification in AA patients. Eight hundred twenty-five women (390 AAs, 435 CAs) referred for bone mineral density (BMD) as part of their clinical care had measurements of the TBS, the BMD of the lumbar spine, total hip, and femoral neck, and vertebral fracture assessment for detection of vertebral fractures. Unadjusted TBS was higher in CA than AA (1.275 vs 1.238, p < 0.001), but this was no longer true after adjusting for age and tissue thickness. Interestingly, differences in TBS were still highly significant in those under 60 yr of age even with adjustment for tissue thickness, but not in older subjects. There were 74 CAs and 56 AAs with vertebral fractures on vertebral fracture assessment (17% vs 14%, p = 0.30). In CA, the odds ratio (OR) for prevalent vertebral fracture per SD decrease in TBS was 2.33 (p < 0.001), whereas in AA, the OR was 1.43 (p = 0.02). In a multivariate logistic regression model that also included age, BMD T-score, and glucocorticoid use, the association between TBS and prevalent vertebral fractures was still highly significant in CAs (OR 1.54, p = 0.008) but not in AAs (OR 1.23, p = 0.21). Our results suggest that TBS may be less discriminatory in regard to fracture risk in AAs than in CAs and that TBS may need to be used differently in these 2 ethnic groups.

Effects of parathyroid hormone rhPTH(1-84) on phosphate homeostasis and vitamin D metabolism in hypoparathyroidism: REPLACE phase 3 study.

In hypoparathyroidism, inappropriately low levels of parathyroid hormone lead to unbalanced mineral homeostasis. The objective of this study was to determine the effect of recombinant human parathyroid hormone, rhPTH(1-84), on phosphate and vitamin D metabolite levels in patients with hypoparathyroidism. Following pretreatment optimization of calcium and vitamin D doses, 124 patients in a phase III, 24-week, randomized, double-blind, placebo-controlled study of adults with hypoparathyroidism received subcutaneous injections of placebo or rhPTH(1-84) (50 µg/day, titrated to 75 and then 100 µg/day, to permit reductions in oral calcium and active vitamin D doses while maintaining serum calcium within 2.0-2.2 mmol/L). Predefined endpoints related to phosphate homeostasis and vitamin D metabolism were analyzed. Serum phosphate levels decreased rapidly from the upper normal range and remained lower with rhPTH(1-84) (P < 0.001 vs. placebo). At week 24, serum calcium-phosphate product was lower with rhPTH(1-84) vs. placebo (P < 0.001). rhPTH(1-84) treatment resulted in significant reductions in oral calcium dose compared with placebo (P < 0.001) while maintaining serum calcium. After pretreatment optimization, baseline serum 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) levels were within the normal range in both groups. After 24 weeks, 1,25(OH)2D levels were unchanged in both treatment groups, despite significantly greater reductions in active vitamin D dose in the rhPTH(1-84) group. In hypoparathyroidism, rhPTH(1-84) reduces serum phosphate levels, improves calcium-phosphate product, and maintains 1,25(OH)2D and serum calcium in the normal range while allowing significant reductions in active vitamin D and oral calcium doses.

Prediction models of prevalent radiographic vertebral fractures among older women.

It is unknown how well prediction models incorporating multiple risk factors identify women with radiographic prevalent vertebral fracture (PVFx) compared with simpler models and what their value might be in clinical practice to select older women for lateral spine imaging. We compared 4 regression models for predicting PVFx in women aged 68 y and older enrolled in the Study of Osteoporotic Fractures with a femoral neck T-score ≤ -1.0, using area under receiving operator characteristic curves (AUROC) and a net reclassification index. The AUROC for a model with age, femoral neck bone mineral density, historical height loss (HHL), prior nonspine fracture, body mass index, back pain, and grip strength was only minimally better than that of a more parsimonious model with age, femoral neck bone mineral density, and historical height loss (AUROC 0.689 vs 0.679, p values for difference in 5 bootstrapped samples <0.001-0.35). The prevalence of PVFx among this older population of Caucasian women remained more than 20% even when women with low probability of PVFx, as estimated by the prediction models, were included in the screened population. These results suggest that lateral spine imaging is appropriate to consider for all Caucasian women aged 70 y and older with low bone mass to identify those with PVFx.

Simplified criteria for selecting patients for vertebral fracture assessment.

The 2013 Position Development Conference of the International Society for Clinical Densitometry (ISCD) has adopted simplified indications for vertebral fracture assessment (VFA) based on an analysis of the Study of Osteoporotic Fractures (SOF). This showed that a simpler regression model, which included only age, bone mineral density (BMD), and height loss, was able to differentiate women with vertebral fractures from those without vertebral fractures almost as well as more complex models. We aimed to verify these findings in 1228 women referred for BMD testing and determine if the 2013 ISCD indications for VFA would perform as well the 2007 indications. The simple and complex SOF-based models were similar in terms of sensitivity (88.4% vs 89.4%), specificity (44.4% vs 45.5%), positive (25.9% vs 26.5%) and negative (94.5% vs 95.1%) predictive values, and area under the receiver operating characteristics curve (AUROC) (0.664 vs 0.674). The 2013 and 2007 ISCD VFA indications did not differ significantly in terms of sensitivity (88.2% vs 91.3%), specificity (41.3% vs 37.5%), positive (25.3% vs 22.9%) and negative (93.9% vs 95.5%) predictive values, and AUROC (0.648 vs 0.644). Our study provides support for the use of the simplified 2013 ISCD VFA indications as a practical approach to VFA testing.

Prediction models of prevalent radiographic vertebral fractures among older men.

No studies have compared how well different prediction models discriminate older men who have a radiographic prevalent vertebral fracture (PVFx) from those who do not. We used area under receiver operating characteristic curves and a net reclassification index to compare how well regression-derived prediction models and nonregression prediction tools identify PVFx among men age ≥65 yr with femoral neck T-score of -1.0 or less enrolled in the Osteoporotic Fractures in Men Study. The area under receiver operating characteristic for a model with age, bone mineral density, and historical height loss (HHL) was 0.682 compared with 0.692 for a complex model with age, bone mineral density, HHL, prior non-spine fracture, body mass index, back pain, grip strength, smoking, and glucocorticoid use (p values for difference in 5 bootstrapped samples 0.14-0.92). This complex model, using a cutpoint prevalence of 5%, correctly reclassified only a net 5.7% (p = 0.13) of men as having or not having a PVFx compared with a simple criteria list (age ≥ 80 yr, HHL >4 cm, or glucocorticoid use). In conclusion, simple criteria identify older men with PVFx and regression-based models. Future research to identify additional risk factors that more accurately identify older men with PVFx is needed.

The Official Positions of the International Society for Clinical Densitometry: vertebral fracture assessment.

Vertebral fracture assessment (VFA) is a low-cost method of accurately identifying individuals who have clinically unrecognized or undocumented vertebral fractures at the time of bone density test. Because prevalent vertebral fractures predict subsequent fractures independent of bone mineral density and other clinical risk factors, their recognition is an important part of strategies to identify those who are at high risk of fracture, so that prevention therapies for those individuals can be implemented. The 2007 Position Development Conference developed detailed guidelines regarding the indications for acquisition of, and interpretation and reporting of densitometric VFA tests. The purpose of the 2013 VFA Task Force was to simplify the indications for VFA yet keep them evidence based. The Task Force reviewed the literature published since the 2007 Position Development Conference and developed prediction models based on 2 large cohort studies (the Study of Osteoporotic Fractures and the Osteoporotic Fractures in Men Study) and the densitometry database of the University of Chicago. Based on these prediction models, indications for VFA were reduced to a simplified set of criteria based on age, historical height loss, use of systemic glucocorticoid therapy, and self-reported but undocumented prior vertebral fracture.

Indications of DXA in women younger than 65 yr and men younger than 70 yr: the 2013 Official Positions.

Dual-energy X-ray absorptiometry (DXA) is the method of choice to assess fracture risk for women 65 yr and older and men 70 yr and older. The 2007 International Society for Clinical Densitometry Official Positions had developed guidelines for assessing bone density in younger women during and after the menopausal transition and in men 50-69 yr and the 2008 National Osteoporosis Foundation (NOF) guidelines recommended testing in postmenopausal women younger than 65 yr and men 50-69 yr only in the presence of clinical risk factors. The purpose of the 2013 DXA Task Force was to reassess the NOF guidelines for ordering DXA in postmenopausal women younger than 65 yr and men 50-69 yr. The Task Force reviewed the literature published since the 2007 Position Development Conference and 2008 NOF, reviewing clinical decision rules such as the Osteoporosis Screening Tool and FRAX and sought to keep recommendations simple to remember and implement. Based on this assessment, the NOF guidelines were endorsed; DXA was recommended in those postmenopausal women younger than 65 yr and men 50-69 yr only in the presence of clinical risk factors for low bone mass, such as low body weight, prior fracture, high-risk medication use, or a disease or condition associated with bone loss.

Reproducibility and sources of variability in radiographic texture analysis of densitometric calcaneal images.

Radiographic texture analysis (RTA) is a computerized analysis of the spatial pattern of radiographic images used as a way of evaluating bone structure. We have shown that RTA performed on high-resolution heel images obtained using a portable densitometer differentiates subjects with and without osteoporotic fractures. In the present study, short-term precision of RTA was examined on densitometric heel images obtained from 33 subjects scanned 8 times each, with 3 observers placing a region of interest (ROI) 3 times on each image. The long-term precision was examined on images obtained from 10 subjects 3 times on each of 3 days separated by 1 week, with 2 observers placing an ROI on each image. The RTA features examined included the root mean square (RMS) variation, a measure of the contrast between the light and dark areas of the image, the first moment of the power spectrum, a measure of the spatial frequency of the trabecular pattern, and Minkowski fractal (MINK), a measure of roughness/smoothness of the trabecular pattern. The precision of the RTA features expressed as coefficient of variation ranged between the lowest of 0.5-0.7% for MINK and the highest of 14-16% for RMS. The short- and long-term precision was similar, and was not significantly influenced by repositioning and rescanning, or by ROI placement by the same or different observers. Significant sources of variability of RTA were the between-subject differences and differences between regions of the heel, but not differences due to repositioning, rescanning in the same position, or ROI placement by the same or different observers. We conclude that technical aspects of image acquisition and processing are adequate to allow further development of RTA of the densitometric images for clinical application as a method for noninvasive assessment of bone structure.

Risk factors for prevalent vertebral fractures in black and white female densitometry patients.

This cross-sectional study compared risk factors for prevalent vertebral fractures (diagnosed using densitometric spine image Vertebral Fracture Assessment [VFA]) in 176 black and 345 white women recruited during their clinical bone mineral density (BMD) testing at the University of Chicago Hospitals. We used logistic regression to assess the association of prevalent vertebral fractures and risk factors (age, height loss, history of nonvertebral fractures, BMD, and use of corticosteroids). The prevalence of vertebral fractures was 21% for both races. All risk factors of interest were significantly associated with vertebral fractures in white women. Among black women, only age and corticosteroid use were found to be significant predictors of presence of vertebral fracture(s). In women without history of corticosteroid use, the probability of having vertebral fracture(s) given age was lower (p=0.02) in black subjects. In 77 patients with a history of corticosteroid use, the probability of having vertebral fracture(s) was higher in black than in white women after adjustment for age (p=0.045), BMD (p=0.045), or cumulative corticosteroid dose (p=0.08). Fewer black women were prescribed pharmacologic therapy for osteoporosis, regardless of their BMD level and corticosteroid use. We conclude that use of corticosteroids may be associated with relatively greater vertebral fracture risk in blacks than in whites.

Comparison of T-scores from different skeletal sites in differentiating postmenopausal women with and without prevalent vertebral fractures.

It is not clear how bone mineral density (BMD) measurements from several regions of lumbar spine and proximal femur should be utilized in assessing fracture risk. We examined how well the newest ISCD recommendations differentiate subjects with and without prevalent vertebral fractures in 187 postmenopausal women presenting for routine bone densitometry. The association between T-scores from proximal femur and lumbar spine sites and the probability of having a vertebral fracture was modeled via logistic regression with adjustment for age. The lowest T-score of any hip or spine sites (the current ISCD recommendation) and the proximal femur measurements, particularly the femoral neck and total hip, displayed the strongest association with the probability of vertebral fractures.Subjects with a T-score < -2.5 at multiple hip sites had a higher probability of having a vertebral fracture. The sensitivity and specificity associated with particular T-score cutoff values varied greatly depending on the site of measurement.Consequently, T-score values from different sites that had comparable sensitivity/specificity for detecting the presence of vertebral fractures differed by as much as 1.5 T-score units. This finding implies that a single cutoff value, such as -2.5, might not be clinically acceptable when applied to T-scores from different sites.

The novel gene encoding a putative transmembrane protein is mutated in gnathodiaphyseal dysplasia (GDD).

Gnathodiaphyseal dysplasia (GDD) is a rare skeletal syndrome characterized by bone fragility, sclerosis of tubular bones, and cemento-osseous lesions of the jawbone. By linkage analysis of a large Japanese family with GDD, we previously mapped the GDD locus to chromosome 11p14.3-15.1. In the critical region determined by recombination mapping, we identified a novel gene (GDD1) that encodes a 913-amino-acid protein containing eight putative transmembrane-spanning domains. Two missense mutations (C356R and C356G) of GDD1 were identified in the two families with GDD (the original Japanese family and a new African American family), and both missense mutations occur at the cysteine residue at amino acid 356, which is evolutionarily conserved among human, mouse, zebrafish, fruit fly, and mosquito. Cellular localization to the endoplasmic reticulum suggests a role for GDD1 in the regulation of intracellular calcium homeostasis.