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

A Full Pharmacological Analysis of the Three Turkey β-Adrenoceptors and Comparison with the Human β-Adrenoceptors

There are three turkey β-adrenoceptors: the original turkey β-adrenoceptor from erythrocytes (tβtrunc, for which the X-ray crystal structure has recently been determined), tβ3C and tβ4C-receptors. This study examined the similarities and differences between these avian receptors and mammalian receptors with regards to binding characteristics and functional high and low affinity agonist conformations.Stable cell lines were constructed with each of the turkey β-adrenoceptors and 3H-CGP12177 whole cell binding, CRE-SPAP production and (3)H-cAMP accumulation assays performed. It was confirmed that the three turkey β-adrenoceptors are distinct from each other in terms of amino acid sequence and binding characteristics. The greatest similarity of any of the turkey β-adrenoceptors to human β-adrenoceptors is between the turkey β3C-receptor and the human β2-adrenoceptor. There are pharmacologically distinct differences between the binding of ligands for the tβtrunc and tβ4C and the human β-adrenoceptors (e.g. with CGP20712A and ICI118551). The tβtrunc and tβ4C-adrenoceptors appear to exist in at least two different agonist conformations in a similar manner to that seen at both the human and rat β1-adrenoceptor and human β3-adrenoceptors. The tβ3C-receptor, similar to the human β2-adrenoceptor, does not, at least so far, appear to exist in more than one agonist conformation.There are several similarities, but also several important differences, between the recently crystallised turkey β-adrenoceptor and the human β-adrenoceptors. These findings are important for those the field of drug discovery using the recently structural information from crystallised receptors to aid drug design. Furthermore, comparison of the amino-acid sequence for the turkey and human adrenoceptors may therefore shed more light on the residues involved in the existence of the secondary β-adrenoceptor conformation

Epidemiology of hip fracture in Belarus: development of a country-specific FRAX model and its comparison to neighboring country models

Summary Fracture probabilities resulting from the newly generated FRAX model for Belarus based on regional estimates of the hip fracture incidence were compared with FRAX models of neighboring countries. Differences between the country-specific FRAX patterns and the rank orders of fracture probabilities were modest. Objective This paper describes the epidemiology of hip fractures in Belarus that was used to develop the country-specific fracture prediction FRAX® tool and illustrates its features compared to models for the neighboring countries of Poland, Russia, and Lithuania. Methods We carried out a population-based study in a region of Belarus (the city of Mozyr) representing approximately 1.2% of the country’s population. We aimed to identify all hip fractures in 2011–2012 from hospital registers and primary care sources. Age- and sex-specific incidence and national mortality rates were incorporated into a FRAX model for Belarus. Fracture probabilities were compared with those derived from FRAX models in neighboring countries. Results The estimated number of hip fractures nationwide in persons over the age of 50 years for 2015 was 8250 in 2015 and is predicted to increase to 12,918 in 2050. The annual incidence of fragility hip fractures in individuals aged 50 years or more was 24.6/10,000 for women and 14.6/10,000 for men, standardized to the world population. The comparison with FRAX models in neighboring countries showed that hip fracture probabilities in men and women in Belarus were similar to those in Poland, Russia, and Lithuania. The difference in incidence rates between the surveys including or excluding data from primary care suggested that 29.1% of patients sustaining a hip fracture were not hospitalized and, therefore, did not receive specialized medical care. Conclusion A substantial proportion of hip fractures in Belarus does not come to hospital attention. The FRAX model should enhance accuracy of determining fracture probability among the Belarus population and help guide decisions about treatment

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

The Value of Intraoperative Parathyroid Hormone Monitoring in Localized Primary Hyperparathyroidism: A Cost Analysis

Minimally invasive parathyroidectomy (MIP) is the preferred approach to primary hyperparathyroidism (PHPT) when a single adenoma can be localized preoperatively. The added value of intraoperative parathyroid hormone (IOPTH) monitoring remains debated because its ability to prevent failed parathyroidectomy due to unrecognized multiple gland disease (MGD) must be balanced against assay-related costs. We used a decision tree and cost analysis model to examine IOPTH monitoring in localized PHPT. Literature review identified 17 studies involving 4,280 unique patients, permitting estimation of base case costs and probabilities. Sensitivity analyses were performed to evaluate the uncertainty of the assumptions associated with IOPTH monitoring and surgical outcomes. IOPTH cost, MGD rate, and reoperation cost were varied to evaluate potential cost savings from IOPTH. The base case assumption was that in well-localized PHPT, IOPTH monitoring would increase the success rate of MIP from 96.3 to 98.8%. The cost of IOPTH varied with operating room time used. IOPTH reduced overall treatment costs only when total assay-related costs fell below $110 per case. Inaccurate localization and high reoperation cost both independently increased the value of IOPTH monitoring. The IOPTH strategy was cost saving when the rate of unrecognized MGD exceeded 6$12,000 (compared with initial MIP cost of $3733). Setting the positive predictive value of IOPTH at 100% and reducing the false-negative rate to 0% did not substantially alter these findings. Institution-specific factors influence the value of IOPTH. In this model, IOPTH increased the cure rate marginally while incurring approximately 4% additional cost

Primary hyperparathyroidism diagnosed after surgical ablation of a costal mass mistaken for giant-cell bone tumor: a case report

<p>Abstract</p> <p>Introduction</p> <p>Primary hyperparathyroidism is a common endocrine disorder characterized by elevated parathyroid hormone levels, which cause continuous osteoclastic bone resorption. Giant cell tumor of bone is an expansile osteolytic tumor that contains numerous osteoclast-like giant cells. There are many similarities in the radiological and histological features of giant cell tumor of bone and brown tumor. This is a rare benign focal osteolytic process most commonly caused by hyperparathyroidism.</p> <p>Case presentation</p> <p>We report the unusual case of a 40-year-old Caucasian woman in which primary hyperparathyroidism was diagnosed after surgical ablation of a costal mass. The mass was suspected of being neoplastic and histopathology was compatible with a giant cell tumor of bone. On the basis of the biochemical results (including serum calcium, phosphorous and intact parathyroid hormone levels) primary hyperparathyroidism was suspected and a brown tumor secondary to refractory hyperparathyroidism was diagnosed.</p> <p>Conclusions</p> <p>Since giant cell tumor is a bone neoplasm that has major implications for the patient, the standard laboratory tests in patients with bone lesions are important for a correct diagnosis.</p

Epidemiology of fractures in Armenia: development of a country-specific FRAX model and comparison to its surrogate

Summary: Fracture probabilities derived from the surrogate FRAX model for Armenia were compared to those from the model based on regional estimates of the incidence of hip fracture. Disparities between the surrogate and authentic FRAX models indicate the importance of developing country-specific FRAX models. Despite large differences between models, differences in the rank order of fracture probabilities were minimal. Objective: Armenia has relied on a surrogate FRAX model based on the fracture epidemiology of Romania. This paper describes the epidemiology of fragility fractures in Armenia used to create an Armenia-specific FRAX model with an aim of comparing this new model with the surrogate model. Methods: We carried out a population-based study in two regions of Armenia (Ararat and Vayots Dzor representing approximately 11% of the country’s population). We aimed to identify all low-energy fractures: retrospectively from hospital registers in 2011–2012 and prospectively in 2013 with the inclusion of primary care sources. Results: The differences in incidence between the surveys with and without data from primary care suggested that 44% of patients sustaining a hip fracture did not receive specialized medical care. A similar proportion of forearm and humeral fractures did not come to hospital attention (48 and 49%, respectively). Only 57.7% of patients sustaining a hip fracture were hospitalized. In 2013, hip fracture incidence at the age of 50 years or more was 201/100,000 for women and 136/100,000 for men, and age- and sex-specific rates were incorporated into the new “authentic” FRAX model for Armenia. Compared to the surrogate model, the authentic model gave lower 10-year fracture probabilities in men and women aged less than 70 years but substantially higher above this age. Notwithstanding, there were very close correlations in fracture probabilities between the surrogate and authentic models ( >  0.99) so that the revisions had little impact on the rank order of risk. Conclusion: A substantial proportion of major osteoporotic fractures in Armenia do not come to hospital attention. The disparities between surrogate and authentic FRAX models indicate the importance of developing country-specific FRAX models. Despite large differences between models, differences in the rank order of fracture probabilities were minimal

Induction of osteogenic markers in differentially treated cultures of embryonic stem cells

<p>Abstract</p> <p>Background</p> <p>Facial trauma or tumor surgery in the head and face area often lead to massive destruction of the facial skeleton. Cell-based bone reconstruction therapies promise to offer new therapeutic opportunities for the repair of bone damaged by disease or injury. Currently, embryonic stem cells (ESCs) are discussed to be a potential cell source for bone tissue engineering. The purpose of this study was to investigate various supplements in culture media with respect to the induction of osteogenic differentiation.</p> <p>Methods</p> <p>Murine ESCs were cultured in the presence of LIF (leukemia inhibitory factor), DAG (dexamethasone, ascorbic acid and β-glycerophosphate) or bone morphogenetic protein-2 (BMP-2). Microscopical analyses were performed using von Kossa staining, and expression of osteogenic marker genes was determined by real time PCR.</p> <p>Results</p> <p>ESCs cultured with DAG showed by far the largest deposition of calcium phosphate-containing minerals. Starting at day 9 of culture, a strong increase in collagen I mRNA expression was detected in the DAG-treated cells. In BMP-2-treated ESCs the collagen I mRNA induction was less increased. Expression of osteocalcin, a highly specific marker for osteogentic differentiation, showed a double-peaked curve in DAG-treated cells. ESCs cultured in the presence of DAG showed a strong increase in osteocalcin mRNA at day 9 followed by a second peak starting at day 17.</p> <p>Conclusion</p> <p>Supplementation of ESC cell cultures with DAG is effective in inducing osteogenic differentiation and appears to be more potent than stimulation with BMP-2 alone. Thus, DAG treatment can be recommended for generating ESC populations with osteogenic differentiation that are intended for use in bone tissue engineering.</p