The Effects of Signaling-Selective Parathyroid Hormone Analogs on Osteoporotic Osteocyte Apoptosis

Objectives: To compare the effects of signaling-selective parathyroid hormone analogs [G1, R19]hPTH(1–28) [GR(1–28)] and [G1, R19]hPTH(1–34) [GR(1–34)] on osteoporotic osteocyte apoptosis, and to explore the mechanism of the anti-osteoporotic difference. Methods: The osteoporosis model was established in eighty adult female C57BL/6 mice aged 12 weeks. The mice were subcutaneously administered with GR(1–28) and GR(1–34) 5 days per week for 8 weeks. Bilateral femur samples were collected at 4 and 8 weeks, and micro-computed tomography (CT), H&E staining and immunohistochemical staining analyses were performed. Results: From micro-CT analysis, GR(1–34) increased proximal femoral bone mineral density (BMD) and relative bone volume (BV/TV), which was higher than GR(1–28) did. In addition, more trabecular number (Tb.N), thinner trabecular thickness (Tb.Th) and wider trabecular separation (Tb.Sp) were measured at week 8 using GR(1–34). From H&E and immunohistochemical staining, a stronger apoptosis inhibition was induced by GR(1–34) with more Bcl-2 secretion but less Bax expression, as opposed to GR(1–28). Conclusions: GR(1–34) shows better anti-osteoporotic effects than GR(1–28), which appears to be attributed to the activation of the PLC-independent PKC signaling pathway triggered by the former, inhibiting osteocyte apoptosis through up-regulation of Bcl-2 and down-regulation of Bax to increase bone mass and improving trabecular bone microstructure to enhance bone quality by reducing trabecular number, increasing trabecular thickness and trabecular space.

Parathyroidectomy May Cause Remission of Uraemic Tumoral Calcinosis in Haemodialysis Patients

Few cases of uraemic tumoral calcinosis (UTC) have been reported. This study aimed to investigate the clinical efficacy of parathyroidectomy for UTC. Historical clinical data of patients with end-stage renal disease and UTC who underwent parathyroidectomy were analysed. Absorption of metastatic calcification was compared before and after operation. Changes in intact parathyroid hormone, serum calcium, phosphorus, and alkaline phosphatase levels were analysed before parathyroidectomy and at 1 week and 3, 6, and 12 months after parathyroidectomy. Eight patients met the enrolment criteria (men, 6; mean age, 38.6 SD 10.9 years). Uraemic tumoral calcinosis, which developed 2–8 years after dialysis began, was caused by secondary hyperparathyroidism. Massive calcium deposition was found in the shoulder (n = 6), hip (n = 3), and elbow (n = 2). Four patients had > 2 joints affected, and a single joint was involved for four patients. Seven patients had rapid remission (< 6 months) of the masses after parathyroidectomy. In one patient, the mass remained unabsorbed until 6 months postoperatively. Hypocalcaemia occurred in all patients where parathyroidectomy was successful, and calcium supplementation was required 1 year postoperatively. Serum intact parathyroid hormone levels on day 7 and at 3 and 6 months postoperatively decreased significantly from baseline and remained low 1 year postoperatively (22.015 SD33.134 pg/mL). Postoperative phosphorus levels were significantly lower than preoperative levels (p < 0.05), but no significant difference was found in alkaline phosphatase levels (p > 0.05). Parathyroidectomy has promising efficacy for UTC treatment and regulation of serum intact parathyroid hormone and phosphorus. Hypocalcaemia is a common complication after parathyroidectomy. Current Controlled Trials ChiCTR2000041311, date of registration: Dec. 23, 2020.

Density-Dependent Differentiation of Tonsil-Derived Mesenchymal Stem Cells into Parathyroid-Hormone-Releasing Cells

Mesenchymal stem cells (MSCs) can differentiate into endoderm lineages, especially parathyroid-hormone (PTH)-releasing cells. We have previously reported that tonsil-derived MSC (T-MSC) can differentiate into PTH-releasing cells (T-MSC-PTHCs), which restored the parathyroid functions in parathyroidectomy (PTX) rats. In this study, we demonstrate quality optimization by standardizing the differentiation rate for a better clinical application of T-MSC-PTHCs to overcome donor-dependent variation of T-MSCs. Quantitation results of PTH mRNA copy number in the differentiated cells and the PTH concentration in the conditioned medium confirmed that the differentiation efficiency largely varied depending on the cells from each donor. In addition, the differentiation rate of the cells from all the donors greatly improved when differentiation was started at a high cell density (100% confluence). The large-scale expression profiling of T-MSC-PTHCs by RNA sequencing indicated that those genes involved in exiting the differentiation and the cell cycle were the major pathways for the differentiation of T-MSC-PTHCs. Furthermore, the implantation of the T-MSC-PTHCs, which were differentiated at a high cell density embedded in hyaluronic acid, resulted in a higher serum PTH in the PTX model. This standardized efficiency of differentiation into PTHC was achieved by initiating differentiation at a high cell density. Our findings provide a potential solution to overcome the limitations due to donor-dependent variation by establishing a standardized differentiation protocol for the clinical application of T-MSC therapy in treating hypoparathyroidism.

Approach to hypercalcemia

Hypercalcemia is a presentation commonly encountered in the clinical setting. Due to its vast differential diagnosis, a systematic approach is necessary when approaching patients with hypercalcemia. This article presents a simple, yet thorough approach to help clinicians determine the etiology of their patient's hypercalcemia. The main components of history taking, physical examination, and laboratory investigations for patients with hypercalcemia are highlighted. Emphasis is put on the importance of determining whether the hypercalcemia is associated with elevated or inappropriately normal parathyroid hormone (PTH) or not. The main etiologies of PTH-dependent hypercalcemia and PTH-independent hypercalcemia are explored. Primary hyperparathyroidism and hypercalcemia secondary to malignancy are highlighted as together, they make up 90% of hypercalcemia cases. A presentation of the management principles of hypercalcemia is also provided.

Prevalence of vitamin D deficiency and association with parathyroid hormone

Objectives We evaluated the prevalence of 25-hydroxyvitamin D (25-(OH)D) deficiency in our setting according to season, sex, and age. We also studied the association with parathyroid hormone (PTH) levels. Methods The study population comprised all patients with requests for assessment of 25-(OH)D between January 1 and December 31, 2018, as registered in the database of the laboratory information system. Major exclusion criteria were pediatric samples (<18 years) and factors affecting 25-(OH)D and/or PTH levels (i.e., kidney injury, liver disease, PTH disorders). Results Among 33,601 patients (24,028 women, 9,573 men), the prevalence of 25-(OH)D deficiency was 48%. Prevalence was greater in males than in females (53% vs. 46%). By age group, deficiency was more prevalent in quartile 1 (Q1, 74–87 years) and less prevalent in quartile 2 (Q2, 60–73 years). By season, deficiency was greater in spring (nonsignificant differences with respect to winter) and lower in summer. The association between 25-(OH)D and PTH was assessed in 9,368 persons. Linear regression analysis showed a weak association (coefficient – 0.303). Multiple logistic regression analysis revealed a significant association between 25-(OH)D deficiency and increased PTH (Odds ratio (OR), 1.63). Other risk factors for increased PTH include female sex (OR, 1.27), season (winter, OR 1.63, spring OR 1.16), and age (quartile 1, OR, 3). Conclusions The prevalence of 25-(OH)D deficiency differed according to sex, age, and season of the year. Furthermore, elevation of PTH is mainly influenced by low 25-(OH)D, female sex, season, and age.

Familial hypocalciuric hypercalcemia as a differential diagnosis of primary hyperparathyroidism with negative images

Introduction. Familial hypocalciuric hypercalcemia is a rare inherited calcium metabolism disorder in which an alteration of the parathyroid hormone secretion set-point causes hypercalcemia with relative hypocalciuria. Some data suggest that its prevalence is around 74.1 per 100,000 inhabitants. Often, patients are asymptomatic. However, they can develop mild symptoms and an overactive parathyroid adenoma, its main differential diagnosis. The objective was to describe a patient’s case and highlight the importance of clinical suspicion and diagnosis to avoid unnecessary surgical neck explorations for parathyroid adenomas. Case report. This is the case of a 40-year-old man with a biochemical profile compatible with primary hyperparathyroidism with anatomical and functional images negative for adenoma and a calcium/creatinine clearance ratio below 0.001, considering familial hypocalciuric hypercalcemia. Genetic studies evidence a mutation in the calcium sensor receptor gene and confirm the diagnosis. Discussion. Familial hypocalciuric hypercalcemia’s main differential diagnosis is an overactive parathyroid adenoma. For both, mild or no symptoms may be present; serum calcium exceeds the upper limit, and parathormone is more than 25pg/ml. The calcium/creatinine clearance ratio should be used to differentiate one from the other and avoid unnecessary surgical neck explorations. Besides the lack of information on this topic, evidence supports the use of calcimimetics to treat symptomatic hypercalcemia. Conclusions. Patients with mild hypercalcemia with parathyroid hormone readings above 25pg/ml and a calcium/creatinine clearance ratio below 0.001, or patients with primary hyperparathyroidism with negative imaging, should not undergo surgical neck explorations. In these cases, familial hypocalciuric hypercalcemia is a reliable diagnosis; Cinacalcet may be administered in cases of symptomatic hypercalcemia.

Parathyroid hormone enhances gap healing and osseointegration in orthopedic porous coated titanium implants: a correlative micro-computed tomographic, histomorphometric and biomechanical analysis

Background Parathyroid hormone, with its anabolic effect on bone formation, has shown excellent outcomes of curing postmenopausal osteoporosis as well as enhancing osseointegration around orthopaedic and stomatologic implants.The purpose of the present study is to test if low-dose intermittent PTH (1–34) treatment could achieve a satisfactory osseointegration in 2-mm peri-implant gaps, as to provide a new idea for improving the stability of such prosthesis, which will be of great clinical value. Methods A custom-made titanium implant was implanted on the calvarium of New Zealand White rabbits. 48 male rabbits were randomly divided into control and PTH group. PTH group received subcutaneous injection of PTH (20 μg/day, 5 days/week). Animals were sacrificed at 4 and 8 weeks after surgery. Quantitative micro-computed tomography, histology and biomechanical pull-out testing were performed to evaluate the gap healing at implantation site. Results Analysis of micro-computed tomography demonstrated that PTH group achieved more new bone formation in 2-mm gaps and on bone-implant interface. Quantitatively, significant differences were observed between two groups in regard to BIC and BV/TV at each time-point. Histological staining revealed that PTH group had a superiority in trabecular number, thickness, separation and better osseointegration compared to control group. As for biomechanical pull-out testing, PTH group also showed significant improvement of ultimate force than control group. Conclusions Low-dose intermittent administration of PTH for 4 and 8 weeks enhances early osseointegration and fixation of orthopedic implants surrounded by a 2-mm gap in terms of increased bone regeneration and mechanical stability. These findings suggest PTH a potential for reducing the postoperative complications of implants by improving bone healing at peri-implant gaps.

Parathyroid hormone promotes maxillary expansion and reduces relapse in the repeated activation maxillary expansion rat model by regulating Wnt/β-catenin pathway

Background Constricted maxillary bone is a common skeletal deformity, which may lead to crowding and posterior crossbite. Mid-palatal suture expansion is often used to increase the maxillary width, but its skeletal effects are limited and tend to relapse, even with prolonged retention. We hypothesized that parathyroid hormone (PTH) may reduce the relapse of maxillary expansion. Methods We established a novel rat maxillary expansion model using palatal tubes with an insertable “W”-shaped spring which can be repeatedly activated. A total of 32 male healthy Wistar rats were randomly divided into six groups: the control group, the PTH group, the expansion group, the expansion + PTH group, the expansion + relapse group and the expansion + PTH + relapse group. All animals in the first 4 groups were killed after 10 days and the 2 relapse groups were killed after 15 days. The maxillary arch widths and histological staining were used to assess the expansion and relapse effects. The immunohistochemical staining, micro-CT, RT-qPCR and Western blot were used to evaluate the bone remodeling during expansion. Results The suture width was increased by the expansion device, and the repeated activation maxillary expansion rat model showed better expansion effects than the conventional model. PTH significantly promoted the expansion width and reduced the relapse ratio. Meanwhile, in the expansion + PTH group, histological and immunohistochemical staining showed that osteoblasts, osteoclasts, new cartilage and osteoid were significantly increased, micro-CT showed increased bone mass, and PCR and Western blot results confirmed up-regulation of RANKL, β-catenin, type II collagen and OCN. Conclusion The novel repeated activation maxillary expansion rat model has better effects than the conventional model. PTH enhances the maxillary expansion and reduces its relapse by regulating Wnt/β-catenin and RANKL pathways. PTH administration may serve as an adjunctive therapy in addition to mechanical expansion for treatment of maxillary constriction.