Parathyroid Hormone Group Research Articles

ASSOCIATION BETWEEN HIGH LEVELS OF PARATHYROID HORMONE AND FRAILTY: THE NEPEAN OSTEOPOROSIS AND FRAILTY (NOF) STUDY

Background: Frailty is associated with poor outcomes hence identification of risks factors is pivotal. Since the independent role of parathyroid hormone (PTH) in frailty remains unexplored, we aimed to determine this in a population of older individuals with a history of falling. Design: Cross-sectional study. Setting: Falls and Fracture Clinic, Nepean Hospital (Penrith, Australia). Participants: 692 subjects (mean age=79, 65% women) assessed between 2009-2015. Measurements: Assessment included clinical examination, mood, nutrition, grip strength, gait velocity, bone densitometry and posturography. Chemistry included serum PTH, calcium, vitamin D (25(OH)D3), creatinine and albumin. Normocalcemic subjects were divided into 4 groups: (1) Normal: 25(OH)D3 >50nmol/L and PTH between 1.6-6.8pmol/L; (2) PTH responsive: low 25(OH)D3 (<50nmol/L) and high PTH (>6.8pmol/L); (3) PTH unresponsive: low 25(OH)D3 and normal PTH; (4) Hyper PTH (>6.8pmol/L) with normal 25(OH)D3. Frailty was defined using Fried’s criteria. Difference between the groups was assessed using one-way ANOVA and X2 analysis. Multinomial logistic regression evaluated the association between the groups and the number of Fried’s criteria adjusted for age, BMI, renal function, 25(OH)D3 levels, and albumin. Results: 22.6% subjects had high PTH levels (>6.8pmol/L). All subjects in the high PTH groups had significantly lower grip strength, gait velocity, limits of stability, and higher BMI. The PTH responsive group had a higher risk of pre-frailty (β=3.8, 95% CI = 3.42 – 5.22, p< 0.01) and frailty (β=8.26, 95% CI = 2.8-16.1, p<0.01). The risk of frailty was also higher in the Hyper PTH group (β=2.3, 95% CI = 1.74-4.32, p<0.01). Conclusion: We have reported an independent association of high PTH levels with high number of falls and with the clinical components of physical frailty in community dwelling older persons. Our results suggest a possible role of PTH in frailty that deserves further exploration.

Triweekly administration of parathyroid hormone (1\u201334) accelerates bone healing in a rat refractory fracture model

BackgroundSome reports have shown that intermittent parathyroid hormone (PTH) (1–34) treatment for patients with delayed union or nonunion have led to successful healing. In this study, we investigated whether systemic intermittent administration of PTH (1–34) has a beneficial effect on bone healing in a rat refractory fracture model.MethodsWe created a refractory femoral fracture model in 32 rats with periosteal cauterization that leads to atrophic nonunion at 8 weeks after surgery. Half the rats received subcutaneous intermittent human PTH (1–34) injections at a dosage of 100 μg/kg, thrice a week for 8 weeks. The other half received the vehicle only. At 8 weeks after fracture, radiographic, histological and mechanical assessments were performed.ResultsRadiographic assessments showed that the union rate was significantly higher in the PTH group than in the control group (P < 0.05). The degree of fracture repair as scored using the Allen grading system in histological assessment was significantly greater in the PTH group than in the control group (P < 0.05). The ultimate stress and stiffness measurements were significantly greater in the PTH group than in the control group (p < 0.05).ConclusionsWe demonstrated that triweekly administration of PTH (1–34) increased union rate and accelerated bone healing in a rat refractory fracture model, suggesting that systemic administration of PTH (1–34) could become a novel and useful therapy for accelerating fracture healing in patients at high risk of delayed union or nonunion.

Childhood Sustained Hypercalcemia: A Diagnostic Challenge.

Objective:This study aimed to call attention to hypercalcemia, a rare finding in children which carries the potential of leading to serious complications without proper intervention.Methods:Diagnosis, treatment, and clinical course of children with sustained hypercalcemia admitted between the years 2006-2016 were reviewed. Group 1 [parathyroid hormone (PTH)-dependent] consisted of patients with high/unsuppressed PTH levels and group 2 (PTH-independent) included cases with normal/suppressed PTH levels.Results:Twenty patients (11 male, 9 female) with a median age of 6.25 (0.03-17.88) years were evaluated. Symptoms were mostly related with the gastrointestinal system, while six patients (30%) were asymptomatic. Physical examination findings were diverse, non-specific, and normal in four patients (20%). Median time of diagnosis was 45 (2-720) days. Patients were divided into group 1 (n=7) and group 2 (n=13). Most frequent etiologies were primary hyperparathyroidism (n=5), idiopathic infantile hypercalcemia (IIH) (n=5), and malignancy (n=4). A moderate positive correlation was noted between serum calcium and creatinine levels (r=0.53, p=0.02). Nephrocalcinosis was the most common complication (n=9) (45%). Treatment was not implemented in 2 patients with mild hypercalcemia, while other patients received medical treatment ± surgery. Treatment-resistant patients were cases of malignancies and neonatal severe hyperparathyroidism. Long-term follow-up displayed resistant hypercalciuria in three infants diagnosed as IIH.Conclusion:Many patients with childhood hypercalcemia are asymptomatic or exhibit a non-specific and heterogeneous clinical presentation, resulting in delayed diagnosis. Mild cases may not be recognized, while symptoms may be missed in the presence of accompanying illnesses. Nevertheless, serious complications may only be avoided with prompt diagnosis and intervention.

Surgery for Primary Hyperparathyroidism with Normal Non-suppressed Parathyroid Hormone can be Both Challenging and Successful.

Criteria for diagnosing primary hyperparathyroidism (PHPT) include hypercalcemia in the presence of parathyroid hormone (PTH) levels that are either elevated (classic PHPT) or normal but non-suppressed. However, there is no standard definition of what constitutes normal non-suppressed levels, and data are lacking regarding the potential for surgical cure in these patients. A retrospective review of patients undergoing parathyroidectomy for sporadic PHPT between 2012 and 2014 was performed. Patients with normal PTH were compared to classic PHPT patients to assess demographics, imaging, operative findings, and outcomes. In total, 332 patients met study criteria, and 60 (18%) had normal PTH levels. Negative sestamibi scans were seen more often with normal PTH levels (18.3 vs. 4.8%, p<0.001). Patients with normal PTH were more likely to have ≥2 glands removed (26.7 vs. 14.3%, p=0.02), and the specimens were more likely to be classified as only mildly hypercellular or normocellular (20 vs. 2.9%, p<0.001). Average follow-up was 24months (range 6-55). Cure rate was 88% in the normal PTH group, compared to 96% in classic PHPT (p=0.02). Among patients with normal PTH, those with PTH≤55pg/mL had an 83% cure rate, whereas those with PTH 56-65 had a 96% cure rate (p=0.12). Parathyroidectomy can have a high cure rate in the context of normal PTH levels despite an increased likelihood of negative imaging and multigland resection. Operative success is equivalent to classic PHPT when PTH levels are >55pg/mL.

Intermittent administration of parathyroid hormone ameliorated alveolar bone loss in experimental periodontitis in streptozotocin-induced diabetic rats

ObjectiveIntermittent administration of parathyroid hormone (PTH) has been demonstrated to have anabolic effects on bone metabolism and is approved for use in the treatment of osteoporosis. This study evaluates the role of intermittent PTH administration on alveolar bone loss in streptozotocin (STZ)-induced diabetic rats. DesignFifty male Sprague Dawley rats were randomly divided into the following five groups: (1) a control group (saline placebo without ligature and STZ injection), (2) a PTH group (PTH administration without ligature and STZ injection), (3) an L group (saline placebo with ligature), (4) an L+STZ group (saline placebo with ligature and STZ injection), and (5) an L+STZ+PTH group (PTH administration with ligature and STZ injection). PTH was administered at 75μg/kg per dose four times a week for 28days. Subsequently, all rats were sacrificed, and their mandibles were extracted for micro-computed tomography (micro-CT) scanning, as well as histological and immunochemical evaluation. ResultsMicro-CT scanning demonstrated the anabolic effect of PTH on alveolar bone metabolism in STZ-induced diabetic rats (P<0.05), and histomorphometry indicated that PTH inhibited inflammation of the periodontium and increased the level of osteoblastic activity (P<0.05). Immunochemical evaluation showed that rats subjected to both ligature placement and STZ injection had the highest receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) ratio and that PTH administration decreased this ratio. ConclusionIntermittent systemic PTH administration effectively reduced alveolar bone loss and ameliorated the manifestation of experimental periodontitis in STZ-induced diabetic rats.

Intermittent Ibandronate Maintains Bone Mass, Bone Structure, and Biomechanical Strength of Trabecular and Cortical Bone After Discontinuation of Parathyroid Hormone Treatment in Ovariectomized Rats

Although parathyroid hormone (PTH) expresses an anabolic effect on bone mass, the increased bone mass disappears once PTH treatment is withdrawn. Therefore, sequential treatment with anti-bone-resorptive agents is required to maintain bone mass after PTH treatment. We examined the effect of sequential treatment with ibandronate (IBN), a nitrogen-containing bisphosphonate, following PTH in ovariectomized (OVX) rats. Wistar-Imamichi rats (27 weeks old) were ovariectomized and treated with PTH (10 µg/kg, s.c.; 5 times/week; PTH group) for 8 weeks from 8 weeks after OVX. Thereafter, PTH was withdrawn and rats were administered IBN (10 µg/kg, s.c.; every 4 weeks; PTH-IBN group) or vehicle (PTH-Veh group) for another 8 weeks. PTH increased bone mineral density (BMD) measured by dual-energy X-ray absorptiometry and biomechanical strength in the lumbar spine and femur as compared to the disease control rats. BMD and biomechanical strength in the PTH-Veh group were lower than in the PTH group, whereas in the PTH-IBN group they were maintained at the level of the PTH group. Microstructure of the trabecular and cortical bone in the PTH-IBN group was not significantly different from that in the PTH group. In histomorphometric analysis of the lumbar vertebra, eroded surface and osteoclast surface in the PTH-Veh group were no different from those in the PTH group, whereas they were lower in the PTH-IBN group. Osteoid surface, osteoblast surface, and mineralize surface decreased in both PTH-IBN and PTH-Veh groups compared to the PTH group, and these parameters in the PTH-IBN group were lower than in the PTH-Veh group. These results indicated that intermittent IBN after PTH treatment suppressed bone turnover and maintained BMD, biomechanical strength, and microstructure in the lumbar spine and femur of OVX rats.

The study on the inhibitive effects of recombinant parathyroid hormone (1-34) on osteolysis in a murine calvarial model induced by wear particles

Objective: To investigate the effect of different doses of recombinant parathyroid hormone (PTH) (1-34) on osteolysis in a murine calvarial model. Methods: In total, 48 adult male C57BL/J6 mice were randomly divided into four groups: the sham group, the vehicle group, the low dose-, and high dose PTH group (n=12 each group). Mice in the PTH groups were treated with local injection of recombinant PTH at 30 or 60 μg·kg-1·d-1, intermittent injection 3 times per week for two weeks. Mice in the sham and vehicle groups received local injection of saline daily. Two weeks after surgery, calvarial tissue and peripheral blood were harvested for further analysis. Osteolysis was assessed by micro-computed tomography. The mRNA and protein expression of osteoprotegerin (OPG) and receptor activator for nuclear factor-κB Ligand (RANKL) of calvarial tissue and peripheral blood were tested by real-time PCR and ELISA, respectively. Results: Compared with the vehicle group, PTH treatment significantly inhibited the severity of osteolysis and improved the bone volume. Real time-PCR and ELISA showed that PTH significantly increased the mRNA and protein expression of OPG and reduced the RANKL/OPG ratio. Conclusion: These findings suggest that local application of PTH could effectively inhibit wear-particle-induced-osteolysis in a murine calvarial model.

Parathyroid Hormone-Induced Bone Marrow Mesenchymal Stem Cell Chondrogenic Differentiation and its Repair of Articular Cartilage Injury in Rabbits.

BackgroundWe explored the effect of parathyroid hormone (PTH)-induced bone marrow stem cells (BMSCs) complexed with fibrin glue (FG) in the repair of articular cartilage injury in rabbits.Material/MethodsForty-eight rabbits randomized into four groups were subjected to articular surgery (cartilage loss). The PTH and non-PTH intervention groups included transplantation with PTH/BMSC/FG xenogeneic and BMSC/FG xenogeneic complexes, respectively, into the injured area. The injured group contained no transplant while the control group comprised rabbits without any articular injury. Samples were monitored for cartilage repair up to three months post-surgery. Immunohistochemistry as well as real-time fluorescent quantitative PCR and Western blot were used to analyze the expression of type II collagen and aggrecan in the repaired tissue.ResultsAt 12 weeks post-surgery, the loss of articular cartilage in the PTH group was fully repaired by hyaline tissue. Typical cartilage lacunae and intact subchondral bone were found. The boundary separating the surrounding normal cartilage tissue disappeared. The gross and International Cartilage Repair Society (ICRS) histological ranking of the repaired tissue was significantly higher in the PTH intervention group than in the non-PTH intervention and injury groups (p<0.05) without any significant difference compared to the control group (p>0.05). Type II collagen and aggrecan stained positive and the average optical density, relative mRNA expression and protein-integrated optical density in the PTH group were higher than in non-PTH and injured groups (p<0.05) but not significantly different from the control group (p>0.05).ConclusionsPTH/BMSC/FG xenogeneic complexes effectively repaired the loss of cartilage in rabbit knee injury.

Analysis of the kinetics of the parathyroid hormone, and of associated patient outcomes, in a cohort of haemodialysis patients.

BackgroundObservational studies have recently associated a decrease in serum parathyroid hormone (PTH) level with a higher rate of mortality among hemodialysis (HD) patients. Decreases in PTH level can result from medical intervention (MPD) and surgical parathyroidectomy (PTX), or may occur spontaneously, usually associated with an underlying malnutrition-inflammation syndrome (SPD). The aim of our study was to prospectively identify the incidence of decreases in PTH level in a cohort of HD patients and the frequency distribution of the different causes (MPD, PTX and SPD), as well as to evaluate the survival outcomes for each PTH group (MPD, PTX and SPD) compared to patients who did not experience a PTH decrease over the first 36 months of the study (NPD).MethodsThe 197 patients receiving HD at our center in January 2010, and meeting our eligibility criteria, were enrolled in our prospective study, and were observed for a period of 60 months. A decrease in PTH level >50 % between two successive PTH measurements obtained within an interval <3 months was defined as a significant event. MPD referred to a decrease in PTH due to an increased oral calcium intake, increased dialysate calcium concentration (DCC), increased alfacalcidol use, or use of cinacalcet therapy. A surgical 7/8 PTX was performed in young patients or in patients in whom cinacalcet therapy failed. SPD referred to a decrease in PTH related to a medical or surgical event. Baseline characteristics among patients in each group (MPD, PTX, SPD, and NPD) were evaluated using Fisher’s exact test. The 60-month survival was evaluated using Kaplan-Meier and Cox multivariable proportional hazards models. Univariate and multivariate Cox analyzes were used identify variables with mortality. The relative risk of mortality was expressed as a hazard ratio (HR).ResultsThe distribution of the 197 patients forming our four study groups was 34 % in the NPD group, 35 % in the SPD group, 25 % in the MSD group and 6 % in the PTX group. Among patients in the SPD group, the main acute comorbid conditions were peripheral vascular and cardiac complications, sepsis, fractures, and cancers with an increase in serum CRP level (from 14.3 ± 18 to 132 ± 90 mg/L) and a decrease in serum albumin (from 33 ± 4.5 to 28.6 ± 4 g/L). In the MPD group, the main therapeutic change was an increase in DCC, either independently or in association with cinacalcet therapy. The median survival rate among patients was 10 months for SPD, compared to 22 months among patients in the MPD group (p < 0.001). Using multivariable Cox model and taking the NPD group as reference, the risk of mortality was lower among patients in the MPD group (HR, 0.42[0.2-0.87] p = 0.01), with survival being comparable for the SPD and NPD groups (HR, 1.3 [0.75-2.2]). No mortality was observed in the PTX group.ConclusionThe poor outcomes associated with SPD, related to acute comorbid conditions, should not lead to undertreat secondary hyperparathyroidism whose appropriate medical or surgical therapies are associated with better outcomes.

Intermittent Parathyroid Hormone Improves Bone Formation Around Titanium Implants in Osteoporotic Rat Maxillae.

Parathyroid hormone (PTH) plays an important role in the treatment of osteoporosis due to its anabolic effect. In this study, PTH was administered intermittently to rats with ovariectomy-induced osteoporosis, titanium implants were placed into the rat maxillae, and the response of surrounding bone was evaluated. A total of 30 female 8-week-old Sprague-Dawley rats were either ovariectomized to induce osteoporosis or sham operated. After 8 weeks, the upper right first molar was extracted and after a 4-week healing period an implant was placed. The animals were then divided into three groups: the PTH group (n = 10), which had been ovariectomized and received postimplant PTH; the OVX group (n = 10), which had been ovariectomized but did not receive postimplant PTH; and the control group (n = 10), which had been sham operated only (n = 10). Following implant placement, the rats in the PTH group received intermittent doses (three times a week) of PTH (30 μg/kg) subcutaneously in the dorsum. All the rats were sacrificed 4 weeks after implantation and specimens of the peri-implant maxillary bone were harvested, including the implant. Samples were evaluated by histomorphometric analysis and three-dimensional microcomputed tomography. Histomorphometric results showed that the mean bone area per tissue area (BA/TA) was 54.16% ± 2.2% in the PTH group and 45.24% ± 6.3% in the OVX group. The percentage of bone-to-implant contact (BIC) was 45.58% ± 9.4% in the PTH group and 32.00% ± 10.9% in the OVX group. Mean BA/TA and mean BIC values in the PTH group were higher than those in the OVX group; however, the differences were not statistically significant (P > .05). Microstructural data also showed differences between the groups. Bone volume was greater and trabecular bone was thicker in the PTH group than in the OVX group and more trabeculae were found in the PTH group. Bone mineral density was also higher in the PTH group. However, statistical analysis failed to show a significant difference between these two groups in any parameters other than trabecular thickness (P = .023). Despite the limitations of this study, intermittent PTH administration in humans may be helpful in accelerating new bone formation around implants. PTH treatment could improve clinical outcomes when dental implants are placed in jaws with low-quality bone.

Elevated Parathyroid Hormone is Associated with Left Ventricular Remodeling in Elderly Patients with Mild to Moderate Chronic Kidney Disease

Background Parathyroid hormone (PTH) plays an important role in bone metabolism. Aging and chronic kidney disease is recognized as an important factor associated with elevation in PTH. Although elevated PTH was associated with cardiovascular mortality, the association of PTH and left ventricular remodeling in elderly patients with mild to moderate kidney disease has not been elucidated. Methods and results238 patients over 65 years with CKD stage 2 or 3 were examined (101 male, 75 years). Subjects with LV dysfunction (LVEF < 50%), atrial fibrillation and advanced chronic kidney disease (eGFR < 15 ml/min/1.73 m2) were excluded. Patients were divided into two groups according to intact PTH level: below 65 pg/ml (normal PTH, n = 201) and above 65 pg/ml (high PTH, n = 37). High PTH groups had lower creatinine-based estimated GFR (57 ± 15 vs 63 ± 13 ml/min/1.73 m2, (ex.)P < .05) and higher cystatin C level (1.21 ± 0.44 vs 1.01 ± 0.30 mg/L, (ex.)P < .01). In echocardiography, high PTH group had lower e (5.3 ± 1.6 vs 5.9 ± 1.7 cm/sec, (ex.)P < .05), higher E/e (16.1 ± 21.9 vs 11.5 ± 3.6, (ex.)P < .01) and higher LVMI (119 ± 28 vs 107 ± 30g/m2, (ex.)P < .05). The intact PTH was significantly associated with LVMI, even after adjustment for confounding factors. Also, high PTH group had high prevalence of LVH in multivariable logistic regression analysis. Conclusion In elderly patients with mild to moderate CKD, higher level of parathyroid hormone is associated with left ventricular remodeling, which may cause cardiovascular event in these patients.

Aerobic exercise training modulates bone mineral status in patients with chronic obstructive pulmonary disease

Background:Chronic obstructive pulmonary disease (COPD) appears to be associated with low bone mineral density (BMD) due to long-term use of corticosteroids as a result patients with COPD are at risk for osteoporosis-related fractures and worsening pulmonary function.Objective:The present study aimed to measure the effects of treadmill walking exercises on bone mineral status in patients with COPD.Methods:Sixty patients with moderate COPD of both sexes, their age ranged from 45 to 58 years. Subjects were divided into two equal groups: training group (group A) received aerobic exercise training on treadmill for six months, where the second group (B) was considered as a control group who received no exercise training. The program consisted of three sessions per week for six months.Results:The results of this study indicated a significant increase in BMD of the lumbar spine & the radius and serum calcium & significant reduction in parathyroid hormone in group (A), while these changes were not significant in group (B).Also; there was a significant difference between both groups at the end of the study.Conclusion:Treadmill walking exercise training is an effective treatment policy to improve bone mineral status in patients with COPD.

Enhancing Effect of Intermittent Parathyroid Hormone Administration on Bone Formation After Titanium Implant Placement in an Ovariectomized Rat Maxilla.

This study examined the effect of intermittent parathyroid hormone (PTH) administration on the bone response around implant on the maxilla of rats with ovariectomy-induced osteoporosis. A total of 27 female Sprague-Dawley rats were divided into 3 groups (n = 9) and were ovariectomized (OVX). Eight weeks after, upper right molar was extracted and an implant was placed at 4 weeks after extraction. The PTH group received PTH, and the OVX group and the control group received vehicle only. Beginning after implant placement, 30 μg/kg of PTH was subcutaneously administered in the dorsum 3 times a week. Three rats in each group were killed at 1, 2, and 4 weeks and histologic sections were evaluated. After 4 weeks, the amount of newly formed bone around implants in the PTH group was comparable with the control group, with bone covering the implant surface in both groups. However, the OVX group displayed relatively small amount of new bone. Intermittent PTH has the potential to increase new bone formation around implant. These findings have clinical implications in prosthetic restoration by implants with poor bone quality.

The Effectiveness of Human Parathyroid Hormone and Low-Intensity Pulsed Ultrasound on the Fracture Healing in Osteoporotic Bones.

Osteoporotic fracture has become a major public health problem, and until today, the treatments available are not satisfactory. While there is growing evidence to support the individual treatment of parathyroid hormone (PTH) administration and low-intensity pulsed ultrasound (LIPUS) exposure as respectively systemic and local therapies during osteoporotic fracture healing, their effects have not yet been investigated when introduced concurrently. This study aimed to evaluate the effects of combined treatment with PTH (1-34) and LIPUS on fracture healing in ovariectomized (OVX) rats. Thirty-two, 12-week-old female Sprague-Dawley rats were OVX to induce osteoporosis. After 12weeks, the rats underwent surgery to create bilateral mid-diaphyseal fractures of proximal tibiae. All animals were randomly divided into 4 groups (n=8 for each): control group as placebo, PTH group, LIPUS group, and combined group. PTH group had PTH administration at a dose of 30μg/kg/day for 3days/week for 6weeks. LIPUS group received ultrasound 5days/week for 20min/day for 6weeks and combined group had both PTH administration and LIPUS exposure for 6weeks. Fracture healing was observed weekly by anteroposterior radiography and micro-CT. Five weeks after the fracture, the tibia were harvested to permit histological assessments and at week 6, for mechanical property of the fracture callus. Micro-CT showed that the PTH and combined groups exhibited significantly higher BMD and trabecular bone integrity than control group at weeks 4-6. Radiography, fracture healing score and mean callus area indicated that the combined group revealed better healing processes than the individual groups. Mechanically, bending moment to failure was significantly higher in LIPUS, PTH and combined groups than in control group. These data suggest that the combined treatment of PTH and LIPUS have been shown to accelerate fracture bone healing and enhance bone properties rather than single agent therapy, and may be considered as a treatment remedy for fracture healing in postmenopausal osteoporosis.

Effect of Intermittent Parathyroid Hormone Administration on the Microstructure of Jaw Bone in the Ovariectomized Rats

Purpose: Parathyroid hormone (PTH) therapy has drawn attention, as an alternative to anti-resorptive drugs since PTH accelerates bone density by anabolic action. The purpose of this study was to identify the effect of intermittent PTH administration on jaw bones of rat undergone bilateral ovariectomy. Materials and Methods: Nine female Sprague-Dawley rats were divided into three groups. PTH group was ovariectomized (OVX) to induce osteoporosis and PTH 30 μg/kg was administered 1 week after the surgery. In OVX group, ovariectomy was performed and only vehicle was administered by subcutaneous injection 3 times per week. Control group was subjected to sham surgery. The animals were sacrificed 8 weeks after the surgery and specimens were obtained from ilium and upper and lower jaw bones. Histological investigation was carried out by using an optical microscope and micro-computed tomography was taken to examine structural property changes in each bone sample. Result: In the ilium, the bone volume ratio (bone volume/total volume, BV/TV) of PTH, OVX and control groups was 53.75%±7.57%, 50.61%±12.89%, 76.20%±5.92% (P=0.061) and bone mineral density (BMD) was 1.12±0.09, 0.88±0.48, 1.38±0.07 g/cm³ (P=0.061). In the mandible, BV/TV of PTH, OVX and control groups was 64.60%±12.17%, 58.26%±9.63%, 67.54%±14.74% (P=0.670) and BMD was 1.21±0.17, 1.19±0.13, 1.27±0.18 g/cm³ (P=0.587). In the maxilla, BV/TV of PTH, OVX and control groups was 61.19%±8.92%, 52.50%±11.22%, 64.60%±12.17% (P=0.430) and BMD was 1.20±0.11, 1.11±0.16, 1.21±0.17 g/cm³ (P=0.561). No statistically significant difference was found in any variables in all groups. Histological observation revealed that the ilium in OVX group demonstrated sparsely formed trabecular bones compared with other groups. However, upper and lower trabecular bones did not present significant differences. Conclusion: Intermittent administration of PTH appears to affect the microstructure of rat jaw bones, but statistical significance was not found. However, the measurements in this study partly implicated the possible anabolic effect of PTH in vivo.

Low parathyroid hormone levels after parathyroidectomy reduce cardiovascular mortality in chronic hemodialysis patients.

The aim of the study is to elucidate whether parathyroid hormone (PTH) levels after parathyroidectomy affect the prognosis of patients with secondary hyperparathyroidism. Two hundred and ninety-five patients, who underwent PTx without autotransplantation from July 1998 to December 2011, were divided into the low (n=148) and high (n=147) PTH groups, using the median value of each mean value of intact PTH after surgery (16.6pg/mL). After observation for 5.00years, we evaluated demographic factors, influences of postoperative mineral metabolism, magnitude of uremia, and vitamin D receptor activators on their prognosis, with the multivariate Cox proportional hazard model. While overall survival rates in the high and low PTH groups were 54.9 and 74.2%, respectively (P=0.1500), cardiovascular survival rates were 71.6 and 94.4%, respectively (P=0.0256). The hazard ratio for cardiovascular mortality in the high PTH group (≥16.6pg/mL) was 3.132 (P=0.0470), and those in groups with the median age more than 59years and with cardiovascular disease were 2.654 (P=0.0589) and 3.377 (P=0.0317), respectively. The intact PTH level 6days after surgery and the mean postoperative intact PTH value showed a strong correlation (Spearman ρ=0.9007, P<0.0001, y=0.4725x+30.395, R 2=0.51798). The present study suggests that maintaining low PTH levels after parathyroidectomy reduces cardiovascular mortality and improves the prognosis. Total parathyroidectomy (more than 4 glands) without autotransplantation seems to be one of the treatment options for managing severe secondary hyperparathyroidism.

Compliance and persistence with treatment with parathyroid hormone for osteoporosis. A Danish national register-based cohort study

Medical intervention is important in the treatment of osteoporosis, and compliance with medical treatment is essential for an optimal outcome. Based on Danish national registers, we found that compliance with parathyroid hormone (PTH) treatment is high and associated with marital status, working status, and type of PTH treatment. Compliance and persistence are essential for an optimal outcome during medical treatment of osteoporosis. We aimed to evaluate compliance and persistence with treatment with PTH in daily clinical practice in Danish patients and to describe factors affecting compliance. Register-based nationwide cohort study on all patients in Denmark initiates PTH or analogue treatment for osteoporosis in 2003-2010 (n = 4281). PTH drugs included were the PTH analogue teriparatide(1-34) and recombinant human PTH (rhPTH(1-84)). Compliance with treatment was calculated by using medication possession ratio (MPR). In the study period, 3702 patients were exclusively treated with teriparatide and 579 were exclusively treated with rhPTH(1-84). We found that for patients persistent with therapy for at least 18 months and with MPR >0.8, 83 % of the patients in the teriparatide group were compliant versus 72 % in the recombinant PTH group (p < 0.01). Being married/cohabiting, still in the labor market, and taking teriparatide were significantly associated with higher compliance, whereas age, gender, level of education, income, alcoholism, and Charlson comorbidity index were not associated with compliance. Compliance with PTH treatment overall is high, with teriparatide compliance higher than rhPTH(1-84), in patients persistent to therapy for 18 months. Compliance is associated with marital status, working status, and type of PTH treatment.

Effect of teriparatide on repair of femoral metaphyseal defect in ovariectomized rats.

This study aimed to investigate the effect exerted by teriparatide on the repair of femoral metaphyseal defect in ovariectomized rats. Female Sprague-Dawley rats were ovariectomized and after 3months a critically sized defect of 3mm in diameter-a through-hole bone defect-was drilled into each distal femur of the ovariectomized rats. The rats were injected with teriparatide (30μg/kg) parathyroid hormone (PTH) in the peritoneum three times per week. After 4 and 8weeks the animals were killed and the blood and bilateral femora were harvested for biochemical analysis, histopathological observation, and micro-computed tomography (CT) examination. The PTH group and control group were compared 4 and 8weeks after surgery. PTH increased bone formation in the defect area. Moreover, PTH showed the strongest effects on bone volume per total volume, trabecular number, trabecular thickness, trabecular separation, and total fluorescence-marked new bone area. Additionally, the PTH treatment group showed inhibited serum concentrations of C-terminal telopeptide of type I collagen and enhanced expression of calcium, phosphorus, and bone alkaline phosphatase. Our findings suggest a positive effect of PTH on defect healing in ovariectomized rats.

Intermittent PTH treatment can delay the transformation of mature osteoblasts into lining cells on the periosteal surfaces.

Mature osteoblasts have three fates: as osteocytes, quiescent lining cells, or osteoblasts that undergo apoptosis. However, whether intermittent parathyroid hormone (PTH) can modulate the fate of mature osteoblasts in vivo is uncertain. We performed a lineage-tracing study using an inducible gene system. Dmp1-CreERt2 mice were crossed with Rosa26R reporter mice to obtain targeted mature osteoblasts and their descendants, lining cells or osteocytes, which were detected using X-gal staining. Rosa26R:Dmp1-CreERt2(+) mice were injected with 0.25mg 4-OH-tamoxifen (4-OHTam) on postnatal days 5, 7, 9, 16, and 23. In a previous study, at 22days after the last 4-OHTam, most LacZ+ cells on the periosteal surface were inactive lining cells. On day 25 (D25), the mice were challenged with an injection of human PTH (1-34, 80μg/kg) or vehicle daily for 10 (D36) or 20days (D46). We evaluated the number and thickness of LacZ+ osteoblast descendants in the calvaria and tibia. In the vehicle group, the number and thickness of LacZ+ osteoblast descendants at both D36 and D46 significantly decreased compared to D25, which was attenuated in the PTH group. In line with these results, PTH inhibited the decrease in the number of LacZ+/osteocalcin-positive cells compared to vehicle at both D36 and D46. As well, the serum levels of sclerostin decreased, as did the protein expression of sclerostin in the cortical bone. These results suggest that intermittent PTH treatment can increase the number of periosteal osteoblasts by preventing mature osteoblasts from transforming into lining cells in vivo.

Quantification of skeletal growth, modeling, and remodeling by in vivo micro computed tomography

In this study we established an image analysis scheme for the investigation of cortical and trabecular bone development during skeletal growth and tested this concept on in vivo μCT images of rats. To evaluate its efficacy, we applied the technique to young (1-month-old) and adult (3-month-old) rat tibiae with vehicle (Veh) or intermittent parathyroid hormone (PTH) treatment. By overlaying 2 sequential scans based on their distinct trabecular microarchitecture, we calculated the linear growth rate of young rats to be 0.31mm/day at the proximal tibia. Due to rapid growth (3.7mm in 12days), the scanned bone region at day 12 had no overlap with the bone tissue scanned at day 0. Instead, the imaged bone region at day 12 represented newly generated bone tissue from the growth plate. The new bone of the PTH-treated rats had significantly greater trabecular bone volume fraction, number, and thickness than those of the Veh-treated rats, indicating PTH's anabolic effect on bone modeling. In contrast, the effect of PTH on adult rat trabecular bone was found to be caused by PTH's anabolic effect on bone remodeling. The cortical bone at the proximal tibia of young rats also thickened more in the PTH group (23%) than the Veh group (14%). This was primarily driven by endosteal bone formation and coalescence of trabecular bone into the cortex. This process can be visualized by aligning the local bone structural changes using image registration. As a result, the cortex after PTH treatment was 31% less porous, and had a 22% greater polar moment of inertia compared to the Veh group. Lastly, we monitored the longitudinal bone growth in adult rats by measuring the distance of bone flow away from the proximal tibial growth plate from 3months to 19months of age and discovered a total of 3.5mm growth in 16months. It was demonstrated that this image analysis scheme can efficiently evaluate bone growth, bone modeling, and bone remodeling, and is ready to be translated into a clinical imaging platform.