PTH Group Research Articles

Intermittent Parathyroid Hormone Injection Can Decrease Femoral Head Collapse in the Vascular Deprivation of Rat Femoral Head Model.

Backgrounds:Intermittent parathyroid hormone (intermittent PTH) injection has been shown to improve osteogenesis. We hypothesized that intermittent PTH injection could stimulate osteogenesis during the early phase of vascular deprivation-induced femoral neck osteonecrosis in a rat model.Materials and Methods:Eighteen Sprague-Dawley rats were divided into three groups (normal saline [CON], PTH 10 μg/kg [PTH-H], and PTH 1 μg/kg [PTH-L]) for 8 weeks by subcutaneous injection. All rats were sacrificed at postoperative 8 weeks, and all underwent a micro-computed tomography (μ-CT) examination for bone quality and quantity evaluation and histomorphometric analysis for microscopic histologic differences.Results:Under μ-CT examination, both the PTH-H and PTH-L groups revealed less bone resorption than the control group. The PTH-H group had a better bone protective effect than the PTH-L group. Bone mineral density was increased in the PTH-H and PTH-L groups compared to the control group. The uninjured left femoral head was enlarged in both PTH groups. The histologic examination showed that both PTH groups had new bone and cartilage formation. The control group had only dead bone without any osteogenesis.Conclusion:Intermittent PTH injection could decrease bone resorption and improve bone density, compared to the control group, in vascular deprivation of the femoral head in a rat model. High-level intermittent PTH injection had a better effect than low-level intermittent PTH injection.

Single injection of PTH improves osteoclastic parameters of remodeling at a stress fracture site in rats.

Stress fractures (SFx) result from repetitive cyclical loading of bone. They are frequent athletic injuries and underlie atypical femoral fractures following long-term bisphosphonate (BP) therapy. We investigated the effect of a single PTH injection on the healing of SFx in the rat ulna. SFx was induced in 120 female Wistar rats (300 ± 15 g) during a single loading session. A single PTH (8 µg.100g-1 ) or vehicle (VEH) saline injection was administered 24 h after loading. Rats were divided into four groups (n = 15) and ulnae were examined 1, 2, 6, or 10 weeks following SFx. Two Toluidine Blue and TRAP-stained sections of the SFx were examined for histomorphometric analysis using Osteomeasure™ software. An increase in osteoclast number (N.Oc) and perimeter (Oc.Pm) was observed two weeks following PTH treatment (p < 0.01). At 6 weeks, bone formation was the main activity in BMUs. At 10 weeks, the proportion of healing along the SFx line remained 50% greater in PTH groups (p = 0.839), leading to a 43% reduction in the porosity area of BMU (p = 0.703). The main effect of time was a significant variable along the entire SFx remodeling cycle, with significant interactions between time and treatment type affecting (N.Oc) (p = 0.047) and (Oc.Pm) (p = 0.002). We conclude that a single PTH injection increases osteoclastogenesis by the second week of the remodeling cycle in a SFx in vivo. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

The fast degradation of β-TCP ceramics facilitates healing of bone defects by the combination of BMP-2 and Teriparatide

Accumulating evidence suggests that the degradation and resorption of calcium phosphate ceramics is always relatively slow, which may inhibit calcium phosphate ceramics’ replacement by new bone tissues and the ultimate bone defect repair. Bone morphogenetic proteins (BMPs) and Teriparatide (PTH) are extensively applied in the treatment of bone pathologies, while their effects on the degradation of calcium phosphate ceramics is limited. In this study, we tested the effects of BMP and PTH on degradation of β-tricalcium phosphate (β-TCP) ceramics and bone formation on β-TCP in ovariectomized (OVX) rat models. After establishment of femur defect model on OVX rats, the BMP + PTH group’s rats were injected Teriparatide (30 μg/kg) subcutaneous every other day, while rats of control group and group BMP were injected equal-to-group volume sterilized saline water. Twelve weeks after femur surgery, all rats were sacrificed for Micro-CT scanning and histology tests. The results showed that BMP facilitated degradation of β-TCP and new bone formation on β-TCP ceramics. And PTH showed an additional effect on degradation of β-TCP when combined with BMP. In addition, the results explained that PTH promoted the remodeling of the bone callus occurred during repair.

Combined treatment with vitamin K2 and PTH enhanced bone formation in ovariectomized rats and increased differentiation of osteoblast in vitro

Osteoporosis is accompanied by insufficient osteogenic capacity. Several lines of evidence suggested that solutions to enhance osteoblastogenesis were important strategies for osteoporotic bone defect repair. This study investigated the effect of combined treatment with vitamin K2 and PTH on bone formation in calvarial bone defect in osteoporotic rats and its influence on osteoblast in vitro. Bilateral ovariectomy was used in SPF Sprague Dawley rats to generate an osteoporosis model. Subsequently, a calvarial defect model was established and all osteoporotic rats were randomly assigned to the following groups: control, VK (vitamin K2, 30 mg/kg everyday), PTH (recombinant human PTH (1–34), 60 μg/kg, three times a week) or VK + PTH (vitamin K2, 30 mg/kg everyday plus PTH, 60 μg/kg three times a week) for 8 weeks. In vitro, bone marrow-derived stem cells (BMSCs) were cultured and treated with vitamin K2, PTH or vitamin K2+PTH. ALP staining and western blot were performed to observe the influence of combined treatment on BMSCs. Bone formation within calvarial defect were assessed by serum γ-carboxylated osteocalcin (Gla-OC), micro-CT, histological and immunofluorescent labeling. In this study, combined treatment of PTH and vitamin K2 showed positive effects on preventing bone loss in femurs in OVX rats. Combined treatment increased serum Gla-OC and promoted bone formation in osteoporotic calvarial bone defects. Immunohistochemistry showed that OCN and RUNX2 were more highly expressed in the VK + PTH group than in the control groups. In vitro studies results suggested that combined treatment with PTH and vitamin K2 increased expression of ALP, BMP2 and RUNX2 in BMSCs. Our data suggested that the combination of vitamin K2 and PTH increased differentiation of osteoblast and had a synergistic effect on bone formation in osteoporotic calvarial bone defect.

Dialysis vintage and risk factors of hyperparathyroidism in hemodialysis patients

Objective The objective of this study was to study the risk factors of hyperparathyroidism based on hemodialysis vintage (duration in months or years that hemodialysis patients spend on dialysis). Background Hyperparathyroidism is associated with high risk of fractures, cardiovascular morbidity, and death; therefore, it is important to identify risk factors predicting or influencing parathyroid gland secretion. Patients and methods Patients were divided into two groups: short dialysis vintage ( Results Short dialysis vintage patients with PTH more than 300 pg/ml have higher alkaline phosphatase (147.9 ± 101.4 vs. 102.1 ± 89.18; P = 0.009), phosphorus (5.913 ± 1.621 vs. 5.044 ± 1.387; P = 0.048), calcium phosphate product (49.60 ± 13.45 vs. 42.35 ± 13.61; P = 0.04), and serum creatinine (10.8 ± 3.353 vs. 8.96 ± 2.311; P = 0.005 for predialysis serum creatinine and 4.987 ± 1.364 vs. 4.035 ± 1.426; P = 0.007 for postdialysis serum creatinine) compared with nonhigh PTH group. Long dialysis vintage patients with PTH more than 300 pg/ml have higher alkaline phosphatase (222.1 ± 184.7 vs. 99 ± 29.47; P = 0.024), lower serum sodium (137.3 ± 2.8 vs. 141.4 ± 2.937; P = 0.004), and lower mean arterial blood pressure (81.42 ± 14.65 vs. 96.38 ± 12.87; P = 0.019) compared with nonhigh PTH group. Conclusion Serum alkaline phosphatase, phosphorus, calcium phosphate product, and serum creatinine were found to be associated with hyperparathyroidism in short hemodialysis vintage patients (

Prevalence of glucocorticoid induced osteonecrosis in the mouse is not affected by treatments that maintain bone vascularity

ObjectiveDetermine if LLP2A-Ale or PTH (1–34) affects the prevalence of glucocorticoid-induced osteonecrosis (ON) in a mouse model. MethodsEight-week-old young adult male BALB/cJ mice were weight-randomized into Control (Con), glucocorticoid (GC)-only, or concurrent treatments with GC and LLP2A-Ale (250 μg/kg or 500 μg/kg, IV, Days 1, 14, 28) or parathyroid hormone hPTH (1–34) (40 μg/kg, 5×/week). Mice were necropsied after 45 days for qualitative evaluation of prevalent ON and quantitative evaluation of vascularity in the distal femoral epiphysis (DFE); and quantitative evaluation of bone mass, microarchitecture, and strength in the distal femoral metaphysis and lumbar vertebral body. ResultsThe prevalence of ON was 14% in the Con group and 36% in the GC-only group (P = 0.07). The prevalence of ON did not differ among GC-only, GC + LLP2A-Ale, and GC + PTH groups. GC-only mice had significantly lower trabecular and cortical bone strength than Con, while GC + LLP2A-Ale (500 μg/kg) and GC + PTH (1–34) groups had significantly greater trabecular bone strength than the GC-only group. GC + LLP2A-Ale (250 μg/kg and 500 μg/kg) and GC + PTH had significantly higher trabecular bone volume than GC-only mice at the vertebrae, distal femoral epiphyses and distal femoral metaphyses. DFE vascularity was lower in GC-only mice than in all other groups. ConclusionNeither LLP2A-Ale nor hPTH (1–34) reduced the prevalence of GC-induced ON, compared to GC-only mice. However, GC-treated mice given LLP2A-Ale or hPTH (1–34) had better bone mass, microarchitecture, and strength in trabecular-rich regions, and higher levels of vascularity than GC-only mice.

Efficacy and safety of recombinant human parathyroid hormone (1-34) are similar to those of alendronate in the treatment of postmenopausal osteoporosis.

The study evaluates efficacy and safety of recombinant human parathyroid hormone (1–34) [rhPTH (1–34)] and alendronate (ALN) in the treatment of postmenopausal osteoporosis.Totally 65 postmenopausal women with osteoporosis were divided into 2 groups. PTH group received daily subcutaneous injection of rhPTH (1–34), and ALN group were treated orally with ALN per week. Bone mineral density (BMD) of lumbar spine (1–4), femoral neck, and total hip, serum levels of calcium, phosphorus, total cholesterol, triglyceride, alkaline phosphatase (ALP), N-terminal propeptide of type I collagen (PINP), and C-telopeptide of type I collagen (CTX) were tested before treatment and at week 24 and 48 after treatment. Serum levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor-BB (PDGF-BB) were measured before treatment and at week 48 after treatment.The rhPTH (1–34) increased BMD of lumbar spine (1–4), but decreased BMD of femoral neck and total hip at week 48 after treatment. By contrast, ALN enhanced BMD of lumbar spine (1–4) and femoral neck, but reduced BMD of total hip at week 48 after treatment. In PTH group, serum levels of PINP, ALP, and β-CTX were significantly elevated above baseline at week 24 and 48 after treatment. Treatment with ALN decreased levels of PINP, ALP, and β-CTX compared with baseline at week 24 and 48 after treatment. rhPTH (1–34) and ALN significantly decreased levels of PDGF-BB, but not levels of VEGF. rhPTH (1–34) increased levels of calcium, phosphorus and triglyceride, but decreased levels of total cholesterol. ALN increased levels of calcium and triglyceride, but reduced levels of phosphorus and total cholesterol. rhPTH (1–34) and ALN were safe in the treatment of postmenopausal osteoporosis.The study demonstrates that efficacy of rhPTH (1–34) on BMD of lumbar spine (1–4) is similar to that of alendronate in the treatment of postmenopausal osteoporosis. The effect of rhPTH (1–34) on BMD of femoral neck or total hip is weaker than that of ALN. In addition, rhPTH (1–34) increases BMD of lumbar spine (1–4) maybe by raising serum levels of VEGF, but reduces BMD of femoral neck and total hip maybe by decreasing serum levels of PDGF-BB.

Histological Effects of the Combined Administration of Eldecalcitol and a Parathyroid Hormone in the Metaphyseal Trabeculae of Ovariectomized Rats

Intermittent administration of human parathyroid hormone (1-34) (hPTH(1-34)) promotes anabolic action in bone by stimulating bone remodeling, while eldecalcitol, an analog of active vitamin D3, suppresses osteoclastic bone resorption, and forms new bone by minimodeling. We have examined the biological effects of combined administration of eldecalcitol and hPTH(1-34) on 9-week-old Wistar rats that underwent an ovariectomy (OVX) or Sham operation. They were divided into a Sham group, OVX with vehicle (OVX group), OVX with 10 µg/kg/day of hPTH(1-34) (PTH group), OVX with 20 ng/kg/day of eldecalcitol (eldecalcitol group) or OVX with 10 μg/kg/day of hPTH(1-34), and 20 ng/kg/day of eldecalcitol (combined group) for 4 or 8 weeks. As a consequence, the combined group showed a marked increase in bone volume/tissue volume (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) than OVX and had the highest bone mineral density (BMD) compared with other groups. OVX and PTH groups exhibited a high osteoblastic surface/bone surface (Ob.S/BS), mineral apposition rate (MAR), and bone formation rate/bone surface (BFR/BS) indices and many TRAP-reactive osteoclasts. Contrastingly, eldecalcitol and combined groups tended to attenuate the indices of osteoclastic surface/bone surface (Oc.S/BS) and Ob.S/BS than that the other groups. The combined group revealed histological profiles of minimodeling- and remodeling-based bone formation. Thus, the combined administration of eldecalcitol and hPTH(1-34) augments their anabolic effects by means of minimodeling and remodeling.

Combined treatment with cinnamaldehyde and PTH enhances the therapeutic effect on glucocorticoid-induced osteoporosis through inhibiting osteoclastogenesis and promoting osteoblastogenesis

The study was to investigate the effect of combining treatment with cinnamaldehyde and parathyroid hormone (1−34) (PTH) on glucocorticoid-induced osteoporosis (GIO) and compare with monotherapy. Forty Sprague-Dawley male rats with GIO were divided into four groups randomly: control group (CON group, N = 10); group that intragastric administration with cinnamaldehyde (CIN group, N = 10); group that subcutaneous injection with PTH, three times per week(PTH group, N = 10); both administration with cinnamaldehyde and PTH (CIN + PTH group, N = 10). Distal femurs were harvested for hematoxylin and eosin (H&E) staining, micro-CT scanning and immunohistochemical analysis. Murine mesenchymal stem cells were cultured and dealt with the presence of dexamethasone(DEX group), DEX + cinnamaldehyde(DEX + CIN group), DEX + PTH(DEX + PTH group) or DEX + cinnamaldehyde + PTH(DEX + CIN + PTH group). Alkaline phosphatase (ALP) staining was performed subsequently. The results showed that bone formation in CIN + PTH group was notably promoted compared with other groups. And the expression of tartrate-resistant acid phosphatase (trap) and runt-related transcription factor 2 (runx2) in CIN + PTH group were down-regulated and up-regulated respectively compared with PTH group. In vitro study revealed that ALP-positive cell number in DEX + CIN + PTH group was obviously enhanced compared with other groups. The study revealed that combined treatment with cinnamaldehyde and PTH enhances the therapeutic effect on GIO through inhibiting osteoclastogenesis and promoting osteoblastogenesis.

Impact of timing of ventriculoperitoneal shunt placement on outcome in posttraumatic hydrocephalus.

Posttraumatic hydrocephalus (PTH) is a frequent sequela of traumatic brain injury (TBI) and complication of related cranial surgery. The roles of PTH and the timing of cerebrospinal fluid (CSF) shunt placement in TBI outcome have not been well described. The goal of this study was to assess the impact of hydrocephalus and timing of ventriculoperitoneal (VP) shunt placement on outcome during inpatient rehabilitation after TBI. In this cohort study, all TBI patients admitted to Craig Hospital between 2009 and 2013 were evaluated for PTH, defined as ventriculomegaly, and hydrocephalus symptoms, delayed or deteriorating recovery, or elevated opening pressure on lumbar puncture. Extent of ventriculomegaly was quantified by the Evans index from CT scans. Outcome measures were emergence from and duration of posttraumatic amnesia (PTA) and functional status as assessed by means of the Functional Independence Measure (FIM). Findings in this group were compared to findings in a group of TBI patients without PTH (controls) who were admitted for inpatient rehabilitation during the same study period and met specific criteria for inclusion. A total of 701 patients were admitted with TBI during the study period. Of these patients, 59 (8%) were diagnosed with PTH and were included in this study as the PTH group, and 204 who were admitted for rehabilitation and met the criteria for inclusion as controls constituted the comparison group (no-PTH group). PTH was associated with initial postinjury failure to follow commands, midline shift or cistern compression, subcortical contusion, and craniotomy or craniectomy. In multivariable analyses, independent predictors of longer PTA duration and lower FIM score at rehabilitation discharge were PTH, emergency department Glasgow Coma Scale motor score < 6, and longer time from injury to rehabilitation admission. PTH accounted for a 51-day increase in PTA duration and a 29-point reduction in discharge FIM score. In 40% of PTH patients with preshunt CT brain imaging analyzed, ventriculomegaly (Evans index > 0.3) was observed 3 or more days before VP shunt placement (median 10 days, range 3-102 days). Among PTH patients who received a VP shunt, earlier placement was associated with better outcome by all measures assessed and independently predicted better FIM total score and shorter PTA duration. Posttraumatic hydrocephalus predicts worse outcome during inpatient rehabilitation, with poorer functional outcomes and longer duration of PTA. In shunt-treated PTH patients, earlier CSF shunting predicted improved recovery. These results suggest that clinical vigilance for PTH onset and additional studies on timing of CSF diversion are warranted.

Short-term daily teriparatide in patients with rheumatoid arthritis

Objective: The aim of this study was to compare the efficacy of six-month teriparatide treatment followed by six-month bisphosphonate therapy with 12-month bisphosphonate monotherapy in Japanese rheumatoid arthritis (RA) patients who had not been previously treated for osteoporosis.Methods: A total of 34 RA patients with osteoporosis were enrolled. Thirteen patients received six-month teriparatide prior to six-month minodronate therapy (PTH group), and 21 patients received 12-month minodronate therapy (BP group). Bone mineral density (BMD), and bone turnover markers were measured prior to and 6 and 12 months after the initiation of treatment.Results: Bone mineral density of the spine was significantly increased after 12 months of treatment in both groups. In the PTH group, the mean percent change of BMD of the spine was significantly higher at 12 months after the initiation of treatment, as compared to the BP group (PTH group: 9.9 ± 1.5%, BP group: 5.5 ± 0.7%). Femoral neck BMD was significantly increased only in the PTH group after 12 months.Conclusion: Therapy involving six-month teriparatide followed by six-month minodronate therapy increased spine BMD to a greater degree than 12-month minodronate monotherapy. The strategy of short-term administration of teriparatide for RA patients with osteoporosis might be useful when additional bisphosphonate therapy is considered.

The local administration of parathyroid hormone encourages the healing of bone defects in the rat calvaria: Micro-computed tomography, histological and histomorphometric evaluation

ObjectiveTo evaluate the effect of a single-dose local administration of PTH on bone healing in rat calvarial bone defects by means of micro-computed tomography, histological and histomorphometric analysis. DesignCritical-size cranial osteotomy defects were created in 42 male rats. The animals were randomly divided into 3 groups. In the C Group, the bone defect was only filled with a blood clot. In the S Group, it was filled with a collagen sponge and covered with bovine cortical membrane. In the PTH Group, the defect was filled with a collagen sponge soaked with PTH and covered with bovine cortical membrane. The groups were further split in two for euthanasia 15 and 60days post-surgery. Data was statistically analyzed with t-tests for independent samples or the nonparametric Mann-Whitney test when applicable. Intragroup comparisons were analyzed with paired t-tests (p<0.05). ResultsMicro-CT analysis results did not demonstrate statistically significant intergroup differences. At 15days post-surgery, the histomorphometric analysis showed that the PTH Group exhibited a significantly higher percentage of bone formation compared with the S Group. At 60days post-surgery, a higher percentage of new bone was observed in the PTH group. ConclusionThe results suggest that the local administration of PTH encouraged the bone healing in critical-size calvarial defects in rats.

Parathyroid Hormone (1-34) Might Not Improve Early Bone Healing after Sinus Augmentation in Healthy Rabbits.

Purpose. This study evaluated the effect of administering intermittent parathyroid hormone [PTH (1-34), henceforth PTH] on the early-stage bone healing of maxillary sinus augmentation in healthy rabbits. Materials and Methods. Bovine bone mineral was grafted on the sinuses of 20 female New Zealand white rabbits. The animals were randomly divided into two groups, PTH (n = 10) or saline (n = 10), in which either PTH or saline was injected subcutaneously 5 days a week for 2 weeks. Half of the animals in each group were killed at 2 weeks postoperatively and the other half were killed at 4 weeks postoperatively. The dosage of PTH was 10 μg/kg/day. Radiographic and histomorphometric analyses were performed. Result. The new bone area (NBA) did not differ significantly between the PTH and saline groups. The NBA in the PTH group in the total augmented area and in the demarcated window, center, and Schneiderian membrane regions increased significantly from 2 to 4 weeks. The number of osteoclasts decreased significantly from 2 to 4 weeks in both groups, with no difference between the two groups. Conclusion. Intermittent PTH might not stimulate new bone formation in healthy rabbits during the first 4 weeks of healing.

Parathyroid hormone(1-34) exhibits more comprehensive effects than celecoxib in cartilage metabolism and maintaining subchondral bone micro-architecture in meniscectomized guinea pigs

To evaluate the effects of PTH(1-34) on cartilage, subchondral bone mass and structure in medial meniscectomized guinea pigs and compare them to those of celecoxib (CLX). Forty-eight 3-month-old male Hartley albino guinea pigs received either sham or medial meniscectomy (MNX) operations. One week after the procedure, meniscectomized animals began 12 weeks of treatment by oral administration of CLX (20mg/kg, daily), subcutaneous injection of PTH (1-34) (24μg/kg, 5 days/week), or normal saline for MNX group. All animals were euthanized 12 weeks later, cartilage degeneration and subchondral bone micro-architecture was analyzed. OARSI scores indicated cartilage degeneration was partially inhibited by either CLX or PTH(1-34). Cartilage was significantly thicker in PTH(1-34)-treated animals than in CLX-treated animals. Both CLX and PTH(1-34) treatment were associated with lower ADAMTS-4 and periostin expression than MNX. MMP-13 expression in PTH(1-34) group was significantly lower than that in CLX group. However, AGG expression and the ratio of Col-II/MMP-13 expression in PTH(1-34) group were significantly higher than in the CLX group. Micro-CT analysis showed BMD, BV/TV, and Tb.Th levels to be significantly lower in the MNX group and CLX groups than in the sham group, but these parameters were significantly higher in the PTH(1-34) group than in either the MNX group or CLX group. Both CLX and PTH(1-34) exhibits protective effects on cartilage degeneration in meniscectomized guinea pigs. However, PTH(1-34) exhibited superior performance to CLX not only in metabolism of cartilage tissue but also in maintenance of subchondral bone micro-architecture.

Intermittent administration of human parathyroid hormone (1-34) increases fixation of strontium-doped hydroxyapatite coating titanium implants via electrochemical deposition in ovariectomized rat femur.

Previous studies have demonstrated the effect of human parathyroid hormone (1-34) (PTH) or strontium-doped hydroxyapatite coating (Sr-HA) on osteoporotic bone implantation. However, reports about effects of PTH plus Sr-HA on bone osseointegration of titanium implants in a state of osteoporosis were limited. This study was designed to investigate the effects of intermittent administration of human parathyroid hormone (1-34) on strontium-doped hydroxyapatite coating (Sr-HA) implant fixation in ovariectomized (OVX) rats. Twelve weeks after bilateral ovariectomy, all animals were randomly divided into four groups including control group, Sr group, PTH group and PTH+Sr group. Forty OVX rats accepted implant insertion in the distal femurs, control group, and PTH group with HA implants and the Sr group and PTH+Sr group with Sr-HA implants. Animals from PTH group and PTH+Sr group then randomly received PTH (60 µg/kg, 3 times a week) until death at 12 weeks. After 12-week healing period, implants from group PTH+Sr revealed improved osseointegration compared with other treatment groups, which is manifested by the exceeding increase of bone area ratio and bone-to-implant contact, the trabecular microarchitecture and the maximal push-out force displayed by tests like histomorphometry, micro-CT, and biomechanics evaluation. These results demonstrated that PTH+ Sr-HA coatings could enhance implant osseointegration in OVX rats, and suggested the feasibility of using this method to improve implant fixation in osteoporotic bone.

Intermittent Administration of Parathyroid Hormone [1-34] Prevents Particle-Induced Periprosthetic Osteolysis in a Rat Model.

We examined whether intermittent administration of parathyroid hormone [1–34] (PTH[1–34]; 60 μg/kg/day) can prevent the negative effects of titanium (Ti) particles on implant fixation and periprosthetic osteolysis in a rat model. Eighteen adult male rats (12 weeks old, bones still growing) received intramedullary Ti implants in their bilateral femurs; 6 rats from the blank group received vehicle injections, and 12 rats from the control group and PTH treatment group received Ti particle injections at the time of operation and intra-articular injections 2 and 4 weeks postoperatively. Six of the rats that received Ti particles from the PTH group also received PTH[1–34] treatment. Six weeks postoperatively, all specimens were collected for assessment by X-ray, micro-CT, biomechanical, scanning electron microscopy (SEM), and dynamic histomorphometry. A lower BMD, BV/TV, Tb.N, maximal fixation strength, and mineral apposition rate were observed in the control group compared to the blank group, demonstrating that a periprosthetic osteolysis model had been successfully established. Administration of PTH[1–34] significantly increased the bone mineral density of the distal femur, BV/TV, Tb.N, Tb.Th, Tb.Sp, Con.D, SMI, and maximal fixation strength in the PTH group compared to that in the control group. SEM revealed higher bone–implant contact, thicker lamellar bone, and larger trabecular bone area in the PTH group than in the control group. A higher mineral apposition rate was observed in the PTH group compared to both the blank and control groups. These findings imply that intermittent administration of PTH[1–34] prevents periprosthetic osteolysis by promoting bone formation. The effects of PTH[1–34] were evaluated at a suprapharmacological dosage to the human equivalent in rats; therefore, additional studies are required to demonstrate its therapeutic potential in periprosthetic osteolysis.

Systemic application of teriparatide for steroid induced osteonecrosis in a rat model.

BackgroundSteroid associated osteonecrosis is difficult to treat. Teriparatide, as the only one bone anabolic drug, has achieved very promising effect in osteoporosis and other bone skeletal diseases. We carried out this animal study to evaluate the effect of subcutaneous injection of teriparatide for the steroid induced femoral head necrosis in a rat model.Methods24 Sprague–Dawley male adult rats were included in the study. All the rats were randomized into 4 groups: 18 rats from LPS/MPS group, LPS/MPS + PTH group and LPS/MPS + NS group were given lipopolysaccharide (20 μg/kg) and methylprednisolone (40 mg/kg) to establish the steroid induced osteonecrosis model. 6 rats from NS group only received normal saline. 4 weeks later, All the rats in LPS/MPS group and NS group were sacrificed and the femoral heads were harvested. After that, the 6 rats in the LPS/MPS + PTH group received subcutaneous injection of 20 μg/kg teriparatide and LPS/MPS + NS group only received equal amount of normal saline. After 4 weeks, the serum bone marker was tested and the femoral head were harvested. Micro-CT and histological examination were performed to compare the incidence of osteonecrosis and trabeculae parameters for the femoral head.ResultsAt 4 weeks, rats in LPS/MPS group showed significant osteonecrosis by histological examination (83.3 %) which suggested successful steroid induced osteronecrosis animal models were established. After the treatment of 4 weeks, the LPS/MPS + PTH group showed significant lower incidence rate of osteonecrosis compared with the LPS/MPS + NS group (16.7 % vs.75 %, P < 0.05). The micro CT examination showed higher bone volume/total volume, trabecula thickness and bone mineral density in the LPS/MPS + PTH group compared with the LPS/MPS + NS group. The serum osteocalcin was a little higher in the LPS/MPS + PTH group (4.54 ± 1.61vs.3.58 ± 1.81, P = 0.358), but it didn’t reach a statistical significance.ConclusionsSystemic application of teriparatide for steroid induced osteonecrosis in rats showed a beneficial effect. This may be one promising therapy for early stage osteonecrosis.

A Quantitative Study of the Effects of High-Dose Parathyroid Hormone (1–34) and Low-Dose rhBMP-2 on Posterolateral Lumbar Spine Fusion in a Rabbit Model

Introduction Parathyroid hormone (1–34) (PTH), which is commonly used in the treatment of osteoporosis, has been shown to increase bone mass and reduce the risk of fracture. Previously, we demonstrated that, while intermittent low-dose (10 µg/kg) PTH (1–34) treatment resulted in increased fusion mass volume, it did not improve biomechanical stiffness over the use of autograft alone, and did not improve fusion when combined with BMP-2 treatment (Lina et al, Spine [Phila Pa 1976]. 2014; 39(5):347). However, studies in other rodent models have indicated that the effects of PTH (1–34) on spinal fusion may be dose-dependent (Ming et al, Spine [Phila. Pa. 1976]. 2012; 37(15): 1275; Abe et al, Bone. 2007; 41(5): 775). These rat and mouse studies used PTH (1–34) doses as high as 20 to 40 µg/kg compared with the 10 µg/kg used in our experiments. We thus aim to evaluate whether increasing the dose of PTH (1–34) administered increases both the volume and biomechanical stiffness of the resulting fusion masses and/or exhibits synergistic effects with low-dose BMP-2 treatment. Materials and Methods A total of 60 rabbits underwent posterolateral intertransverse process lumbar spinal fusion surgery, and were assigned to one of the six groups depending upon the fusion grafting group employed: iliac crest autograft alone ( n = 10), iliac crest autograft + 20 µg/kg PTH (1–34) ( n = 10), iliac crest autograft + 40 µg/kg PTH (1–34) ( n = 10), rhBMP-2 alone ( n = 10), rhBMP-2 + 20 µg/kg PTH (1–34) and, rhBMP-2 + 40 µg/kg PTH (1–34). Fusion mass and quality were assessed using manual palpation, CT analysis of fusion mass volume, and four-point nondestructive biomechanical testing. Results/Conclusions: Although manual palpation is used as the standard measure of fusion, we found that CT analysis proved more effective in differentiating fused masses based on bone formation, not fibrous tissue. Both the PTH (1–34) group and BMP-2 increased bone density and volume of the fusion masses. Biomechanical analysis of fusion mass strength is currently underway.

Individual and combining effects of anti-RANKL monoclonal antibody and teriparatide in ovariectomized mice

We examined the individual and combined effects of teriparatide and anti-RANKL (receptor activator of nuclear factor κB ligand) monoclonal antibody in ovariectomized mice. Three-month-old female C57BL/6 mice were ovariectomized (OVX) or sham operated. Four weeks after OVX, they were assigned to 3 different groups to receive anti-RANKL monoclonal antibody (Ab) alone (5mg/kgsingle injection at 4weeks after OVX, Ab group), teriparatide alone (80μg/kg daily injection for 4weeks from 4weeks after OVX, PTH group), or mAb plus teriparatide (Ab+PTH group). Mice were sacrificed 8weeks after OVX. Bone mineral density (BMD) was measured at the femur and lumbar spine. Hind limbs were subjected to histological and histomorphometric analysis. Serum osteocalcin and CTX-I levels were measured to investigate the bone turnover. Compared with Ab group, Ab+PTH group showed a significant increase in BMD at distal femur and femoral shaft. Cortical bone volume was significantly increased in PTH and Ab+PTH groups compared with Ab group. Bone turnover in Ab+PTH group was suppressed to the same degree as in Ab group. The number of TRAP-positive multinucleated cells was markedly reduced in Ab and Ab+PTH groups. These results suggest that combined treatment of teriparatide with anti-RANKL antibody has additive effects on BMD in OVX mice compared with individual treatment.

Comparison between different bone treatments on areal bone mineral density (aBMD) and bone microarchitectural texture as assessed by the trabecular bone score (TBS)

PurposeThe objective of the study was to assess longitudinal effects of different osteoporosis treatments on TBS and aBMD at lumbar spine. MethodWe analyzed 390 patients (men: 72; women: 318; age>40years; mean follow-up of 20months and BMI<37kg/m2). We stratified the cohort by treatments: Naive of treatment (Naive, n=67), Calcium and Vitamin D (CaVitD, n=87), Testosterone (Te, n=36), Alendronate (AL, n=88), Risedronate (Ri, n=39), Denosumab (Dmb, n=43) and Teriparatide (PTH, n=30). The follow-up changes from baseline were normalized at 24months. ResultsAfter 24months, Naive group TBS decreased by 3.1% (p<0.05) whereas a non-significant increase was observed for spine aBMD (Δ=+0.5%). Compared to the Naive group, significant improvement (p<0.05) was observed in both TBS and aBMD for Te, AL, Ri, Dmb and PTH groups and in the CaVitD group for TBS. At the end of the follow-up, significant improvement have been observed for aBMD in Te (+4.4%), AL (+4.1%), Ri (+4.8), D (+8.8%) and PTH (+8.8%) groups. Significant improvement was observed only in the AL (+1.4%), Dmb (+2.8%) and PTH (+3.6%) groups for TBS. ConclusionAs expected, TBS of Naive subjects decreased with age. As expected a TBS preservation has been observed under AL and Ri. Te and CaVitD effects on TBS were evaluated for the first time: a similar preservation effect has been observed. A significant TBS increase was observed under Denosumab and PTH. TBS could be a useful tool to monitor treatment effects.