Effects Of Intermittent Parathyroid Hormone Research Articles

The effect of intermittent parathyroid hormone on bone lengthening: current evidence to inform future effective interventions.

Recent studies have demonstrated the positive effects of parathyroid hormone (PTH) on bone healing, and findings support the use of PTH to accelerate bone healing following distraction osteogenesis. The goal of this review was to compile and discuss the mechanisms potentially underlying the effects of PTH on newly formed bone following a bone-lengthening procedure incorporating all relevant evidence in both animal and clinical studies. This review summarized all evidence from in vivo to clinical studies regarding the effects of PTH administration on a bone-lengthening model. In addition, a comprehensive evaluation of what is currently known regarding the potential mechanisms underlying the potential benefits of PTH in bone lengthening was presented. Some controversial findings regarding the optimal dosage and timing of administration of PTH in this model were also discussed. The findings demonstrated that the potential mechanisms associated with the action of PTH on the acceleration of bone regeneration after distraction osteogenesis are involvement in mesenchymal cell proliferation and differentiation, endochondral bone formation, membranous bone formation, and callus remodeling. In the last 20 years, a number of animal and clinical studies have indicated that there is a prospective role for PTH treatment in human bone lengthening as an anabolic agent that accelerates the mineralization and strength of the regenerated bone. Therefore, PTH treatment can be viewed as a potential treatment to increase the amount of new calcified bone and the mechanical strength of the bone in order to shorten the consolidation stage after bone lengthening.

Regional modular responses in different bone compartments to the anabolic effect of PTH (1-34) and axial loading in mice.

Beneficial effects of intermittent parathyroid hormone (PTH) on bone mass and architecture are described to either simply add to, or to synergise with those of mechanical loading. We evaluate whether interaction with in vivo loading is reinforced by PTH dosing regimen and exhibits compartment-specific sensitivities. Female 12-week-old C57Bl6 mice received daily (7/7) or interrupted 5day/week (5/7) PTH for 3weeks (two vehicle groups). All mice had six loading episodes (12N) applied to right tibia (left, non-loaded) for the last 2weeks. Micro-CT scans were used to evaluate mass and architecture in almost the entire cortical and proximal trabecular regions. Epiphyseal cortical, trabecular and marrow space volumes, and bony growth-plate bridge incidence were evaluated. Statistical analyses employed a linear mixed-effects model at each percentile and 2-way ANOVA with post-hoc test for epiphyses and bridging. We found that daily PTH enhances cortical mass and modifies shape along almost the entire tibia and that these effects are partly mitigated by brief interruption in treatment. Mechanical loading alone augments cortical mass and modifies shape but only in a region proximal to the tibiofibular junction. The effect of combining load and daily PTH dosing is solely additive for cortical bone mass with no significant load: PTH interaction, but exhibits clear synergy with interrupted PTH treatment. Daily, not interrupted PTH stimulates trabecular bone gains, yet load:PTH interaction is present at limited regions with both daily and interrupted treatment. PTH treatment, but not loading, modifies epiphyseal bone but, in contrast, only loading modifies bridge number and areal density. Our findings demonstrate impressive local effects on tibial mass and shape of combined loading and PTH that are sensitive to dosing regimen and exert their effects modularly. These findings emphasise a need to clarify PTH dosing regimens and that advantages could be accrued by aligning treatment accordingly to patient requirements and life-style.

Intermittent Parathyroid Hormone Alters Gut Microbiota in Ovariectomized Osteoporotic Rats.

ObjectiveTo investigate the effect of intermittent parathyroid hormone (PTH) on gut microbiota (GM) in ovariectomized (OVX) osteoporotic rats.MethodsThirty female Sprague–Dawley rats were divided into three groups: sham‐operation (SHAM) group, OVX group and PTH treatment group. After 3 months of treatment, the femurs, serum and feces were acquired for micro‐CT, biochemical analysis and 16S rRNA sequencing, respectively. For 16S rRNA sequencing, after raw reads filtrated and chimera sequences removed, the clean reads were obtained. According to these clean reads, the operational taxonomic units (OTUs) were clustered. Venn diagram analysis was conducted to explore common and unique GM among the three groups. The α‐diversity analysis including Shannon and Simpson indexes were used to evaluate the richness and diversity of the GM. The β‐diversity analysis was performed to estimate the structure of GM. The metabolic function was predicted by Tax4Fun analysis.ResultsWith micro‐CT and biochemical analysis, significant improvements were found in the PTH group compared with the OVX group. In Venn diagram analysis, more unique OTUs were found in the SHAM and PTH groups than the OVX group. According to the rank abundance curve, the SHAM and PTH groups had similar richness and evenness, which were higher than the OVX group. Simpson and Shannon indexes were higher in the SHAM and PTH groups compared with the OVX group, indicating that the SHAM and PTH groups had higher microbiota complexity than the OVX group. In β‐diversity analysis, apparent separation was found in the OVX group from the PTH and SHAM groups, which suggested that osteoporosis is the critical factor influencing the GM composition and PTH treatment and can restore the structure of GM. Compared with the OVX group, treatment with PTH increased the abundances of GM which were reported to increase bone mass, such as Lactobacillus_reuteri, Muribaculaceae, Ruminococcaceae, and Clostridia, and inhibited the relative abundance of Rikenellaceae, which was reported to be potentially related to osteoporosis. GM function analysis showed that PTH could promote butyrate synthesis. In Tax4Fun analysis, the function of butanoate metabolism is more vital in the PTH group than the OVX and SHAM groups, suggesting PTH treatment could regulate microbial metabolic function, including butanoate metabolism.ConclusionIntermittent PTH can interact with GM through increasing the abundance of probiotics and reducing the abundance of the pathogenic bacteria to enhance the bone mass.

Effects of intermittent parathyroid hormone on cementoblast-mediated periodontal repair.

To investigate the effects of intermittent parathyroid hormone on cementoblast-mediated periodontal repair in the context of orthodontic-induced root resorption. The rat model of orthodontic-induced root resorption was established. Sixty rats were randomly allocated into the experiment group (n=30) and the control group (n=30), either receiving a daily subcutaneous injection of recombinant human PTH or placebo vehicle. Enzyme-linked immunosorbent assay, Micro-computed tomography, hematoxylin and eosin staining, and immunohistochemistry staining were performed to detect the periodontal repair. In vitro, OCCM-30 cells were exposed to intermittent PTH (incubated with PTH for the first 6h in each 24-h cycle). After three cycles, flow cytometry assay, alkaline phosphatase staining, and Alizarin red staining were performed. Quantitative real-time polymerase chain reaction and Western blotting were employed to further determine the effects of intermittent PTH. Intermittent PTH-responsive repair enhancement was detected with the expression of bone sialoprotein, osteocalcin, collagen-1, and alkaline phosphatase significantly upregulated. Increased expressions of cementoblastic proteins were positively correlated to cycles of PTH administration. The proportion of cementoblasts in S and G2/M phases was increased; namely, intermittent PTH promoted cementoblast cell proliferation. Intermittent parathyroid hormone administration promotes cementoblast-mediated cementogenesis during periodontal repair in a time-dependent manner.

Intermittent parathyroid hormone treatment affects the bone structural parameters and mechanical strength of the femoral neck after ovariectomy-induced osteoporosis in rats

BackgroundMenopause-induced decline in estrogen levels in women is a main factor leading to osteoporosis. The objective of this study was to investigate the effect of intermittent parathyroid hormone (PTH) on bone structural parameters of the femoral neck in ovariectomized rats, in addition to correlations of maximum fracture force.MethodsFifteen female Wister rats were divided into three groups: (1) control group; (2) ovariectomized (OVX) group; and (3) OVX + PTH group. All rats were then killed and the femurs extracted for microcomputed tomography scanning to measure volumetric bone mineral density (vBMD) and bone structural parameters of the femoral neck. Furthermore, the fracture forces of femoral neck were measured using a material testing system.ResultsCompared with the control and OVX + PTH groups, the OVX group had significantly lower aBMD, bone parameter, and mechanical strength values. A comparison between OVX and OVX + PTH groups indicated that PTH treatment increased several bone parameters. However, the OVX + PTH groups did not significantly differ with the control group with respect to the bone structural parameters, except for trabecular bone thickness of cancellous bone, which was greater. In addition, among the bone structural parameters, the CSA and BSI of cortical bone were significantly correlated with the maximum fracture force of the femoral neck, with correlations of, respectively, 0.682 (p = 0.005) and 0.700 (p = 0.004).ConclusionIntermittent PTH helped treat ovariectomy-induced osteoporosis of cancellous bone and cortical bone in the femoral necks of rats. The ability of the femoral neck to resist fracture was highly correlated with the two parameters, namely cross-sectional area (CSA) and bone strength index (= vBMD × CSA), of cortical bone in the femoral neck and was less correlated with aBMD or other bone structural parameters.

Short Cyclic Regimen With Parathyroid Hormone (PTH) Results in Prolonged Anabolic Effect Relative to Continuous Treatment Followed by Discontinuation in Ovariectomized Rats.

Despite the potent effect of intermittent parathyroid hormone (PTH) treatment on promoting new bone formation, bone mineral density (BMD) rapidly decreases upon discontinuation of PTH administration. To uncover the mechanisms behind this adverse phenomenon, we investigated the immediate responses in bone microstructure and bone cell activities to PTH treatment withdrawal and the associated long-term consequences. Unexpectedly, intact female and estrogen-deficient female rats had distinct responses to the discontinuation of PTH treatment. Significant tibial bone loss and bone microarchitecture deterioration occurred in estrogen-deficient rats, with the treatment benefits of PTH completely lost 9 weeks after discontinuation. In contrast, no adverse effect was observed in intact rats, with sustained treatment benefit 9 weeks after discontinuation. Intriguingly, there is an extended anabolic period during the first week of treatment withdrawal in estrogen-deficient rats, during which no significant change occurred in the number of osteoclasts, whereas the number of osteoblasts remained elevated compared with vehicle-treated rats. However, increases in number of osteoclasts and decreases in number of osteoblasts occurred 2 weeks after discontinuation of PTH treatment, leading to significant reduction in bone mass and bone microarchitecture. To leverage the extended anabolic period upon early withdrawal from PTH, a cyclic administration regimen with repeated cycles of on and off PTH treatment was explored. We demonstrated that the cyclic treatment regimen efficiently alleviated the PTH withdrawal-induced bone loss, improved bone mass, bone microarchitecture, and whole-bone mechanical properties, and extended the treatment duration. © 2021 American Society for Bone and Mineral Research (ASBMR).

Intermittent parathyroid hormone improves orthodontic retention via insulin-like growth factor-1.

This study aimed to investigate the effects of intermittent parathyroid hormone (iPTH) on the stability of orthodontic retention and to explore the possible regulatory role of insulin-like growth factor-1 (IGF-1) in this process. Forty-eight 6-week-old male Wistar rats were adopted in this study. An orthodontic relapsing model was established to investigate the effects of iPTH on orthodontic retention. In vitro, an immortalized mouse cementoblast cell line OCCM-30 was detected by flow cytometry to study the effects of iPTH on cell proliferation and apoptosis. By application of a specific IGF-1 receptor inhibitor, the role of IGF-1 was also explored. In vivo study found that daily injection of PTH significantly reduced the relapsing distance. Histological staining and ELISA assay showed faster periodontal regeneration during retention period in PTH group with increased RANKL/OPG ratio and greater amount of OCN, ALP, and IGF-1 in gingival cervical fluid (GCF). Cell experiment revealed that iPTH promoted proliferation and suppressed apoptosis of cementoblast. IGF-1 receptor inhibitor significantly restrained the anabolic effect of iPTH on OCCM-30 cells. These findings suggest that iPTH could improve the stability of tooth movement by promoting periodontal regeneration. IGF-1 is essential in mediating the anabolic effects of iPTH.

Short-term intermittent parathyroid hormone (1-34) administration increased angiogenesis and matrix metalloproteinase 9 in femora of mature and middle-aged C57BL/6 mice.

What is the central question of this study? We sought to assess the effects of intermittent parathyroid hormone (1-34) administration on bone angiogenesis, the redistribution of bone marrow blood vessels, and matrix metalloproteinase9 as a function of advancing age in mice. What is the main finding and its importance? Short-term (i.e. 10 days) intermittent parathyroid hormone (1-34) administration increased the number of small (≤29-µm-diameter) bone marrow blood vessels and augmented matrix metalloproteinase9. These changes occurred before alterations in trabecular bone. Given the rapid response in bone angiogenesis, this investigation highlights the impact of intermittent parathyroid hormone (1-34) administration on the bone vascular network. Intermittent parathyroid hormone (PTH) administration augments bone, stimulates the production of matrix metalloproteinase9 (Mmp9) and relocates bone marrow blood vessels closer to osteoid seams. Discrepancies exist, however, regarding bone angiogenesis. Given that Mmp9 participates in cellular homing and migration, it might aid in blood vessel relocation. We examined the influence of short-term intermittent PTH administration on angiogenesis, Mmp9 secretion and the distance between blood vessels and bone. Mature (6- to 8-month-old) and middle-aged (10- to 12-month-old) male and female C57BL/6 mice were divided into three groups: control (CON), and 5 (5dPTH) and 10days (10dPTH) of intermittent PTH administration. Mice were given PBS (50µlday-1 ) or PTH(1-34) (43µgkg-1 day-1 ). Frontal sections (5µm thick) of the right distal femoral metaphysis were triple-immunolabelled to identify endothelial cells (anti-CD31), vascular smooth muscle cells (anti-αSMA) and Mmp9 (anti-Mmp9). Vascular density, Mmp9 density, area and localization, and blood vessel distance from bone were analysed. Blood vessels were analysed according to diameter: 1-29, 30-100 and 101-200µm. Trabecular bone microarchitecture and bone static and dynamic properties were assessed. No main effects of age were observed for any variable. The density of CD31-labelled blood vessels 1-29 and 30-100µm in diameter was higher (P<0.05) and tended (P=0.055) to be higher, respectively, in 10dPTH versus 5dPTH and CON. Mmp9 was augmented (P<0.05) in 10dPTH versus the other groups. Mmp9 was closer (P<0.05) to blood vessels 1-29µm in diameter and furthest (P<0.05) from bone. In conclusion, bone angiogenesis occurred by day10 of intermittent PTH administration, coinciding with augmented Mmp9 secretion near the smallest blood vessels (1-29µm in diameter).

Enhancement of the effects of intermittent parathyroid hormone (1-34) by bone morphogenetic protein in a rat femoral open fracture model

BackgroundNonunion in cases of open fracture is common. Both bone morphogenetic protein 2 (BMP-2) and parathyroid hormone (PTH) have been used to enhance bone healing. We investigated the combination of BMP-2 and PTH and examined the effects on a rat model of open femoral fractures.MethodsGroup I (n = 11) was implanted with control carrier. Group II (n = 12) was implanted with carrier containing 1 μg of recombinant human BMP-2 (rhBMP-2). Group III (n = 12) was implanted with carrier alone, followed by injections of PTH 1-34. Group IV (n = 11) was implanted with carrier containing 1 μg of rhBMP-2, followed by injections of PTH 1-34. Group V (n = 11) was implanted with carrier containing 10 μg of rhBMP-2. Group VI (n = 11) was implanted with carrier containing 10 μg of rhBMP-2, followed by injections of PTH 1-34. Rats were euthanized after 8 weeks, and their fractured femurs were explanted and assessed by manual palpation, radiographs, micro-computerized tomography, and histological analysis.ResultsManual palpation tests showed that the fusion rates of groups III (66.7%), IV (63.6%), V (81.8%), and VI (81.8%) were considerably higher than those of group I. Groups V and VI had higher radiographic scores compared to group I. Micro-CT analysis revealed enhanced bone marrow density expressed as bone volume/tissue volume in groups V (61.88 ± 3.16%) and VI (71.14 ± 3.89%) versus group I (58.26 ± 1.86%). A histological analysis indicated that group VI had enhanced remodeling.ConclusionThe combination of abundant rhBMP-2 and PTH enhanced bone healing and remodeling of newly formed bone in a rat femoral open fracture model.

Effects of Intermittent Administration of Parathyroid Hormone and Parathyroid Hormone-Related Protein on Fracture Healing: A Narrative Review of Animal and Human Studies.

ABSTRACTIntermittent administration of parathyroid hormone (PTH) stimulates skeletal remodeling and is a potent anabolic agent in bone. PTH‐related protein (PTHrP) is anabolic acting on the same PTH1 receptor and is in therapeutic use for osteoporosis. The body of literature for PTH actions in fracture healing is emerging with promising yet not entirely consistent results. The objective of this review was to perform a literature analysis to extract up‐to‐date knowledge on the effects of intermittent PTH and PTHrP therapy in bone fracture healing. A literature search of the PubMed database was performed. Clinical case studies and articles related to “regeneration,” “implant,” and “distraction osteogenesis” were excluded. A narrative review was performed to deliberate the therapeutic potential of intermittent PTH administration on fracture healing. A smaller number of studies centered on the use of PTHrP or a PTHrP analog were also reviewed. Animal studies clearly show that intermittent PTH therapy promotes fracture healing and revealed the strong therapeutic potential of PTH. Human subject studies were fewer and not as consistent as the animal studies yet provide insight into the potential of intermittent PTH administration on fracture healing. Differences in outcomes for animal and human studies appear to be attributed partly to variable doses, fracture sites, age, remodeling patterns, and bone architectures, although other factors are involved. Future studies to examine the dose, timing, and duration of PTH administration will be necessary to further delineate the therapeutic potential of PTH for fracture healing in humans. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

CD8+ T lymphocytes enhance the anabolic effect of intermittent parathyroid hormone on cementoblasts

Root resorption is usually inflammatory in nature and has a tight link with immune system. Intermittent parathyroid hormone (iPTH) could promote cementum regeneration. The cross-talk of immune cells and cementoblasts may play an important role in the regeneration which stayed to be elucidated. In this study, a CD8+ T cells-OCCM-30 cells coculture system was established in vitro to investigate whether CD8+ T cells could enhance the anabolic effect of iPTH on cementoblasts and to find out the potential link of the effect with Wnt signal pathway. Determined by real-time PCR and Western Blot, we found an amplified cementogenesis in the OCCM-30 cells from coculture system, including increased mRNA and protein expression of Alp, Opn and Runx2, ALP activity and mineralization. We also found iPTH could increase the expression of Wnt10b in CD8+ T cells by ELISA. In addition, Wnt10b would promote the proliferation of OCCM-30 cells, while the effect on differentiation was various in different culture medium. These results demonstrated that the stimulating effect of iPTH on cementoblasts could be mediated through an interaction with CD8+ T cells, and T-cell-induced Wnt10b might be a key mechanism in the mediation.

Intermittent Parathyroid Hormone [1-34] Augments Chondrogenesis of the Mandibular Condylar Cartilage of the Temporomandibular Joint.

To characterize the long-term effects of intermittent parathyroid hormone (I-PTH) on the mandibular condylar cartilage (MCC) and subchondral bone of the temporomandibular joint, in vivo and in vitro. For the in vivo experiments, sixteen 10-week-old mice were divided into 2 groups: (1) I-PTH (n = 8)-subcutaneous daily injection of PTH; (2) control group (n = 8)-subcutaneous daily injection of saline solution. Experiments were carried out for 4 weeks. Mice were injected with calcein, alizarin complexone, and cell proliferation marker before euthanasia. For the in vitro experiments, primary chondrocyte cultures from the MCC of eight 10-week-old mice were treated with I-PTH for 14 days. There was a significant increase in bone volume, tissue density, mineral deposition, osteoclastic activity, cell proliferation in the cartilage, and cartilage thickness in the I-PTH-treated mice when compared with the control group. In addition, immunohistochemistry in cartilage revealed that I-PTH administration led to an increase in expression of vascular endothelial growth factor and to a decreased expression of sclerostin, matrix metallopeptidase 13, and aggreganase-1 (ADAM-TS4). Quantitative polymerase chain reaction analysis of the I-PTH-treated chondrocytes revealed significantly decreased relative expression of collagen type X (Col10a1), alkaline phosphatase (Alp), and Indian Hedgehog (Ihh) and remarkable increased expression of Sox9, fibroblast growth factor 2 (Fgf2), and proteoglycan 4 (Prg4). I-PTH administration causes anabolic effects at the subchondral region of the mandibular condyle while triggers anabolic and protective effects at the MCC.

Effects of Intermittent Parathyroid Hormone 1-34 Administration on Circulating Mesenchymal Stem Cells in Postmenopausal Osteoporotic Women.

BackgroundIntermittent parathyroid hormone (PTH) 1–34 administration stimulates osteogenesis and increases bone marrow mesenchymal stem cell (MSC) density; however, its effect on the circulating MSCs is unknown. This study aimed to examine the effect of intermittent PTH 1–34 administration on circulating MSCs in the peripheral blood of postmenopausal osteoporotic women.Material/MethodsFifty-four postmenopausal osteoporotic women at high risk of fracture were enrolled and administered either teriparatide (PTH 1–34) or alendronate for 12 months. Whole blood samples were obtained at baseline, 1, 3, 6, and 12 months after initiation of treatment. Flow cytometry analyses were performed to identify circulating MSCs (CD73+, CD90+, CD105+, CD34−, and CD45−). Serum markers of bone formation, bone resorption, as well as bone mineral density (BMD) were serially measured. Circulating MSCs were isolated from peripheral blood of teriparatide treated women and cultured in osteogenic medium to examine their osteogenic differentiation potential.ResultsTeriparatide treatment increased circulating MSCs to 141±96% (P<0.001) by month 1, persisting until month 12; this increase was positively associated with increases in bone formation and bone resorption biomarkers (at month 6) and spine BMD (at month 12). Furthermore, intermittent PTH 1–34 administration promoted in vitro osteogenic differentiation of circulating MSCs, evident from increased alkaline phosphatase (ALP) activity, ALP-expressing cell density, calcium deposition, and Runx-2, OSX, COL 1a1, and osteocalcin mRNA upregulation.ConclusionsIntermittent PTH 1–34 administration increased circulating MSC density in women with postmenopausal osteoporosis and enhanced in vitro osteogenic differentiation potential of these cells.

PTH [1\u201334] induced differentiation and mineralization of mandibular condylar cartilage

Intermittent Parathyroid Hormone (I-PTH) is the only FDA approved anabolic drug therapy available for the treatment of osteoporosis in males and postmenopausal females. The effects of I-PTH on the chondrogenic lineage of the mandibular condylar cartilage (MCC) are not well understood. To investigate the role of I-PTH on the MCC and subchondral bone, we carried out our studies using 4 to 5 week old triple transgenic mice (Col1a1XCol2a1XCol10a1). The experimental group was injected with PTH (80 μg/kg) daily for 2 weeks, while control group was injected with saline. Our histology showed that the I-PTH treatment led to an increased number of cells expressing Col1a1, Col2a1 and Col10a1. Additionally, there was an increase in cellular proliferation, increased proteoglycan distribution, increased cartilage thickness, increased TRAP activity, and mineralization. Immunohistochemical staining showed increased expression of pSMAD158 and VEGF in the MCC and subchondral bone. Furthermore our microCT data showed that I-PTH treatment led to an increased bone volume fraction, tissue density and trabecular thickness, with a decrease in trabecular spacing. Morphometric measurements showed increased mandibular length and condyle head length following I-PTH treatment. In conclusion, our study suggests that I-PTH plays a critical role in cellular proliferation, proteoglycan distribution, and mineralization of the MCC.

PTH [1-34]-induced alterations predispose the mandibular condylar cartilage to mineralization.

To study the effects of intermittent parathyroid hormone (PTH [1-34]) on the mandibular condylar cartilage (MCC) and subchondral bone in adult female mice. Twenty-two, 20-week-old female mice were used for in vivo experiments. The experimental mice (n=11) received daily intraperitoneal injections of PTH [1-34] for 3weeks, while control mice (n=11) received intraperitoneal injections of 0.9% saline solution. Mice were euthanized and then micro-computed tomography (micro-CT); histology and immunostaining were carried out to assess the response. Intermittent PTH [1-34] led to early MCC breakdown and surface irregularities. Micro-CT analyses indicated that PTH [1-34] treatment led to increased bone volume fraction, tissue density and trabecular thickness, while decreasing the trabecular spacing. Histological analyses showed decreased proteoglycan secretion, increased bone turnover (TRAP staining) and increased mineralization. Furthermore, PTH [1-34] treatment showed increased apoptosis of the cells. Our immunohistochemistry showed increased expression of pSMAD158 in the MCC and subchondral bone with PTH administration, whereas sclerostin (SOST) expression was decreased. Intermittent PTH [1-34] results in early mineralization of the MCC, which may result in cartilage degeneration. Our results identified a novel mechanism by which PTH [1-34] induces alteration in the microarchitecture of the MCC and the subchondral bone.

Intermittent Parathyroid Hormone After Prolonged Alendronate Treatment Induces Substantial New Bone Formation and Increases Bone Tissue Heterogeneity in Ovariectomized Rats.

Postmenopausal osteoporosis is often treated with bisphosphonates (eg, alendronate, [ALN]), but oversuppression of bone turnover by long-term bisphosphonate treatment may decrease bone tissue heterogeneity. Thus, alternate treatment strategies after long-term bisphosphonates are of great clinical interest. The objective of the current study was to determine the effect of intermittent parathyroid hormone (PTH) following 12 weeks of ALN (a bisphosphonate) treatment in 6-month-old, ovariectomized (OVX) rats on bone microarchitecture, bone remodeling dynamics, and bone mechanical properties at multiple length scales. By using in vivo μCT and 3D in vivo dynamic bone histomorphometry techniques, we demonstrated the efficacy of PTH following ALN therapy for stimulating new bone formation, and increasing trabecular thickness and bone volume fraction. In healthy bone, resorption and formation are coupled and balanced to sustain bone mass. OVX results in resorption outpacing formation, and subsequent bone loss and reduction in bone tissue modulus and tissue heterogeneity. We showed that ALN treatment effectively reduced bone resorption activity and regained the balance with bone formation, preventing additional bone loss. However, ALN treatment also resulted in significant reductions in the heterogeneity of bone tissue mineral density and tissue modulus. On the other hand, PTH treatment was able to shift the bone remodeling balance in favor of formation, with or without a prior treatment with ALN. Moreover, by altering the tissue mineralization, PTH alleviated the reduction in heterogeneity of tissue material properties induced by prolonged ALN treatment. Furthermore, switching to PTH treatment from ALN improved bone's postyield mechanical properties at both the whole bone and apparent level compared to ALN alone. The current findings suggest that intermittent PTH treatment should be considered as a viable treatment option for patients with prior treatment with bisphosphonates. © 2017 American Society for Bone and Mineral Research.

Intermittent parathyroid hormone (PTH) promotes cementogenesis and alleviates the catabolic effects of mechanical strain in cementoblasts

BackgroundExternal root resorption, commonly starting from cementum, is a severe side effect of orthodontic treatment. In this pathological process and repairing course followed, cementoblasts play a significant role. Previous studies implicated that parathyroid hormone (PTH) could act on committed osteoblast precursors to promote differentiation, and inhibit apoptosis. But little was known about the role of PTH in cementoblasts. The purpose of this study was to investigate the effects of intermittent PTH on cementoblasts and its influence after mechanical strain treatment.ResultsHigher levels of cementogenesis- and differentiation-related biomarkers (bone sialoprotein (BSP), osteocalcin (OCN), Collagen type I (COL1) and Osterix (Osx)) were shown in 1–3 cycles of intermittent PTH treated groups than the control group. Additionally, intermittent PTH increased alkaline phosphatase (ALP) activity and mineralized nodules formation, as measured by ALP staining, quantitative ALP assay, Alizarin red S staining and quantitative calcium assay. The morphology of OCCM-30 cells changed after mechanical strain exertion. Expression of BSP, ALP, OCN, osteopontin (OPN) and Osx was restrained after 18 h mechanical strain. Furthermore, intermittent PTH significantly increased the expression of cementogenesis- and differentiation-related biomarkers in mechanical strain treated OCCM-30 cells.ConclusionsTaken together, these data suggested that intermittent PTH promoted cementum formation through activating cementogenesis- and differentiation-related biomarkers, and attenuated the catabolic effects of mechanical strain in immortalized cementoblasts OCCM-30.

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.

Intermittent parathyroid hormone (1-34) application regulates cAMP-response element binding protein activity to promote the proliferation and osteogenic differentiation of bone mesenchymal stromal cells, via the cAMP/PKA signaling pathway.

The potential effects of intermittent parathyroid hormone (1-34) [PTH (1-34)] administration on bone formation have previously been investigated. A number of studies have suggested that the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway is associated with PTH-induced osteogenic differentiation. However, the precise signaling pathways and molecular mechanism by which PTH (1-34) induces the osteogenic differentiation of bone mesenchymal stromal cells (BMSCs) remain elusive. The purpose of the present study was to investigate the mechanism underlying the effect of intermittent PTH (1-34) application on the proliferation and osteogenic differentiation of BMSCs. BMSCs were randomly divided into four groups, as follows: Osteogenic medium (control group); osteogenic medium and intermittent PTH (1-34); osteogenic medium and intermittent PTH (1-34) plus the adenylyl cyclase activator forskolin; and osteogenic medium and intermittent PTH (1-34) plus the PKA inhibitor H-89. A cell proliferation assay revealed that PTH (1-34) stimulates BMSC proliferation via the cAMP/PKA pathway. Furthermore, reverse transcription-quantitative polymerase chain reaction, alkaline phosphatase activity testing and cell examination using Alizarin Red S staining demonstrated that PTH (1-34) administration promotes osteogenic differentiation and mineralization, mediated by the cAMP/PKA pathway. Crucially, the results of western blot analyses suggested that PTH (1-34) treatment and, to a greater degree, PTH (1-34) plus forskolin treatment caused an increase in phosphorylated cAMP response element binding protein (p-CREB) expression, but the effect of PTH on p-CREB expression was blocked by H-89. In conclusion, the current study demonstrated that intermittent PTH (1-34) administration regulates downstream proteins, particularly p-CREB, in the cAMP/PKA signaling pathway, to enhance the proliferation, osteogenic differentiation and mineralization of BMSCs.

Effect of intermittent PTH (1–34) on posterolateral spinal fusion with iliac crest bone graft in an ovariectomized rat model

Intermittent treatment with high-dose parathyroid hormone (PTH) enhances the quantity and quality of the fusion callus and reduces healing time of posterolateral spinal fusion with autologous iliac bone grafts in ovariectomized osteoporotic female Sprague-Dawley rats. Intermittent PTH (1-34) could be an appropriate adjunctive therapy for osteoporotic patients undergoing posterolateral intertransverse process fusion. The study was designed to test the hypothesis that intermittent administration of PTH improves spinal fusion rates in a randomized controlled, ovariectomized osteoporotic rat spinal fusion model. Thirty-six 10-week-old Sprague-Dawley rats were ovariectomized and underwent bilateral posterolateral L4-L5 spinal fusion with autologous iliac bone graft 6 weeks later. The experimental (PTH) group (18 rats) received daily subcutaneously administered injections of PTH (1-34) at 30 μg/kg/day starting on the day of operation. The control group (18 rats) received a subcutaneously administered injection of normal saline of the same volume. Nine rats from each group were sacrificed at 4 and 6 weeks. After sacrifice, the L4-L5 vertebral segments were removed and analyzed by plain radiographs, μ-CT, histomorphometry, and serum bone metabolism marker. The PTH group had a significantly higher fusion rate and X-ray fusion score than the control group at 4 and 6 weeks (p < 0.05). μ-CT and histological analysis showed that the fusion bone volume and cortical thickness for the PTH group were significantly higher than those for the control group at 4 and 6 weeks (p < 0.05). Metabolic marker analysis also showed significant difference between the two groups. The serum osteocalcin was significantly higher in the PTH group at 4 and 6 weeks, and levels of N-terminal peptide of type I collagen were significantly higher at 4 weeks (p < 0.05). Intermittent treatment with high-dose PTH enhances the quantity of the fusion callus and reduces the healing time of posterolateral spinal fusion with autologous iliac bone grafts in ovariectomized osteoporotic female Sprague-Dawley rats.