Intermittently administered parathyroid hormone (PTH 1-34) has been shown to promote bone formation in both human and animal studies. The hormone and its analogues stimulate both bone formation and resorption, and as such at low doses are now in clinical use for the treatment of severe osteoporosis. By varying the duration of exposure, parathyroid hormone can modulate genes leading to increased bone formation within a so-called ‘anabolic window’. The osteogenic mechanisms involved are multiple, affecting the stimulation of osteoprogenitor cells, osteoblasts, osteocytes and the stem cell niche, and ultimately leading to increased osteoblast activation, reduced osteoblast apoptosis, upregulation of Wnt/β-catenin signalling, increased stem cell mobilisation, and mediation of the RANKL/OPG pathway. Ongoing investigation into their effect on bone formation through ‘coupled’ and ‘uncoupled’ mechanisms further underlines the impact of intermittent PTH on both cortical and cancellous bone. Given the principally catabolic actions of continuous PTH, this article reviews the skeletal actions of intermittent PTH 1-34 and the mechanisms underlying its effect. Cite this article: L. Osagie-Clouard, A. Sanghani, M. Coathup, T. Briggs, M. Bostrom, G. Blunn. Parathyroid hormone 1-34 and skeletal anabolic action: The use of parathyroid hormone in bone formation. Bone Joint Res 2017;6:14–21. DOI: 10.1302/2046-3758.61.BJR-2016-0085.R1

Objectives. Mesenchymal stem cells (MSCs) are of growing interest in terms of bone regeneration. Most preclinical trials utilize bone-marrow-derived mesenchymal stem cells (bMSCs), although this is not without isolation and expansion difficulties. The aim of this study was: to compare the characteristics of bMSCs and adipose-derived mesenchymal stem cells (AdMSCs) from juvenile, adult, and ovarectomized (OVX) rats; and to assess the effect of human parathyroid hormone (hPTH) 1-34 on their osteogenic potential and migration to stromal cell-derived factor-1 (SDF-1). Methods. Cells were isolated from the adipose and bone marrow of juvenile, adult, and previously OVX Wistar rats, and were characterized with flow cytometry, proliferation assays, osteogenic and adipogenic differentiation, and migration to SDF-1. Experiments were repeated with and without intermittent hPTH 1-34. Results. Juvenile and adult MSCs demonstrated significantly increased osteogenic and adipogenic differentiation and superior migration towards SDF-1 compared with OVX groups; this was the case for AdMSCs and bMSCs equally. Parathyroid hormone (PTH) increased parameters of osteogenic differentiation and migration to SDF-1. This was significant for all cell types, although it had the most significant effect on cells derived from OVX animals. bMSCs from all groups showed increased mineralization and migration to SDF-1 compared with AdMSCs. Conclusion. Juvenile MSCs showed significantly greater migration to SDF-1 and significantly greater osteogenic and adipogenic differentiation compared with cells from osteopenic rats; this was true for bMSCs and AdMSCs. The addition of PTH increased these characteristics, with the most significant effect on cells derived from OVX animals, further illustrating possible clinical application of both PTH and MSCs in bone regenerative therapies. Cite this article:L. Osagie-Clouard, A. Sanghani-Kerai, M. Coathup, R. Meeson, T. Briggs, G. Blunn. The influence of parathyroid hormone 1-34 on the osteogenic characteristics of adipose- and bone-marrow-derived mesenchymal stem cells from juvenile and ovarectomized rats. Bone Joint Res 2019;8:397–404. DOI: 10.1302/2046-3758.88.BJR-2019-0018.R1

Aims. Osteoarthritis (OA) is prevalent among the elderly and incurable. Intra-articular parathyroid hormone (PTH) ameliorated OA in papain-induced and anterior cruciate ligament transection-induced OA models; therefore, we hypothesized that PTH improved OA in a preclinical age-related OA model. Methods. Guinea pigs aged between six and seven months of age were randomized into control or treatment groups. Three- or four-month-old guinea pigs served as the young control group. The knees were administered 40 μl intra-articular injections of 10 nM PTH or vehicle once a week for three months. Their endurance as determined from time on the treadmill was evaluated before kill. Their tibial plateaus were analyzed using microcalculated tomography (μCT) and histological studies. Results. PTH increased the endurance on the treadmill test, preserved glycosaminoglycans, and reduced Osteoarthritis Research Society International score and chondrocyte apoptosis rate. No difference was observed in the subchondral plate bone density or metaphyseal trabecular bone volume and bone morphogenetic 2 protein staining. Conclusion. Subchondral bone is crucial in the initiation and progression of OA. Although previous studies have shown that subcutaneous PTH alleviates knee OA by improving subchondral and metaphyseal bone mass, we demonstrated that intra-articular PTH injections improved spontaneous OA by directly affecting the cartilage rather than the subchondral or metaphyseal bone in a preclinical age-related OA model. Cite this article: Bone Joint Res 2021;10(8):514–525

Impaction allograft is an established method of securing initial stability of an implant in arthroplasty. Subsequent bone integration can be prolonged, and the volume of allograft may not be maintained. Intermittent administration of parathyroid hormone has an anabolic effect on bone and may therefore improve integration of an implant. Using a canine implant model we tested the hypothesis that administration of parathyroid hormone may improve osseointegration of implants surrounded by bone graft. In 20 dogs a cylindrical porous-coated titanium alloy implant was inserted into normal cancellous bone in the proximal humerus and surrounded by a circumferential gap of 2.5 mm. Morsellised allograft was impacted around the implant. Half of the animals were given daily injections of human parathyroid hormone (1–34) 5 μg/kg for four weeks and half received control injections. The two groups were compared by mechanical testing and histomorphometry. We observed a significant increase in new bone formation within the bone graft in the parathyroid hormone group. There were no significant differences in the volume of allograft, bone-implant contact or in the mechanical parameters. These findings suggest that parathyroid hormone improves new bone formation in impacted morsellised allograft around an implant and retains the graft volume without significant resorption. Fixation of the implant was neither improved nor compromised at the final follow-up of four weeks

Aims. To develop an early implant instability murine model and explore the use of intermittent parathyroid hormone (iPTH) treatment for initially unstable implants. Methods. 3D-printed titanium implants were inserted into an oversized drill-hole in the tibiae of C57Bl/6 mice (n = 54). After implantation, the mice were randomly divided into three treatment groups (phosphate buffered saline (PBS)-control, iPTH, and delayed iPTH). Radiological analysis, micro-CT (µCT), and biomechanical pull-out testing were performed to assess implant loosening, bone formation, and osseointegration. Peri-implant tissue formation and cellular composition were evaluated by histology. Results. iPTH reduced radiological signs of loosening and led to an increase in peri-implant bone formation over the course of four weeks (timepoints: one week, two weeks, and four weeks). Observational histological analysis shows that iPTH prohibits the progression of fibrosis. Delaying iPTH treatment until after onset of peri-implant fibrosis still resulted in enhanced osseointegration and implant stability. Despite initial instability, iPTH increased the mean pull-out strength of the implant from 8.41 N (SD 8.15) in the PBS-control group to 21.49 N (SD 10.45) and 23.68 N (SD 8.99) in the immediate and delayed iPTH groups, respectively. Immediate and delayed iPTH increased mean peri-implant bone volume fraction (BV/TV) to 0.46 (SD 0.07) and 0.34 (SD 0.10), respectively, compared to PBS-control mean BV/TV of 0.23 (SD 0.03) (PBS-control vs immediate iPTH, p < 0.001; PBS-control vs delayed iPTH, p = 0.048; immediate iPTH vs delayed iPTH, p = 0.111). Conclusion. iPTH treatment mediated successful osseointegration and increased bone mechanical strength, despite initial implant instability. Clinically, this suggests that initially unstable implants may be osseointegrated with iPTH treatment. Cite this article: Bone Joint Res 2022;11(5):260–269

Introduction: Hip arthroplasty can present surgeons with difficult bone loss. Impacted allografting is a well-established way of initally securing implant stability. However subsequent bone integration and fusion can be prolonged. Also concerns relate on maintaining bone volume of allograft during integration. Intermittent administration of parathyroid hormone (PTH) is bone anabolic and improves fracture healing. As adjuvant in implant surgery PTH has only recently been introduced experimentally predominantly showing improved implant integration within empty peri-implant bone defects. Given the desire to improve the graft incorporation process, the purpose of our study is to examine whether PTH improves early implant integration by accelerating healing of peri-implant bone allograft. We test the hypothesis that systemic intermittent administration of PTH increases new bone formation in allograft inserted in a gap with impacted morselized bone allograft around an experimental orthopaedic implant. We hypothesize that parathyroid hormone will improve new bone formation in allograft and preserve allograft. Methods: An unpaired canine study was carried out following approval of our Institutional Animal Care and Use Committee. In 20 skeletally mature dogs cylindrical titanium alloy porous coated implants (6x10mm) were inserted in a 2.5 mm circumferential gap in the extraarticular cancellous bone site of the proximal humeri. Cancellous bone was milled on fine setting and impacted in the gap. Test animal were postoperatively randomised to daily treatment of placebo or parathyroid hormon rhPTH (1–34)(teriparatide)(Bachem) 5 μg / kg s.c. After 4 weeks observation time specimen blocks were harvested, sectioned and evaluated by unbiased stereological histomor-phometry (newCast, Visiopharm, Horsholm, Denmark). The endpoints were bone-to-implant contact and tissue density in an outer gap region of 1500 μm and an inner gap region reaching the implant. Since data were not normally distributed a non-parametric analysis two-sample Wilcoxon rank-sum test was applied with p-value < 0.05 considered statistically significant. Data are accordingly presented as median and interquartile ranges. Results: Two implants in the PTH group were excluded. In the peri-centric region new bone improved significantly (outer region: PTH 21.1 (12.9–16.3) / control 15.2 (13.9–16.2), inner region: PTH 19.8 (15.8–21.5)/control 14.0 (12.9–16.3)). There were no significant differences in the amount of allograft. At the implant interface new bone for PTH was 11.5 (8.1–14.0), as for control 10.5 (7.2–14.8). Old bone for PTH was 1.5 (0.8–2.0), and old bone 1.4 (0.8–1.7). Bone tissue showed no significant differences. Conclusion: Parathyroid hormone shows promise in significant inducing bone formation in impacted morselized allograft around implant without resorbing it significantly retaining graft volume

Introduction: Treatment of osteoarthritis by total joint replacement generally shows a high success rate; however challenges remain. Prostheses inserted without cement are popular worldwide. Insertion of uncemented implants is intended to be pressfit. Early bone growth on the implant is critical to long-term fixation. Parathyroid hormone (PTH) is a regulator of bone metabolism. When PTH is administered intermittently it induces strong anabolic effect by increasing osteoblastic activity. Our understanding of PTH is mainly based on research on osteoporosis, in which bone formation is known to be coupled to the bone resorption. In the orthopaedic situation of a joint replacement other conditions apply. We therefore find it of interest to examine PTH’s role as an adjuvant in implant surgery. We examine the effect of PTH on the osseointegration of an experimental orthopaedic implant in which the implant due to insertion initiates a bone repair in the implant bed. We hypothesize that parathyroid hormone will improve the bone ongrowth at the bone-implant interface. Methods: An unpaired canine study was carried out following approval of our Institutional Animal Care and Use Committee. In 20 skeletally mature dogs cylindrical titanium alloy porous coated implants (6×10mm) were inserted pressfit (0.1 mm under-drill) in the extraarticular cancellous bone site of the proximal tibia. Test animal were postoperatively randomised to daily treatment of placebo or parathyroid hormon rhPTH (1–34)(t eriparatide)(Bachem) 5 μg/kg s.c. After 4 weeks observation time specimen blocks were harvested, sectioned and evaluated by unbiased stereological histomorphometry (CAST-grid system (Olympus Denmark)). The endpoints were bone-to-implant contact and tissue density in a 500 μm region of interest. Since data were not normally distributed a non-parametric analysis two-sample Wilcoxon rank-sum test was applied with p-value < 0.05 considered statistically significant. Data are accordingly presented as median and interquartile ranges. Results: Two implants in the PTH group were excluded. At the implant interface tissue density for PTH was 0,193 (0,157–0,229) for bone, 0,796 (0,764–0,821) for marrow and 0 (0–0,009) for fibrous tissue, as for control 0,163 (0,141–0,193) for bone, 0,837 (0,805–0,859) for marrow and 0 (0-0) for fibrous tissue. Bone tissue showed no significant differences. In the peri-centric region the tissue fraction for PTH was 0,238 (0,211–0,276) for bone, 0,752 (0,724–0,785) for marrow and 0 (0–0,007) for fibrous tissue, as for control 0,223 (0,201–0,235) for bone, 0,777 (0,765–0,799) for marrow and 0 (0–0) for fibrous tissue. Conclusion: In conclusion parathyroid hormone does not show significantly induced bone formation at a titanium alloy implant that has a porous coating of titanium alloy and inserted pressfit

Aims. Parathyroid hormone (PTH) (1-34) exhibits potential in preventing degeneration in both cartilage and subchondral bone in osteoarthritis (OA) development. We assessed the effects of PTH (1-34) at different concentrations on bone and cartilage metabolism in a collagenase-induced mouse model of OA and examined whether PTH (1-34) affects the JAK2/STAT3 signalling pathway in this process. Methods. Collagenase-induced OA was established in C57Bl/6 mice. Therapy with PTH (1-34) (10 μg/kg/day or 40 μg/kg/day) was initiated immediately after surgery and continued for six weeks. Cartilage pathology was evaluated by gross visual, histology, and immunohistochemical assessments. Cell apoptosis was analyzed by TUNEL staining. Microcomputed tomography (micro-CT) was used to evaluate the bone mass and the microarchitecture in subchondral bone. Results. Enhanced matrix catabolism, increased apoptosis of chondrocytes in cartilage, and overexpressed JAK2/STAT3 and p-JAK2/p-STAT3 were observed in cartilage in this model. All of these changes were prevented by PTH (1-34) treatment, with no significant difference between the low-dose and high-dose groups. Micro-CT analysis indicated that bone mineral density (BMD), bone volume/trabecular volume (BV/TV), and trabecular thickness (Tb.Th) levels were significantly lower in the OA group than those in the Sham, PTH 10 μg, and PTH 40 μg groups, but these parameters were significantly higher in the PTH 40 μg group than in the PTH 10 μg group. Conclusion. Intermittent administration of PTH (1-34) exhibits protective effects on both cartilage and subchondral bone in a dose-dependent manner on the latter in a collagenase-induced OA mouse model, which may be involved in regulating the JAK2/STAT3 signalling pathway. Cite this article: Bone Joint Res 2020;9(10):675–688

We have examined the deterioration of implant fixation after withdrawal of parathyroid hormone (PTH) in rats. First, the pull-out force for stainless-steel screws in the proximal tibia was measured at different times after withdrawal. The stimulatory effect of PTH on fixation was lost after 16 days. We then studied whether bisphosphonates could block this withdrawal effect. Mechanical and histomorphometric measurements were conducted for five weeks after implantation. Subcutaneous injections were given daily. Specimens treated with either PTH or saline during the first two weeks showed no difference in the mechanical or histological results (pull-out force 76 N vs 81 N; bone volume density 19% vs 20%). Treatment with PTH for two weeks followed by pamidronate almost doubled the pull-out force (152 N; p < 0.001) and the bone volume density (37%; ANOVA, p < 0.001). Pamidronate alone did not have this effect (89 N and 25%, respectively). Thus, the deterioration can be blocked by bisphosphonates. The clinical implications are discussed

Abstract. Objectives. Current therapies for osteoporosis are limited to generalised antiresorptive or anabolic interventions, which do not target specific regions to improve skeletal health. Moreover, the adaptive changes of separate and combined pharmacological and biomechanical treatments in the ovariectomised (OVX) mouse tibia has not been studied yet. Therefore, this study combines micro- computed tomography (micro-CT) imaging and computational modelling to evaluate the efficacies of treatments in reducing bone loss. Methodology. In vivo micro-CT (10.4µm/voxel) images of the right tibiae of N=18 female OVX C57BL/6 mice were acquired at weeks 14, 16, 18, 20 and 22 of age for 3 groups: mechanical loading (ML), parathyroid hormone (PTH) or combined therapies (PTHML). All mice received either injection of PTH (100μg/kg/day, 5days/week) or vehicle from week 18. The right tibiae were mechanically loaded in vivo at week 19 and 21 with a 12N peak load, 40 cycles/day and 3 days/week. Bone adaptation was quantified through spatial changes in bone mineral density (BMD) and strain distribution was obtained from micro-CT-based finite element models. Results. Densitometric parameters improved for all treatment between week 18–20 (10–21%), with the strongest benefits due to loading in the proximal regions (16–35%). At week 22, PTHML treatment induced 23–76% higher bone apposition in the proximal tibia than either monotherapy. Compared to the OVX control, all treatments reduced periosteal resorption at weeks 18–20 and 20–22 (20–87%). However, resorption in weeks 20–22 were 29–55% higher than weeks 18–20, increasing the strain in the proximal tibia. Synergistic effects of PTH and ML were observed on the periosteal surface of proximal tibia, but additive effects were seen predominately on the distal and lateral tibia. Conclusions. ML had a more dominant effect in improving bone health. PTH enhances bone's osteogenic response to ML additively and synergistically in a site- and time-dependent manner

The intermittent administration of parathyroid hormone (PTH) increases the formation of bone by stimulating osteoblastic activity. Our study evaluates the possibility that intermittent treatment with PTH (1-34) may also enhance the implant-bone fixation of stainless-steel screws. Twenty-eight rats received one screw in either one (n = 8) or in both (n = 20) proximal tibiae. We administered either PTH (1-34) in a dosage of 60 μg/kg/day (n = 14) or vehicle (n = 14) over a period of four weeks. At the end of this time, the degree of fixation was assessed by measuring the removal torque on one screw in each rat (n = 28) and the pull-out strength on the contralateral screw (n = 20). PTH increased the mean removal torque from 1.1 to 3.5 Ncm (p = 0.001) and the mean pull-out strength from 66 to 145 N (p = 0.002). No significant differences in body-weight or ash weight of the femora were seen. Histological examination showed that both groups had areas of soft tissue at the implant-bone interface, but these appeared less in the PTH group. These results indicate that intermittent treatment with PTH may enhance the early fixation of orthopaedic implants

The changes in serum adjusted ionised calcium and parathyroid hormone (PTH) were prospectively studied in 32 patients with isolated tibial fractures, treated conservatively. We measured serum albumin, adjusted total calcium, phosphate, pH, adjusted ionised calcium and PTH at intervals until the fractures had healed. The mean ionised calcium adjusted for pH fell within 24 hours of injury, and then rose to a peak at between four and six weeks. These changes cannot be explained by changes in serum pH or PTH. The restoration of normal ionised calcium levels after fracture coincided with the period when the callus was being calcified. Analysis of the changes in ionised calcium, phosphate and PTH suggests that PTH levels alter in response to changes in ionised calcium levels. PTH is highest immediately after fracture and lowest, often not recordable, at six weeks. The cause of the changes in the ionised calcium level has yet to be elucidated

Introduction: Since Albright first proposed the concept of diabetic osteopenia, many studies have investigated the levels of mineral bone density (BMD) and risk of osteoporosis. In this study we investigate the effect of exercise, alfacalcidol and parathyroid hormone (1–34) on bone marker, BMD and bone mechanical properties in spontaneously diabetic GK/Jcl rats. Methods: 18 week-old male GK/Jcl rats were divided into 4 groups; no treatment (NT), exercise (Ex), alfacalcidol (ALF), and parathyroid hormone (PTH). The bone mineral density (BMD) of the lumbar vertebrae (L2-L4) and the left femur was measured by dual energy X-ray absorptiometry (DXA). Serum calcium (Ca), inorganic phosphorus (Pi) and osteocalcin (OC) were measured. Urinary Ca, Po, and creatinine (Cre) were measured. Urinary deoxypyridinoline (D-Pyr) was measured and the data were corrected for urinary Cre concentration. Mechanical strength of L5 was measured by the compression test. The mechanical strength of the right femur was measured by the three-point bending test. Results: The serum Oc levels in Ex and ALF group slightly increased (mean 5%). The serum Oc in PTH group increased significantly compared with that in the NT group (mean 70%). The urinary D-Pyr/Cre in the Ex group decreased compared with that in the NT group (mean 9 %). The urinary D-Pyr/Cre in the groups treated with ALF for 3 months were significantly decreased compared with that in the NT group (mean 20%). The urinary D-Pyr/Cre in the PTH group significantly increased compared with that in the NT group (mean 10%). The BMD of the L2–L4 in ALF group increased compared with NT group (mean 12%). The BMD of the L2–L4 in PTH group significantly increased compared with NT group (mean 10%). In the ALF group, however, the mechanical strength of the lumber vertebra was significantly higher (mean 25%) than that in the NT group. In the PTH group, the compressive load of the lumber vertebra (mean 70%) and breaking strength of the femur (mean 9%) was significantly higher than that in the NT group. Discussion: Treatment of osteoporosis has so far mainly utilized anti-resorptive agents such as estrogen, calcitonin and bisphosphonate, and bone anabolic agents stimulating bone resorption would be useful especially in low-turnover type of osteoporosis such as diabetic osteopenia. ALF treatment suppressed osteoclastic bone resorption while maintaining or even stimulating bone formation, and consequently increased bone mass with a parallel improvement in the mechanical strength of bone. PTH (1–34) had strong effects for improve the mechanical strength of the spine. In conclusion, it was demonstrated that ALF and PTH differed in their potency for improving the strength of the spine. Our results of biochemical parameter analysis demonstrated that ALF caused a significant suppression of bone resorption and maintained formation. The other hand, PTH had a strong effect on stimulating the bone turnover and bone strength, whereas it could affect the bone quality and reduce the risk of the spine fracture. These results provide important clues in understanding the action mechanisms of these agents on bone metabolism in the treatment of diabetic osteopenia

Intermittent treatment with parathyroid hormone (PTH) has an anabolic effect on both intact cancellous and cortical bone. Very little is known about the effect of the administration of PTH on the healing of fractures or the incorporation of orthopaedic implants. We have investigated the spontaneous ingrowth of callus and the formation of bone in a titanium chamber implanted at the medioproximal aspect of the tibial metaphysis of the rat. Four groups of ten male rats weighing approximately 350 g were injected with human PTH (1-34) in a dosage of 0, 15, 60 or 240 μg/kg/day, respectively, for 42 days from the day of implantation of the chamber. During the observation period the chamber became only partly filled with callus and bone and no difference in ingrowth distance into the chamber was found between the groups. The cancellous density was increased by 90%, 132% and 173% in the groups given PTH in a dosage of 15, 60 or 240 μg/kg/day, respectively. There was a linear correlation between bone density and the log PTH doses (r. 2. = 0.6). Our findings suggest that treatment with PTH may have a potential for enhancement of the incorporation of orthopaedic implants as well as a beneficial effect on the healing of fractures when it is given in low dosages

Introduction. Recently, some case reports have been published, in which nonunions were successfully healed with parathyroid hormone 1–34 (PTH) administration. Previously, we demonstrated that the intervening tissue at the nonunion site contains multilineage mesenchymal progenitor cells and plays an important role during the healing process of nonunion. We investigated the effect of PTH on osteogenic differentiation of human nonunion tissue-derived cells (NCs) in vitro. Hypothesis. We hypothesized that PTH directly promoted osteogenic differentiation of NCs. Materials & Methods. NCs were isolated from 4 patients, and cultured. The cells were divided into two groups: (1) PTH (−) group: cells cultured in osteogenic medium (OM), (2) PTH (+) group: cells cultured in OM with PTH. Osteogenic differentiation potential was analyzed. Results. Real-time PCR analysis showed that gene expression levels of Runx2, ALP, OC and PTHR1 in PTH (+) group were lower than PTH (−) group at day 14. In both groups, there was no significant difference in ALP activity at days 8 and 14, and in the intensity of Alizarin red S staining at day 20. Discussion. Treatment of PTH did not lead to increase osteogenic differentiation of NCs. Nonunion healing by PTH administration may be caused by other mechanisms such as mobilization and recruitment of osteoprogenitor cells

Introduction. Parathyroid hormone 1–34 (PTH) has been reported to accelerate fracture healing. Previously, we demonstrated human fracture hematoma contained osteo-/chondro-progenitor cells. To date, there has been no study investigating the effect of PTH on fracture hematoma-derived cells (HCs) in vitro. Hypothesis. We hypothesized PTH treatment affected osteogenesis and chondrogenesis of HCs. Materials & Methods. HCs were divided into 3 groups: control (growth medium), PTH (−) (osteogenic or chondrogenic medium (OM or CM)), and PTH (+) group (OM or CM with PTH). Cell proliferation was assessed by MTS assay. Osteogenesis was assessed by alkaline phosphatase (ALP) activity, real-time PCR, and Alizarin red S staining. Chondrogenesis was assessed by real-time PCR and Safranin-O staining. Results. There was no significant difference in proliferation among 3 groups. ALP activity and expression levels of ALP and Runx2 in PTH (+) group were comparable with PTH (−) group. HCs in PTH (−) and PTH (+) group were strongly stained with Alizarin red S staining. The expression levels of collagen-II and -X in PTH (+) group were significantly lower than PTH (−) group. Pellets in PTH (+) group were slightly stained with Safranin-O staining. Discussion & Conclusion. Our results revealed that PTH treatment did not affect osteogenesis and inhibited chondrogenesis of HCs. PTH treatment after fracture may positively affect other cells such as periosteum-derived cells and circulating stem cells

Since the approval of parathyroid hormone (PTH) as an anabolic treatment for osteoporosis, PTH has increasingly been investigated for other potential clinical uses such as bone repair and regeneration. The microstructure of newly formed bone during distraction osteogenesis enhanced by PTH treatment has yet to be studied. Therefore, the purpose of the study was to investigate the effects of intermittent parathyroid hormone PTH (1–34) treatment on the microstructure of regenerated bone during distraction osteogenesis in rabbits. After tibial mid-diaphyseal osteotomy the callus was distracted 1 mm/day for 10 days. The rabbits were divided in to 3 groups, which daily received a PTH injection for 30 days, a saline injection for 10 days and a PTH injection for 20 days, or a saline injection for 30 days. The new-trabecular structure of the regenerate callus was assessed by micro computed tomography (μCT). In all 51 specimen obtained from the lengthened tibia were scanned and evaluated morphometrically using three different volume of interests. The investigated μCT parameters included trabecular number Tb.N*, trabecular thickness Tb.Th*, trabecular separation Tb.Sp*, bone volume fraction (BV/TV), bone volume (BV), connectivity density (CD), and degree of anisotropy (DA). The results showed that intermittent treatment with PTH during distraction osteogensis resulted in a significantly higher Tb.N*, a more isotropic trabecular orientation, a higher connectivity density, and a higher bone mass. We also found preliminary evidence suggesting that the newly regenerated calluses treated with PTH were more mature than the non-treated calluses. In conclusion: the study demonstrated that treatment with PTH resulted in an enhanced microstructure of the newly regenerated bone indicating that PTH has a potential role as a stimulating agent for distraction osteogenesis

Improving periprosthetic bone is essential for implant fixation and reducing peri-implant fracture risk. This studied examined the individual and combined effects of iPTH and mechanical loading at the cellular, molecular, and tissue level for periprosthetic cancellous bone. Adult rabbits had a porous titanium implant inserted bilaterally on the cancellous bone beneath a mechanical loading device on the distal lateral femur. The right femur was loaded daily, the left femur received a sham loading device, and half of the rabbits received daily PTH. Periprosthetic bone was processed up to 28 days for qPCR, histology, and uCT analysis. We observed an increase in cellular and molecular markers of osteoblast activity and decrease in adipocytic markers for both treatments, with small additional effects in the combined group. Loading and iPTH led to a decrease and increase, respectively, in osteoclast number, acting through changes in RANKL/OPG expression. Changes in SOST and beta-catenin mRNA levels suggested an integral role for the Wnt pathway. We observed strong singular effects on BV/TV of both loading (1.53 fold) and iPTH (1.54 fold). Combined treatment showed a small additive effect on bone volume. In conclusion, loading and iPTH act through a pro-osteoblastic/anti-adipocytic response and through control of bone turnover via changes in the RANKL/OPG pathway. These changes led to a small additional, but not synergistic, increase in bone volume with the combined therapy.

The aim of our study was to evaluate if PTH is able to increase the trabecular density of osteoporotic bone at the site of an implant and whether the anabolic effect of PTH at this side is stronger then the effect of an osteoclast inhibitor like alendronate.

48 cement rod was inserted in the tibia of 48 female rats, of which 36 had been ovariectomized. The cement rods, which served as implants, were made of Palacos R bone cement. After implantation, the 36 ovariectomized rats were divided in 3 groups. One was injected subcutaneusly with PTH (1–34) at a dose of 60 g/kg BW. The second was injected with alendronate at a dose of 205 g/kg BW. The third with vehicle only. The remaining 12 sham operated rats were also injected with vehicle only. All injections were given three times a week and the rats were killed 2 weeks after implantation.

The tibial segments around the hole of the rods were prepared histologically. Thus the surfaces which had been in contact with the rod appeared as straight lines and could be analyzed histomorphometricly. The trabecular density of the bone closest to the implant was measured. One femur of all animals was used for measurement by DEXA.

There was a substantial increase in the trabecular density close to the rods with PTH treatment (Anova p=0.002). PTH lead to a trabecular density of 89%, where as the ovariectomized animals revealed a trabecular density of 58% and the sham operated control of 68%. No significant increase of implant related trabecular density could be found in the alendronate treated group. In this group a density of 72% was established. DEXA showed the expected differences in bone mineral content (Anova p=0.001).

In this study, intermittent PTH treatment increased implant-related trabecular density in osteoporotic bone after 2 weeks. No such positive effect could be found with alendronate treatment at such a short period of time. We think the reason for this phenomenon could be the early onset of the anabolic PTH effect on regenerating bone, whereas alendronate is thought to only inhibit bone resorption, which might lead to a later effect.

The early onset of PTH effects even in osteoporotic bone suggests that intermittent PTH treatment might lead to an increased micro-interlock between implant and bone and might therefore be considered as a possible drug to enhance incorporation of orthopedic implants.