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

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

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

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

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.

Aims. We wished to assess the feasibility of a future randomised controlled trial of parathyroid hormone (PTH) supplements to aid healing of trochanteric fractures of the hip, by an open label prospective feasibility and pilot study with a nested qualitative sub study. This aimed to inform the design of a future powered study comparing the functional recovery after trochanteric hip fracture in patients undergoing standard care, versus those who undergo administration of subcutaneous injection of PTH for six weeks. Patients and Methods. We undertook a pilot study comparing the functional recovery after trochanteric hip fracture in patients 60 years or older, admitted with a trochanteric hip fracture, and potentially eligible to be randomised to either standard care or the administration of subcutaneous PTH for six weeks. Our desired outcomes were functional testing and measures to assess the feasibility and acceptability of the study. Results. A total of 724 patients were screened, of whom 143 (20%) were eligible for recruitment. Of these, 123 were approached and 29 (4%) elected to take part. However, seven patients did not complete the study. Compliance with the injections was 11 out of 15 (73%) showing the intervention to be acceptable and feasible in this patient population. Take home message: Only 4% of patients who met the inclusion criteria were both eligible and willing to consent to a study involving injections of PTH, so delivering this study on a large scale would carry challenges in recruitment and retention. Methodological and sample size planning would have to take this into account. PTH administration to patients to enhance fracture healing should still be considered experimental. Cite this article: Bone Joint J 2016;98-B:840–5

Objectives. Osteoporosis has become an increasing concern for older people as it may potentially lead to osteoporotic fractures. This study is designed to assess the efficacy and safety of ten therapies for post-menopausal women using network meta-analysis. Methods. We conducted a systematic search in several databases, including PubMed and Embase. A random-effects model was employed and results were assessed by the odds ratio (OR) and corresponding 95% confidence intervals (CI). Furthermore, with respect to each outcome, each intervention was ranked according to the surface under the cumulative ranking curve (SUCRA) value. Results. With respect to preventing new vertebral fractures (NVF), all ten drugs outperformed placebo, and etidronate proved to be the most effective treatment (OR 0.24, 95% CI 0.14 to 0.39). In addition, zoledronic acid and parathyroid hormone ranked higher compared with the other drugs. With respect to preventing clinical vertebral fractures (CVF), zoledronic acid proved to be the most effective drug (OR = 0.25, 95% CI 0.08 to 0.92), with denosumab as a desirable second option (OR = 0.48, 95% CI 0.22 to 0.96), when both were compared with placebo. As for adverse events (AE) and severe adverse events (SAE), no significant difference was observed. According to SUCRA, etidronate ranked first in preventing CVF; parathyroid hormone and zoledronic acid ranked highly in preventing NVF and CVF. Raloxifene was safe with a high rank in preventing AEs and SAEs though performed unsatisfactorily in efficacy. Conclusions. This study suggests that, taking efficacy and safety into account, parathyroid hormone and zoledronic acid had the highest probability of satisfactory performance in preventing osteoporotic fractures. Cite this article: G. Wang, L. Sui, P. Gai, G. Li, X. Qi, X. Jiang. The efficacy and safety of vertebral fracture prevention therapies in post-menopausal osteoporosis treatment: Which therapies work best? a network meta-analysis. Bone Joint Res 2017;6:452–463. DOI: 10.1302/2046-3758.67.BJR-2016-0292.R1

Aims. Osteoporosis is common in total hip arthroplasty (THA) patients. It plays a substantial factor in the surgery’s outcome, and previous studies have revealed that pharmacological treatment for osteoporosis influences implant survival rate. The purpose of this study was to examine the prevalence of and treatment rates for osteoporosis prior to THA, and to explore differences in osteoporosis-related biomarkers between patients treated and untreated for osteoporosis. Methods. This single-centre retrospective study included 398 hip joints of patients who underwent THA. Using medical records, we examined preoperative bone mineral density measures of the hip and lumbar spine using dual energy X-ray absorptiometry (DXA) scans and the medications used to treat osteoporosis at the time of admission. We also assessed the following osteoporosis-related biomarkers: tartrate-resistant acid phosphatase 5b (TRACP-5b); total procollagen type 1 amino-terminal propeptide (total P1NP); intact parathyroid hormone; and homocysteine. Results. The prevalence of DXA-proven hip osteoporosis (T-score ≤ -2.5) among THA patients was 8.8% (35 of 398). The spinal osteoporosis prevalence rate was 4.5% (18 of 398), and 244 patients (61.3%; 244 of 398) had osteopenia (-2.5 < T-score ≤ -1) or osteoporosis of either the hip or spine. The rate of pharmacological osteoporosis treatment was 22.1% (88 of 398). TRACP-5b was significantly lower in the osteoporosis-treated group than in the untreated group (p < 0.001). Conclusion. Osteoporosis is common in patients undergoing THA, but the diagnosis and treatment for osteoporosis were insufficient. The lower TRACP-5b levels in the osteoporosis-treated group — that is, osteoclast suppression — may contribute to the reduction of the postoperative revision rate after THA. Cite this article: Bone Joint Res 2022;11(12):873–880

Aims. A growing number of fractures progress to delayed or nonunion, causing significant morbidity and socioeconomic impact. Localized delivery of stem cells and subcutaneous parathyroid hormone (PTH) has been shown individually to accelerate bony regeneration. This study aimed to combine the therapies with the aim of upregulating fracture healing. Methods. A 1.5 mm femoral osteotomy (delayed union model) was created in 48 female juvenile Wistar rats, aged six to nine months, and stabilized using an external fixator. At day 0, animals were treated with intrafracture injections of 1 × 10. 6. cells/kg bone marrow mesenchymal stem cells (MSCs) suspended in fibrin, daily subcutaneous injections of high (100 μg/kg) or low (25 μg/kg) dose PTH 1-34, or a combination of PTH and MSCs. A group with an empty gap served as a control. Five weeks post-surgery, the femur was excised for radiological, histomorphometric, micro-CT, and mechanical analysis. Results. Combination therapy treatment led to increased callus formation compared to controls. In the high-dose combination group there was significantly greater mineralized tissue volume and trabecular parameters compared to controls (p = 0.039). This translated to significantly improved stiffness (and ultimate load to failure (p = 0.049). The high-dose combination therapy group had the most significant improvement in mean modified Radiographic Union Score for Tibia fractures (RUST) compared to controls (13.8 (SD 1.3) vs 5.8 (SD 0.5)). All groups demonstrated significant increases in the radiological scores – RUST and Allen score – histologically compared to controls. Conclusion. We demonstrate the beneficial effect of localized MSC injections on fracture healing combined with low- or high-dose teriparatide, with efficacy dependent on PTH dose. Cite this article: Bone Joint Res 2021;10(10):659–667

Objectives. Oxidative stress plays a major role in the onset and progression of involutional osteoporosis. However, classical antioxidants fail to restore osteoblast function. Interestingly, the bone anabolism of parathyroid hormone (PTH) has been shown to be associated with its ability to counteract oxidative stress in osteoblasts. The PTH counterpart in bone, which is the PTH-related protein (PTHrP), displays osteogenic actions through both its N-terminal PTH-like region and the C-terminal domain. Methods. We examined and compared the antioxidant capacity of PTHrP (1-37) with the C-terminal PTHrP domain comprising the 107-111 epitope (osteostatin) in both murine osteoblastic MC3T3-E1 cells and primary human osteoblastic cells. Results. We showed that both N- and C-terminal PTHrP peptides at 100 nM decreased reactive oxygen species production and forkhead box protein O activation following hydrogen peroxide (H. 2. O. 2. )-induced oxidation, which was related to decreased lipid oxidative damage and caspase-3 activation in these cells. This was associated with their ability to restore the deleterious effects of H. 2. O. 2. on cell growth and alkaline phosphatase activity, as well as on the expression of various osteoblast differentiation genes. The addition of Rp-cyclic 3′,5′-hydrogen phosphorothioate adenosine triethylammonium salt (a cyclic 3',5'-adenosine monophosphate antagonist) and calphostin C (a protein kinase C inhibitor), or a PTH type 1 receptor antagonist, abrogated the effects of N-terminal PTHrP, whereas protein phosphatase 1 (an Src kinase activity inhibitor), SU1498 (a vascular endothelial growth factor receptor 2 inhibitor), or an anti osteostatin antiserum, inhibited the effects of C-terminal PTHrP. Conclusion. These findings indicate that the antioxidant properties of PTHrP act through its N- and C-terminal domains and provide novel insights into the osteogenic action of PTHrP. Cite this article: S. Portal-Núñez, J. A. Ardura, D. Lozano, I. Martínez de Toda, M. De la Fuente, G. Herrero-Beaumont, R. Largo, P. Esbrit. Parathyroid hormone-related protein exhibits antioxidant features in osteoblastic cells through its N-terminal and osteostatin domains. Bone Joint Res 2018;7:58–68. DOI: 10.1302/2046-3758.71.BJR-2016-0242.R2

Re-rupture rates after rotator cuff repair remain high because of inadequate biological healing at the tendon-bone interface. Single-growth factor therapies to augment healing at the enthesis have so far yielded inconsistent results. An emerging approach is to combine multiple growth factors over a spatiotemporal distribution that mimics normal healing. We propose a novel combination treatment of insulin-like growth factor 1 (IGF-1), transforming growth factor β1 (TGF-β1) and parathyroid hormone (PTH) incorporated into a controlled-release tyraminated poly-vinyl-alcohol hydrogel to improve healing after rotator cuff repair. We aimed to evaluate this growth factor treatment in a rat chronic rotator cuff tear model. A total of 30 male Sprague-Dawley rats underwent unilateral supraspinatus tenotomy. Delayed rotator cuff repairs were then performed after 3 weeks, to allow tendon degeneration that resembles the human clinical scenario. Animals were randomly assigned to: [1] a control group with repair alone; or [2] a treatment group in which the hydrogel was applied at the repair site. All animals were euthanized 12 weeks after rotator cuff surgery and the explanted shoulders were analyzed for biomechanical strength and histological quality of healing at the repair site. In the treatment group had significantly higher stress at failure (73% improvement, P=0.003) and Young's modulus (56% improvement, P=0.028) compared to the control group. Histological assessment revealed improved healing with significantly higher overall histological scores (10.1 of 15 vs 6.55 of 15, P=0.032), and lower inflammation and vascularity. This novel combination growth factor treatment improved the quality of healing and strength of the repaired enthesis in a chronic rotator cuff tear model. Further optimization and tailoring of the growth factors hydrogel is required prior to consideration for clinical use in the treatment of rotator cuff tears. This novel treatment approach holds promise for improving biological healing of this clinically challenging problem