Teriparatide Administration Research Articles

Effect of intermittent administration of teriparatide on the mechanical and histological changes in bone grafted with β-tricalcium phosphate using a rabbit bone defect model.

Grafting β-tricalcium phosphate (TCP) is a well-established method for restoring bone defects; however, there is concern that the mechanical stability of the grafted β-TCP is not maintained during bone translation. Teriparatide has an anabolic effect, stimulating bone formation and increasing bone mineral density for the treatment of osteoporosis. The aim of the present study was to evaluate the effect of intermittent teriparatide treatment on changes in bone grafted with β-TCP using a rabbit bone defect model. Bone defects (5×15 mm) were created in the distal femoral condyle of Japanese white rabbits, and β-TCP granules of two different total porosities were manually grafted. Teriparatide (40 µg/kg) or 0.2% rabbit serum albumin solution as a vehicle control was subcutaneously injected three times per week following the surgery. At 4 or 8 weeks post-surgery, serum samples were obtained and the levels of γ-carboxylated osteocalcin (Gla-OC) were quantified using ELISA. Histomorphometry was also performed using sections of graft sites following staining for tartrate resistant acid phosphatase. Activity and mechanical strength (maximum shear strength, maximum shear stiffness and total energy absorption) were evaluated using an axial push-out load to failure test. Teriparatide treatment significantly increased (P<0.05) the serum levels of Gla-OC, a specific marker for bone formation, suggesting that teriparatide enhances bone formation in β-TCP-grafted rabbits. Furthermore teriparatide increased the degradation of β-TCP by bone remodeling (P<0.05) and promoted the formation of new bone following application of the graft compared with the control group (P<0.01). Furthermore, teriparatide suppressed the reduction in mechanical strength (P<0.05) during bone translation in bone defects grafted with β-TCP. The results of the present study demonstrate that teriparatide is effective in maintaining the mechanical stability of grafted β-TCP, possibly by promoting new bone formation.

Single-dose local administration of teriparatide with a octacalcium phosphate collagen composite enhances bone regeneration in a rodent critical-sized calvarial defect.

Octacalcium phosphate and collagen composite (OCP/Col) achieves stable bone regeneration without cell transplantation in preclinical studies. Recently, a sponsor‐initiated clinical trial was conducted to commercialize the material. The present study investigated bone regeneration by OCP/Col with the single local administration of teriparatide (parathyroid hormone 1‐34; TPTD). OCP/Col was prepared by mixing sieved granules of OCP and atelocollagen for medical use and a disk was molded. After the creation of a rodent critical‐sized calvarial defect, OCP/Col or OCP/Col with dripped TPTD solution (1.0 or 0.1 µg; OCP/Col/TPTDd1.0 or OCP/Col/TPTDd0.1) was implanted into the defect. Six defects in each group were fixed 12 weeks after implantation. Radiographic examinations indicated that radiopaque figures in defects treated with OCP/Col with TPTD (OCP/Col/TPTDd) occupied a wider range than those treated with OCP/Col. Histological results demonstrated that most of the defect in OCP/Col/TPTDd was filled with newly formed bone. A histomorphometrical examination indicated that the percentage of newly formed bone was significantly higher in the defects of OCP/Col/TPTDd 1.0 (53.6 ± 4.3%) and OCP/Col/TPTDd 0.1 (52.2 ± 7.4%) than in those of OCP/Col (40.1 ± 8.4%), whereas no significant differences were observed between OCP/Col/TPTDd1.0 and OCP/Col/TPTDd0.1. These results suggest that OCP/Col with the single local administration of TPTD enhances bone regeneration in a rodent calvarial critical‐sized bone defect. © 2017 The Authors Journal of Biomedical Materials Research Part B: Applied Biomaterials Published by Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1851–1857, 2018.

Short-term daily teriparatide in patients with rheumatoid arthritis

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

Parathyroid hormone regulates fates of murine osteoblast precursors in vivo

Teriparatide, a recombinant form of parathyroid hormone (PTH), is the only approved treatment for osteoporosis that increases the rate of bone formation. Teriparatide increases osteoblast numbers by suppressing osteoblast apoptosis and activating bone-lining cells. No direct evidence for teriparatide's actions on early cells of the osteoblast lineage has been demonstrated. Here, we have employed a lineage-tracing strategy that uses a tamoxifen-dependent, promoter-driven cre to mark early cells of the osteoblast lineage in adult mice. We show that teriparatide increases the numbers of osteoblast precursors and drives their differentiation into mature osteoblasts. Unexpectedly, following withdrawal of teriparatide therapy, bone marrow adipocytes increased dramatically in number. Some of these adipocytes derived from cells marked by Sox9-cre expression weeks earlier. Continued therapy with teriparatide prevented the appearance of adipocytes. Selective, inducible deletion of the PTH receptor in Sox9-cre cells demonstrated that PTH receptor expression is required for teriparatide-mediated increases in early osteoblast precursors. The increase in early precursors after teriparatide administration was associated with robust suppression of precursor apoptosis without affecting their rate of proliferation. Thus, teriparatide increases the numbers of early cells of the osteoblast lineage, hastens their differentiation into osteoblasts, and suppresses their differentiation into adipocytes in vivo.

Role of teriparatide in fracture healing: A prospective study

Background: The biology of bone repair and healing is interesting and a huge number of studies have been done in this aspect with the potential technologies for enhancing fracture-healing. Teriparatide an anabolic agent a recombinant parathyroid hormone preparation that activates osteoblastic bone formation has been used in the treatment of postmenopausal osteoporosis. It has also been reported to be effective in accelerating the rate of fracture healing. The conclusion that PTH as an effective anabolic therapy for the enhancement of bone repair after fracture has been studied in animals and very few case studies. This prospective study was conducted to determine and establish the role of recombinant teriparatide in fracture healing in delayed union fractures, osteoporotic fractures, periprosthetic fractures. Materials and Methods: The study was done on 20 patients with fractures selected on the basis of inclusion and exclusion criteria at Shashwat hospital, Pune during the period of September 2011 to September 2015. All patients were administered 20ug of teriparatide injections daily. The injections were given for 2 - 4 months depending on type of fracture and the time required for radiological evidence of union. Radiographs were taken every 4 weeks to see for callus and fracture union. The primary endpoint of fracture healing was taken as the time of cortical bridging in three of four cortices Results: The fractures treated with 20ug of teriparatide exhibited early signs of union with abundant callus formation significant decrease in radiological union time and early rehabilitation of patients in all three groups. Conclusions: This study shows that the daily systemic administration of recombinant teriparatide enhances fracture-healing by increasing bone mineral content, density and strength. It also produces a sustained anabolic effect throughout the remodeling phase of fracture-healing. It also emphasizes that teriparatide is a relatively safe drug. Economical compared to other options of fracture healing like bone grafting, second surgery and is less invasive and has better patient compliance.

Effect of Time of Administration of Teriparatide on Bone Mineral Density in Glucocorticoid-Induced Osteoporosis

Teriparatide (TPTD) (recombinant DNA origin human parathormone [1–34]) is approved for the treatment of glucocorticoid-induced osteoporosis (GIO). There are reports of factors that affect the response to TPTD in GIO treatment. This work describes the case of a 71-yr-old woman diagnosed with lupus nephropathy treated with 40 mg/d of meprednisone, and who suffered multiple vertebral fractures. Despite treatment with a single 5 mg dose of zoledronic acid, the patient continued to have vertebral fractures. Treatment with 20 µg/d of subcutaneous TPTD (PTH1-34, Forteo; Eli Lilly Co., Indianapolis, IN) was initiated. Nine months after the onset of treatment, bone mineral density (BMD) assessment showed a 5% decrease in lumbar spine BMD. Factors potentially affecting the results were analyzed. The patient reported injecting TPTD at night and was instructed to inject TPTD in the morning before breakfast. After changing the time of TPTD administration and 22 mo after initiating treatment, BMD assessment was repeated and showed an 18% increase at the lumbar spine and no new vertebral fractures. The time of TPTD administration might affect the response to TPTD in GIO treatment.

A case report of severe calciphylaxis \u2013 suggested approach for diagnosis and treatment

BackgroundCalciphylaxis is a serious complication in patients with chronic kidney disease associated mineral and bone disorder. It can occur in conditions with low and high bone turnover. So far, there are no definite diagnostic and therapeutic guidelines which may prevent the devastating outcome in many calciphylaxis patients. We report a case which clearly illustrates that knowledge of the underlying bone disorder is essential for a directed treatment. Based on this experience we discuss a systematic diagnostic and therapeutic approach in patients with calciphylaxis.Case presentationWe report a patient with severe calciphylaxis. Initial evaluation showed an elevated serum parathormone concentration and a bone-specific alkaline phosphatase activity in the upper normal range; however, the bone biopsy clearly showed adynamic bone disease. Extended dialysis with low calcium dialysate concentration and citrate anticoagulation, and administration of teriparatide led to a further increase in bone-specific alkaline phosphatase activity and most importantly, resulted in an activated bone turnover as confirmed by a second bone biopsy 11 weeks later.ConclusionsThis case illustrates that laboratory tests cannot reliably differentiate between high and low bone turnover in calciphylaxis patients. More importantly, this case highlights the fact that specific therapies that alter bone metabolism cannot be applied without knowledge of the bone status. On this background, we suggest that bone biopsies should be an integral part in the diagnosis and therapeutic decision in these patients and should be evaluated in further studies.

Acute development of cortical porosity and endosteal naïve bone formation from the daily but not weekly short-term administration of PTH in rabbit.

Teriparatide [human parathyroid hormone (1–34)], which exerts an anabolic effect on bone, is used for the treatment of osteoporosis in patients who are at a high risk for fracture. That the once-daily administration of teriparatide causes an increase in cortical porosity in animal models and clinical studies has been a matter of concern. However, it is not well documented that the frequency of administration and/or the total dose of teriparatide affect the cortical porosity. The present study developed 4 teriparatide regimens [20 μg/kg/day (D20), 40 μg/kg/day (D40), 140 μg/kg/week (W140) and 280 μg/kg/week (W280)] in the rabbit as a model animal with a well-developed Haversian system and osteons. The total weekly doses were equivalent in the low-dose groups (D20 and W140) and in the high-dose groups (D40 and W280). After the short-term (1 month) administration of TPDT, micro-CT, histomorphometry and three-dimensional second harmonic generation (3D-SHG) imaging to visualize the bone collagen demonstrated that daily regimens but not weekly regimens were associated with the significant development of cortical porosity and endosteal naïve bone formation by marrow fibrosis. We concomitantly monitored the pharmacokinetics of the plasma teriparatide levels as well as the temporal changes in markers of bone formation and resorption. The analyses in the present study suggested that the daily repeated administration of teriparatide causes more deleterious changes in the cortical microarchitecture than the less frequent administration of higher doses. The findings of the present study may have some implications for use of teriparatide in clinical treatment.

Increased cortical porosity is associated with daily, not weekly, administration of equivalent doses of teriparatide

IntroductionThe pharmacokinetic profile of parathyroid hormone (PTH) determines its effects on bone resorption and formation. When administered intermittently, anabolic effects are favored in comparison with the continuous treatment. Among the intermittent treatment regimens, lower frequency of administration may have a lower effect on bone remodeling. We therefore hypothesized that weekly administration of teriparatide will produce less increase in intracortical remodeling and porosity than reported using daily treatment. MethodsWe treated 17 female New Zealand white rabbits aged 6months for 1month with teriparatide [human PTH(1-34)] as follows. (i) Vehicle-treated Control (n=4); (ii) 20μg/kg daily (n=3); (iii) 40μg/kg daily (n=3); (iv) 140μg/kg weekly (n=3); (v) 280μg/kg weekly (n=4). Proximal femurs were imaged ex vivo using micro-CT (Scanco Viva CT-40) at 15μmvoxel size. Areas, pore size, and porosity were analyzed on the total, compact cortex (CC), and transitional zones in a 10mm length region of interest (ROI) starting at the midshaft using StrAx1.0. ResultsCompared to controls, the 20μg/kg daily was associated with 3.0% higher porosity in the transitional zone (p=0.09) while the 40μg/kg daily was associated with a higher porosity in the cortex (8.7%; p=0.04) and in the transitional zone (5.7%; p=0.007). The daily regimens were also associated with a greater proportion of porosity due to pores >15μm2; particularly in the transitional zone where 20 and 40μg/kg daily increased porosity 2 fold (p=0.06) and 5 fold (p=0.04) relative controls respectively. The 140 and 280μg/kg weekly were not associated with an increase in porosity. There was no difference in total, compact or transitional zone cross sectional areas between the groups. ConclusionEffects of intermittent teriparatide depend on the dose and frequency of administration. Daily dosing, particularly the higher dose, but not weekly dosing, increased cortical porosity. Work is needed to investigate the effects of the regimens on bone formation.

Importance of prompt antiresorptive therapy in postmenopausal women discontinuing teriparatide or denosumab: The Denosumab and Teriparatide Follow-up study (DATA-Follow-up)

When teriparatide and denosumab are discontinued, bone mineral density (BMD) abruptly decreases. To compare rates of bone loss in postmenopausal women who discontinue denosumab or teriparatide and receive no additional prescription osteoporosis medications to women who discontinue these drugs followed by prompt antiresorptive therapy, we asked women concluding the Denosumab and Teriparatide Administration (DATA) study and its extension, DATA-Switch, to return for BMD measurements 1–2years after study completion. In these studies, women received 2-years of either teriparatide, denosumab or both medications followed by 2-years of the alternate therapy (women who received combination therapy initially received an additional 2-years of denosumab alone).Fifty of 69 women who completed DATA-Switch returned after a mean of 15.4±3.5months. Of the 28 women who received antiresorptive therapy (10 denosumab, 10 oral bisphosphonates, 8 intravenous zoledronic acid), the mean interval between ending DATA-Switch and beginning antiresorptive therapy was 3.8±3.1months. In the 22 women not receiving follow-up therapy, femoral neck, total hip, and spine BMD decreased by −4.2±4.3%, −4.5±3.6%, and −10.0±5.4%, respectively, while BMD was maintained in those who did receive follow-up antiresorptive drugs (femoral neck, total hip, and spine BMD changes of −0.6±2.7%, −0.8±3.1%, and −1.2±4.7%, respectively, P<0.001 for all between-group comparisons). Among untreated women, femoral neck BMD decreased more in those discontinuing denosumab (−5.8±4.0%) than in those discontinuing teriparatide (−0.8±2.6%, P=0.008). Total hip BMD, but not spine BMD, showed a similar pattern. Among treated women, denosumab increased femoral neck and total hip BMD more than bisphosphonates while BMD changes at the spine did not differ significantly.In summary, the large teriparatide and denosumab-induced gains in BMD achieved with 4years of intensive therapy in the DATA and DATA-Switch studies were maintained in patients who received prompt antiresorptive therapy but not in those left untreated. These results demonstrate the negative consequences of delaying consolidation therapy in women treated with these drugs and underscore the importance of timely medication transitions in such patients.

Role of Weekly Teriparatide Administration in Osseous Union Enhancement within Six Months After Posterior or Transforaminal Lumbar Interbody Fusion for Osteoporosis-Associated Lumbar Degenerative Disorders: A Multicenter, Prospective Randomized Study.

For elderly patients, posterior lumbar interbody fusion (PLIF) or transforaminal lumbar interbody fusion (TLIF) is usually performed to treat lumbar degenerative diseases. However, some patients exhibit pseudarthrosis following such procedures. The anabolic agent teriparatide is an approved treatment for promoting bone formation in osteoporotic patients. Our multicenter, prospective randomized study assessed the role of once-weekly teriparatide administration on patient outcomes following interbody fusion. Patients were females who were ≥50 years of age, had a bone mineral density (BMD) of <80% of the sex-matched young adult mean and/or previous spinal compression or femoral fractures, and had lumbar degenerative disease. Patients were randomly allocated to receive either weekly teriparatide, administered subcutaneously starting at week 1, for 6 months postoperatively (the teriparatide arm), or no teriparatide (the control arm). Blinded radiographic evaluations were performed using dynamic radiography and computed tomography (CT) and assessed by modified intention-to-treat analysis and per-protocol analysis. Clinical and neurological symptoms were evaluated using the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOA-BPEQ) and the Oswestry Disability Index (ODI). Seventy-five patients were randomized to treatment, and 66 patients completed treatment. At 4 months postoperatively, bone fusion in the 2 center CT slices was significantly higher in the teriparatide arm compared with the control arm in the age-adjusted modified intention-to-treat analysis and was significantly higher at 6 months in the per-protocol analysis. Radiographic examinations showed no disc-space narrowing and no intervertebral disc instability. JOA-BPEQ and ODI results were improved postoperatively in both treatment arms. Weekly administration of teriparatide promoted bone formation at the surgical fusion site and decreased bone resorption, as indicated by bone metabolic marker results, within the early postoperative period. Our findings suggest that combining lumbar interbody fusion and teriparatide treatment may be an effective option for managing lumbar degenerative disease in elderly patients. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Teriparatide Enhancement of Lumbar Fusion: Bone Enhancement Versus Cost, Convenience, and Risk of Cancer: Commentary on an article by Shigeto Ebata, MD, PhD, et al.: "Role of Weekly Teriparatide Administration in Osseous Union Enhancement within Six Months After Posterior or Transforaminal Lumbar Interbody Fusion for Osteoporosis-Associated Lumbar Degenerative Disorders. A Multicenter, Prospective Randomized Study".

Commentary The article by Ebata et al. contains several interesting and important points. However, the encouraging aspects of the study must be tempered by its short follow-up duration as well as the cost and potential for serious side-effects with the use of teriparatide. Those of us who perform spinal fusion surgery are interested in options that will stimulate healing, optimize the percentage of solid fusions, and improve patient outcomes. We are particularly looking for enhancements for challenging clinical situations, such as osteoporosis, where the quality of osseous fusion, the subsidence of implants, and screw pullout have been concerns. Teriparatide holds appeal as an intervention to address these issues, as teriparatide has been generally shown to improve bone mineral density and reduce fracture rates when compared with bisphosphonates in postmenopausal osteoporosis1,2. It is also germane that bisphosphonates have been shown to improve bone formation in osteoporotic patients who undergo posterior lumbar interbody fusion (PLIF)3. Thus, a logical research question is whether teriparatide would further enhance fusion following PLIF or TLIF (transforaminal lumbar interbody fusion)? While the short-term follow-up of 6 months in the present study limits the conclusions that can be drawn, it is encouraging that enhanced bone formation was seen within this short time frame. Fusion enhancement then leads us to look at whether teriparatide is likely to be generally applicable in day-to-day patient care. The limitations in the clinical scenario tend to be cost, convenience, and side-effects and/or complications. Teriparatide is clearly more expensive than other medications for osteoporosis. The estimated cost of daily subcutaneous injection is approximately $560 (USD) per month4 compared with $10 to $20 for the use of bisphosphonates5. One of the interesting aspects of the study by Ebata et al. is the efficacy of treatment involving the administration of a weekly dose of teriparatide compared with a daily regimen, as was studied by other authors investigating treatment following lumbar posterolateral fusion6. Weekly dosing would clearly be substantially cheaper than daily. In terms of patient convenience, a weekly dosing regimen would also have important implications, as the route of administration, subcutaneous injection, is somewhat invasive. Considering side-effects and/or complications, the potential inducement of cancer, particularly osteosarcoma, has been the primary concern with teriparatide. This has translated to a recommendation that teriparatide be used for a maximum 2-year time frame7,8. Osteosarcoma has been observed in small-animal studies involving rats at doses 3 to 60 times the standard prescription for humans7,8. However, the post-market surveillance funded by Eli Lilly but overseen by the U.S. Food and Drug Administration has not identified any cases of osteosarcoma7,8. To substantiate the encouraging early enhancement of healing, longer-term follow-up is needed. A treatment effect seen with a once-weekly dose (as opposed to the traditional daily dosing) suggests that additional investigation is necessary to further define the dose-response curve for teriparatide. Surgeons should be aware of the concern regarding the inducement of osteosarcoma with teriparatide treatment, even though this appears to be a relatively low risk. Similarly, the relatively high cost and the inconvenience of teriparatide administration by subcutaneous injection remain issues to be considered when evaluating treatment options.

Tarsal navicular stress fractures

Navicular stress fractures are common in athletes and management is debated. This article will review the evaluation and management of navicular stress fractures. Various operative and non-operative adjunctive treatment modalities are reviewed including the relevance of vitamin D levels, use of shock wave therapy and bone marrow aspirate concentrate (BMAC), and administration of teriparatide. Surgical treatment may be associated with earlier return to sports. The author's preferred treatment algorithm with corresponding images is presented which allows for safe and rapid return to activities in the athletic patient. Future research is needed in evaluating the preventative effects of vitamin D and use of other adjunctive treatments to increase the healing rates of this fracture.

Osteocytes signaling events induced by intermittent vs continuous Teriparatide treatment affect in vitro osteoblast differentiation and mineralization

PTH(1-34), also known as Teriparatide, is an active anabolic drug used in the treatment of some forms of osteoporosis and occasionally exploited to speed fracture healing. The effect of such therapies are dependent on the type of administration, in fact it has been largely demonstrated that a short administration of Teriparatide (also called intermittent) increases the bone mass, meanwhile a long administration of the same agent (known as continuous) leads to an increased resorption. The molecular reason why the type of administration is so critical for the fate of the bone remodeling is still largely unknown but it is probably due to the fact that it affects several signaling pathways and alters the biological activity of a cohort of cells: osteoblasts, lining cells, osteoclasts, and osteocytes. In the present work, we firstly focused the attention on molecular events induced by intermittent vs continuous Teriparatide treatment in a well-known osteocytes in vitro model, the MLO-Y4 cells. By the use of a gene array platform, we found many molecules upregulated or downregulated depending on the the temporal administration modes, suggesting that the drug affects in diverse manner the osteocytes related signaling pathways. In particular, we paid attention to Wisp-2, a protein of the Wnt pathway that has been demonstrated to be able to interact and influence the differentiation of osteoblasts into osteocytes and their mineralization. Secondly, through the mineralization assay, we analyzed the functional effects, involving the differentiation of osteoblast IDG-SW3 cell line, upon the conditioning culture with MLO-Y4 medium, that were pre-treated with short and long time administration of Teriparatide. These findings, consistent with the crucial role performed by osteocytes on osteoblast differentiation, clarify the molecular events downstream the short treatment with Teriparatide, suggesting that the perturbation of certain signaling patwhays, such as the Wnt pathway, is crucial for the positive regulation of bone formation.

Effectiveness of Teriparatide on Fracture Healing: A Systematic Review and Meta-Analysis.

PurposeNowadays, the efficacy of teriparatide in treating osteoporosis was widely accepted, but the discussion about using teriparatide to enhance fracture healing hasn’t come to an agreement. This meta-analysis was conducted to evaluate the effectiveness of teriparatide for fracture healing.MethodsWe searched PubMed, the Cochrane Library, and Embase in August 2016 for randomized controlled trials (RCTs) which concerned the treatment of teriparatide for fracture healing.ResultsFinally, a total of 380 patients were randomly assigned in the 5 trials included in this meta-analysis. There was a significant effectiveness with regards to function improvement in patients following fracture, however, there was no significant effectiveness with regards to time of radiographic fracture healing, fracture healing rate and reduction in pain.ConclusionsThis analysis showed that administration of teriparatide following fracture lacked the effectiveness for fracture healing. Moreover, teriparatide administration had no apparent adverse effects. These results should be interpreted with caution because of some clear limitations. If we want to confirm whether teriparatide improves fracture healing, more high-quality randomized controlled trials are needed.

Effects of teriparatide on cementless bipolar hemiarthroplasty in patients with osteoporotic femoral neck fractures.

BackgroundFor osteoporotic femoral neck fractures, suitable bone-implant stability is critical for pain relief, early return to daily activities and reduction of complications. Teriparatide (parathyroid hormone [PTH1-34]) can improve bone-implant stability in some basic studies. However it’s use in osteoporotic femoral neck fractures treated by cementless hemiarthroplasties for the beneficial effects on bone-implant stability is sparse in the literature. The aim of this study was to determine if post-operative teriparatide administration can reduce femoral stem migration and improve early functional recovery and health-related quality of life (HRQoL).MethodsBetween 2010 and 2014, patients with osteoporotic femoral neck fracture who underwent cementless bipolar hemiarthroplasty were included into this retrospective cohort study. Group A included patients treated with cementless bipolar hemiarthroplasty only; Group B patients had additional teriparatide. Demographic data, complications, radiographic and functional outcomes as well as health-related quality of life (HRQoL) were compared.ResultsThere were 52 hips in group A (no teriparatide) and 40 hips in group B (patient who received teriparatide). The subsidence of the femoral stem tended to be significantly decreased in the teriparatide group at 6 and 12 weeks post-operatively (p = 0.003 and p = 0.008, respectively). The Harris Hip Score (HHS) increased significantly from pre-operation to 6 weeks post-operatively and thereafter up to one year in both groups. However, there were no significant differences in terms of subsequent fracture, mortality, HHS, and HRQoL between two groups during the entire study period.ConclusionsTeriparatide significantly reduces the subsidence of the cementless femoral stem in elderly patients in the early post-operative period, but this benefit does not reflect better functional outcomes and HRQoL. Further prospective randomized large-scale cohort study is warranted for evidence-based recommendations.

Modeling and remodeling effects of intermittent administration of teriparatide (parathyroid hormone 1-34) on bone morphogenetic protein-induced bone in a rat spinal fusion model

BackgroundBone morphogenetic protein (BMP)-based tissue engineering has focused on inducing new bone efficiently. However, modeling and remodeling of BMP-induced bone have rarely been discussed. Teriparatide (parathyroid hormone [PTH] 1-34) administration initially increases markers of bone formation, followed by an increase in bone resorption markers. This unique activity would be expected to accelerate the modeling and remodeling of new BMP-induced bone. MethodsMale Sprague-Dawley rats underwent posterolateral spinal fusion surgery and implantation of collagen sponge containing either 50μg recombinant human (rh)BMP-2 or saline. PTH 1-34 (60μg/kg, 3 times/week) or saline injections were continued from preoperative week 2 week to postoperative week 12. The volume and quality of newly formed bone were monitored by in vivo micro-computed tomography and analyses of bone histomorphometry and serum bone metabolism markers were conducted at postoperative week 12. ResultsMicrostructural indices of the newly formed bone were significantly improved by PTH 1-34 administration, which significantly decreased the tissue volumes of the fusion mass at postoperative week 12 compared to that at postoperative week 2. Bone histomorphometry and serum analyses showed that PTH administration significantly increased both bone formation and resorption markers. Analysis of the histomorphometry of cortical bone identified predominant periosteal bone resorption and endosteal bone formation. ConclusionsLong-term intermittent administration of PTH 1-34 significantly accelerated the modeling and remodeling of new BMP-induced bone. Clinical relevanceOur results suggest that the combined administration of rhBMP-2 and PTH 1-34 facilitates qualitative and quantitative improvements in bone regeneration, by accelerating bone modeling and remodeling.

Short-term effects of teriparatide versus placebo on bone biomarkers, structure, and fracture healing in women with lower-extremity stress fractures: A pilot study

AimsIn this pilot, placebo-controlled study, we evaluated whether brief administration of teriparatide (TPTD) in premenopausal women with lower-extremity stress fractures would increase markers of bone formation in advance of bone resorption, improve bone structure, and hasten fracture healing according to magnetic resonance imaging (MRI). MethodsPremenopausal women with acute lower-extremity stress fractures were randomized to injection of TPTD 20-µg subcutaneous (s.c.) (n = 6) or placebo s.c. (n = 7) for 8 weeks. Biomarkers for bone formation N-terminal propeptide of type I procollagen (P1NP) and osteocalcin (OC) and resorption collagen type-1 cross-linked C-telopeptide (CTX) and collagen type 1 cross-linked N-telopeptide (NTX) were measured at baseline, 4 and 8 weeks. The area between the percent change of P1NP and CTX over study duration is defined as the anabolic window. To assess structural changes, peripheral quantitative computed topography (pQCT) was measured at baseline, 8 and 12 weeks at the unaffected tibia and distal radius. The MRI of the affected bone assessed stress fracture healing at baseline and 8 weeks. ResultsAfter 8 weeks of treatment, bone biomarkers P1NP and OC increased more in the TPTD- versus placebo-treated group (both p ≤ 0.01), resulting in a marked anabolic window (p ≤ 0.05). Results from pQCT demonstrated that TPTD-treated women showed a larger cortical area and thickness compared to placebo at the weight bearing tibial site, while placebo-treated women had a greater total tibia and cortical density. No changes at the radial sites were observed between groups. According to MRI, 83.3% of the TPTD- and 57.1% of the placebo-treated group had improved or healed stress fractures (p = 0.18). ConclusionsIn this randomized, pilot study, brief administration of TPTD showed anabolic effects that TPTD may help hasten fracture healing in premenopausal women with lower-extremity stress fractures. Larger prospective studies are warranted to determine the effects of TPTD treatment on stress fracture healing in premenopausal women.

Frequency of Teriparatide Administration Affects the Histological Pattern of Bone Formation in Young Adult Male Mice.

Evidence supports that daily and once-weekly administration of teriparatide, human (h)PTH(1-34), enhance bone mass in osteoporotic patients. However, it is uncertain whether different frequencies of hPTH(1-34) administration would induce bone formation similarly in terms of quantity and quality. To investigate that issue, mice were subjected to different frequencies of PTH administration, and their bones were histologically examined. Frequencies of administration were 1 time/2 days, 1 time a day, and 2 and 4 times a day. Mice were allocated to either to control or to 3 different dosing regimens: 80 μg/kg of hPTH(1-34) per injection (80 μg/kg per dose), 80 μg/kg of hPTH(1-34) per day (80 μg/kg · d), or 20 μg/kg of hPTH(1-34) per day (20 μg/kg · d). With the regimens of 80 μg/kg per dose and 80 μg/kg · d, high-frequency hPTH(1-34) administration increased metaphyseal trabecular number. However, 4 doses per day induced the formation of thin trabeculae, whereas the daily PTH regimen resulted in thicker trabeculae. A similar pattern was observed with the lower daily hPTH(1-34) dose (20 μg/kg · d): more frequent PTH administration led to the formation of thin trabeculae, showing a thick preosteoblastic cell layer, several osteoclasts, and scalloped cement lines that indicated accelerated bone remodeling. On the other hand, low-frequency PTH administration induced new bone with mature osteoblasts lying on mildly convex surfaces representative of arrest lines, which suggests minimodeling-based bone formation. Thus, high-frequency PTH administration seems to increase bone mass rapidly by forming thin trabeculae through accelerated bone remodeling. Alternatively, low-frequency PTH administration leads to the formation of thicker trabeculae through bone remodeling and minimodeling.

Effect of intermittent administration of teriparatide (PTH 1-34) on BMP induced bone regeneration in a rat critical-sized femoral defect model

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)