Teriparatide Research Articles

Teriparatide:benefit and safety for bone disease in CKD patients undergoing hemodialysis

Teriparatide, 1-34 parathyroid hormone, is one of effective treatments for osteoporosis. Teriparatide shows an anabolic effect for bone formation, as a result, increases bone mineral density as well as prevention of fractures in the general population. On the other hand, there are a few report about the effect of teriparatide on increase of bone mineral density in maintenance hemodialysis patients. In addition to CKD-MBD, osteoporosis is also an important pathological change in ESRD patients, therefore its safety and efficacy should be discussed in more detail.

Treatment of bone disorders with parathyroid hormone: success and pitfalls.

Bone diseases such as osteoporosis, osteoarthritis, bone tumours and bone fractures are rather common and not just in the elderly. Parathyroid hormone (PTH) is responsible for maintaining calcium homeostasis, increasing bone mineral density (BMD), increasing cortical and trabecular bone thickness and thus increasing bone strength. Teriparatide (PTH 1-34) has the same effects as endogenous PTH and is pharmacologically used to treat bone diseases such as osteoporosis, osteoarthritis, bone fractures and bone tumours. This review discusses how PTH 1-34 plays a role in managing bone diseases. Clinical studies have shown that short or intermittent dosing of PTH 1-34 has minimal adverse effects, while long-term dosing (over two years) has been linked to de novo osteoarthritis and bone deformation. Currently PTH therapy is only approved in the treatment of post-menopausal osteoporosis, however it is also proven to have effects in treating osteoarthritis, bone tumours and bone fractures. If the patient undergoing therapy is closely monitored, the major pitfalls are very unlikely to take place, thus it is highly recommended that patients be closely monitored by a medical practitioner.

Drug therapy for primary osteoporosis in men

Overall, drug therapies for osteoporosis in men are less defined than in women, mainly due to the fact that there are fewer RCTs performed in male populations, to the relatively smaller sample sizes, and to the lack of long-term extension studies. In a series of well-designed RCTs, alendronate, risedronate, zoledronic acid, and teriparatide were demonstrated to reduce the risk of new vertebral fractures in men presenting with primary osteoporosis(including osteoporosis associated with low testosterone levels)and to improve the bone mineral density(BMD). In preliminary studies, ibandronate and denosumab also showed their beneficial effects on surrogate outcomes(BMD and markers of bone turnover)in men with osteoporosis. Although direct evidence about their non-vertebral anti-fracture efficacy are lacking, the effects of bisphosphonates, denosumab and teriparatide on surrogate outcomes were similar to those reported in pivotal RCTs undertaken in postmenopausal women, in which vertebral and non-vertebral anti-fracture efficacy have been clearly demonstrated.

The Importance of teriparatide in the treatment of osteoporosis

The anabolic agent teriparatide (TPTD) clearly increases bone mineral density both in daily and weekly formulations. In addition, the effectiveness of daily TPTD in reducing the risks of vertebral and non-vertebral fractures and of weekly TPTD in reducing the risk of vertebral fractures has been established. TPTD is indicated for severe osteoporosis, such as cases of multiple fractures, hip fractures, and fractures sustained during antiresorptive therapy. TPTD has also been shown to be effective for male osteoporosis and glucocorticoid-induced osteoporosis. Furthermore, TPTD can only be given for a limited duration, and requires sequential antiresorptive therapy following completion of administration. TPTD is the only anabolic agent that is currently available, and more effective methods of use such as combination and sequential therapies are being investigated. Moreover, clinical development of novel anabolic agents such as abaloparatide, a parathyroid hormone-related protein(PTHrP)analog, is being actively undertaken.

Intermittent low-dose administration of recombinant human parathyroid hormone (1-34) promotes the expression of Osterix during early stage of fracture healing

Objective To study the effects of intermittent low-dose administration of recombinant human parathyroid hormone (1-34) [rhPTH(1-34)] in the expression of Osterix (Osx) during early stage of fracture healing. Methods Forty-eight 2-month old male Sprague-Dawley rats were underwent close unilateral femoral fracture and intramedullary nail fixation. The subjects were divided into 2 equal groups randomly: treatment group undergoing subcutaneous injection of rhPTH(1-34) 10 mg/kg/d immediately after the operation and control group undergoing subcutaneous injection of normal saline of the same dose. Six rats in each group were sacrifice at 2, 7, 14, and 21 days after operation. X-ray photography study was conducted at 7, 14 and 21 days. Tissue RNA and protein were extracted from the bone tissues of bilateral femurs and the expression levels of Osx mRNA and protein were evaluated via real time quantitative PCR and Western-blotting. Results Fracture healing was significant at 14 days after operation, and the progress of fracture healing was better in the rhPTH(1-34) group than in the control group at 14 and 21 days. The relative expression of Osx mRNA and protein in the fractured femurs of the rhPTH(1-34) group (5.02±0.5 and 10.03±0.8 for Osx mRNA, 3164.03±131 and 3509.02±126 for protein) at 14 and 21 days after the operation were significantly higher than those of the control group (2.30±0.4 and 4.01±0.7 for Osx mRNA, 1053.04±121 and 2721.03±123 for protein). However, there was no significant difference at 2 and 7 days after operation between the rhPTH(1-34) and control group. Conclusion Intermittent low-dose administration of rhPTH(1-34) up-regulates the expression levels of osteogenesis-specific Osx mRNA and protein in rats. It will accelerate the early phase of fracture healing process. Key words: Fracture healing; Teriparatide; Gene expression

Relationship of pharmacokinetics, changes of bone turnover markers and BMD/fractures efficacy during treatment with anabolic agents;Teriparatide daily and once weekly subcutaneous injections.

Teriparatide(recombinant human PTH1-34, 20 μg daily subcutaneous injection)has been approved for osteoporosis patients at high risk of fracture in many countries including Japan. Teriparatide daily injection therapy has been reported to increase BMD, improve microarchitecture of bone, and reduce the risk of new vertebral fractures and that of non-vertebral fractures. Pharmakokinetic(PK)study after a single Teriparatide injection of the daily dose in healthy Japanese postmenopausal women(n=18)revealed very rapid achievement of peak blood level(median of tmax=0.25 hr)followed by fast disappearance from the blood(mean t1/2=0.708 hr, n=17). Consistent with these PK characteristics, a rapid increase in bone formation marker and later increase in bone resorption marker has previously been observed, which was described as a bone anabolic window. More recently, once weekly subcutaneous injection of teriparatide acetate(56.5 μg)has been reported to reduce the risk of new vertebral fractures compared with placebo and has been approved in Japan. PK study after injection of the higher weekly dose in healthy Japanese postmenopausal women(n=10)revealed a relatively slow achievement of the peak blood level(mean tmax=0.875 hr)compared to daily injections, followed by relatively slow disappearance from the blood(mean t1/2=1.295 hr). Consistent with these PK characteristics, an initial(<24 hr)transient decrease of bone formation markers(serum osteocalcin and P1NP)and transient increase of bone resorption markers(serum NTX and urinary CTX)were observed. However, afterword, the bone formation and resorption markers were increased and decreased, respectively, for longer than 1 week from the baseline levels. The relationship of pharmacokinetics, changes of bone turnover markers and BMD/fractures efficacy during daily versus weekly teriparatide treatment needs to be clarified.

Changes in bone quality and strength with bone-forming agents

Among the anti-osteoporotic agents clinically available in Japan, teriparatide is the only bone anabolic agent offering potent osteogenic effects. Regarding bone quality, studies have shown that teriparatide increases bone collagen content and enzymatic cross-links and decreases pentosidine, a surrogate marker of advanced glycation end-products. In addition to these improvements in bone collagen cross-links, increased bone mineral density and improvement of bone microarchitecture contribute to increases in bone strength with teriparatide administration. Teriparatide has been shown to markedly reduce the risk of new vertebral fractures in patients with osteoporosis. Recent clinical studies have suggested a role for teriparatide in accelerating healing for osteoporotic fractures. Teriparatide is promising for the prevention of vertebral collapse progression after vertebral fracture.

Management of osteoporosis associated with rheumatoid arthritis and glucocorticoid-induced osteoporosis

Mechanism of generalized osteoporosis associated with rheumatoid arthritis(RA)is multifactorial and following factors has been proposed:systemic effect of RA synovitis, glucocorticoids, weight loss, and endocrine changes. In addition to control of RA inflammation and management of glucocorticoid-induced osteoporosis(GIO), antiresorptive therapy, such as bisphosphonates is expected to show efficacy. Recently, anti-RANKL monoclonal antibodies have been shown to inhibit bone erosion and bone loss in combination with methotrexate in RA. GC-induced bone loss is most rapid during the initial 3 ~ 6 months and more slowly thereafter. Therefore, both primary and secondary prevention are important. The Japanese Society for Bone and Mineral Research(JSBMR)has updated the Guidelines on the Management and Treatment of GIO and has incorporated a new scoring method. By analyzing five GIO cohorts from primary and secondary prevention studies, age, GC dose, lumbar BMD, and prior fragility fractures were identified as risk factors and the fracture risk for an individual can be calculated as the sum of the scores for each risk factor. Pharmacological intervention should be started on the basis of a score of 3 as the optimal cut-off score. Both alendronate and risedronate are recommended as first-line treatment. Ibandronate,teriparatide, and active vitamin D3 derivatives are recommended as alternative option.

Teriparatide Improves Trabecular Osteoporosis but Simultaneously Promotes Ankylosis of the Spine in the Twy Mouse Model for Diffuse Idiopathic Skeletal Hyperostosis.

Diffuse idiopathic skeletal hyperostosis (DISH) is a common skeletal disorder in the elderly, which can develop into periosteal hyperostosis and paradoxically into immobilization-associated trabecular osteoporosis. The bone anabolic agent, teriparatide (TPD), seems to be a rational treatment for the immobilization-associated osteoporosis. However, it can lead to development of hyperostosis lesions in DISH patients. Here, we demonstrate TPD effectively treats trabecular osteoporosis while simultaneously promoting ankylosis of the spine in DISH model tiptoe-walking Yoshimura (twy) mice, compared with the ICR mice. Eighteen male twy mice were divided into three groups, and ICR mice were used as a normal control. Subcutaneous injections of TPD or phosphate-buffered saline (PBS) were performed according to three dosing regimens; 40 µg/kg once daily (TPD × 1 group), 40 µg/kg three times daily (TPD × 3 group), and PBS (control; Ctl group). Treatment was commenced at the age of 7 weeks and continued for 5 weeks. Micro-computed tomography (µCT) and histological analysis were performed. Longitudinal µCT study revealed that trabecular bone volume in both the vertebral body and distal femur decreased with time in the Ctl group, but increased dramatically in the TPD × 3 group. The twy mice developed ankylosis of the spine, the progression of which was accelerated with TPD therapy. We also confirmed that TPD therapy promoted ossification of spinal ligaments. Histomorphometrical study revealed that TPD treatment increased bone formation at the vertebrae enthesis region and in the trabecular bone. TPD therapy effectively treats trabecular osteoporosis, but potentially promotes ankylosis of the spine in patients with DISH.

Bone Cell Biology Assessed by Microscopic Approach. The effect of parathyroid hormone and teriparatide on bone

Continuous exposure to parathyroid hormone (PTH) leads to hypercalcemia and a decrease in bone volume, which is referred to as its catabolic effect, while intermittent exogenously administered PTH leads to an anabolic effect on bone. Intermittent administration of PTH dramatically increases bone remodeling and modeling through their direct and indirect effects on the functional cells of bone remodeling units and their precursors. These effects on bone metabolism differ according to dosing frequency of PTH. Therefore, different dosing frequency of PTH shows different therapeutic effects on bone in terms of bone volume and bone quality in patients with osteoporosis.

On "2015 Guidelines for Prevention and Treatment of Osteoporosis". Medical treatment for osteoporosis

The main revisions to the item of medical treatment in the 2015 edition of the Guidelines for Prevention and Treatment of Osteoporosis are the additions of the drugs such as ibandronate, teriparatide acetate (once-weekly preparation), and denosumab, which were approved after the release of the 2011 edition, and of information on new dosage forms for existing drugs. Furthermore, the heading "Evaluation and Recommendations" for each drug was changed to "Evaluation of Efficacy" . The choice of drug is determined based on evidence for the effectiveness of each drug and in accordance with the age, fracture risk, and pathophysiology of each patient. As for the selection and combined use of the various drugs, accumulation of evidence is anticipated, but sequential therapy using antiresorptive agents following treatment with teriparatide preparations is recommended.

On "2015 Guidelines for Prevention and Treatment of Osteoporosis". Drug-induced osteoporosis: glucocorticoid-induced osteoporosis

Osteoporosis is the most common and important adverse effect of glucocorticoid (GC) therapy. Since GC-induced bone loss is most rapid during the initial 3 - 6 months and primary prevention of bone loss is especially important, guidelines for management of GC-induced osteoporosis have been published overseas and in Japan. The Japanese Society for Bone and Mineral Research (JSBMR) has updated the Guidelines on the Management and Treatment of Glucocorticoid-induced Osteoporosis (GIO) and has incorporated a new scoring method. By analyzing five Japanese GIO cohorts from primary and secondary prevention studies, age, GC dose, lumbar BMD, and prior fragility fractures were identified as factors predicting future fracture and the fracture risk for an individual can be calculated as the sum of the scores for each risk factor. The guidelines were updated on the basis of a score of 3 as the optimal cut-off score for pharmacological intervention. Among the agents approved for the treatment of osteoporosis in Japan, the committee comprehensively reviewed validity for both primary and secondary prevention and assessed the benefit for both BMD and fracture prevention based on the results of clinical studies. Both alendronate and risedronate are recommended as first-line treatment. Ibandronate, teriparatide, and active vitamin D3 derivatives are recommended as alternative option.

Effects of PTH(1-34) during fracture healing after experimental bone drilling in rat femur: novel aspects

The study concerns the role of PTH(1-34) during bone lesion repair. 3-month-old male Sprague-Dawley rats, in which trans-cortical holes were drilled at femur mid-diaphysis, were divided in groups with/without Teriparatide administration (40𝜇g/ Kg/day), and sacrificed at different times (10, 28, 45 days). In 2002 (1) we demonstrated the occurrence of two successive bone forming processes during both skeletal organogenesis and bone repair, i.e. static (SO) and dynamic (DO) osteogenesis: the former (due to stationary osteoblasts, haphazardly grouped in cords) producing pre- liminary bad quality trabecular bone, the latter (due to typical polarized osteoblasts organized in ordered movable laminae) producing mechanically valid bone tissue. In brief, the primary function of SO is to provide a rigid scaffold, containing osteocytes (i.e. mechano-sensors), to DO-osteoblastic laminae; therefore, in DO mechanical factors can play a crucial role in transduction of mechanical stresses into biological signals. In the present work, histomorphometric analysis showed that, already after 10 days from drilling, notwithstanding the holes are temporarily filled by the same amount of newly-formed trabecular bone (produced by SO) independently from the treatment, the number of movable osteoblast laminae (typical of DO), covering the trabecular surface, is statistically higher in animals submitted to PTH(1-34) administration than in the control ones; this suggests that the mere effect of Teriparatide is to anticipate the occurrence of dynamic osteogenesis involved in the production of good quality bone more suitable to loading. These findings are also supported by the higher values of microhardness as well as the more ordered-fibered texture (observed by polarized light) in treated animals with respect to control ones that strongly indi- cates the qualitative (instead of quantitative) effect of PTH (1-34) in improving bone healing. The present investigation could be of crucial importance in further translational clinical research in humans to define the best therapeutic strategies in recovering skeletal lesions, particularly in terms of time of administration of PTH(1-34).

The Effect of Teriparatide in Women with Osteoporosis after Lumbar Posterolateral Fusion or Posterior Lumbar Interbody Fusion

Study Design: Retrospective study. Objectives: To i�vesti��te r�dio�o�ic ��d c�i�ic�� outco�es o� terip�r�tide i� �o�e� �it� osteoporosis ��ter i�stru�e�ted �u���r pos� tero��ter�� �usio� (PLF) or posterior �u���r i�ter�ody �usio� (PLIF). Summary of Literature Review: Terip�r�tide �cce�er�ted �u���r postero��ter�� �usio� i� �o�e� �it� post�e�op�us�� osteoporosis. M�teri��s ��d Met�ods: Ei��ty�six �o�e� o�der t��� 65 ye�rs o�d �it� osteoporosis u�der�e�t PLF or PLIF �it� �o�e �r��t �et�ee� Fe�ru�r, 2011 �to M�y, 2012 pP�tie�ts �ere divided i�to �our �roup: terip�r�tide �roup �it� �oc�� �o�e (A�1: 13 p�tie�ts;, terip�r�tide �roup �it� co�posite �o�e (A�2: 27 p�tie�ts; �o��terip�r�tide �roup �it� �oc�� �o�e (B�1: 14 p�tie�ts; ��d �o��terip�r�tide �roup �it� co�posite �o�e (B�2: 32 p�tie�ts). At 3, 6, ��d 12 �o�t�s postoper�tive�y, t�e Os�estry Dis��i�ity I�dex (ODI), visu�� ����o� sc��e (VAS), �usio� r�te, ��d period o� �o�e u�io� �ere ev��u�ted. Results: VAS ��d ODI i�proved ��ter sur�ery i� ��� �roups, �ut �o si��ific��t di��ere�ces �ere �ote�� ��o�� t�e �roupses Furt�er, t�ere ��s �o si��ific��t di��ere�ce ��o�� t�e �roups �or ��e� �usio� �eve�, ��d �usiops(p>0.05). Fusio� r�te ��s 94.44% i� t�e A�1 �roup, 92.59% i� t�e A�2 �roup, 79.17% i� t�e B�1 �roup, ��d 76.92% i� t�e B�2 �roup. Aver��e period o� �o�e u�io� ��s 3.25 �o�t�s, 3.65 �o�t�s, 5.67 �o�t�s, ��d 5.65 �o�t�s respective�y. Fusio� r�te ��d �ver��e �o�e u�io� ti�e ��de �o si��ific��t di��ere�ee� ��o�� t�e �roups divided �y �r��t ��teri��s (p>0.05). Ho�ever, t�ose i� t�e terip�r�tide �roup �ere si��ific��t�y superior to t�ose i� t�e �o�� terip�r�tide �roup (p<0.05). Conclusions: I� �o�e� �it� osteoporosis ��ter PLF or PLIF �it� �o�e�r��t, terip�r�tide s�o�ed superiority i� t�e r�te o� �usio� ��d t�e period o� �o�e u�io�.

Updates on Lifestyle-Related Diseases and Bone Metabolism. Teriparatide for osteoporosis associated with lifestyle-related diseases

Teriparatide is a peptide with 34 amino acids that corresponds to N-terminal portion of parathyroid hormone (PTH) . Teriparatide is the only anabolic agent currently available and prevent fractures by increasing bone mass and improving bone architecture. PTH and bone turnover are reported to be low in some patients with type 2 diabetes and chronic kidney disease. For these patients, it seems to be theoretically reasonable to use teriparatide. However, it has not been shown that teriparatide is more effective for patients with low bone turnover than other subjects.

Glucocorticoid and Bone. Beneficial effect of teriparatide on fracture risk as well as bone mineral density in patients with glucocorticoid-induced osteoporosis

Bone metablism of glucocorticoid-induced osteopororsis (GIO) is characterised by transient increase in bone resorption and persistent suppression of bone formation caused by glucocorticoid. Teriparatide is an ideal drug for GIO, because of antagonistic effect against that pathophysiological conditions. Based on new findings of treatment for GIO around the world, teriparatide was selected as one of alternative drugs of the first line agents for GIO in revised version of the guidelines on the management and treatment of GIO of the Japanese Society for Bone and Mineral Research : 2014 update.

Glucocorticoid and bone

Oral glucocorticoids are prescribed for a wide variety of medical disorders. Reduced bone formation is the key process in glucocorticoid-induced osteoporosis. Glucocorticoid-induced osteoporosis is characterized by relative dissociation between the BMD values and the fracture risk, which is higher than expected based on the BMD values. 2014 revised Japanese guidelines indicated that Age, GC dose, lumbar BMD, and prior fragility fractures were identified as factors predicting future fracture and each factor was scored according to the category. Since an age of 65 years or older, prednisolone dose of 7.5mg/day or more, and a history of fragility fracture are independent risk for future fractures, initiation of drug therapy can be decided more easily without evaluation of BMD by DXA when one of these risk factors exists. Alendronate and risedronate were recommended as first-line treatment and teriparatide (rDNA origin) , ibandronate, alfacalcidol and calcitriol were recommended as alternative option.

SAT0481 Clinical Factors for Incident Vertebral Fractures Treated with Bisphosphonates in Glucocorticoid-Induced Osteoporosis. Who Needs to Use Other Anti-Osteoporotic Agents?

BackgroundAlthough bisphosphonates (BP) is a popular choice for prevention and treatment of Glucocorticoid-induced osteoporosis (GIO), other agents such as teriparatide (TPT) or denosmab have been also available for the treatment....

Association between the efficacy of alendronate and serum level of vitamin D in patients with osteoporosis

Objective To examine the association between vitamin D and alendronate response,and to investigate the proper vitamin D levels for the efficacy of alendronate treatment of osteoporosis.Methods In this retrospective study,559 post-menopausal women with osteoporosis were devided into two groups:non-responders and responders,based on the European Study of Forsteo (EUROFORS).Demographic and clinical data including mean 25-hydroxy vitamin D (25-OHD) levels between dual-energy X-ray absorptiometry (DEXA) scans were obtained.Mean 25-OHD levels were compared between responders and non-responders and multiple logistic regression analysis was performed to identify factors associated with non-response.Results There were 437 (75.5％) responsers to alendronate therapy and 142 (24.5％) non-responders.Responders with a mean serum 25-OHD level of (59.96 ±12.56) nmol/L,obtained a more favorable result than non-responders,whose serum 25-OHD level was (47.50 ±9.92) nmol/L (P＜0.01).25-OHD level was significantly associated with response.Conclusion Patients with a mean 25-OHD ≥50 nmol/L had a substantially greater likelihood of maintaining bisphosphonate response. Key words: Osteoporosis; Alendronate ; Biphosphonates ; Vitamin D

Teriparatide infusion for post-thyroidectomy hypocalcaemia: a case report

2 Jul 2012 2.39 1.90 Calcitriol 2.25 mcg BD + Sandocal 1g (1 tab QDS)+ Weekly intravenous calcium & magnesium infusion 3 Aug 2012 1.78 2.04 Calcitriol 2.25 mcg BD + Sandocal 1g (1 tab QDS) + Teriparatide 20 mcg SC injections BD ) + Weekly intravenous calcium & magnesium infusion 4 Jan 2013 1.94 1.64 Calcitriol 2.25 mcg BD + Sandocal 1g (1 tab QDS) + Teriparatide 40mcg BD SC injections )+ Weekly intravenous calcium & magnesium infusion 5 Jun 2013 1.70 1.89 Teriparatide infusion 40 mcg / 24 hours only