Effect of human parathyroid hormone hPTH (1–34) applied at different regimes on fracture healing and muscle in ovariectomized and healthy rats

Komrakova, Marina; Stuermer, Ewa Klara; Werner, Carsten; Wicke, Michael; Kolios, Leila; Sehmisch, Stephan; Tezval, Mohammad; Daub, F.; Martens, Timo; Witzenhausen, Peter; Dullin, Christian; Stuermer, Klaus Michael

doi:10.1016/j.bone.2010.05.013

Cited by 76 publications

(78 citation statements)

References 36 publications

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“…The study also is one of only a few well-controlled studies of clinical outcomes with a systemically active biologic drug in patients with fracture. Although preclinical studies using PTH in animal models are promising [1,20,28,32] and sporadic case reports of humans [8,19,31,33,37,38] showed an anecdotal benefit of teriparatide in various fractures, there were no well-controlled clinical trials to support the hypothesis that teriparatide improve fracture healing and our study with a much-reduced sample size showed no such benefit. Thus, the effect of teriparatide on fracture healing remains uncertain.…”

Section: Discussioncontrasting

confidence: 56%

“…Systemic therapy with teriparatide has been shown to improve healing in preclinical fracture models [1,20,28,32], in clinical studies of wrist fractures [2], and in case reports [8,19,31,33,37,38]. However, the results from these pooled trials revealed no treatment effect of teriparatide versus placebo in the rates of revision surgery or radiographic fracture healing in femoral neck fractures.…”

Section: Discussionmentioning

confidence: 99%

“…Teriparatide (recombinant human parathyroid hormone [PTH] ; Forteo 1 / Forsteo 1 , Eli Lilly and Company, Indianapolis, IN, USA) is approved for treating osteoporosis and glucocorticoid-induced osteoporosis in patients at high fracture risk [12,29]. Teriparatide enhanced bone healing in preclinical models [1,20,28,32], and in a controlled clinical trial accelerated radiographic healing of wrist fractures at a dosage of 20 lg/day (post hoc analysis) but not 40 lg/day (primary endpoint) [2]. PTH 1-84 also improved fracture healing in a controlled trial of patients with pelvic fractures [30].…”

Section: Introductionmentioning

confidence: 99%

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Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo-controlled Trial

Bhandari

Jin

See

et al. 2016

Clinical Orthopaedics &Amp; Related Research

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Background There is a medical need for therapies that improve hip fracture healing. Teriparatide (Forteo 1 / Forsteo 1 , recombinant human parathyroid hormone) is a bone anabolic drug that is approved for treatment of osteoporosis and glucocorticoid-induced osteoporosis in men and postmenopausal women at high fracture risk. Preclinical and preliminary clinical data also suggest that teriparatide may enhance bone healing.Questions/purposes We wished to test the hypotheses that treatment with teriparatide versus placebo would improve femoral neck fracture healing after internal fixation as measured by (1) frequency of revision surgery, (2) radiographic fracture healing, and (3) other outcomes including pain control, gait speed, and safety. Methods We initiated two separate, but identically designed, clinical trials to meet FDA requirements to provide substantial evidence to support approval of a new indication. The two prospective, randomized double-blind, placebo-controlled Phase III studies were designed to evaluate the effect of subcutaneous teriparatide (20 lg/day) for 6 months versus placebo on fracture healing at 24 months. The trials were conducted concurrently with a planned enrollment of 1220 patients per trial. However, enrollment was stopped owing to very slow patient accrual, and an a priori decision was made to pool the results of those studies for statistical analyses before study completion; pooling was specified in both protocols. Randomization was stratified by fixation (sliding hip screw or multiple cancellous screws) and fracture type (displaced or nondisplaced). An independent Central Adjudication Committee reviewed revision surgical procedures and radiographs. A total of 159 patients were randomized in the two trials (81 placebo, 78 teriparatide). The combined program had very low power to detect the originally This study was sponsored by Eli Lilly and Company. The institutions of authors (MB, NG, RW) have received, during the study period, funding from Eli Lilly and Company. One author (MB), or a member of his or her immediate family, has or may receive payments or benefits, during the study period, an amount of less than USD 10,000 from Eli Lilly and Company. One or more of the authors (LJ, KS, RB, KDK, MRW, BM) are employees of Eli Lilly and Company, that provided funding for this study. One of the authors (QIA) was an employee of Eli Lilly and Company at the time of the study but he no longer is employed by them. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research 1 editors and board members are on file with the publication and can be viewed on request. Each author certifies that his or her institution approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained. This study was conducted at the authors' various institutions. Clinical Orthopaedics and Related Research ®A Publication of The ...

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo-controlled Trial

Bhandari

Jin

See

et al. 2016

Clinical Orthopaedics &Amp; Related Research

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“…Estrogen has been demonstrated to have diverse effects on bone healing in Ovx rats. Whereas Stuermer et al (2010) reported improved callus and bone parameters after estrogen supplementation, Jahng & Kim (2000) and Komrakova et al (2010) found no advantage of estrogen treatment for fracture healing. In this study, despite anti-catabolic stimulus, estrogen treatment in Ovx rats impeded healing processes.…”

Section: Discussionmentioning

confidence: 99%

Impact of 4-methylbenzylidene camphor, daidzein, and estrogen on intact and osteotomized bone in osteopenic rats

Komrakova¹,

Sehmisch²,

Tezval³

et al. 2011

Journal of Endocrinology

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The study investigated the influence of 4-methylbenzylidene camphor (4-MBC), daidzein, and estradiol-17b-benzoate (E 2 ) on either intact or osteotomized cancellous bone in ovariectomized (Ovx) rats. Three-month old Ovx rats were fed with soy-free (SF) diet over 8 weeks; thereafter, bilateral transverse metaphyseal osteotomy of tibia was performed and rats were divided into groups: rats fed with SF diet and SF diet supplemented with 4-MBC (200 mg), daidzein (50 mg), or E 2 (0 . 4 mg) per kilogram body weight. After 5 or 10 weeks, computed tomographical, biomechanical, histological, and ashing analyses were performed in lumbar spine and tibia of 12 rats from each group. 4-MBC and E 2 improved bone parameters in lumbar spine and tibia, were not favorable for osteotomy healing, and decreased serum osteocalcin level. However, daidzein improved bone parameters to a lesser extent and facilitated osteotomy healing. For lumbar spine, the bone mineral density was 338G9, 346G5, 361G6, and 360G5 mg/cm 3 in SF, daidzein, 4-MBC, and E 2 , respectively, after 10 weeks. For tibia, the yield load was 98G5, 114G3, 90G2, and 52G4 N in SF, daidzein, 4-MBC, and E 2 , respectively, after 10 weeks. Serum daidzein was 54G6 ng/ml in daidzein group and equol was not detected. Alp and Igf1 genes were down-regulated in callus after daidzein and E 2 compared with 4-MBC (week 5). The response of bone tissue and serum markers of bone metabolism could be ordered: daidzein!4-MBC!E 2 . Treatments were more effective after 5 vs 10 weeks. In SF group, bone structure was impaired after 5 weeks and improved after 10 weeks probably due to adaptation mechanisms to osteoporosis. In conclusion, it is conceivable that 4-MBC may improve bone tissue in osteoporotic organisms; osteoporotic patients with fractures could benefit from daidzein treatment.

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“…Several studies have reported that intermittent administration of human PTH also enhances fracture healing of cortical bones such as the shaft of the femur or tibia after surgical intervention in animals (Andeassen et al 1999;Holzer et al 1999;Nakazawa et al 2005), even in an osteoporotic animal model (Jahng and Kim 2000). However, very few studies have addressed fracture healing of cancellous bones, which are frequent fracture sites in osteoporosis patients, after injury or surgical intervention (Komrakova et al 2010). Therefore, a cancellous bone fracture model was created and an osteotomy of the proximal tibia was performed.…”

mentioning

confidence: 99%

Intermittent Administration of Human Parathyroid Hormone before Osteosynthesis Stimulates Cancellous Bone Union in Ovariectomized Rats

Tsuchie

Miyakoshi

Kasukawa

et al. 2013

Tohoku J. Exp. Med.

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It has been reported that intermittent administration of human parathyroid hormone (h-PTH) promotes bone healing after surgery for osteoporotic fractures. If bone healing is promoted by the administration of h-PTH during pre-operative waiting period, we can prevent prolonged bed rest. Therefore, we evaluated the effects of pre-operative h-PTH treatment on cancellous bone union and its mechanism for fracture healing in ovariectomized rats as a model for osteoporosis. Ovariectomized 7-month-old female Sprague-Dawley rats underwent an osteotomy of the proximal tibia as a fracture model, and h-PTH (30 µg/kg body weight) or vehicle was administered as a pre-operative treatment for one week. After the one-week treatment, tibiae were fixed with wire for osteosynthesis, and h-PTH or vehicle was administered for 1 or 3 weeks following wire fixation. In addition to bone histomorphometry, we used alcian blue/hematoxylin stained sections for evaluating cartilage volume and immunostained sections for analyzing the expression of proliferating cell nuclear antigen (PCNA) for cell proliferation and that of Sox9 and Runx2, differentiation markers for cartilage cells and osteoblasts, respectively. Pre-operative treatment with PTH significantly increased bone volume. Pre-operative and pre-to post-operative treatment with PTH for 2 weeks significantly promoted bone union. Pre-operative treatment with PTH significantly increased cartilage volume, and pre-to post-operative treatment with PTH for 2 weeks significantly increased the percentage of cells positive for Runx2 (p < 0.01), but not PCNA or Sox9. Pre-operative administration of h-PTH enhances bone union by promoting cartilage formation and cell differentiation to osteoblasts, but not by promoting cell proliferation.

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Effect of human parathyroid hormone hPTH (1–34) applied at different regimes on fracture healing and muscle in ovariectomized and healthy rats

Cited by 76 publications

References 36 publications

Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo-controlled Trial

Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo-controlled Trial

Impact of 4-methylbenzylidene camphor, daidzein, and estrogen on intact and osteotomized bone in osteopenic rats

Intermittent Administration of Human Parathyroid Hormone before Osteosynthesis Stimulates Cancellous Bone Union in Ovariectomized Rats

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