Teriparatide rapidly improves pain-like behavior in ovariectomized mice in association with the downregulation of inflammatory cytokine expression

Dohke, Takayuki; Iba, Kousuke; Hanaka, Megumi; Kanaya, Kumiko; Okazaki, Shunichiro; Yamashita, Toshihiko

doi:10.1007/s00774-017-0865-0

Cited by 15 publications

(8 citation statements)

References 26 publications

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“…Whilst the main source of pain in osteoporotic patients is typically considered to be complex or micro fractures due to the lower bone mineral density [13,14], a subset of these patients have pain without showing signs of fracture suggesting that osteoporotic bone loss itself can be painful [38,39]. This is supported by numerous reports of mice developing mechanical and thermal hypersensitivity following OVX surgery [40,41]. Here, we show a similar pain-like phenotype, with OVX mice developing mechanical and thermal hypersensitivity 1 week postsurgery whilst naturalistic behaviour remained unchanged.…”

Section: Discussionmentioning

confidence: 99%

Fracture-induced pain-like behaviours in a femoral fracture mouse model

et al. 2021

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Summary This study is the first comprehensive characterisation of the pain phenotype after fracture using both evoked and naturalistic behaviours in adult male and ovariectomised female mice. It also shows that an anti-nerve growth factor (NGF) therapy could be considered to reduce pain after fracture surgery. Introduction Bone fractures are common due to the ageing population and very painful even after healing. The phenotype of this pain is still poorly understood. We aimed to characterise it in a femoral fracture model in mice. Methods We employed both adult male, and female ovariectomised (OVX) mice to mimic osteoporotic fractures. Mice underwent a unilateral femoral fracture maintained by an external fixator or a sham surgery. Pain behaviours, including mechanical and thermal sensitivity, weight bearing and LABORAS, were measured from baseline to 6 weeks after fracture. The effect on pain of an antibody against nerve growth factor (anti-NGF) was assessed. Changes in nerve density at the fracture callus were analysed by immunohistochemistry. Results Following surgery, all groups exhibited high levels of invoked nociception. Mechanical and thermal hyperalgesia were observed from 1 week after surgery, with nociceptive sensitization in the fracture group maintained for the 6 weeks, whereas it resolved in the sham group after 3 weeks. OVX induced reduction in pain thresholds, which was maintained after fracture. The frequency of naturalistic behaviours did not change between groups. Anti-NGF administered before and weekly after surgery alleviated fracture-induced mechanical nociception. The density of nerve fibres in the fracture callus was similar in all groups 6 weeks after surgery. Conclusions Fractures in rodent models are highly painful in both sexes. This pain-like phenotype is prolonged and should be routinely considered in fracture healing studies as it can affect the study outcome. The anti-NGF alleviates fracture-induced mechanical pain.

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Section: Discussionmentioning

confidence: 99%

Fracture-induced pain-like behaviours in a femoral fracture mouse model

et al. 2021

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“…With regard to the analgesic effect of teriparatide, it has been reported that the VAS of low back pain in patients with fresh osteoporotic vertebral fractures was significantly lower in daily and once-weekly teriparatide administration compared with risedronate [11]. Improvement in pain by teriparatide has furthermore been reported, for example, in a meta-analysis [12] and in osteoporosis animal models [13].…”

Section: Discussionmentioning

confidence: 99%

Safety and efficacy in actual clinical practice of once-weekly subcutaneous teriparatide for osteoporosis patients with a high fracture risk

Ifuku

Yoshimura

Uzawa

et al. 2019

Osteoporosis and Sarcopenia

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Objectives To reassess the safety and efficacy of once-weekly teriparatide 56.5 μg in osteoporosis patients with a high fracture risk. Methods This postmarketing observational study was conducted at 72 weeks according to the package insert. Of the 3573 Japanese osteoporosis patients in the safety analysis set, 91.80% were women, the mean age was 78.1 years, and 69.89% had a history of prevalent fragility fractures, indicating that a high proportion of patients at high risk of fracture were enrolled. Results Persistence with weekly teriparatide treatment was 59.36%, and 38.95% at 24 and 72 weeks, respectively. Adverse drug reactions (ADRs) were reported in 898 patients (25.13%), and serious ADRs were reported in 26 patients (0.73%). The most frequent ADRs were nausea, vomiting, and headache. The cumulative incidence of new vertebral fractures 72 weeks after the start of treatment was 3.31%. Increases in the bone mineral density were observed in the lumbar spine, femoral neck, and proximal femur. The serum levels of the bone formation markers, procollagen type I N-terminal propeptide and bone-type alkaline phosphatase, increased slightly at 24 weeks and then decreased to baseline levels. At 24 and 72 weeks, the bone resorption markers, serum cross-linked N-terminal telopeptide of type I collagen and urinary cross-linked N-terminal telopeptide of type I collagen, were the same as or slightly lower than at baseline. Visual analogue scale scores for low back pain also decreased. Conclusions The present results showed that once-weekly teriparatide may also be useful for osteoporosis patients with a high risk of fracture.

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“…In addition, the improvement effect on pain-like behavior in OVX mice was associated with the downregulation of inflammatory cytokine expression, including interleukin (IL)-1b, IL-6, and tumor necrosis factor-a. 31 In a recent study, although anti-IL-6 R antibody treatment had no effect on ovariectomy-induced bone loss, the treatment prevented ovariectomy-induced mechanical hyperalgesia in the hind limbs and suppressed CGRP expression in DRG neurons. 13 TPTD may inhibit bone nociceptors sensitized by lowering pH and by inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 96%

Teriparatide improves pain-related behavior and prevents bone loss in ovariectomized mice

Kato

Wakabayashi

Nakagawa

et al. 2019

J Orthop Surg (Hong Kong)

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Purpose: The aim of this study was to examine the inhibitory effect of teriparatide (TPTD) on pain and on bone loss in ovariectomized (OVX) mice. The mechanism of osteoporotic pain in OVX mice was evaluated through an examination of pain-related behavior as well as immunohistochemical examinations. Methods: Eight-week-old female ddY mice were OVX and assigned to one of three groups: (1) OVX mice treated with vehicle (OVX), (2) OVX mice treated with teriparatide (OVX-TPTD), or (3) SHAM-operated mice treated with vehicle (SHAM). Starting immediately after surgery, vehicle or TPTD was injected subcutaneously. After a 4-week treatment, mechanical sensitivity was tested using von Frey filaments. The proximal tibial metaphyses were analyzed three-dimensionally by microcomputed tomography (μCT). Calcitonin gene-related peptide (CGRP) and transient receptor potential channel vanilloid 1 (TRPV1) expressions in L3–5 dorsal root ganglion (DRG) neurons were examined using immunohistochemistry. Results: Ovariectomy induced bone loss and mechanical hyperalgesia in the hind limbs with upregulation of CGRP and TRPV1 expressions in DRG neurons innervating the hind limbs. Bone loss was prevented more effectively in the OVX-TPTD mice than in the OVX mice. Furthermore, mechanical hyperalgesia and upregulation of CGRP and TRPV1 expressions were significantly lower in the OVX-TPTD mice than in the OVX mice. Conclusion: TPTD treatment prevented ovariectomy-induced bone loss and ovariectomy-induced mechanical hyperalgesia in hind limbs, and it suppressed CGRP and TRPV1 expressions in DRG neurons. These results suggest that TPTD is useful for the treatment of osteoporotic pain in postmenopausal women.

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Teriparatide rapidly improves pain-like behavior in ovariectomized mice in association with the downregulation of inflammatory cytokine expression

Cited by 15 publications

References 26 publications

Fracture-induced pain-like behaviours in a femoral fracture mouse model

Fracture-induced pain-like behaviours in a femoral fracture mouse model

Safety and efficacy in actual clinical practice of once-weekly subcutaneous teriparatide for osteoporosis patients with a high fracture risk

Teriparatide improves pain-related behavior and prevents bone loss in ovariectomized mice

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