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Maree T Smith - One of the best experts on this subject based on the ideXlab platform.

  • assessment of the anti allodynic efficacy of a glycine transporter 2 inhibitor relative to pregabalin and duloxetine in a rat model of prostate cancer induced Bone Pain
    Pharmacological Reports, 2020
    Co-Authors: Mohammad Zafar Imam, Andy Kuo, Laura Corradini, Janet R Nicholson, Maree T Smith
    Abstract:

    The pathobiology of prostate cancer-induced Bone Pain (PCIBP) is underpinned by both inflammatory and neuropathic components. Here, we used a rat model of PCIBP to assess the analgesic efficacy of a glycine transporter 2 (GlyT2) inhibitor (N-(6-((1,3-dihydroxypropan-2-yl)amino)-2-(dimethylamino)pyridin-3-yl)-3,5-dimethoxy-4-(4-(trifluoromethyl)phenoxy) benzamide) relative to two clinically available adjuvant drugs that are recommended for the relief of neuropathic Pain, viz, pregabalin and duloxetine. PCIBP was induced in male Wistar Han rats following intra-tibial injection (ITI) of rat prostate cancer (AT3B) cells into the left tibia. Sham-rats received an ITI of heat-killed AT3B cells. PCIBP rats with fully developed mechanical allodynia in the ipsilateral hindpaws as assessed using von Frey filaments, received single oral (p.o.) bolus doses of the GlyT2 inhibitor (3–30 mg/kg), pregabalin (3–100 mg/kg), duloxetine (3–100 mg/kg), or vehicle. Baseline paw withdrawal thresholds (PWTs) were determined in the ipsilateral (injured side) and contralateral hindpaws immediately prior to dosing and at scheduled times for 3 h post dosing in individual animals. Single oral bolus doses of the GlyT2 inhibitor (3–30 mg/kg) evoked partial Pain relief at the doses tested in the ipsilateral hindpaws of PCIBP rats without any discernible behavioural side effects. By contrast, single oral bolus doses of pregabalin at 10–100 mg/kg evoked dose-dependent and complete alleviation of mechanical allodynia. By comparison, single oral bolus doses of duloxetine at doses up to 100 mg/kg lacked efficacy. Oral administration of this GlyT2 inhibitor evoked partial Pain relief in PCIBP rats and did not evoke central nervous system side effects in contrast to GlyT2 inhibitors reported by others.

  • Optimization and In Vivo Profiling of a Refined Rat Model of Walker 256 Breast Cancer Cell-Induced Bone Pain Using Behavioral, Radiological, Histological, Immunohistochemical and Pharmacological Methods
    Frontiers Media S.A., 2017
    Co-Authors: Andy Kuo, Maree T Smith, Priyank Shenoy, Irina Vetter
    Abstract:

    In the majority of patients with advanced breast cancer, there is metastatic spread to Bones resulting in Pain. Clinically available drug treatments for alleviation of breast cancer-induced Bone Pain (BCIBP) often produce inadequate Pain relief due to dose-limiting side-effects. A major impediment to the discovery of novel well-tolerated analgesic agents for the relief of Pain due to bony metastases is the fact that most cancer-induced Bone Pain models in rodents relied on the systemic injection of cancer cells, causing widespread formation of cancer metastases and poor general animal health. Herein, we have established an optimized, clinically relevant Wistar Han female rat model of breast cancer induced Bone Pain which was characterized using behavioral assessments, radiology, histology, immunohistochemistry and pharmacological methods. In this model that is based on unilateral intra-tibial injection (ITI) of Walker 256 carcinoma cells, animals maintained good health for at least 66 days post-ITI. The temporal development of hindpaw hypersensitivity depended on the initial number of Walker 256 cells inoculated in the tibiae. Hindpaw hypersensitivity resolved after approximately 25 days, in the continued presence of Bone tumors as evidenced by ex vivo histology, micro-computed tomography scans and immunohistochemical assessments of tibiae. A possible role for the endogenous opioid system as an internal factor mediating the self-resolving nature of BCIBP was identified based upon the observation that naloxone, a non-selective opioid antagonist, caused the re-emergence of hindpaw hypersensitivity. Bolus dose injections of morphine, gabapentin, amitriptyline and meloxicam all alleviated hindpaw hypersensitivity in a dose-dependent manner. This is a first systematic pharmacological profiling of this model by testing standard analgesic drugs from four important diverse classes, which are used to treat cancer induced Bone Pain in the clinical setting. Our refined rat model more closely mimics the pathophysiology of this condition in humans and hence is well-suited for probing the mechanisms underpinning breast cancer induced Bone Pain. In addition, the model may be suitable for efficacy profiling of new molecules from drug discovery programs with potential to be developed as novel agents for alleviation of intractable Pain associated with disseminated breast cancer induced bony metastases

  • analgesic efficacy and mode of action of a selective small molecule angiotensin ii type 2 receptor antagonist in a rat model of prostate cancer induced Bone Pain
    Pain Medicine, 2014
    Co-Authors: Arjun Muralidharan, Bruce D Wyse, Maree T Smith
    Abstract:

    Objective The pathobiology of prostate cancer (PCa)-induced Bone Pain (PCIBP) has both inflammatory and neuropathic components. Previously, we showed that small molecule angiotensin II type 2 receptor (AT2R) antagonists with >1,000-fold selectivity over the angiotensin II type 1 receptor produced dose-dependent analgesia in a rat model of neuropathic Pain. Here, we assessed the analgesic efficacy and mode of action of the AT2R antagonist, EMA200, in a rat model of PCIBP. Methods At 14–21 days after unilateral intratibial injection of AT3B PCa cells, rats exhibiting hindpaw hypersensitivity received single intravenous bolus doses of EMA200 (0.3–10 mg/kg) or vehicle, and analgesic efficacy was assessed. The mode of action was investigated using immunohistochemical, Western blot, and/or molecular biological methods in lumbar dorsal root ganglia (DRGs) removed from drug-naive and EMA200-treated PCIBP rats relative to sham-control rats. Results Intravenous bolus doses of EMA200 produced dose-dependent analgesia in PCIBP rats. Lumbar DRG levels of angiotensin II, nerve growth factor (NGF), tyrosine kinase A (TrkA), phospho-p38 mitogen-activated protein kinase (MAPK), and phospho-p44/p42 MAPK, but not the AT2R, were increased significantly ( P < 0.05) in PCIBP rats, c.f. the corresponding levels for sham controls. EMA200 produced analgesia in PCIBP rats by reducing elevated angiotensin II levels in the lumbar DRGs to attenuate augmented angiotensin II/AT2R signaling. This in turn reduced augmented NGF/TrkA signaling in the lumbar DRGs. The net result was inhibition of p38 MAPK and p44/p42 MAPK activation. Conclusion Small molecule AT2R antagonists are worthy of further investigation as novel analgesics for relief of intractable PCIBP and other Pain types where hyperalgesia worsens symptoms.

Fei Cao - One of the best experts on this subject based on the ideXlab platform.

  • sinomenine attenuates cancer induced Bone Pain via suppressing microglial jak2 stat3 and neuronal camkii creb cascades in rat models
    Molecular Pain, 2018
    Co-Authors: Shuping Chen, Jia Sun, Yaqun Zhou, Fei Cao, Cody Braun, Fang Luo, Yuke Tian
    Abstract:

    Cancer-induced Bone Pain is one of the most severe types of pathological Pain, which often occurs in patients with advanced prostate, breast, and lung cancer. It is of great significance to improve the therapies of cancer-induced Bone Pain due to the opioids' side effects including addiction, sedation, pruritus, and vomiting. Sinomenine, a traditional Chinese medicine, showed obvious analgesic effects on a rat model of chronic inflammatory Pain, but has never been proven to treat cancer-induced Bone Pain. In the present study, we investigated the analgesic effect of sinomenine after tumor cell implantation and specific cellular mechanisms in cancer-induced Bone Pain. Our results indicated that single administration of sinomenine significantly and dose-dependently alleviated mechanical allodynia in rats with cancer-induced Bone Pain and the effect lasted for 4 h. After tumor cell implantation, the protein levels of phosphorylated-Janus family tyrosine kinase 2 (p-JAK2), phosphorylated-signal transducers and activators of transcription 3 (p-STAT3), phosphorylated-Ca2+/calmodulin-dependent protein kinase II (p-CAMKII), and phosphorylated-cyclic adenosine monophosphate response element-binding protein (p-CREB) were persistently up-regulated in the spinal cord horn. Chronic intraperitoneal treatment with sinomenine markedly suppressed the activation of microglia and effectively inhibited the expression of JAK2/STAT3 and CAMKII/CREB signaling pathways. We are the first to reveal that up-regulation of microglial JAK2/STAT3 pathway are involved in the development and maintenance of cancer-induced Bone Pain. Moreover, our investigation provides the first evidence that sinomenine alleviates cancer-induced Bone Pain by inhibiting microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades.

  • spinal ifn γ induced protein 10 cxcl10 mediates metastatic breast cancer induced Bone Pain by activation of microglia in rat models
    Breast Cancer Research and Treatment, 2014
    Co-Authors: Bin Shu, Hui Yang, Fei Cao, Feng Gao, Cheng Liu, Xuehai Guan, Antentor Othrell Hinton, Hongbing Xiang, Xuebi Tian
    Abstract:

    Cancer-induced Bone Pain (CIBP) is a common clinical problem in breast cancer patients with Bone metastasis. Recent studies shows chemokines are novel targets for treatment of CIBP. In this study, we intra-tibial inoculated with Walker 256 rat mammary gland carcinoma cells into rat Bone to established metastatic breast cancer. Then we measured the expression of CXCL10 in the spinal cord of metastatic Bone cancer rats, investigated the role of CXCL10 in the development of CIBP, and the underlying mechanism. Results revealed that after intra-tibial inoculation with Walker 256 cells, rats showed up-regulation of CXCL10 and its receptor CXCR3 in the spinal cord. Interestingly, intrathecally injection of recombinant CXCL10 protein induced mechanical allodynia in naive rats. Blocking the function of CXCL10/CXCR3 pathway via anti-CXCL10 antibody or CXCR3 antagonist prevented the development of CIBP and microglial activation. Moreover, CXCL10-induced mechanical allodynia was rescued by minocycline treatment during the late-stage of CIBP, days 10–14. The regulation of CXCL10 expression involved microglial activation in a manner of autocrine positive feedback. These results suggest that CXCL10 may be a necessary algogenic molecule, especially in the development of CIBP. Its function was partly mediated via spinal microglial activation. This study provides a novel insight into the biological function of chemokine CXCL10 in the molecular mechanism underlying cancer Pain. It also provides new target for clinical treatment of metastatic breast cancer-induced Bone Pain in future.

Xuebi Tian - One of the best experts on this subject based on the ideXlab platform.

  • Involvement of chemokine CXCL11 in the development of morphine tolerance in rats with cancer-induced Bone Pain.
    Journal of Neurochemistry, 2017
    Co-Authors: Yawen Peng, Huilian Bu, Bingrui Xiong, Xuebi Tian, Hui Yang, Zhen Wu
    Abstract:

    Morphine is viewed as one of the classical treatments for intractable Pain, but its role is limited by side effects, including analgesic tolerance. A few chemokines have been reported to be engaged in the mechanisms of morphine tolerance. However, the exact roles of CXC chemokine 11 (CXCL11) in chronic morphine tolerance remain unknown. In this study, Walker 256 mammary gland carcinoma cells were inoculated into the tibia of rats to provoke cancer-induced Bone Pain. Then, morphine was intrathecally administered twice daily for seven consecutive days to induce drug tolerance. We found that the level of CXCL11 in lumbar spinal cord was increased during the development of morphine tolerance in cancer-induced Bone Pain rats. Meanwhile, CXCL11 was co-localized with markers of astrocytes and neurons in the spinal cord. Inhibition of CXCL11 by neutralizing antibodies could remarkably attenuate the degree of morphine tolerance and decrease the activation of astrocytes. Moreover, blocking astrocyte activation by d, l-Fluorocitric acid could distinctly alleviate morphine tolerance and reduce the expression of CXCL11. Finally, morphine stimulation could induce the release of CXCL11 by cultured astrocytes and neurons in vitro. In summary, our results provide evidence that spinal CXCL11 plays a powerful modulatory role in the development of morphine tolerance through cross-talking between astrocytes and neurons. Read the Review series “Pain”.

  • spinal ifn γ induced protein 10 cxcl10 mediates metastatic breast cancer induced Bone Pain by activation of microglia in rat models
    Breast Cancer Research and Treatment, 2014
    Co-Authors: Bin Shu, Hui Yang, Fei Cao, Feng Gao, Cheng Liu, Xuehai Guan, Antentor Othrell Hinton, Hongbing Xiang, Xuebi Tian
    Abstract:

    Cancer-induced Bone Pain (CIBP) is a common clinical problem in breast cancer patients with Bone metastasis. Recent studies shows chemokines are novel targets for treatment of CIBP. In this study, we intra-tibial inoculated with Walker 256 rat mammary gland carcinoma cells into rat Bone to established metastatic breast cancer. Then we measured the expression of CXCL10 in the spinal cord of metastatic Bone cancer rats, investigated the role of CXCL10 in the development of CIBP, and the underlying mechanism. Results revealed that after intra-tibial inoculation with Walker 256 cells, rats showed up-regulation of CXCL10 and its receptor CXCR3 in the spinal cord. Interestingly, intrathecally injection of recombinant CXCL10 protein induced mechanical allodynia in naive rats. Blocking the function of CXCL10/CXCR3 pathway via anti-CXCL10 antibody or CXCR3 antagonist prevented the development of CIBP and microglial activation. Moreover, CXCL10-induced mechanical allodynia was rescued by minocycline treatment during the late-stage of CIBP, days 10–14. The regulation of CXCL10 expression involved microglial activation in a manner of autocrine positive feedback. These results suggest that CXCL10 may be a necessary algogenic molecule, especially in the development of CIBP. Its function was partly mediated via spinal microglial activation. This study provides a novel insight into the biological function of chemokine CXCL10 in the molecular mechanism underlying cancer Pain. It also provides new target for clinical treatment of metastatic breast cancer-induced Bone Pain in future.

  • inhibition of glial activation in rostral ventromedial medulla attenuates mechanical allodynia in a rat model of cancer induced Bone Pain
    Journal of Huazhong University of Science and Technology-medical Sciences, 2012
    Co-Authors: Huilian Bu, Xuebi Tian, Hui Yang, Aijun Xu, Zhijun Chen, Yuke Tian
    Abstract:

    Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced Bone Pain (CIBP). Rostral ventromedial medulla (RVM) is a critical component of descending nociceptive facilitation circuitry, but so far the mechanisms are poorly known. In this study, we investigated the role of RVM glial activation in the descending nociceptive facilitation circuitry in a CIBP rat model. CIBP rats showed significant activation of microglia and astrocytes, and also up-regulation of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and pro-inflammatory mediators released by glial cells (IL-1β, IL-6, TNF-α and brain-derived neurotrophic factor) in the RVM. Stereotaxic microinjection of the glial inhibitors (minocycline and fluorocitrate) into CIBP rats’ RVM could reverse the glial activation and significantly attenuate mechanical allodynia in a time-dependent manner. RVM microinjection of p38 MAPK inhibitor (SB203580) abolished the activation of microglia, reversed the associated up-regulation of pro-inflammatory mediators and significantly attenuated mechanical allodynia. Taken together, these results suggest that RVM glial activation is involved in the pathogenesis of CIBP. RVM microglial p38 MAPK signaling pathway is activated and leads to the release of downstream pro-inflammatory mediators, which contribute to the descending facilitation of CIBP.

Todd W. Vanderah - One of the best experts on this subject based on the ideXlab platform.

  • peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer induced Bone Pain
    Pain, 2018
    Co-Authors: Hong Zhang, Tally M Largentmilnes, William D Staatz, Herbert H Seltzman, Dominique M Lund, Haley A Ciccone, Mohab M Ibrahim, Igor Spigelman, Todd W. Vanderah
    Abstract:

    Many malignant cancers, including breast cancer, have a propensity to invade Bones, leading to excruciating Bone Pain. Opioids are the primary analgesics used to alleviate this cancer-induced Bone Pain (CIBP) but are associated with numerous severe side effects, including enhanced Bone degradation, which significantly impairs patients' quality of life. By contrast, agonists activating only peripheral CB1 receptors (CB1Rs) have been shown to effectively alleviate multiple chronic Pain conditions with limited side effects, yet no studies have evaluated their role(s) in CIBP. Here, we demonstrate for the first time that a peripherally selective CB1R agonist can effectively suppress CIBP. Our studies using a syngeneic murine model of CIBP show that both acute and sustained administration of a peripherally restricted CB1R agonist, 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI), significantly alleviated spontaneous Pain behaviors in the animals. This analgesic effect by PrNMI can be reversed by a systemic administration but not spinal injection of SR141716, a selective CB1R antagonist. In addition, the cancer-induced Bone loss in the animals was not exacerbated by a repeated administration of PrNMI. Furthermore, catalepsy and hypothermia, the common side effects induced by cannabinoids, were measured at the supratherapeutic doses of PrNMI tested. PrNMI induced mild sedation, yet no anxiety or a decrease in limb movements was detected. Overall, our studies demonstrate that CIBP can be effectively managed by using a peripherally restricted CB1R agonist, PrNMI, without inducing dose-limiting central side effects. Thus, targeting peripheral CB1Rs could be an alternative therapeutic strategy for the treatment of CIBP.

  • targeting the s1p s1pr1 axis mitigates cancer induced Bone Pain and neuroinflammation
    Pain, 2017
    Co-Authors: Shaness A Grenald, Tally M Largentmilnes, Lauren M Slosky, Todd W. Vanderah, Hong Zhang, Timothy M Doyle, Zhoumou Chen, Sarah Spiegel, Daniela Salvemini
    Abstract:

    Metastatic Bone Pain is the single most common form of cancer Pain and persists as a result of peripheral and central inflammatory, as well as neuropathic mechanisms. Here, we provide the first characterization of sphingolipid metabolism alterations in the spinal cord occurring during cancer-induced Bone Pain (CIBP). Following femoral arthrotomy and syngenic tumor implantation in mice, ceramides decreased with corresponding increases in sphingosine and the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P). Intriguingly, de novo sphingolipid biosynthesis was increased as shown by the elevations of dihydro-ceramides and dihydro-S1P. We next identified the S1P receptor subtype 1 (S1PR1) as a novel target for therapeutic intervention. Intrathecal or systemic administration of the competitive and functional S1PR1 antagonists, TASP0277308 and FTY720/Fingolimod, respectively, attenuated cancer-induced spontaneous flinching and guarding. Inhibiting CIBP by systemic delivery of FTY720 did not result in antinociceptive tolerance over 7 days. FTY720 administration enhanced IL-10 in the lumbar ipsilateral spinal cord of CIBP animals and intrathecal injection of an IL-10 neutralizing antibody mitigated the ability of systemic FTY720 to reverse CIBP. FTY720 treatment was not associated with alterations in Bone metabolism in vivo. Studies here identify a novel mechanism to inhibit Bone cancer Pain by blocking the actions of the bioactive metabolites S1P and dihydro-S1P in lumbar spinal cord induced by Bone cancer and support potential fast-track clinical application of the FDA-approved drug, FTY720, as a therapeutic avenue for CIBP.

  • angiotensin 1 7 mas receptor as an antinociceptive agent in cancer induced Bone Pain
    Pain, 2016
    Co-Authors: Brittany L Forte, Tally M Largentmilnes, Lauren M Slosky, Moriah R Arnold, William D Staatz, Hong Zhang, Todd W. Vanderah
    Abstract:

    Many cancerous solid tumors metastasize to the Bone and induce Pain (cancer-induced Bone Pain [CIBP]). Cancer-induced Bone Pain is often severe because of enhanced inflammation, rapid Bone degradation, and disease progression. Opioids are prescribed to manage this Pain, but they may enhance Bone loss and increase tumor proliferation, further compromising patient quality of life. Angiotensin-(1-7) (Ang-(1-7)) binds and activates the Mas receptor (MasR). Angiotensin-(1-7)/MasR activation modulates inflammatory signaling after acute tissue insult, yet no studies have investigated whether Ang-(1-7)/MasR play a role in CIBP. We hypothesized that Ang-(1-7) inhibits CIBP by targeting MasR in a murine model of breast CIBP. 66.1 breast cancer cells were implanted into the femur of BALB/cAnNHsd mice as a model of CIBP. Spontaneous and evoked Pain behaviors were assessed before and after acute and chronic administration of Ang-(1-7). Tissues were collected from animals for ex vivo analyses of MasR expression, tumor burden, and Bone integrity. Cancer inoculation increased spontaneous Pain behaviors by day 7 that were significantly reduced after a single injection of Ang-(1-7) and after sustained administration. Preadministration of A-779 a selective MasR antagonist prevented this reduction, whereas pretreatment with the AT2 antagonist had no effect; an AT1 antagonist enhanced the antinociceptive activity of Ang-(1-7) in CIBP. Repeated Ang-(1-7) administration did not significantly change tumor burden or Bone remodeling. Data here suggest that Ang-(1-7)/MasR activation significantly attenuates CIBP, while lacking many side effects seen with opioids. Thus, Ang-(1-7) may be an alternative therapeutic strategy for the nearly 90% of patients with advanced-stage cancer who experience excruciating Pain.

Roland Chapurlat - One of the best experts on this subject based on the ideXlab platform.

  • Pathophysiology and medical treatment of Pain in fibrous dysplasia of Bone
    Orphanet Journal of Rare Diseases, 2012
    Co-Authors: Roland Chapurlat, Deborah Gensburger, Juan M Jimenez-andrade, Joseph R Ghilardi, Marilyn Kelly, Patrick Mantyh
    Abstract:

    One of the most common complications of fibrous dysplasia of Bone (FD) is Bone Pain. Usual Pain killers are often of inadequate efficacy to control this Bone Pain. The mechanism of Bone Pain in FD remains uncertain, but by analogy with Bone tumors one may consider that ectopic sprouting and formation of neuroma-like structures by sensory and sympathetic nerve fibers also occur in the dysplastic skeleton. Bone Pain has been reported in up to 81% of adults and 49% of children. It affects predominantly the lower limbs and the spine. The degree of Pain is highly variable and adults reports more Pain than children. Bisphosphonates have been shown to reduce Bone Pain in uncontrolled studies. Their influence on Bone strength remains unknown. In a randomized trial testing alendronate, Bone Pain was not significantly improved. Another trial assessing the effect of risedronate is ongoing. Possible future therapies include tocilizumab, denosumab and drugs targeting nerve growth factor and its receptor TrkA.

  • medical therapy in adults with fibrous dysplasia of Bone
    Journal of Bone and Mineral Research, 2006
    Co-Authors: Roland Chapurlat
    Abstract:

    In open studies, bisphosphonate therapy (pamidronate, alendronate) reduced Bone Pain associated with fibrous dysplasia of Bone and was associated to some radiological improvement. Calcium, vitamin D, and phosphorus supplements may be useful in patients with deficiency. We are awaiting results from controlled trials testing bisphosphonates. Introduction: Fibrous dysplasia of Bone (FD), a rare disease caused by osteoblastic lineage differentiation defects, is associated with Bone Pain, fracture, and Bone deformity, but few therapeutic options are available. Materials and Methods: We reviewed published data on the treatment of FD with bisphosphonates (pamidronate, alendronate), calcium, vitamin D, and phosphorus. We also present new results on FD therapy with a more potent bisphosphonate, zoledronic acid, given intravenously at the dose of 4 mg every 6 months. Results: Pamidronate therapy, given intravenously every 6 months at a dose of 180 mg in adults, relieved Bone Pain, decreased Bone resorption, and improved the radiological aspect (filling of lytic lesions and/or thickening of cortices) in -50% of patients. BMD in affected sites was also significantly increased after pamidronate treatment. Those results have been obtained only in open studies, without controls, by several research groups. In a series of nine patients on long-term pamidronate treatment, but resisting to this medication and switched to intravenous zoledronic acid, no substantial improvement was observed. There is some biological rationale supporting the use of calcium and vitamin D in patients with deficiency to improve FD lesions by limiting secondary hyperparathyroidism. Phosphorus supplementation may prevent mineralization defects in those patients who have both FD and renal phosphate wasting. However, we are lacking clinical evidence for the efficacy of such supplements. Conclusions: Bisphosphonate treatment reduces increased osteoclastic activity in FD and probably improves Bone Pain, but their use should be better studied in randomized controlled trials.

  • long term effects of intravenous pamidronate in fibrous dysplasia of Bone
    Journal of Bone and Mineral Research, 1997
    Co-Authors: Roland Chapurlat, Pierre D Delmas, Daniel Liens, Pierre J Meunier
    Abstract:

    Fibrous dysplasia of Bone (FD) is a rare disorder characterized by proliferation of fibrous tissue in Bone marrow leading to osteolytic lesions. It causes Bone Pain and fractures. To date the only treatment is orthopedic. Histological and biochemical similarities between FD and Paget's Bone disease related to increased osteoclastic resorption led us to propose treatment with the bisphosphonate pamidronate. The aim of the study was to assess the long-term effects of intravenous pamidronate in FD. In this open label phase III study, 20 patients with FD (11 males and 9 females; mean age 31 years) received courses of 180 mg of intravenous pamidronate every 6 months (60 mg/day during 3 days by infusion). The mean duration of follow-up was 39 months (range 18-64). Severity of Bone Pain, number of Painful skeletal sites per patient, X-rays of all involved areas, serum alkaline phosphatase, fasting urinary hydroxyproline, and urinary type I collagen C-telopeptide were assessed every 6 months. The severity of Bone Pain and the number of Painful sites appeared to be significantly reduced. All biochemical markers of Bone remodeling were substantially lowered. We observed a radiographic response in nine patients with refilling of osteolytic lesions. A mineralization defect proven by Bone biopsy was observed in one case. Four patients sustained Bone stress lines, but no fracture occurred. We suggest that intravenous pamidronate alleviates Bone Pain, reduces the rate of Bone turnover assessed by biochemical markers, and improves radiological lesions of FD. Few side effects were observed.