Clinical utility of clodronate in the prevention and management of osteoporosis in patients intolerant of oral bisphosphonates

Muratore, Maurizio; Quarta, E.; Quarta, L.

doi:10.2147/dddt.s12139

Cited by 20 publications

(16 citation statements)

References 53 publications

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“…Antiresorptive drugs include calcium, estrogen, calcitonin and bisphosphonates [5-8]. Plant estrogens, known as phytoestrogens, were recommended for prevention of bone resorption [9].…”

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confidence: 99%

Specific nephrotoxicity and cardiotoxicity of BT-CAL®, Sigma Anti-bonding Molecule Calcium Carbonate, in mice

et al. 2013

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According to a high anti-osteoporotic efficacy of Sigma Anti-bonding Molecule Calcium Carbonate (SAC), repeated-dose toxicities of SAC were investigated to assess its feasibility as drug or functional food ingredient. Male ICR mice were given drinking water containing 0.006, 0.02 or 0.06% SAC for 4 weeks. SAC feeding decreased the body weights and feed and water consumptions of mice in a dose-dependent manner, especially, leading to severe emaciation and 70% death in 3 weeks in the high-dose (0.06%) group. Not only kidney and heart weights, but also the levels of blood urea nitrogen, creatinine, aspartate transaminase, and creatine phospokinase significantly increased after SAC administration, indicative of nephrotoxicity and cardiotoxicity. Such renal and cardiac toxicities were also confirmed by microscopic findings, exhibiting renal crystals and cardiac fibrosis, which may be due to the insoluble crystal formation and calcium overload, respectively. In conclusion, it is suggested that no observed adverse effect level of SAC is lower than 0.006% in mice, and that a long-term intake may cause serious adverse effects on renal and cardiac functions.

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“…Antiresorptive drugs include calcium, estrogen, calcitonin and bisphosphonates [5-8]. Plant estrogens, known as phytoestrogens, were recommended for prevention of bone resorption [9].…”

mentioning

confidence: 99%

Specific nephrotoxicity and cardiotoxicity of BT-CAL®, Sigma Anti-bonding Molecule Calcium Carbonate, in mice

et al. 2013

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“…Our current and previous results 13 strongly implicate macrophages as the major contributors to the immune dysregulation that occurs in HD. In order to ascertain the role of these cells, we utilized the toxic clodronate immunosuppressive drug, commonly used for the treatment of osteoporosis 36 . In order to specifically deplete monocyte and macrophage cells in vivo , clodronate packaged in liposomes were administered via IV or IP injection into R6/2 mice at 13–14 weeks of age 37 – 39 .…”

Section: Resultsmentioning

confidence: 99%

In vivo neutralization of the protagonist role of macrophages during the chronic inflammatory stage of Huntington’s disease

Pido-Lopez

André

Benjamin

et al. 2018

Sci Rep

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Neurodegenerative diseases, characterised by the progressive and selective neuronal death in the central nervous system, are frequently accompanied by an activated immune system. In Huntington’s disease (HD), clinical and animal studies show evidence of immune activity, along with hyper-reactive monocyte/macrophage responses, while application of immunosuppressive regimens have imparted beneficial effects to HD mice. These findings suggest a contributory role of the immune system in HD pathology, with immune-based interventions offering a potential therapeutic strategy. Herein, we show that peripheral and CNS immune system activity increased with disease progression in HD mouse models and defined the phenotype of the immune response. Additionally, the depletion of monocytes and macrophages in vivo, via clodronate liposome treatment, revealed a major contributory role of these innate immune cells to the chronic inflammatory milieu observed during the course of the disease. This suggests that peripheral immunomodulatory strategies targeting monocytes and macrophages could be relevant for HD.

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“…Notably, clodronate is approved for clinical use in the treatment of osteoporosis in many countries, and its clinical safety in humans is well established (21). Therefore, it is important to evaluate analgesic effects of clodronate for painful diseases independent of bone abnormalities in humans.…”

Section: Discussionmentioning

confidence: 99%

“…Although they are used to treat bone diseases accompanied by chronic neuropathic or inflammatory pain (16)(17)(18), the mechanism underlying this analgesic effect is unknown. Notably, non-nitrogen-containing bisphosphonates (first generation) result in less inhibition of bone resorption but have fewer side effects than nitrogen-containing bisphosphonates (second and third generations) (19)(20)(21) (Fig. S1).…”

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confidence: 99%

Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain

Kato

Hiasa

Ichikawa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Despite the high incidence of neuropathic and inflammatory pain worldwide, effective drugs with few side effects are currently unavailable for the treatment of chronic pain. Recently, researchers have proposed that inhibitors of purinergic chemical transmission, which plays a key role in the pathological pain response, may allow for targeted treatment of pathological neuropathic and inflammatory pain. However, such therapeutic analgesic agents have yet to be developed. In the present study, we demonstrated that clodronate, a first-generation bisphosphonate with comparatively fewer side effects than traditional treatments, significantly attenuates neuropathic and inflammatory pain unrelated to bone abnormalities via inhibition of vesicular nucleotide transporter (VNUT), a key molecule for the initiation of purinergic chemical transmission. In vitro analyses indicated that clodronate inhibits VNUT at a halfmaximal inhibitory concentration of 15.6 nM without affecting other vesicular neurotransmitter transporters, acting as an allosteric modulator through competition with Cl − . A low concentration of clodronate impaired vesicular ATP release from neurons, microglia, and immune cells. In vivo analyses revealed that clodronate is more effective than other therapeutic agents in attenuating neuropathic and inflammatory pain, as well as the accompanying inflammation, in wild-type but not VNUT −/− mice, without affecting basal nociception. These findings indicate that clodronate may represent a unique treatment strategy for chronic neuropathic and inflammatory pain via inhibition of vesicular ATP release. vesicular nucleotide transporter | purinergic chemical transmission | analgesic effect | antiinflammatory effect | clodronate

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Clinical utility of clodronate in the prevention and management of osteoporosis in patients intolerant of oral bisphosphonates

Cited by 20 publications

References 53 publications

Specific nephrotoxicity and cardiotoxicity of BT-CAL®, Sigma Anti-bonding Molecule Calcium Carbonate, in mice

Specific nephrotoxicity and cardiotoxicity of BT-CAL®, Sigma Anti-bonding Molecule Calcium Carbonate, in mice

In vivo neutralization of the protagonist role of macrophages during the chronic inflammatory stage of Huntington’s disease

Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain

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