Adaptative, Multicenter, Randomized, Double-blind, Parallel-group, Placebo Controlled, Clinical Trial, on the Efficacy and Tolerability of Different Escalating Doses of Intra-articular Clodronate in Patients With Painful Knee Osteoarthritis

The goal of this clinical trial is to to clarify which is the best dose of administration, to select a dose and to confirm the therapeutic efficacy of clodronate in patients with painful knee osteoarthritis (OA). The clinical trial will be divided in two parts.
The main questions it aims to answer are:
in Phase II, to assess the safety and tolerability of different escalating doses of intra articular (IA) clodronate
in Phase II, to set a defined therapeutic dose (DTD) to be used in Phase III
in Phase III, to assess the safety and tolerability of different escalating doses of IA clodronate to confirm and extensively evaluate the therapeutic efficacy and safety of the clodronate DTD in patients with knee OA

Start Date12 Oct 2023

Sponsor / Collaborator

Società Prodotti Antibiotici SpA

EUCTR2021-003124-33-IT / Unknown statusPhase 2/3

Adaptative, multicenter, randomized, double-blind, parallel-group, placebo controlled, clinical trial, on the efficacy and tolerability of different escalating doses of intra-articular clodronate in patients with painful knee osteoarthritis - SPA-S-899-01-21

Start Date15 May 2023

Sponsor / Collaborator-

ChiCTR1900024141 / RecruitingEarly Phase 1IIT

Phase II clinical study for skull base osteoradionecrosis by treatment with a pentoxifylline-tocopherol-clodronate combination (PENTOCLO)

Start Date01 Jul 2019

Sponsor / Collaborator

Jiangxi Provincial Cancer Hospital

100 Clinical Results associated with Clodronate Disodium

100 Translational Medicine associated with Clodronate Disodium

100 Patents (Medical) associated with Clodronate Disodium

2,571

Literatures (Medical) associated with Clodronate Disodium

01 Jan 2025·BONE

Macrophage-derived amphiregulin promoted the osteogenic differentiation of chondrocytes through EGFR/Yap axis and TGF-β activation

Article

Author: Dong, Wei ; Wang, Shuo ; Wang, Xinru ; Mu, Hailin ; Wang, Xinyi ; Wang, Jaiwei ; Yang, Chang

Endochondral ossification represents a crucial biological process in skeletal development and bone defect repair. Macrophages, recognized as key players in the immune system, are now acknowledged for their substantial role in promoting endochondral ossification within cartilage. Concurrently, the epidermal growth factor receptor (EGFR) ligand amphiregulin (Areg) has been documented for its contributory role in restoring bone tissue homeostasis post-injury. However, the mechanism by which macrophage-secreted Areg facilitates bone repair remains elusive. In this study, the induction of macrophage depletion through in vivo administration of clodronate liposomes was employed in a standard open tibial fracture mouse model to assess bone healing using micro-computed tomography (micro-CT) analysis, histomorphology, and ELISA serum evaluations. The investigation revealed sustained expression of Areg during the fracture healing period in wild-type mice. Macrophage depletion significantly reduced the number of macrophages on the local bone surface and vital organs. This reduction led to diminished Areg secretion, decreased collagen production, and delayed fracture healing. However, histological and micro-CT assessments at 7 and 21 days post-local Areg treatment exhibited a marked improvement of bone healing compared to the vehicle control. In vitro studies demonstrated an increase of Areg secretion by the Raw264.7 cells upon ATP stimulation. Indirect co-culture of Raw264.7 and ATDC5 cells indicated that Areg overexpression enhanced the osteogenic potential of chondrocytes, and vice versa. This osteogenic promotion was attributed to Areg's activation of the membrane receptor EGFR in the ATDC5 cell line, the enhanced phosphorylation of transcription factor Yap, and the facilitation of the expression of bioactive TGF-β by chondrocytes. Collectively, this research elucidates the direct mechanistic effects of macrophage-secreted Areg in promoting bone homeostasis following bone injury.

01 Dec 2024·Current computer-aided drug design

Clodronic Acid has Strong Inhibitory Interactions with the Urease Enzyme of Helicobacter pylori: Computer-aided Design and in vitro Confirmation

Article

Author: Fath, Mohsen Karami ; Boojar, Masoud Mashhadi Akbar ; Khalili, Saeed ; Hashemi, Zahra Sadat ; Zarei, Mahboubeh

Background::

Helicobacter Pylori (HP) infection could lead to various gastrointestinal diseases. Urease is the most important virulence factor of HP. It protects the bacterium against gastric acid.

Objective::

Therefore, we aimed to design urease inhibitors as drugs against HP infection.

Methods::

The DrugBank-approved library was assigned with 3D conformations and the structure of the urease was prepared. Using a re-docking strategy, the proper settings were determined for docking by PyRx and GOLD software. Virtual screening was performed to select the best inhibitory drugs based on binding affinity, FitnessScore, and binding orientation to critical amino acids of the active site. The best inhibitory drug was then evaluated by IC50 and the diameter of the zone of inhibition for bacterial growth.

Results::

The structures of prepared drugs were screened against urease structure using the determined settings. Clodronic acid was determined to be the best-identified drug, due to higher PyRx binding energy, better GOLD FitnessScore, and interaction with critical amino acids of urease. In vitro results were also in line with the computational data. IC50 values of Clodronic acid and Acetohydroxamic Acid (AHA) were 29.78 ± 1.13 and 47.29 ± 2.06 μg/ml, respectively. Diameters of the zones of inhibition were 18 and 15 mm for Clodronic acid and AHA, respectively.

Conclusion::

Clodronic acid has better HP urease inhibition potential than AHA. Given its approved status, the development of a repurposed drug based on Clodronic acid would require less time and cost. Further, in vivo studies would unveil the efficacy of Clodronic acid as a urease inhibitor.

01 Dec 2024·Molecular biology reports

Mycobacterium marinum mediates regulation of prostaglandin E2 expression on host immune response through cyclooxygenase pathway

Article

Author: Xu, Cheng ; Zhou, Lei ; Chen, Zhenhua ; Mo, Liyi ; Lin, Bingyao ; Luo, Yanwen ; Lin, Dongzi ; Tian, Honghong ; Wang, Xuezhi

PURPOSE:

Investigate the role of COX signaling in activating the PGE2-EP2 pathway.

METHODS:

Utilized a marine Mycobacterium infection model in zebrafish. Marine mycobacteria were stained with fluorescein isothiocyanate. The COX inhibitor indomethacin, EP2 receptor inhibitor AH6809, EP4 receptor inhibitor AH23848 and clodronate Liposomes were used to investigate the role of COX, EP2, EP4 and macrophage whether participating in combat marine mycobacterial infection. The expression level of the target gene was detected using real-time fluorescence quantitative PCR instrument.

RESULTS:

The findings revealed that larvae exposed to the COX inhibitor indomethacin or the EP2 receptor inhibitor AH6809 demonstrated a significantly higher mortality rate due to marine mycobacterium infection than those in the control group. Administration of exogenous prostaglandin E2 (PGE2) rescued the survival of zebrafish infected with marine mycobacteria and treated with indomethacin. Additionally, a significant reduction in survival rate was noted in macrophage-depleted zebrafish infected with marine mycobacteria.

CONCLUSION:

The host may combat marine mycobacterium infection via COX signaling, which activates the PGE2-EP2 pathway and mediates macrophage resistance.

News (Medical) associated with Clodronate Disodium

30 May 2023

·www.pharmaceutical-technology.com

Abiogen acquires EffRx to fortify bone disease portfolio

Akosua Mireku @AkosuaMireku1 A man sitting on living room sofa holding his painful shoulder. Abiogen develops drugs for osteoarthritis. Credit: RealPeopleGroup via Getty Images The Italian pharmaceutical company Abiogen Pharma completed an acquisition of a 97.09% stake in the Swiss orphan conditions-focused EffRx Pharmaceuticals on May 29. This deal follows Abiogen’s recent acquisition of the Cologne, Germany-based Altamedics in December 2022. Altamedics specialises in pharmaceutical distribution in hospital settings. The €8 million ($8,559,480) deal was Abiogen’s first move in its global expansion plan and the deal with EffRx is a continuation of this. Abiogen Pharma specialises in osteoarticular and bone metabolism diseases amongst other therapy areas. The company has developed three bisphosphonates, clodronate, alendronate and Nerixia (neridronate), for the treatment of bone pathologies such as osteoarthritis . Bisphosphonates are drugs that slow the progression of bone loss. EffRx has received several European regulatory approvals for drugs in its portfolio . For example, in July 2022, EffRx launched its paediatric adrenal insufficiency replacement therapy Alkindi (hydrocortisone) in Switzerland. Alkindi is one of EffRx’s three marketed drugs. The company developed and launched Binosto (alendronate sodium) as the first and only buffered solution for osteoporosis. The European Medicines Agency has also approved Efmody for the treatment of congenital adrenal hyperplasia medicine in patients ages 12 years and above in the European Union. The company’s last deal included an exclusive license agreement with the Cardiff, UK-headquartered specialty pharmaceuticals company Diurnal group for the commercialisation of Efmody (hydrocortisone) in Switzerland. In Italy, Abiogen began distributing its bisphosphonates in 2014 and has since seen some successful drug approvals. The biotech transferred the rights for alendronate to Merck which marketed the drug under the brand name Vancapsi. The Italian health authorities also gave Abiogen’s Nerixia the country’s first rare disease designation for Osteogenesis Imperfecta and Complex regional pain syndrome, for which the drug is now approved in Italy. Separate from drug development, the Italian company also offers contract manufacturing and clinical supply services. In a press release , Abiogen’s International Business Unit Head, Prisca Di Martino said, “We are working towards developing Abiogen into an international business, without losing sight of our nature as an Italian and family-run undertaking, and we are pursuing this target by entering into agreements with foreign businesses that share our goals and therapeutic areas.”

Drug ApprovalAcquisitionLicense out/in

14 Jul 2022

·www.prnewswire.com

Study shows that selection of breast cancer patients for adjuvant bisphosphonate therapy based on Inbiomotion's MAFTEST® reduces the risk of death in comparison with current clinical guidance

MAFTEST® analyses of the NSABP-B34 and AZURE landmark clinical trials confirmed clinical utility of the MAFTEST® for selection of early-stage breast cancer patients that benefit from adjuvant clodronate treatment. Reduces the risk of death at 5 and 10 years by 26% and 23% respectively. Identifies almost twice as many patients able to benefit from the intervention than are selected using current clinical guidelines. Data published in Annals of Oncology, (33), SUPPLEMENT 3, S152, 2022. BARCELONA, Spain, July 14, 2022 /PRNewswire/ -- Inbiomotion SL, a company developing a unique single-gene-based biomarker for the personalized adjuvant treatment of early-stage (stage I-III) breast cancer patients, announces the results of comparing the clinical efficacy of implementing the proprietary MAFTEST® for selection of patients for adjuvant bisphosphonates therapy with current clinical guidance. The results were presented at the ESMO 2022 Breast Cancer Symposium. The data show that stratification of early breast cancer patients according to MAF status reduced the risk of death and relapse in MAF negative patients by 26% and 23% respectively, compared to a 12% and 15% reduction in the risk of death or relapse seen with stratification by menopausal status recommended by current ESMO and ASCO Clinical Guidelines. The data also indicate that adjuvant treatment with bisphosphonates should be avoided in MAF positive patients as the risk of death and relapse is increased 16% and 15% respectively in these patients. In addition, the study shows that the use of MAF status for selection of early breast cancer patients for treatment with bisphosphonates allows the treatment of young premenopausal patients currently excluded by existing clinical guidance. "The MAF biomarker allows a new paradigm for selection of patients for adjuvant bisphosphonate treatment of early breast cancer that not only identifies those patients that will benefit from treatment (MAF negatives) but also excludes patients that could be harmed (MAF positives). This new selection criteria not only reduces the risk of death and relapse for selected patients but also provides a new treatment option for young patients currently excluded from this treatment in current clinical practice," said Robert Coleman, Professor Emeritus, Department of Oncology and Metabolism, University of Sheffield, UK. Currently, clodronate and other bisphosphonates are not approved by the regulatory agencies for use in adjuvant treatment of the broad population of early-stage breast cancer patients. However, they are recommended in the ASCO/CCO and ESMO clinical guidelines for adjuvant treatment of breast cancer in postmenopausal patients. The study shows that identifying MAF-negative patients for selection for adjuvant treatment with bisphosphonates outperforms current selection by menopausal status and could give more patients, particularly younger patients, the opportunity to benefit from adjuvant bisphosphonates, while avoiding potential harm (or no benefit), than solely using menopausal status as a selection criterion. "Our results indicate that adjuvant clodronate treatment has a large clinical benefit if restricted to MAF-negative patients," said Prof. Alexander Paterson, principal investigator of the NSABP-B34 clinical trial and Emeritus Clinical Professor at the Department of Oncology, University of Calgary. "Our data provide an objective criterion for patient selection for bisphosphonate adjuvant treatment that outperforms current selection based on menopausal status." "This study confirms our previous findings and the clinical utility of MAFTEST® as a unique tool for precision medicine in early breast cancer. Every year approximately 355,000 women are diagnosed with early breast cancer in Europe with a 10% risk of death at 5 years. Using MAF Test these deaths could be reduced by 26%, which would translate to 9,230 lives saved," said Joël Jean-Mairet, Executive Chairman of the Board of Inbiomotion. "We have discovered and developed a new biomarker, MAF gene amplification, that if used as selection criteria for adjuvant treatment with bisphosphonates improves the clinical outcome of breast cancer patients compared with current clinical practice, " said Prof. Roger Gomis, ICREA Research Professor at IRB Barcelona. "MAF Test is a biomarker that is easy to implement in any clinical pathology lab and should be considered for routine characterization of breast cancer tumors." Recently the MAFTEST® obtained the CE-mark as an in vitro diagnostic medical device for prognostic purposes. Since clodronate and other bisphosphonates are not approved by the regulatory agencies for use in adjuvant treatment of early-stage breast cancer patients, Inbiomotion's MAFTEST® is not authorized to be used as a companion diagnostic as described in the above-mentioned study. Reference articles: Impact of MAF selection of patients for adjuvant bisphosphonate therapy and comparison with current clinical guidance Robert Coleman, Roger R Gomis, Alexander H G Paterson. Full text article : (22)00461-6/fulltext MAF amplification and adjuvant clodronate outcomes in early-stage breast cancer in NSABP B-34 and potential impact on clinical practice Alexander H G Paterson et al. Full text article: Effect of MAF amplification on treatment outcomes with adjuvant zoledronic acid in early breast cancer: a secondary analysis of international, open-label, randomized, controlled, phase 3 AZURE (BIG 01/04) trial Robert Coleman et al. Full text article: (17)30603-4/fulltext Benefits and risks of adjuvant treatment with zoledronic acid in stage II/III breast cancer. 10 years follow-up of the AZURE randomized clinical trial (BIG 01/04) Robert Coleman et al. Full text article: About Inbiomotion: Inbiomotion SL, a company founded by Prof. Roger Gomis, is developing a unique single gene-based biomarker for the personalized adjuvant treatment of early-stage breast cancer patients. The biomarker has been technically and analytically validated. The results of the first trial using well annotated archived specimens of the AZURE registrational clinical trial, now confirmed in the NSABP-B34 trial, indicate its potential use as a companion diagnostic. The company holds over 200 patents and patent applications covering its proprietary FISH MAFTEST® and the use of bisphosphonates in the adjuvant treatment of early-stage breast cancer patients. About MAF: MAF (mesenchymal aponeurotic fibrosarcoma gene, an AP-1 family transcription factor) is expressed in primary cancer tumors. This is associated with increased metastasis, especially bone metastasis. MAF transcriptionally controls genes such PTHrP, which regulate metastasis-related cellular processes, including survival, initiation, metabolic rewiring, and particularly, adhesion to bone marrow–derived cells and osteoclast differentiation. These observations point to MAF having a key hierarchical role in metastasis. SOURCE Inbiomotion

ASCO

100 Deals associated with Clodronate Disodium

External Link

KEGG	Wiki	ATC	Drug Bank
D03544	Clodronate Disodium	M05BA02	DB00720

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Bone metastases	FR	-	27 Nov 1994
Humoral Hypercalcemia of Malignancy	CA	Bayer, Inc.	31 Dec 1992
Hypercalcemia	-	-	01 Jan 1986
Osteoporosis	-	-	01 Jan 1986

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Osteoarthritis	Phase 3	IT	Abiogen Pharma SpA	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASGCT2023	Not Applicable	-	-	Clodronate liposomes	iruppcovpn(pfxyrnzhpy) = jrgxdeedgo pcasfhmshr (eppphagpsv )	-	01 May 2023
				Control (no clodronate pre-treatment)	iruppcovpn(pfxyrnzhpy) = esssdfssdf pcasfhmshr (eppphagpsv )
EULAR2014	Not Applicable	Complex Regional Pain Syndromes	52	Intravenous Clodronate 300 mg/day for 2 weeks followed by 200 mg/weekly for 3 months	aeksrqmtah(qgnvcxwgid) = nhjbieosdm pyokfvhlgt (hglbiwwsbd )	Positive	11 Jun 2014
				Non-steroidal anti-inflammatory drugs (NSAID), calcium, Vitamin D, physical therapy	aeksrqmtah(qgnvcxwgid) = cmzdpptkqr pyokfvhlgt (hglbiwwsbd )
EULAR2010	Not Applicable	Osteoarthritis, Knee	122	Clodronate i.v. 300mg/die	zminnnnqly(cverqoxugo) = nvktjrsoxc thrrlncvly (jmyyojjony )	-	16 Jun 2010
MRC PR04 and PR05 (Pubmed \| Lancet Oncol)	Not Applicable	Metastatic Prostate Carcinoma Adjuvant	-	Sodium clodronate	cyjrescrrl(sviqfiwrcb): HR = 0.77 (95% CI, 0.6 - 0.98), P-Value = 0.032	Positive	01 Sep 2009
				Placebo
ASCO2007	Phase 3	Bone metastases	46	Oral Clodronate	spowtearla(tghkslqbhu) = soodzfpdil ljianbwuat (tkgbuezwtz ) View more	-	20 Jun 2007
				Oral Ibandronate	spowtearla(tghkslqbhu) = ofkynhmmyn ljianbwuat (tkgbuezwtz ) View more
ASCO2006	Not Applicable	Early Stage Breast Carcinoma Adjuvant	268	Clodronate	qffarebivx(rcnfgdzwfl) = pdppnfqpwv bxeqsifqeo (wdzdgkptbe ) View more	-	20 Jun 2006
ASCO2005	Not Applicable	Breast Cancer	1,069	Oral clodronate 1600mg	gzzpdgjndd(pliipjbdml) = igtxwjvylr snsjbqzrzf (yftobtqdzd, 0.010–0.021)	-	01 Jun 2005
ASCO2004	Not Applicable	Node-positive breast cancer Adjuvant	299	Clodronate 1600 mg daily	fhvbxagufl(tuuguqpobm) = frwmhuyghm gvmoptociv (mjikhjipvm ) View more	Negative	15 Jul 2004
				clodronate (Control)	fhvbxagufl(tuuguqpobm) = llrhrcwwyo gvmoptociv (mjikhjipvm ) View more
NCT00009945 (Pubmed \| Drug Saf)	Phase 3	Breast Cancer Adjuvant	1,079	Oral clodronate 1600 mg/day	tdxbekdfqa(jpeecrzfmn) = bjxvtassjg hzhwfxxukk (hvpyzumjct ) View more	-	01 Jan 2003
				Placebo	tdxbekdfqa(jpeecrzfmn) = efkhsfavez hzhwfxxukk (hvpyzumjct, 4.0 - 15.6) View more
NCT00009945 (Pubmed \| J Urol)	Phase 3	Breast Cancer	3,323	Clodronate 1,600 mg/d	(fkrrafivjb): HR = 0.77 (95% CI, 0.56 - 1.08)	Positive	01 Aug 2002
				Placebo

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