Potent Inhibitor Of Bone Resorption Research Articles

PSAT188 Keeping An Eye On Bisphosphonates: Drug Induced Uveitis

Abstract Introduction Bisphosphonates are considered the treatment of choice for osteoporosis. They have strong anti-osteoclastic activity and are potent inhibitors of bone resorption. Ocular inflammation, including conjunctivitis, uveitis, episcleritis and scleritis, is a rare side effect of bisphosphonates. A few cases in the literature have reported ocular inflammation secondary to bisphosphonate use. But largely, it has been an underrecognized cause of uveitis. We report a case of unilateral uveitis secondary to bisphosphonate therapy that was completely resolved after discontinuation of the medication. Case report A 68-year-old female with a history of osteoporosis diagnosed in 2019 on routine bone density scan presented for treatment evaluation. She had a history of multiple fractures after falling from standing height but no history of kidney stones, hypercalcemia, or GERD. She was started on alendronate 70mg once a week in 2019 with stabilization in bone density on repeat scan in 2020. After several weeks of treatment, she developed left eye uveitis and was treated with phenylephrine 2.5% and prednisolone acetate 1% ophthalmic solution. Because of these symptoms, the patient had diagnostic studies done which revealed positive ANA. She then had an extensive rheumatology workup, including serum SM antibody, ANCA screen, RNP antibody, Sjogren's antibodies, DNA (DS) antibody, and HLA-B27 DNA typing, which were all negative. Due to some case reports citing an association of bisphosphonate use with eye inflammation, the bisphosphonate was stopped with gradual improvement in her eye symptoms. An attempt to restart alendronate resulted in worsening eye symptoms, so the therapy was ultimately switched to denosumab. Discussion The incidence of ocular inflammation after bisphosphonate initiation is 0.08%. Symptoms usually develop 24 hours to a few weeks after starting treatment. The potential pathogenesis of bisphosphonate-induced ocular inflammation is thought to be secondary to bloodstream absorption and secretion of the medication into tears from the lacrimal gland causing irritation to the eyes’ mucous membranes. Originally it was thought that ocular inflammation only occurred with nitrogen-containing bisphosphonates, due to the nitrogen group possibly playing a role in activating gamma delta T cells leading to the release of acute phase reactants, such as cytokines. More recently, both nitrogen and non-nitrogen containing bisphosphonates have been associated with reported cases of ocular inflammation. Presentation can be either unilateral or bilateral, but the majority of reported cases were unilateral. All patients receiving bisphosphonates who develop signs and symptoms of ocular inflammation should be referred promptly to an ophthalmologist. The drug should be discontinued once the diagnosis is made to prevent further progression. In conclusion, clinicians should be aware of the potential for ocular inflammation upon bisphosphonate initiation. Patients may benefit from switching to a different class of medication, such as denosumab, if they experience symptoms of ocular inflammation with bisphosphonates. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Beneficial effects of switching to denosumab from bisphosphonates or selective estrogen receptor modulators in postmenopausal women with type2 diabetes and osteopenia/osteoporosis.

Aims/IntroductionPatients with type 2 diabetes mellitus have a higher bone fracture risk than patients without diabetes. Although denosumab (Dmab) is a potent bone resorption inhibitor, its efficacy in patients with type 2 diabetes mellitus has not been elucidated. In this study, we investigated the effects of switching to Dmab from bisphosphonates (BP) or a selective estrogen receptor modulator (SERM) in postmenopausal type 2 diabetes mellitus patients.Materials and MethodsThis was a three medical institutions, prospective, observational study for postmenopausal patients with type 2 diabetes mellitus whose T‐score of femoral neck or lumbar spine bone mineral density was under −1.0 standard deviation, even after >6 months of BP or SERM administration. After obtaining consent, participants were treated for osteopenia/osteoporosis by either continuing BP (BP‐BP group)/SERM (SERM‐SERM group), or by switching to Dmab (BP‐Dmab or SERM‐Dmab groups). Changes in bone mineral density and bone metabolism marker levels were evaluated after 6 months.ResultsA total of 48 patients were included in this study, and each group comprised 12 patients. No significant difference existed in baseline characteristics among the groups. The average age and glycated hemoglobin were 71 ± 8 years and 7.2 ± 0.9%, respectively. In the SERM‐Dmab group, lumbar spine bone mineral density was significantly increased by 5.0% compared with the SERM‐SERM group (P < 0.04). Serum bone‐specific alkaline phosphatase and tartrate‐resistant acid phosphatase 5b were significantly decreased in the BP‐Dmab and SERM‐Dmab groups compared with the BP‐BP and SERM‐SERM groups, respectively.ConclusionsSwitching to Dmab from BP or SERM is beneficial to prevent osteoporosis progression in postmenopausal patients with type 2 diabetes mellitus patients.

History of alendronate.

Alendronate was synthesized in 1970s in a search for inhibitors of calcification. Istituto Gentili investigators identified it as a potent inhibitor of bone resorption and obtained a patent covering its use in the treatment of osteoporosis and other disorders of excessive bone resorption in the 1980s. Merck licensed alendronate in 1988 and its pharmaceutical chemists reformulated it as a sodium salt with good solubility in a tablet that reduced its potential for esophageal irritation. Clinical trials proved that it reduced bone turnover, increased BMD and reduced the risk of vertebral fractures in postmenopausal osteoporotic women. Merck sponsored a large clinical trials that won FDA approval for treatment of osteoporosis in postmenopausal women and showed that it reduced the risk of spine and hip fractures. Its approval in the US in 1995 spurred sales of bone densitometers and BMD testing to screen for low bone mineral density and identify osteoporosis. Bone mass measurement was supported by medical society guidelines and reimbursement by Medicare and other insurers in the USA. A 70 mg weekly instead of 10 mg daily dose of alendronate produced the same effect on BMD and biochemical markers of bone remodelling with greater convenience and reduced potential for upper GI adverse events. Consequently, by 2006, about 30 million prescriptions for alendronate were written annually in the U.S. for about 15% of postmenopausal women in the U.S. Thereafter, publicity about rare but concerning atypical femoral fractures (AFF) and osteonecrosis of the jaw (ONJ) along with the expiry of Merck's patent (in 2008) and cessation of their promotion of alendronate, and a decline in use of densitometry led to a steady slide in its use even among patients for whom the benefits of alendronate far outweigh its potential risks. Nevertheless, in 25years since its regulatory approval, alendronate has undoubtedly prevented millions of fractures world-wide.

Clinical efficacy of amino bisphosphonate on periodontal disease status in postmenopausal women: Randomized double-blind placebo-controlled trial.

Objectives:Osteoporosis is a common skeletal disorder affecting postmenopausal women. Data suggest that postmenopausal women are at increased risk of periodontal diseases. Amino bisphosphonates are potent inhibitors of bone resorption and effectively used in the treatment of osteoporosis. Preliminary data indicate that there is a potential role for bisphosphonates in the management of periodontitis. Hence, this randomized placebo-controlled trial was designed to investigate the clinical efficacy of amino bisphosphonate on periodontal disease status among postmenopausal women.Materials and Methods:Thirty patients were randomly allocated to two treatment groups: Group A, which received scaling and root debridement and 70 mg weekly single oral dose of alendronate drug, and Group B, which received scaling and root debridement and placebo drug for 6 months. Clinical periodontal measurements were carried out for all patients at the baseline and 6 months later. Mandibular bone mineral density (BMD) was measured using a dual energy X-ray absorptiometer at the beginning of the study and the end of 6 months.Results:A weekly single oral dose of 70 mg alendronate was well-tolerated. The intragroup comparison showed significant improvement in periodontal parameters in both groups. The intergroup comparison showed a significant increase in BMD after 6 months in Group A when compared with Group B (P = 0.0179).Conclusion:Single oral dose of 70 mg alendronate per week is well-tolerable, gastro-intestinally safe, and improves the clinical outcome of nonsurgical periodontal therapy.

QbD Approach for Novel Crosslinker-Free Ionotropic Gelation of Risedronate Sodium-Chitosan Nebulizable Microspheres: Optimization and Characterization.

Risedronate sodium (RS) is a potent inhibitor of bone resorption, having an extreme poor permeability and limited oral bioavailability (0.62%). RS should be orally administered under fasting conditions while keeping in an upright posture for at least 30 min to diminish common gastroesophageal injuries. To surmount such limitations, novel risedronate-chitosan (RS-CS) crosslinker-free nebulizable microspheres were developed adopting the quality by design (QbD) approach and risk assessment (RA) thinking. RS:CS ratio, surfactant (Pluronic® F127) concentration, homogenization duration, speed, and temperature were identified using Ishikawa diagrams as the highest formulation and process risk factors affecting the critical quality attributes (CQAs), average particle size (PS), and entrapment efficiency (EE%). The risk factors were screened using the Plackett-Burman design, and the levels of the most significant factors were optimized using a multilevel factorial design to explore the optimized system with the least PS, maximum EE%, and a prolonged drug release profile. The optimized system (B6) was developed at a RS:CS ratio of 1:7, a surfactant concentration of 2% (w/v), and a homogenization speed of 14,000 rpm. It revealed good correlation with QbD theoretical prediction, where positively charged (47.9 ± 3.39 mV) discrete, spherical microspheres (3.47 ± 0.16 μm) having a high EE% (94.58 ± 0.19%) and prolonged RS release over 12 h (Q12 h, 89.70 ± 0.64%) were achieved. In vivo lung deposition after intratracheal instillation of B6 confirmed the delivery of high RS percentage to rat lung tissues (87 ± 3.54%) and its persistence for 24 h. This investigation demonstrated the effectiveness of QbD philosophy in developing RS-CS crosslinker-free nebulizable microspheres.

Effects of topical application of 1% sodium alendronate gel in the surgical treatment of periodontal intrabony defects: A 6-month randomized controlled clinical trial.

Sodium alendronate (ALN) is an aminobisphosphonate and potent inhibitor of bone resorption. It has been suggested that ALN might be a promising carrier of biomolecules for periodontal bone repair. The aim of this randomized split-mouth clinical trial was to evaluate the effects of the topical application of 1% ALN gel in intrabony defects during the surgical treatment of patients with periodontitis. Sixty-four intrabony defects from 32 patients with periodontitis were randomly treated with either 1% ALN gel or placebo gel during periodontal surgeries. Full-mouth periodontal examination was performed at baseline and at 3 and 6 months after surgical treatment. Clinical attachment level (CAL), probing depth (PD), and bleeding on probing (BOP) were recorded as the clinical outcomes. Bone defects were evaluated by digital subtraction radiography (DSR) at baseline and 6 months post-treatment. Analyses were performed through Fisher, Kruskal-Wallis, and ANOVA tests and a generalized estimation equations method. Both ALN and placebo groups showed significant improvements in BOP, PD, and CAL after periodontal surgical procedures (P<0.001). Intergroup analysis showed significantly better outcomes in the ALN group with higher PD reduction and clinical attachment gain. DSR showed positive effects on periodontal bone repair strongly associated in the ALN group (P<0.001). Topical application of 1% ALN may be a promising and beneficial adjuvant for the treatment of intrabony defects during surgical periodontal therapy.

The Activity of Peptides of the Calcitonin Family in Bone.

Calcitonin was discovered over 50 yr ago as a new hormone that rapidly lowers circulating calcium levels. This effect is caused by the inhibition of calcium efflux from bone, as calcitonin is a potent inhibitor of bone resorption. Calcitonin has been in clinical use for conditions of accelerated bone turnover, including Paget's disease and osteoporosis; although in recent years, with the development of drugs that are more potent inhibitors of bone resorption, its use has declined. A number of peptides that are structurally similar to calcitonin form the calcitonin family, which currently includes calcitonin gene-related peptides (αCGRP and βCGRP), amylin, adrenomedullin, and intermedin. Apart from being structurally similar, the peptides signal through related receptors and have some overlapping biological activities, although other activities are peptide specific. In bone, in vitro studies and administration of the peptides to animals generally found inhibitory effects on osteoclasts and bone resorption and positive effects on osteoblasts and bone formation. Surprisingly, studies in genetically modified mice have demonstrated that the physiological role of calcitonin appears to be the inhibition of osteoblast activity and bone turnover, whereas amylin inhibits osteoclast activity. The review article focuses on the activities of peptides of the calcitonin family in bone and the challenges in understanding the relationship between the pharmacological effects and the physiological roles of these peptides.

Design, Synthesis, and Pharmacokinetics of a Bone-Targeting Dual-Action Prodrug for the Treatment of Osteoporosis.

A dual-action bone-targeting prodrug has been designed, synthesized, and evaluated for in vitro and in vivo metabolic stability, in vivo tissue distribution, and rates of release of the active constituents after binding to bones through the use of differentially double-labeled derivatives. The conjugate (general structure 7) embodies the merger of a very potent and proven anabolic selective agonist of the prostaglandin EP4 receptor, compound 5, and alendronic acid, a potent inhibitor of bone resorption, optimally linked through a differentially hydrolyzable linker unit, N-4-carboxymethylphenyl-methyloxycarbonyl-leucinyl-argininyl-para-aminophenylmethylalcohol (Leu-Arg-PABA). Optimized conjugate 16 was designed so that esterase activity will liberate 5 and cathepsin K cleavage of the Leu-Arg-PABA element will liberate alendronic acid. Studies with doubly radiolabeled 16 provide a proof-of-concept for the use of a cathepsin K cleavable peptide-linked conjugate for targeting of bisphosphonate prodrugs to bone and slow release liberation of the active constituents in vivo. Such conjugates are potential therapies for the treatment of bone disorders such as osteoporosis.

Medication-Related Osteonecrosis of the Jaw; a Case Series and Review of Treatment Modalities

Introduction: Medication related osteonecrosis of the jaw (MRONJ) adversely affects quality of life, producing significant morbidity. MRONJ is reported in patients taking oral and intravenous bisphosphonates as potent inhibitors of bone resorption. Concomitant use with newer medications such as RANKL inhibitors and anti-angiogenic medications also predispose to the development of jaw osteonecrosis.

Preadmission Bisphosphonate and Mortality in Critically Ill Patients.

Increased bone resorption predicts mortality and bone resorption heightens during critical illness. Bisphosphonates are potent inhibitors of bone resorption. Whether bisphosphonate impacts clinical outcome of intensive care unit (ICU) admission is unknown. We investigated the relationship between preadmission bisphosphonate use and clinical outcome in critically ill patients. This was a retrospective hospital-based analysis. The study was conducted at a tertiary referral hospital ICU. A total of 7830 critically ill patients between 2003 and 2014 participated in the study. The intervention included bisphosphonate treatment. In-hospital mortality in the main study (n = 7830) and bone density loss and biochemical and hematological changes in the mechanistic substudy (n = 111) were measured. A total of 245 patients received preadmission bisphosphonate. Bisphosphonate users were older (66 ± 16 vs 58 ± 18 y, P < .01) and had greater comorbid disease burden (Charlson comorbidity index: 5.7 ± 3.6 vs 4.6 ± 3.8, P < .01), yet bisphosphonate use was associated with a lower in-hospital mortality (mortality rate ratio: 0.41, 95% confidence interval 0.24-0.71, P < .01), which remained significant after adjusting for age, sex, principal diagnosis, admitting unit, comorbidities and admission year. Bisphosphonate-associated survival benefit was independent of vitamin D, but bisphosphonate/vitamin D co-use was associated with additive reduction in mortality (mortality rate ratio 0.38, 95% confidence interval 0.20-0.71, P < .01). Bone density decreased during ICU admission (-13% ± 19% per week, P < .01) but was significantly attenuated among bisphosphonate users compared with nonusers (-3% ± 13% per week v. -15% ± 14% per week, P < .01), despite similar disease severity on admission. All bisphosphonate users in the substudy survived, whereas six nonusers died. Preadmission bisphosphonate use was associated with superior survival among critically ill patients. Prospective studies examining the effects of bisphosphonate in critical illness are required.

Histomorphometric study of the alendronate and monofluorophosphate effect in rat bones

Introduction: Previous studies have shown that biophosphonates, such as alendronate sodium (AL), are potent inhibitors of bone resorption and increment bone mineral density.Objective: The aim was to study the effect of the combined treatment of AL, subcutaneously, and of MFP, supplied orally, over the tissue regeneration of neoformed bone cavities. Materials and methods: The pharmaceutical formulations with a dosage of 0.50 mg/kg of the weight for AL and 5 Mm for MFP were prepared. Sixty-four Wistar male rats 160 ± 20 g of weight were divided into 4 groups. Control (C) group received a subcutaneous dosage of saline solution of 0.3 ml/100g of the corporal weight given weekly, injected near the surgery intervention zone. Group (AL) received a dosage of 0.5 mg of the corporal weight in the left leg. Group (MFP) received in their drinkable water, during all the research time, and was injected subcutaneously with saline solution, same as (C). Group (AL +MFP) received a combined treatment of AL injected subcutaneously plus a MFP dosage in their drinkable water. The animals were sacrificed on the 15th, 30th, 60th and 90th days of the research. The comparison of the data was conducted by analysis of variancewith two and three criteria of classification. Results: The histologic analysis showed that AL andMFP presented a higher osteogenic activity, where thicker and anastomosed trabeculeswere observed, with a higher relevance in day 60 and steadily stabilized in time 90. The histomorphometry revealed a rise in the percentage of the trabecular bone through time for AL and MFP being the most relevant day 60. Conclusion: The analysis of the combined treatment shows that there is no summative synergy and no potentiation synergy.

ChemInform Abstract: Copper‐Mediated 1,4‐Conjugate Addition of Boronic Acids and Indoles to Vinylidenebisphosphonate Leading to gem‐Bisphosphonates as Potential Antiresorption Bone Drugs.

A wide range of gem-bisphosphonate tetraethyl esters as precursors for bisphosphonic acids, which are potent inhibitors of bone resorption, bearing alkyl, aryl, and indole substituents in the β position were prepared through the CuII-catalyzed 1,4-conjugate addition of boronic acids and indoles to vinylidenebisphosphonate tetraethyl ester.

Preclinical evidence of potential craniofacial adverse effect of zoledronic acid in pediatric patients with bone malignancies

High doses of zoledronic acid (ZOL), one of the most potent inhibitors of bone resorption, are currently evaluated in phase III clinical trials in Europe for the treatment of malignant pediatric primary bone tumors. The impact of such an intensive treatment on the craniofacial skeleton growth is a critical question in the context of patients with actively growing skeleton; in particular, in light of our previous studies evidencing that endochondral bone formation was transiently disturbed by high doses of ZOL. Two protocols adapted from pediatric treatments were developed for newborn mice (a total of 5 or 10 injections of ZOL 50μg/kg every two days). Their impact on skull bones and teeth growth was analyzed by X-rays, microCT and histology up to 3months after the last injection.ZOL administrations induced a transient delay of skull bone growth and an irreversible delay in incisor, first molar eruption and root elongation. Other teeth were affected, but most were erupted by 3months. Root histogenesis was severely impacted for all molars and massive odontogenic tumor-like structures were observed in all mandibular incisors.High doses of ZOL irreversibly disturbed teeth eruption and elongation, and delayed skull bone formation. These preclinical observations are essential for the follow-up of onco-pediatric patients treated with ZOL.

Copper‐mediated 1,4‐Conjugate Addition of Boronic Acids and Indoles to Vinylidenebisphosphonate leading to gem‐Bisphosphonates as Potential Antiresorption Bone Drugs

AbstractA wide range of gem‐bisphosphonate tetraethyl esters as precursors for bisphosphonic acids, which are potent inhibitors of bone resorption, bearing alkyl, aryl, and indole substituents in the β position were prepared through the CuII‐catalyzed 1,4‐conjugate addition of boronic acids and indoles to vinylidenebisphosphonate tetraethyl ester.

Preclinical evidence of positive effect of l-MTP-PE alone or combined with zoledronic acid in osteosarcoma.

10048 Background: Zoledronic Acid (ZA), a potent inhibitor of bone resorption is currently evaluated in phase III clinical trials in Europe for the treatment of malignant primary bone tumors. The b...

Bisphosphonates in the management of thalassemia-associated osteoporosis: a systematic review of randomised controlled trials.

Bisphosphonates are potent inhibitors of bone resorption, widely used for the management of osteoporosis and fracture prevention. Recent evidence suggests that bisphosphonates may have beneficial effects in the treatment of thalassemia-associated osteoporosis, a complex and multifactorial condition. Here we summarise available data about the efficacy and tolerability of bisphosphonates in beta--thalassemic patients. Randomised controlled trials (RCTs) of bisphosphonates in beta-thalassemia were identified searching PubMed. Studies were reviewed to retrieve relevant clinical information. The following variables were considered to assess the safety and efficacy of bisphosphonates-bone mineral density (BMD), markers of bone turnover, incidence of fragility fracture, bone pain, back pain, and clinical adverse events. Five RCTs were identified, investigating alendronate, clodronate, zoledronic acid and neridronate. All bisphosphonates produced a significant decrease of the markers of bone turnover. Alendronate, neridronate, and zoledronic acid significantly improved BMD at the lumbar spine, femoral neck and total hip. Zoledronic acid and neridronate were also shown to reduce bone and back pain. Probably due to the small sample sizes and to the short duration of the trials, it was not possible to establish the anti-fracture efficacy of bisphosphonates; however, they were well tolerated and adverse events were rare but expected on the basis of previous studies. Sufficient evidence exists to support the use of bisphosphonates in the management of thalassemia-associated osteoporosis (to prevent bone loss and improve the BMD). Further research is warranted to establish their anti-fracture efficacy and long-term safety.

Osteoblastic protein tyrosine phosphatases inhibition and connexin 43 phosphorylation by alendronate

Bisphosphonates (BPs), potent inhibitors of bone resorption which inhibit osteoclasts, have also been shown to act on osteocytes and osteoblasts preventing apoptosis via connexin (Cx) 43 hemichannels and activating the extracellular signal regulated kinases ERKs. We previously demonstrated the presence of a saturable, specific and high affinity binding site for alendronate (ALN) in osteoblastic cells which express Cx43. However, cells lacking Cx43 also bound BPs. Herein we show that bound [3H]-alendronate is displaced by phosphatase substrates. Moreover, similar to Na3VO4, ALN inhibited the activity of transmembrane and cytoplasmic PTPs, pointing out the catalytic domain of phosphatases as a putative BP target. In addition, anti-phospho-tyrosine immunoblot analysis revealed that ALN stimulates tyrosine phosphorylation of several proteins of whole cell lysates, among which the major targets of the BP could be immunochemically identified as Cx43. Additionally, the transmembrane receptor-like PTPs, RPTPµ and RPTPα, as well as the cytoplasmic PTP1B, are highly expressed in ROS 17/2.8 cells. Furthermore, we evidenced that Cx43 interacts with RPTPµ in ROS 17/2.8 and ALN decreases their association. These results support the hypothesis that BPs bind and inhibit PTPs associated to Cx43 or not, which would lead to the activation of signaling pathways in osteoblasts.

Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration

BackgroundEwing’s sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties.MethodsInvasion assays were performed in vitro in Boyden’s chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 106 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 μg/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology.ResultsZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and −9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases.ConclusionThese results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs.

Serum brain-type creatine kinase increases in children with osteogenesis imperfecta during neridronate treatment

Creatine kinase (Ck) catalyzes the reversible transfer of high-energy phosphate groups between adenosine triphosphate and phosphocreatine. The brain isoform (Ckbb) is greatly induced in mature osteoclasts, playing an important role in bone-resorbing function during osteoclastogenesis. High Ckbb serum level has been found in patients with osteopetrosis and in patients with bisphosphonate (BP)-induced osteopetrosis. BPs are considered the treatment of choice for children with osteogenesis imperfecta (OI), acting as potent inhibitors of bone resorption by suppressing the activity of osteoclasts. We determined total serum Ck and isoform activity in 18 prepubertal children with type I OI, before and during treatment with the BP neridronate infusions. Basal serum Ckbb levels were slightly elevated with respect to controls (mean ± SD = 3.0 ± 2.7 vs. 2.0 ± 2.2) and progressively increased after neridronate treatment (t0 vs. t4: mean ± SD = 3.0 ± 2.7 to 10.8 ± 8.1), with significant increment after first, second, and fourth infusions (P < 0.01). An inverse correlation was found between serum Ckbb and serum CTx at basal level. Our results support previous observations that increased serum Ckbb reflects failure of osteoclasts or, at least, suppression of osteoclasts. Upon considering that BPs are long acting, this information could be useful to prevent the risk of overtreatment after long-term BP exposure in pediatric patients with OI.

Gallium compounds in nuclear medicine and oncology

An overview of the most important gallium compounds in nuclear medicine and oncology in the two last decades, with an emphasis on the last decade (especially the last 5 years), is given in this review. You can also find here some recent knowledge about 68 Ge/ 68 Ga radionuclide generator modern automated synthesis modules. Gallium has long been known to concentrate in skeletal tissue, particularly regions of bone deposition and remodeling. Elemental gallium is a potent inhibitor of bone resorption that acts to maintain or restore bone mass. There are several medically useful gallium radionuclides that have made extensive contribution in both the diagnosis and therapy of diseases. A huge variety of monofunctional and bifunctional chelators have been developed that allow the formation of stable 68 Ga(III) complexes and convenient coupling to biomolecules such as amino acids, peptides, nanoparticles, or even whole cells. Gallium pharmaceuticals can be divided into two groups according to radioactivity, i.e., radiopharmaceuticals – using radioactive Ga(III) isotopes, and conventional pharmaceuticals – using non-radioactive Ga(III) ion. The pharmaceuticals can also be divided according to the target site of a drug, i.e., those having an impact on soft tissue (most of the drugs) and hard tissue (bones and bone metastasis). In oncology and nuclear medicine, gallium and its compounds have been applied for imaging as well as therapy, and their importance in this field is still growing.