Unusual high 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) tracer deposition on a heart scintigraphy in a patient with AL amyloidosis: A case report.

We present a case of a 40-year-old Spanish man with cardiac amyloidosis in which a Tc-99m-3,3-diphosphono-1,2-propanodicarboxylic acid (Tc-99m-DPD) scintigraphy was strongly suggestive of cardiac amyloidosis by transthyretin (ATTR) but endomyocardial biopsy (EB) analyzed by immunohistochemistry demonstrated a light chain amyloidosis (AL). Even though the Tc-99m-DPD has proven in different published papers that has high sensibility and specificity for differentiating AL and ATTR cardiac amyloidosis, we present an unusual case of an AL cardiac amyloidosis with a Perugini grade 3 on the scintigraphy. Diagnostic approach of cardiac amyloidosis following consensus documents is discussed to avoid diagnostic mistakes based on imaging techniques.

Standardized uptake values of 99mTc-MDP in normal vertebrae assessed using quantitative SPECT/CT for differentiation diagnosis of benign and malignant bone lesions.

BACKGROUND: Quantitative bone SPECT/CT is useful for disease follow up and inter-patient comparison. For bone metastatic malignant lesions, spine is the most commonly invaded site. However, Quantitative studies with large sample size investigating all the segments of normal cervical, thoracic and lumbar vertebrae are seldom reported. This study was to evaluate the quantitative tomography of normal vertebrae using 99mTc-MDP with SPECT/CT to investigate the feasibility of standardized uptake value (SUV) for differential diagnosis of benign and malignant bone lesions. METHODS: A retrospective study was carried out involving 221 patients (116 males and 105 females) who underwent SPECT/CT scan using 99mTc-MDP. The maximum SUV (SUVmax), mean SUV (SUVmean) and CT values (Hounsfield Unit, HU) of 2416 normal vertebrae bodies, 157 benign bone lesions and 118 malignant bone metastasis foci were obtained. The correlations between SUVmax of normal vertebrae and CT values of normal vertebrae, age, height, weight, BMI of patients were analyzed. Statistical analysis was performed with data of normal, benign and malignant groups corresponding to same sites and gender. RESULTS: The SUVmax and SUVmean of normal vertebrae in males were markedly higher than those in females (P < 0.0009). The SUVmax of each normal vertebral segment showed a strong negative correlation with CT values in both males and females (r = - 0.89 and - 0.92, respectively; P < 0.0009). The SUVmax of normal vertebrae also showed significant correlation with weight, height, and BMI in males (r = 0.4, P < 0.0009; r = 0.28, P = 0.005; r = 0.22, P = 0.026), and significant correlation with weight and BMI in females (r = 0.32, P = 0.009; r = 0.23, P = 0.031). The SUVmax of normal group, benign bone lesion group and malignant bone metastasis foci group showed statistical differences in both males and females. CONCLUSION: Our study evaluated SUVmax and SUVmean of normal vertebrae, benign bone lesion and malignant bone metastasis foci with a large sample population. Preliminary results proved the potential value of SUVmax in differentiation benign and malignant bone lesions. The results may provide a quantitative reference for clinical diagnosis and the evaluation of therapeutic response in vertebral lesions.

Quantitative 99mTc-DPD SPECT/CT in patients with suspected ATTR cardiac amyloidosis: Feasibility and correlation with visual scores.

PURPOSE: While a visual interpretation of 99mTc-DPD scintigraphy by means of Perugini score can provide a reliable diagnosis of transthyretin-related (ATTR) cardiac amyloidosis (CA), a quantitative approach is expected to play a major role in risk stratification and therapy evaluation. The aim of our study was to test the feasibility of a quantitative assessment and to correlate various parameters to Perugini score. METHODS: in this retrospective study, consecutive patients underwent a 99mTc-DPD whole-body bone scintigraphy and a SPECT/CT of the thorax. XSPECT-QUANT software was used to quantify the DPD uptake in the heart. RESULTS: Thirteen patients were included. CA was confirmed in 8 and rejected in 5. Myocardial SUVmax and SUVpeak showed a fairly strong correlation with Perugini score (both ρ = .71, P = .006). Same held true for to-bone normalized values (both ρ = .75, P = .003). There was a great degree of overlap for quantitative values in patients with Perugini score 2 and 3. CONCLUSION: Quantitative 99mTc-DPD SPECT/CT in suspected ATTR CA patients is feasible and allows for a more accurate assessment of myocardial uptake.

Imaging cardiac innervation in hereditary transthyretin (ATTRm) amyloidosis: A marker for neuropathy or cardiomyopathy in case of heart failure?

BACKGROUND: Nuclear imaging modalities using 123Iodine-metaiodobenzylguanidine (123I-MIBG) and bone seeking tracers identify early cardiac involvement in ATTRm amyloidosis patients. However, little is known whether results from 123I-MIBG scintigraphy actually correlate to markers for either cardiac autonomic neuropathy or cardiomyopathy. METHODS: All TTR mutation carriers and ATTRm patients who underwent both 123I-MIBG and 99mTechnetium-hydroxymethylene diphosphonate (99mTc-HDP) scintigraphy were included. Cardiomyopathy was defined as NT-proBNP > 365 ng/L, and cardiac autonomic neuropathy as abnormal cardiovascular reflexes at autonomic function tests. Late 123I-MIBG heart-to-mediastinum ratio (HMR) < 2.0 or wash-out > 20%, and any cardiac 99mTc-HDP uptake were considered as abnormal. RESULTS: 39 patients (13 carriers and 26 ATTRm patients) were included in this study. Patients with cardiomyopathy, with or without cardiac autonomic neuropathy, had lower late HMR than similar patients without cardiomyopathy [median 1.1 (range 1.0-1.5) and 1.5(1.2-2.6) vs 2.4 (1.4-3.8) and 2.5 (1.5-3.7), respectively, P < 0.001]. Late HMR and wash-out (inversely) correlated with NT-proBNP r = - 0.652 (P < 0.001) and r = 0.756 (P < 0.001), respectively. Furthermore, late HMR and wash-out (inversely) correlated with cardiac 99mTc-HDP uptake r = - 0.663 (P < 0.001) and r = 0.617 (P < 0.001), respectively. CONCLUSION: In case of heart failure, 123I-MIBG scintigraphy reflects cardiomyopathy rather than cardiac autonomic neuropathy in ATTRm patients and TTR mutation carriers. 123I-MIBG scintigraphy may already be abnormal before any cardiac bone tracer uptake is visible.

A Comparative Study of the Pharmacokinetics of Bis- and Pentaphosphonic Acids Labeled with Gallium-68 in Rats with Experimental Model of Bone Callus.

We analyzed biodistribution of 68Ga-labeled hydroxyethylidenediphosphonic acid (68Ga-HEDP) and diethylenetriaminepentakis(methylenephosphonic acid) (68Ga-DTPMP) in Wistar rats with experimental model of bone callus. It was shown that the content of 68Ga-DTPMP and 68Ga-HEDP in bone callus was ~1.5-fold higher than in intact femur. 68Ga-DTPMP was characterized by higher stability in vivo, higher uptake in the bone tissue, and lower uptake in others visceral organs in comparison with 68Ga-HEDP. Thus, 68Ga-DTPMP had more suitable pharmacokinetic properties than 68Ga-HEDP.

12b80 - Hydroxybisphosphonate Linked Doxorubicin: Bone Targeted Strategy for Treatment of Osteosarcoma.

To reply to as yet unmet medical needs to treat osteosarcoma, a form of primary bone cancer, we conceived the 12b80 compound by covalently conjugating antineoplastic compound doxorubicin to a bone targeting hydroxybisphosphonate vector and turned it into a prodrug through a custom linker designed to specifically trigger doxorubicin release in acidic bone tumor microenvironment. Synthesis of 12b80 was thoroughly optimized to be produced at gram scale. 12b80 was evaluated in vitro for high bone support affinity, specific release of doxorubicin in acidic condition, lower cytotoxicity, and cellular uptake of the prodrug. In vivo in rodents, 12b80 displayed rapid and sustained targeting of bone tissue and tumor-associated heterotopic bone and permitted a higher doxorubicin payload in tumor bone environment compared to nonvectorized doxorubicin. Consequently, 12b80 showed much lower toxicity compared to doxorubicin, promoted strong antitumor effects on rodent orthotopic osteosarcoma, displayed a dose-response therapeutic effect, and was more potent than doxorubicin/zoledronate combination.

Pharmacology of bisphosphonates.

The biological effects of the bisphosphonates (BPs) as inhibitors of calcification and bone resorption were first described in the late 1960s. In the 50 years that have elapsed since then, the BPs have become the leading drugs for the treatment of skeletal disorders characterized by increased bone resorption, including Paget's disease of bone, bone metastases, multiple myeloma, osteoporosis and several childhood inherited disorders. The discovery and development of the BPs as a major class of drugs for the treatment of bone diseases is a paradigm for the successful journey from "bench to bedside and back again". Several of the leading BPs achieved "blockbuster" status as branded drugs. However, these BPs have now come to the end of their patent life, making them highly affordable. The opportunity for new clinical applications for BPs also exists in other areas of medicine such as ageing, cardiovascular disease and radiation protection. Their use as inexpensive generic medicines is therefore likely to continue for many years to come. Fifty years of research into the pharmacology of bisphosphonates have led to a fairly good understanding about how these drugs work and how they can be used safely in patients with metabolic bone diseases. However, while we seemingly know much about these drugs, a number of key aspects related to BP distribution and action remain incompletely understood. This review summarizes the existing knowledge of the (pre)clinical and translational pharmacology of BPs, and highlights areas in which understanding is lacking.

Antiresorptive agents' bone-protective and adjuvant effects in postmenopausal women with early breast cancer.

Potent antiresorptive drugs (bisphosphonate and denosumab) are often used to protect bone health in postmenopausal breast cancer patients. In addition, clinical trials have shown that these drugs increase disease-free survival, though the mechanism of adjuvant benefit is largely unknown. Here we review the bone health and adjuvant data for both classes of antiresorptive drugs and highlight differences in their pharmacology. Inhibition of bone resorption is vitally important to protect against osteoporotic fractures, and may also contribute to adjuvant survival benefits by making the bone microenvironment less amenable to breast cancer metastasis. After a course of therapy, stoppage of bisphosphonates yields a persistent antiresorptive effect, whereas discontinuation of denosumab causes a rebound increase in bone resorption markers and a loss of bone mineral density to baseline levels. Whether the potential adjuvant benefits of denosumab are also rapidly lost after drug discontinuation deserves further investigation.

Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis.

Malignant osteolysis associated with inoperable primary bone tumors and multifocal skeletal metastases remains a challenging clinical problem in cancer patients. Nanomedicine that is able to target and deliver therapeutic agents to diseased bone sites could potentially provide an effective treatment option for different types of skeletal cancers. Here, we report the development of polylactide nanoparticles (NPs) loaded with doxorubicin (Doxo) and coated with bone-seeking pamidronate (Pam) for the targeted treatment of malignant skeletal tumors. In vivo biodistribution of radiolabeled targeted Pam-NPs demonstrated enhanced bone tumor accumulation and prolonged retention compared with nontargeted NPs. In a murine model of focal malignant osteolysis, Pam-functionalized, Doxo-loaded NPs (Pam-Doxo-NPs) significantly attenuated localized osteosarcoma (OS) progression compared with nontargeted Doxo-NPs. Importantly, we report on the first evaluation to our knowlege of Pam-Doxo-NPs in dogs with OS, which possess tumors of anatomic size and physiology comparable to those in humans. The repeat dosing of Pam-Doxo-NPs in dogs with naturally occurring OS indicated the therapeutic was well tolerated without hematologic, nonhematologic, and cardiac toxicities. By nuclear scintigraphy, the biodistribution of Pam-Doxo-NPs demonstrated malignant bone-targeting capability and exerted measurable anticancer activities as confirmed with percent tumor necrosis histopathology assessment.

Early-phase myocardial uptake intensity of 99mTc-HMDP vs 99mTc-DPD in patients with hereditary transthyretin-related cardiac amyloidosis.

BACKGROUND: This study sought to compare the intensity of early-phase myocardial uptake of two phosphonate-based radiotracers, 99mTc-hydroxymethylene diphosphonate (HMDP) and 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), in patients with hereditary transthyretin-related cardiac amyloidosis (TTR-CA). METHODS: Six patients with biopsy-proven diagnosis of TTR-CA and characteristic amyloid fibril composition underwent early-phase 99mTc-HMDP myocardial scintigraphy as part of their routine workup; they were later assessed by 99mTc-DPD scintigraphy after having signed informed written consent. Heart-to-mediastinum-ratio was measured at both time points as well as regional distribution on 17-segment analysis. RESULTS: All patients had an H/M ratio >1.28 on both imaging. 99mTc-DPD uptake was slightly higher than 99mTc-HMDP uptake in 3 patients, but no statistical difference was found (P = 0.13). Regional distribution of the two radiotracers was well correlated on bull's eyes analysis, with only slight underestimation of 99mTc-DPD uptake in the anterior/apical segments, compared with 99mTc-HMDP. CONCLUSION: 99mTc-HMDP and 99mTc-DPD show comparable myocardial uptake intensity on early-phase scintigraphy and can be used alternatively for the diagnosis of TTR-CA.

Safety, pharmacokinetics, and changes in bone metabolism associated with zoledronic acid treatment in Japanese patients with primary osteoporosis.

Although once-yearly intravenous administration of zoledronic acid has been reported to inhibit bone resorption and increase bone mineral density, no studies have evaluated its effectiveness in treating osteoporosis in Japanese patients. Therefore, the purpose of this study was to investigate the pharmacokinetics and assess the safety of and changes in bone metabolism associated with zoledronic acid treatment in Japanese patients with primary osteoporosis. This was a single-administration study with a single-blind parallel-group design. The study participants were 24 Japanese patients with primary osteoporosis. The patients were divided into two groups, with each group receiving a single injection of zoledronic acid (4 or 5 mg). Pharmacokinetics and urinary excretion were then compared, and drug-related adverse events and changes in the levels of bone turnover markers were assessed at 12 months. Mean plasma concentrations of zoledronic acid peaked in both groups immediately after administration, and decreased to 1% or less of peak levels after 24 h. Noncompartmental analysis revealed that C max and the area under the curve from time zero to infinity increased in proportion to the dose. The levels of bone resorption and formation markers decreased from day 15 and from 3 months after administration respectively, and suppression of these markers remained constant for the entire study period. No serious adverse events were reported. There was no large difference between the 4- and 5-mg groups in terms of pharmacokinetics, changes in the levels of bone turnover markers, and safety profiles. This study demonstrated acceptable pharmacokinetics and changes in bone metabolism associated with zoledronic acid treatment in female Japanese osteoporosis patients. Both the 4-mg dose and the 5-mg dose demonstrated acceptable safety and sustained antiresorptive effects for the duration of the study.

A model of fracture risk used to examine the link between bone mineral density and the impact of different therapeutic mechanisms on fracture outcomes in patients with osteoporosis.

A hazard model of fracture was developed using individual patient data (IPD) from the NHANES (2005-2008) database and summary-level data from an aggregate dataset (AD). The AD was built by performing a comprehensive and systematic literature search of clinical studies published from 1995 to 2015, recording fracture rate and bone mineral density (BMD) for both treatment and placebo arms. The search resulted in a metadata set comprised of 21 studies investigating the effects of various bisphosphonates, teriparatide, denosumab, and raloxifene in 65,254 patients over a cumulative 56.75 years of study. The IPD was used to augment an AD in a model-based meta-analysis (MBMA) hierarchical modeling approach. The resulting model predicts the probability of fracture events in patients with osteoporosis. The object of model building using this approach was to promote understanding of the impact of therapeutic drug effects on the probability of fracture together with, or independent of their effects on BMD. Candidate models were evaluated by deviance information criteria and posterior predictive check. The model with covariates for lumbar spine BMD with interaction with a drug effect on BMD, and patient body mass index, years post-menopause, fracture measure method (clinical or radiological) and an additional drug effect outperformed those models without interaction and without additional drug effects. The model quantitatively supports the widely held notion that changes in bone microarchitecture, which cannot be measured by areal BMD elicited by therapy contribute in a significant way to a reduction in fracture. Furthermore, this model can be used to simulate fracture risk in a clinical cohort similar to those contained in the MBMA.

Synthesis, preclinical, and pharmacokinetic evaluation of a new zoledronate derivative as a promising antiosteoporotic candidate using radiolabeling technique.

A novel zoledronic acid (ZL) derivative, 3-(2-ethyl-4-methyi-1H-imidazole-1-yl)-1-hydroxy-1-phosphonopropyl phosphonic acid (EMIHPBP), was synthesized, characterized, and successfully radiolabeled with 99m Tc. The in vivo biodistribution of 99m Tc-EMIHPBP was investigated and compared with the previously reported zoledronate derivatives aiming to formulate a novel zoledronate derivative with a high-potential uptake to bone as a promising antiosteoporotic candidate. To further evaluate the bone uptake efficiency, the pharmacokinetics of 99m Tc-EMIHPBP was investigated and showed that maximum concentration in bone (Cmax ) was 31.60 ± 0.15%ID/gram after 60 minutes (tmax ). Cumulative residence of 99m Tc-EMIHPBP in the bone [AUC (0-∞) (%ID∙min/gram bone)] was 3685.23, mean residence time was 384.354 minutes, and the calculated bone bioavailability was 15.831%. Finally, the time needed for half of the 99m Tc-EMIHPBP formulation to be eliminated from bone (t1/2 ) was 263.914 minutes. Excellent bone uptake can be obtained 1-hour postinjection with high bone/blood ratio of 23.76 detected with gamma counter. The biodistribution and kinetic studies could recommend EMIHPBP as a promising antiosteoporotic candidate with high selectivity to the skeletal system and rapid clearance from soft tissues.

Zolendronic Acid-Conjugated PLGA Ultrasmall Nanoparticle Loaded with Methotrexate as a Supercarrier for Bone-Targeted Drug Delivery.

Drug delivery to deep-seated tissues such as bone has been a major complication till date. This preferential drug delivery is further important in targeting anti-tumour agents to bone metastasis owing to its complexity. The present study involves the formulation of PLGA nanoparticles and conjugation with zolendronic acid-a bisphosphonate which will anchor the nanosystem to bone due to its selective bone affinity. The conjugated nanosystem was characterized for particle size by TEM (average 36 nm) and morphology by AFM depicting surface irregularities due to ZOL conjugation on the surface of nanoparticles. NMR spectral data also showed the involvement of terminal -OH group of PLGA in bond formation with ZOL. Bone localization studies showed higher accumulation of the ZOL-conjugated nanosystem in bone than non-conjugated nanoparticles. This was confirmed with bone mineral affinity and specificity assay wherein the conjugated nanosystem was found to selectively bind to hydroxyapatite in comparison to other bone minerals. The biodistribution studies depicted that the conjugated nanosystem was selectively targeted to the bone area with concentrations of methotrexate reaching up to 127.4 ± 1.41 µg in 1 h. Hence, this multipronged approach using (1) ultrasmall size of nanoparticles, (2) bone selective polymer and (3) suitable bone-targeting agent resulted in mutual synergism for the specific delivery of the anti-tumour agent to the bone.

Synthesis, Characterization, and Application of Core-Shell Co0.16Fe2.84O4@NaYF4(Yb, Er) and Fe3O4@NaYF4(Yb, Tm) Nanoparticle as Trimodal (MRI, PET/SPECT, and Optical) Imaging Agents.

Multimodal nanoparticulate materials are described, offering magnetic, radionuclide, and fluorescent imaging capabilities to exploit the complementary advantages of magnetic resonance imaging (MRI), positron emission tomography/single-photon emission commuted tomography (PET/SPECT), and optical imaging. They comprise Fe3O4@NaYF4 core/shell nanoparticles (NPs) with different cation dopants in the shell or core, including Co0.16Fe2.84O4@NaYF4(Yb, Er) and Fe3O4@NaYF4(Yb, Tm). These NPs are stabilized by bisphosphonate polyethylene glycol conjugates (BP-PEG), and then show a high transverse relaxivity (r2) up to 326 mM(-1) s(-1) at 3T, a high affinity to [(18)F]-fluoride or radiometal-bisphosphonate conjugates (e.g., (64)Cu and (99m)Tc), and fluorescent emissions from 500 to 800 nm under excitation at 980 nm. The biodistribution of intravenously administered particles determined by PET/MR imaging suggests that negatively charged Co0.16Fe2.84O4@NaYF4(Yb, Er)-BP-PEG (10K) NPs cleared from the blood pool more slowly than positively charged NPs Fe3O4@NaYF4(Yb, Tm)-BP-PEG (2K). Preliminary results in sentinel lymph node imaging in mice indicate the advantages of multimodal imaging.

[Pharmacokinetics of bisphosphonate.]

The objective of treating osteoporosis is to prevent fractures. Bisphosphonates inhibit bone resorption and increase bone density, thereby suppressing the occurrence of fractures. Bisphosphonates have a high affinity for hydroxyapatite. About 20-80%of bisphosphonates absorbed in vivo is adsorbed onto the bone surface. However, the absorption rates of orally ingested bisphosphonates are less than 1%. Bisphosphonates adhered to the bone surface are specifically incorporated into cells upon bone resorption by osteoclasts. Thus, the cytoskeleton of osteoclasts is destroyed, and apoptosis is induced to suppress bone resorption. This article overviews the mechanisms of action and pharmacokinetics of bisphosphonates.

[Pharmacokinetics of Zoledronic acid[once-yearly bisphosphonate(intravenous infusion)].]

Zoledronic acid hydrate(zoledronic acid)is an osteoporosis therapeutic agent which shows the fracture suppression effect with once-yearly intravenous infusion. Although zoledronic acid is quickly disappeared from the blood after intravenous infusion, it is taken into the bone immediately and incorporated into the bone tissue. In addition, zoledronic acid shows the potent suppression effect on bone resorption by inhibiting farnesyl diphosphate synthase of the mevalonate pathway(FPPS)strongly. In vivo study, the single intravenous administration of zoledronic acid to the mature ovariectomized(OVX)rats demonstrated to suppress the decreasing bone strength dose-dependently in 32 weeks, corresponding to more than one year in human. Changes in bone resorption markers in the study of Japanese osteoporosis patients(ZONE Study)indicated that bone resorption inhibition action was maintained also over one year. The fracture suppression and increase of bone density with once-yealy administration was demonstrated in clinical trials in the osteoporosis patients in Japan and other countries, and zoledronic acid was currently approved for osteoporosis in September 2016 in Japan. Zoledronic acid is expected to contribute to the treatment of osteoporosis as a new bisphosphonate with once-yearly administration.

Determination of the rat in vivo pharmacokinetic profile of a bone-targeting dual-action pro-drug for treatment of osteoporosis.

The in vivo hydrolytic pathway of a dual-function bone-targeting EP4 receptor agonist-bisphosphonate pro-drug was deduced from radiolabeling experiments. A (14)C labeled pro-drug was used to monitor liberation of the bisphosphonate and results were compared to parallel studies where the EP4 receptor agonist was labeled with (3)H. The bone-adsorption of the (14)C pro-drug following an IV bolus was about 10% compared to 7.8% for the tritiated pro-drug. The difference in release half-life (5.2 and 19.7 days from (3)H and (14)C experiments, respectively) indicated that, after binding to bone, the initial hydrolysis occurred at the ester moiety of the linker releasing the EP4 agonist. The conjugate was found to concentrate in more porous, high-surface-area regions of the long bones. Both (3)H and (14)C experiments indicated a short circulating half-life (1-2 h) in blood.

Pharmacology of Bisphosphonates in Patients with Chronic Kidney Disease.

Bisphosphonates are medications which bind strongly to mineral. They are ingested by osteoclasts and inhibit an enzyme necessary for bone resorption. The gastrointestinal absorption is poor and the only method of excretion is renal. Therefore, in patients with CKD the body accumulates a higher percentage of a dose of bisphosphonate. These medications remain attached to bone mineral for many years. Although the primary action is to inhibit bone resorption, secondarily bone formation is also inhibited, and in patients with CKD bisphosphonate use often leads to adynamic bone. In some experimental models in animals, the bisphosphonates can inhibit vascular calcification but this effect has not been seen in humans. Intravenous bisphosphonates may cause renal damage but oral doses do not reduce creatinine clearance. In stage 3 CKD, in patients who still have normal PTH, calcium, and alkaline phosphatase, randomized trials show similar benefits as in patients without CKD. Data from stage 4 and 5 CKD are very limited and no clear benefit has been shown.

Neutrophil uptake of nitrogen-bisphosphonates leads to the suppression of human peripheral blood γδ T cells.

Nitrogen-bisphosphonates (n-BP), such as zoledronate, are the main class of drugs used for the prevention of osteoporotic fractures and the management of cancer-associated bone disease. However, long-term or high-dose use has been associated with certain adverse drug effects, such as osteonecrosis of the jaw and the loss of peripheral of blood Vγ9Vδ2 T cells, which appear to be linked to drug-induced immune dysfunction. In this report we show that neutrophils present in human peripheral blood readily take up zoledronate, and this phenomenon is associated with the potent immune suppression of human peripheral blood Vγ9Vδ2 T cells. Furthermore, we found this zoledronate-mediated inhibition by neutrophils could be overcome to fully reconstitute Vγ9Vδ2 T cell proliferation by concomitantly targeting neutrophil-derived hydrogen peroxide, serine proteases, and arginase I activity. These findings will enable the development of targeted strategies to mitigate some of the adverse effects of n-BP treatment on immune homeostasis and to improve the success of immunotherapy trials based on harnessing the anticancer potential of peripheral blood γδ T cells in the context of n-BP treatment.