Biochemical and molecular mechanisms of action of bisphosphonates

Rogers, Michael J.; Crockett, Julie C.; Coxon, Fraser P.; Mönkkönen, Jukka

doi:10.1016/j.bone.2010.11.008

Cited by 440 publications

(404 citation statements)

References 94 publications

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“…By way of contrast, treatment with a bisphosphonate is known to induce a change to osteoclast cell morphology and eventual cell death. 19 Thus, ALN reduces the amount of bone resorption, but also indirectly lowers the activity of cathepsin-K enzyme, which is consistent with observation that ALN treatment partially prevents changes to Type I collagen microstructure. Recently, Reznikov et al 20 reported that the human lamellar bone consists of two different materials that differ substantially in terms of collagen fibril order.…”

Section: Resultssupporting

confidence: 89%

Alteration of Type I collagen microstructure induced by estrogen depletion can be prevented with drug treatment

Cauble¹,

Rothman²,

Welch³

et al. 2015

BoneKEy Reports

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Two independent biological replicates of estrogen depletion were employed with differing drug treatment conditions. Data Set I consisted of 9-month-old New Zealand white female rabbits treated as follows: sham-operated (n ¼ 11), ovariectomized (OVX; n ¼ 12), OVX þ 200 mg kg À 1 alendronate (ALN), 3 Â a week for 27 weeks (n ¼ 12) and OVX þ 10 mg kg À 1 Cathepsin-K inhibitor (CatKI) daily for 27 weeks. Data Set II consisted of 6-month-old New Zealand white female rabbits that were sham-operated (n ¼ 12), OVX (n ¼ 12) or OVX þ 0.05 mg kg À 1 17b-estradiol (ERT) 3 Â a week for 13 weeks (n ¼ 12). Samples from the cortical femur were polished and demineralized to make them suitable for atomic force microscopy (AFM) imaging. Type I collagen fibrils present in bundles or sheets, running parallel to each other, were combined into a class termed Parallel. Fibrils present outside of such structures, typically in images with an angular range of non-parallel fibrils, were combined into a class termed Oblique. The percentage of fibrils coded as Parallel for Sham animals in Data Sets I and II was 52% and 53%, respectively. The percentage of fibrils coded as Parallel for OVX animals in Data Sets I and II was 35% in both cases. ALN and ERT drug treatments reduced the change from 18 to 12%, whereas CatKI treatment reduced the change to 5%.

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Section: Resultssupporting

confidence: 89%

Alteration of Type I collagen microstructure induced by estrogen depletion can be prevented with drug treatment

Cauble¹,

Rothman²,

Welch³

et al. 2015

BoneKEy Reports

View full text Add to dashboard Cite

show abstract

“…Both in vitro and in vivo assays were carried out with dose-dependent zoledronate sensitizations of a GBM cell line and primary human GBM cells in order to trigger strong Vg9Vd2 T cell recognition, as already used for enhancing such reactivities in other oncological contexts. 38 Phase I/II trials 39 have shown that zoledronate, indicated for other human pathologies (eg. osteoporosis, multiple myeloma), 40 leads to significant IL-2-dependent gd T cell expansions, correlating to partial or complete clinical responses, thus indicating the feasibility and efficacy of this approach in some cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Stereotaxic administrations of allogeneic human Vγ9Vδ2 T cells efficiently control the development of human glioblastoma brain tumors

et al. 2016

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“…Nitrogen-containing BPs (N-BPs) are selectively taken up by osteoclasts, where they inhibit the intracellular enzyme FPP synthase and disrupt cell function. (1)(2)(3) BP treatment can lead to increases in bone mineral density and significant reductions in fracture risk. BPs are a frontline intervention for osteoporosis, and at-risk individuals remain on these drugs for many years if not for the remainder of their lives.…”

Section: Introductionmentioning

confidence: 99%

PTH(1-34) Treatment Increases Bisphosphonate Turnover in Fracture Repair in Rats

Murphy

Schindeler

Cantrill

et al. 2014

Journal of Bone and Mineral Research

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Bisphosphonates (BP) are antiresorptive drugs with a high affinity for bone. Despite the therapeutic success in treating osteoporosis and metabolic bone diseases, chronic BP usage has been associated with reduced repair of microdamage and atypical femoral fracture (AFF). The latter has a poor prognosis, and although anabolic interventions such as teriparatide ) have been suggested as treatment options, there is a limited evidence base in support of their efficacy. Because PTH acts to increase bone turnover, we hypothesized that it may be able to increase BP in turnover in the skeleton, which, in turn, may improve bone healing. To test this, we employed a mixture of fluorescent Alexa647-labelled pamidronate (Pam) and radiolabeled 14 C-ZA (zoledronic acid). These traceable BPs were dosed to Wistar rats in models of normal growth and closed fracture repair. Rats were cotreated with saline or 25 mg/kg/d PTH , and the effects on BP liberation and bone healing were examined by X-ray, micro-CT, autoradiography, and fluorescent confocal microscopy. Consistent with increased BP remobilization with PTH , there was a significant decrease in fluorescence in both the long bones and in the fracture callus in treated animals compared with controls. This was further confirmed by autoradiography for 14 C-ZA. In this model of acute BP treatment, callus bone volume (BV) was significantly increased in fractured limbs, and although we noted significant decreases in callus-bound BP with PTH (1-34) , these were not sufficient to alter this BV. However, increased intracellular BP was noted in resorbing osteoclasts, confirming that, in principle, PTH increases bone turnover as well as BP turnover.

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Biochemical and molecular mechanisms of action of bisphosphonates

Cited by 440 publications

References 94 publications

Alteration of Type I collagen microstructure induced by estrogen depletion can be prevented with drug treatment

Alteration of Type I collagen microstructure induced by estrogen depletion can be prevented with drug treatment

Stereotaxic administrations of allogeneic human Vγ9Vδ2 T cells efficiently control the development of human glioblastoma brain tumors

PTH(1-34) Treatment Increases Bisphosphonate Turnover in Fracture Repair in Rats

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