Cellular and molecular mechanisms of action of bisphosphonates

Rogers, Michael J.; Gordon, Sharon; Benford, Helena L.; Coxon, Fraser P.; Luckman, Steven P.; Mönkkönen, Jukka; Frith, Julie C.

doi:10.1002/1097-0142(20000615)88:12+<2961::aid-cncr12>3.3.co;2-c

Cited by 427 publications

(456 citation statements)

References 107 publications

Supporting

Mentioning

434

Contrasting

Unclassified

Order By: Relevance

“…At both 6 weeks and 12 weeks post-surgery, the net bone volume (BV, mm 3 ) and tissue volume (TV, mm 3 ) in the BP and PTH þ BP-treated groups was significantly greater compared with the saline control group (p < 0.01). PTH treatment had no effect on BV or TV in the BP-treated fracture groups at either time point (Fig.…”

Section: Pth (1-34) Distribution and Remobilization Of Bp In Fracturementioning

confidence: 94%

“…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%

See 1 more Smart Citation

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

Murphy

Schindeler

Cantrill

et al. 2014

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

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.

show abstract

Section: Pth (1-34) Distribution and Remobilization Of Bp In Fracturementioning

confidence: 94%

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

View full text Add to dashboard Cite

show abstract

“…Biphosphonates inhibit osteoclast-mediated bone resorption in vivo by several routes. They have a direct effect on bone resorption by impairing the osteoclast function and inducing osteoclast apoptosis [63]. Denosumab inhibits the osteoclast function by inhibiting the RANK-RANKL pathway [64].…”

Section: Onjmentioning

confidence: 99%

The use of low-level light therapy in supportive care for patients with breast cancer: review of the literature

et al. 2016

View full text Add to dashboard Cite

Breast cancer is the most common cancer in women worldwide, with an incidence of 1.7 million in 2012. Breast cancer and its treatments can bring along serious side effects such as fatigue, skin toxicity, lymphedema, pain, nausea, etc. These can substantially affect the patients' quality of life. Therefore, supportive care for breast cancer patients is an essential mainstay in the treatment. Low-level light therapy (LLLT) also named photobiomodulation therapy (PBMT) has proven its efficiency in general medicine for already more than 40 years. It is a noninvasive treatment option used to stimulate wound healing and reduce inflammation, edema, and pain. LLLT is used in different medical settings ranging from dermatology, physiotherapy, and neurology to dentistry. Since the last twenty years, LLLT is becoming a new treatment modality in supportive care for breast cancer. For this review, all existing literature concerning the use of LLLT for breast cancer was used to provide evidence in the following domains: oral mucositis (OM), radiodermatitis (RD), lymphedema, chemotherapy-induced peripheral neuropathy (CIPN), and osteonecrosis of the jaw (ONJ). The findings of this review suggest that LLLT is a promising option for the management of breast cancer treatment-related side effects. However, it still remains important to define appropriate treatment and irradiation parameters for each condition in order to ensure the effectiveness of LLLT.

show abstract

“…These isoprenoids are requisite for posttranslation lipid modification (i.e., farnesylation and geranylgeranylation) of signaling GTPases, such as Ras, Rho and Rac. 6 As these control a variety of important osteoclast cell functions, their loss ultimately leads to osteoclast apoptosis through caspase-3 enzyme activation. 7 In addition to their inhibitory effect on osteoclasts, there is increasing preclinical data to indicate that bisphosphonates have direct antitumor activity.…”

mentioning

confidence: 99%

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

Neville-Webbe

Rostami‐Hodjegan

Evans

et al. 2004

Intl Journal of Cancer

146

104

View full text Add to dashboard Cite

We investigated whether the combination of zoledronic acid and doxorubicin induced apoptosis of breast and prostate cancer cell lines, and if synergistic interaction was present. We investigated whether the levels of cell death altered depending on the sequence in which the drugs were administered and the possible mechanism of action responsible for the increased cell death following combined treatments. Breast and prostate cancer cells were treated with zoledronic acid alone, doxorubicin alone, or drugs in sequence (doxorubicin before, after, or with zoledronic acid), and the levels of apoptotic death were determined by evaluation of nuclear morphology. We found that clinically relevant concentrations of doxorubicin and zoledronic acid induced sequence-and schedule-dependent apoptosis of breast and prostate cancer cells. For maximal apoptosis, cells had to be pretreated for 24 hr with doxorubicin before immediate treatment with zoledronic acid for 1 hr. This observation is a characteristic feature of cell cycle phase-specific synergistic effect. Replacing zoledronic acid with the nonnitrogen-containing bisphosphonate clodronate did not induce increased apoptosis. Induction of apoptosis was mainly via inhibition of the mevalonate (MVA) pathway, as addition of the MVA pathway intermediary geranylgeraniol inhibited the induction of apoptosis by doxorubicin followed by zoledronic acid. In conclusion, combined treatment of breast and prostate cancer cell lines with clinically relevant doses of doxorubicin and zoledronic acid induces apoptosis in a synergistic fashion. These findings may have relevance for the clinical setting, particularly breast cancer patients receiving these drugs in the adjuvant setting.Key words: breast cancer; apoptosis; zoledronic acid; doxorubicin; synergistic interaction Zoledronic acid is a potent third-generation nitrogen-containing bisphosphonate and is the only bisphosphonate licensed to treat bone metastases from a variety of solid tumors and in multiple myeloma. In clinical practice, an increasing number of breast and prostate cancer patients are receiving zoledronic acid at earlier stages of their treatment in order to manage their metastatic bone disease.Zoledronic acid inhibits osteoclastic bone resorption, which occurs at an accelerated pace due to the presence of tumor cells in the bone microenvironment. 1 Nitrogen-containing bisphosphonates affect osteoclast action by inhibition of enzymes of the mevalonate pathway. 2 Target enzymes include farnesyl pyrophosphate synthase 3,4 and/or geranylgeranylpyrophosphate synthase, 5 leading to a lack of formation of farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These isoprenoids are requisite for posttranslation lipid modification (i.e., farnesylation and geranylgeranylation) of signaling GTPases, such as Ras, Rho and Rac. 6 As these control a variety of important osteoclast cell functions, their loss ultimately leads to osteoclast apoptosis through caspase-3 enzyme activation. 7 In addition to their inhibitory effect on osteocl...

show abstract

Cellular and molecular mechanisms of action of bisphosphonates

Abstract: Bisphosphonates are highly effective inhibitors of bone resorption that selectively affect osteoclasts. After more than 30 years of clinical use, their molecular mechanisms of action are only just becoming clear.

Cited by 427 publications

References 107 publications

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

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

The use of low-level light therapy in supportive care for patients with breast cancer: review of the literature

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

Contact Info

Product

Resources

About