Bisphosphonates: mechanisms of action.

Rodan, Gideon A.; Fleisch, H.

doi:10.1172/jci118722

Cited by 759 publications

(554 citation statements)

References 46 publications

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“…Bisphosphonate treatment increases bone mineral density due to decreased bone turnover at the tissue level, with osteoclast proliferation and recruitment of osteoclast precursors inhibited at the cellular level [26][27][28]. It was recently reported that treatment with zolendronate (ZA) exerted an antiproliferative effect on immortalized human fetal osteoblast cells and enhanced differentiation and bone-forming activities [29].…”

Section: Discussionmentioning

confidence: 99%

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

Pettway

Meganck

Koh

et al. 2008

Bone

107

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PTH (1-34) is the only FDA-approved anabolic agent for osteoporosis treatment in the U.S., but its mechanisms are not completely understood. This study investigated PTH effects on osteogenic cells at various stages of differentiation and proliferation using an engineered bone growth model in vivo. Ossicles were generated from bone marrow stromal cells (BMSCs) implanted in immunocompromised mice. Three weeks of PTH (40μg/kg/d) or vehicle treatment initiated 1 day, 1, 2, or 3wks after BMSC implantation resulted in an anabolic response in PTH-treated implants (via histomorphometry and microCT) in all treatment groups. A novel in vivo tracking strategy with luciferase tagged BMSCs and weekly bioluminescent imaging of ossicles revealed increased donor cell proliferation in PTH-treated ossicles. The greatest increase occurred during the first week, and the activity remained elevated in PTH-treated implants over time. Zoledronic acid (ZA) was combined with PTH to delineate interactive mechanisms of these bone active agents. Combining ZA with PTH treatment reduced the PTH-mediated increase in luciferase BMSC activity, serum osteocalcin, and serum tartrate resistant acid phosphotase-5b (TRAP-5b) but ZA did not reduce the PTH-induced increase in total bone. Since zoledronic acid reduced PTH-induced proliferation without reducing bone volume, these data suggests that combining PTH and bisphosphonate therapy warrants further investigation in the treatment of bone disorders.

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Section: Discussionmentioning

confidence: 99%

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

Pettway

Meganck

Koh

et al. 2008

Bone

107

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“…The most prominent and most clearly understood action of BPs is to suppress the initiation of osteoclast activity [1,2]. By suppressing osteoclast activity, the number of active bone remodeling sites is reduced although BPs have also been shown to significantly reduce the size of the resorption cavities that form [3] (Fig 1).…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Bisphosphonate effects on bone turnover, microdamage, and mechanical properties: What we think we know and what we know that we don't know

Allen

Burr

2011

Bone

195

159

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This is the author's manuscript of the article published in final edited form as: Allen M. R., Burr D.B. (2011 A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT AbstractThe bisphosphonates (BPs) have been useful tools in our understanding of the role that bone remodeling plays in skeletal health. The purpose of this paper is to outline what we know, and what is still unknown, about the role that BPs play in modulating bone turnover, how this affects microdamage accumulation, and ultimately what the effects of these changes elicited by BPs are to the structural and the material biomechanical properties of the skeleton. We know thatBPs suppress remodeling site-specifically, probably do not have a direct effect on formation, and that the individual BPs vary with respect to speed of onset, duration of effect and magnitude of suppression. However, we do not know if these differences are meaningful in a clinical sense, how much remodeling is sufficient, the optimal duration of treatment, or how long it takes to restore remodeling to pre-treatment levels. We also know that suppression is intimately tied to microdamage accumulation, which is also site-specific, that BPs impair targeted repair of damage, and that they can reduce the energy absorption capacity of bone at the tissue level.However, the BPs are clearly effective at preventing fracture, and generally increase bone mineral density and whole bone strength, so we do not know whether these changes in damage accumulation and repair, or the mechanical effects at the tissue level, are clinically meaningful.The mechanical effects of BPs to the fatigue life of bone, or BP effects on bone subject to an impact, are entirely unknown. This paper reviews the literature on these topics, and identifies gaps in knowledge that can be addressed with further research.

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“…1). As such, they have been shown to be efficacious in preventing osteoclast-mediated osteolytic bone disease in several different malignancies.…”

Section: Introductionmentioning

confidence: 99%

In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates

Aparicio¹,

Gardner²,

Tu³

et al. 1998

Leukemia

241

117

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In a double blind randomized study, the bisphosphonate drug Pamidronate (Aredia) significantly protected Durie-Salmon stage III multiple myeloma patients from osteolytic bone disease. In the patient sub-group on salvage chemotherapy. Pamidronate treatment was also significantly associated with prolonged survival. To test if this drug could induce direct antitumor effects, we exposed myeloma cells to increasing concentrations of Pamidronate or a more potent bisphosphonate, Zoledronate. A concentration-and time-dependent cytotoxic effect was detected on four of five myeloma cell lines as well as three specimens obtained directly from myeloma patients. Zoledronate-induced cytotoxicity was significantly greater than that of Pamidronate. Cytotoxicity could not be explained by bisphosphonate-induced chelation of extracellular calcium or secondary decrease in production of the myeloma growth factor interleukin-6. Morphological examination, DNA electrophoresis and cell cycle analysis indicated that the bisphosphonate-induced cytotoxic effect consisted of a combination of cytostasis and apoptotic myeloma cell death. Enforced expression of BCL-2 protected against the apoptotic death but not against cytostasis. Most cytotoxic effects were seen between 10 and 100 M of drug. The results suggest a possible direct anti-tumor effect in myeloma patients treated with bisphosphonates which may participate in their significantly increased survival. This hypothesis should now be further tested in clinical trials.

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Bisphosphonates: mechanisms of action.

Cited by 759 publications

References 46 publications

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

Bisphosphonate effects on bone turnover, microdamage, and mechanical properties: What we think we know and what we know that we don't know

In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates

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