No anti-angiogenic effect of clinical dosing regimens of a single zoledronic acid injection in an experimental bone healing site

Vieillard, Marie-Hélène; Cortet, Bernard; Salleron, Julia; Falgayrac, Guillaume; Penel, Guillaume

doi:10.1016/j.bone.2009.10.034

Cited by 13 publications

(8 citation statements)

References 27 publications

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“…Therefore, the vascular effects of bisphosphonates were seen as potentially involved in the pathophysiology of the bisphosphonate‐related osteonecrosis of the jaw (the avascular theory). In a bone‐remodeling situation such as OVX‐induced bone loss, we did not observe any reduction in tibia bone marrow vessel density after zoledronate at anti‐osteoporotic dose, in line with previous work in unchallenged animals . Furthermore, we observed an unexpected ability of zoledronate to prevent the OVX‐induced reduction in blood perfusion, consistent with one clinical study in which Frost and colleagues, using Pet Scan in osteoporotic women, showed no negative impact of a 6‐month treatment with risedronate on vertebral perfusion.…”

Section: Discussionsupporting

confidence: 91%

“…In a bone-remodeling situation such as OVX-induced bone loss, we did not observe any reduction in tibia bone marrow vessel density after zoledronate at anti-osteoporotic dose, in line with previous work in unchallenged animals. (46,47) Furthermore, we observed an unexpected ability of zoledronate to prevent the OVX-induced reduction in blood perfusion, consistent with one clinical study in which Frost and colleagues, (48) using Pet Scan in osteoporotic women, showed no negative impact of a 6-month treatment with risedronate on vertebral perfusion. Interestingly, Kaczmarczyk-Sedlak and colleagues (49) showed evidence of a potential direct effect of pamidronate on bone marrow vasoregulation.…”

Section: Journal Of Bone and Mineral Researchsupporting

confidence: 88%

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Parathyroid Hormone 1-84 Targets Bone Vascular Structure and Perfusion in Mice: Impacts of Its Administration Regimen and of Ovariectomy

Roche

Vanden‐Bossche

Malaval

et al. 2014

Journal of Bone and Mineral Research

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Bone vessel functions during bone remodeling are poorly understood. They depend on both vessel network structure and vasomotor regulation. Parathyroid hormone (PTH) is a systemic vasodilator that may modulate microvascularization. Moreover, although intermittent PTH is anti-osteoporotic, continuous PTH administration can be catabolic for bone. Finally, ovariectomy (OVX) reduces bone perfusion and vessel density in mice. We reasoned that the effects of PTH on bone vascularization might depend on its administration regimen and be impacted by ovariectomy. A 100-mg/kg PTH 1-84 daily dose was administered for 15 days to 4-monthold female C57BL/6 mice, either as daily sc injection (iPTH) or continuously (cPTH; ALZET minipump). Blood pressure (BP) and tibia bone perfusion were measured in vivo with a laser Doppler device. Histomorphometry of bone and barium-contrasted vascular network were performed on the same tibia. Compared with untreated controls, both iPTH and cPTH increased bone formation but had opposite effects on resorption. Both iPTH and cPTH were slightly angiogenic. Intermittent PTH increased microvessel size (þ48%, p < 0.001), whereas cPTH decreased it (-29%, p ¼ 0.009). iPTH increased bone perfusion (27%, p < 0.001) with no change in BP, whereas cPTH did not. The vascular effects of a 15-day iPTH treatment were analyzed in OVX mice and compared with sham-operated and OVX untreated controls. Two other anti-osteoporotic drugs, zoledronate (one injection, 70 mg/kg) and propranolol, (5 mg/kg/d) were tested in OVX mice. Although no change in bone mass was observed, iPTH stimulated bone formation and prevented the OVX-induced reduction in bone perfusion and vessel density. Both zoledronate and propranolol strongly lowered bone turnover, but surprisingly, zoledronate prevented OVX-induced reduction in bone perfusion but propranolol did not. Our integrative approach thus demonstrates that the effects of PTH on bone vessel structure and function depend on its mode of administration as well as on the HPG-axis hormonal status, and that OVX-induced vascular changes are prevented by iPTH.

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Section: Discussionsupporting

confidence: 91%

Section: Journal Of Bone and Mineral Researchsupporting

confidence: 88%

Parathyroid Hormone 1-84 Targets Bone Vascular Structure and Perfusion in Mice: Impacts of Its Administration Regimen and of Ovariectomy

Roche

Vanden‐Bossche

Malaval

et al. 2014

Journal of Bone and Mineral Research

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“…These differences indicate that Bps could exert a dose‐dependent effect on vascularization, and no anti‐angiogenic effect is observed with clinical dosing regimens (Biver et al . ). Furthermore, considering that at 3 days no differences in the degree of vascularization were found in either group, the 8‐week pretreatment with ALN did not seem to interfere significantly with angiogenesis, at least in this phase.…”

Section: Discussionmentioning

confidence: 97%

Experimental development of bisphosphonate‐related osteonecrosis of the jaws in rodents

Neto

Spolidório

Andrade

et al. 2013

Int J Experimental Path

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Osteonecrosis of the jaw (ONJ) following the use of bisphosphonates has become of increased interest in the scientific community, due in particular to its as-yet-unsolved pathogenesis. An experimental model of ONJ was induced in normal male rats [alendronate (ALN); 1 mg/Kg/day; n = 10] and matched controls (saline solution; n = 10). After 60 days of drug treatment, all animals were subjected to extractions of the left first lower molars and were euthanized at 3 and 28 days postsurgery. The following analyses were performed: (i) descriptive and quantitative (scores) histological evaluation, (ii) stereometry of distal sockets and (iii) biochemical measurement of C-telopeptide cross-linked collagen type I (CTX) and bone-specific alkaline phosphatase (BALP). The results showed that 28 days postsurgery the animals treated with ALN had areas of exposed and necrotic bone, associated with significant infection, especially in the interalveolar septum area and crestal regions, compared with controls. The levels of CTX, BALP and bone volume, as well as the degrees of inflammation and vascularization, were significantly reduced in these animals. Therefore, analysis of the data presented suggests that ALN therapy is associated with the development of osteonecrosis in the jaws of rodents after tooth extraction.

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“…Moreover, cancer patients demonstrate decreased levels of circulating vascular endothelial growth factor (VEGF) following zoledronate treatment, suggesting an inhibitory effect on angiogenesis [53]. However, this effect seems to be restricted to individuals receiving multiple doses of bisphosphonate, as no inhibition of angiogenesis is seen in a single-dose zoledronate model in rats mimicking once yearly injections administered for osteoporosis treatment [54]. Therefore, although the effect is likely dose-and time-dependent, bisphosphonates clearly inhibit VEGF and angiogenesis.…”

Section: Angiogenesis Is Inhibited By Bisphosphonate Administrationmentioning

confidence: 96%

Bisphosphonates and Osteonecrosis of the Jaws: A Review of Clinical Features and the Drug Effect on Oral Soft Tissues

Kramer

Fantasia

2011

Clinic Rev Bone Miner Metab

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The beneficial effects of the nitrogen-containing bisphosphonate drugs have been clearly defined, especially for the treatment for osteoporosis, metastatic or primary bone malignancies, and some rare bone diseases. The adverse effects of these drugs on oral hard and soft tissues are significant and recognized with increasing frequency. The clinical, radiographic, and histopathologic features of osteonecrosis of the jaws (ONJ) are well characterized; the effects of bisphosphonates on oral soft tissues are an emerging area of study. This review will provide an overview of ONJ from a clinical perspective and also discuss recent findings related to bisphosphonateinduced soft tissue pathology.

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No anti-angiogenic effect of clinical dosing regimens of a single zoledronic acid injection in an experimental bone healing site

Cited by 13 publications

References 27 publications

Parathyroid Hormone 1-84 Targets Bone Vascular Structure and Perfusion in Mice: Impacts of Its Administration Regimen and of Ovariectomy

Parathyroid Hormone 1-84 Targets Bone Vascular Structure and Perfusion in Mice: Impacts of Its Administration Regimen and of Ovariectomy

Experimental development of bisphosphonate‐related osteonecrosis of the jaws in rodents

Bisphosphonates and Osteonecrosis of the Jaws: A Review of Clinical Features and the Drug Effect on Oral Soft Tissues

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