The Role of Microcirculatory Disorders in the Pathogenesis of Bisphosphonate-Associated Osteonecrosis

Due to the gradual aging of the population, the share of age-associated diseases, including osteoporosis, is increasing. In addition, the main method of treating osteoporosis is the use of drugs that improve bone tissue metabolism — bisphosphonates. However, their use may be accompanied by long-term side effects, among which osteonecrosis of the jaw is highlighted. This article presents a review of the current literature on the independent role of microcirculation disorders as one of the important mechanisms in the development of bisphosphonate-associated osteonecrosis.

Due to the gradual aging of the population, the share of age-associated diseases, including osteoporosis, which affects more than 200 million people worldwide, is increasing. According to statistics, osteoporosis is diagnosed in 33.8% of women and 26.9% of men aged 50 and older in Russia, while signs of osteopenia are identified in 43.3% of women and 44.1% of men.
The main method of treating osteoporosis is bisphosphonates. The primary mechanism of their action is the suppression of osteoclast activity and, consequently, a decrease in bone tissue resorption. Bisphosphonates are drugs that improve bone tissue metabolism. However, their use may be accompanied by long-term side effects, which include early and late (delayed) complications, particularly osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw is a serious medical problem that is often encountered by maxillofacial surgeons and doctors of other specialties. In addition to the medical aspect, this disease significantly worsens the quality of life for patients receiving bisphosphonates due to the underlying condition. Given that the frequency of the latter and, consequently, bisphosphonate-related osteonecrosis is increasing every year, the relevance of this disease will only grow.
One of the important mechanisms in the development of bisphosphonate-associated osteonecrosis (BON) is the independent role of microcirculation disorders, as mentioned in several studies. However, systematic research in this area has not been conducted.

Disruption of blood flow as an important mechanism of bisphosphonate-related osteonecrosis (BON) was discussed in the pioneering work of R.E. Marx (2003), which described the jaw necrosis that occurred against the background of bisphosphonate administration. In this work, this necrosis was referred to as "avascular." The term "avascular osteonecrosis" had previously been used in traumatology, and this type of necrosis often occurs in the femoral head, with the mechanism related to blood circulation disruption being considered predominant, regardless of the cause, including in atraumatic osteonecrosis. E.V. Ilyinykh and co-authors (2013) also refer to avascular osteonecrosis as "ischemic osteonecrosis."

It is interesting to note that just a year before the description of bisphosphonate-related avascular osteonecrosis, S. Agarwala (2002) mentioned the use of bisphosphonates in the comprehensive treatment of avascular osteonecrosis of the femoral head. Currently, there is also mention of such a treatment method for the latter (S. Agarwala, 2018), as well as rare cases of osteonecrosis of the foot and shin (S. Agarwala, 2019).

Reduction of blood flow in the maxillofacial area in cases of osteonecrosis is also noted objectively when using diagnostic research methods. Thus, when studying blood pressure in the labial (upper and lower) and facial arteries using transillumination compression angiotensometry in patients with osteonecrosis of the jaw, data was obtained indicating a significant deterioration in the vascularization of the jaws, and this method is proposed by M.M. Valiev and co-authors (2018) for the early diagnosis of osteonecrosis.
Experimental studies have also provided data on the suppression of bone blood flow under the influence of bisphosphonates. When assessing the vascular bed in the mandible of rats with a bisphosphonate osteonecrosis model at different time points, after tooth extraction using micro-CT, it was noted that the administration of zoledronic acid (ZA) led to thickening of large vessels but a decrease in the number of thinner and smaller vessels necessary for adequate blood supply to this area of bone. Furthermore, the vessels of rats receiving ZA had a lower degree of anastomosis and branching, which also leads to a decrease in trophism.

In a similar study modeling bisphosphonate osteonecrosis using micro-CT, data were obtained on a significant decrease in bone blood flow in the area of osteonecrosis development after tooth extraction. In this case, the extraction of molars in the control group of rats receiving saline was accompanied by hyperemia. The role of blood flow disruption in the pathogenesis of osteonecrosis is supported by other authors who note paresis, emptiness, and even necrosis of the endothelium, leading to insufficient blood supply to the tissue and the development of aseptic osteonecrosis.

However, some data indicate that bisphosphonates affect blood flow systemically, not only in the area of the mandible. Thus, when assessing the state of microcirculation in the periosteum of the tibia during ischemia/reperfusion of the limb in rats that had previously received bisphosphonates, an increase in leukocyte adhesion was noted during reperfusion in periosteal venules. The authors suggested that the administration of bisphosphonates is accompanied by a more pronounced inflammatory reaction, which may be significant in the pathogenesis of bisphosphonate osteonecrosis. Thus, the literature data suggest endothelial damage under the influence of zoledronic acid, which subsequently leads to impaired circulation.

To confirm the role of the endothelium under the influence of bisphosphonates (BPs), we conducted a study on endothelium-dependent vasodilation and the state of bone blood flow in the mandibles of rats following the administration of zoledronic acid. Blood flow was investigated using laser and high-frequency ultrasound Dopplerography in the periodontal area, while endothelium-dependent vasodilation was assessed in the oral mucosa of rats through the application of a 3% acetylcholine solution. We noted that the administration of zoledronic acid for 3 and 6 weeks leads to a decrease in the endothelium-dependent response of blood vessels, as well as a reduction in blood flow in the bone tissue of the mandible. We suggest that it is the damage to the endothelium and the associated disruption of tissue trophism in the periodontium that are important mechanisms in the development of bisphosphonate-related osteonecrosis. To further prove the role of microvascular disruption in the development of osteonecrosis, we used the anticoagulant sulodexide both to prevent osteonecrosis and to investigate its effect on vascular reactivity and the state of microcirculation in intact periodontium.

The introduction of sulodexide not only led to a reduction in the severity of osteonecrosis but also improved blood flow, as the reactivity of the microvessels in the mucous membrane to acetylcholine application was partially restored, and blood flow in the bone tissue was almost completely restored. The data we obtained also confirm the role of the vascular component in the development of bisphosphonate osteonecrosis. Possible mechanisms of the positive action of sulodexide include not only its weak anticoagulant effect but also its influence on the state of the endothelial glycocalyx and the reduction of endothelial dysfunction severity.

Another mechanism explaining the decrease in vascularization when using bisphosphonates is their antiangiogenic effect. Thus, in vitro data show that zoledronate inhibits the proliferation of human endothelial cell cultures and accelerates their apoptosis. The antiangiogenic effect of bisphosphonates manifests at the systemic level. For instance, in the work of D. Sharma (2016), it was noted that nitrogen-containing bisphosphonates in vitro disrupt the differentiation of placental multipotent stem cells into endothelial cells, which is a manifestation of a specific action unrelated to the toxic effect of bisphosphonates. According to the authors, this action of the latter is part of a complex negative impact on angiogenesis and disrupts bone healing in cases of damage, including in BON. The role of endothelial cells in the pathogenesis of BON is apparently critical, as in experiments on rats modeling this pathology, injections of both early and late endothelial progenitor cells into the gum around the area of damage led to a significant positive effect, manifested by rapid healing and a smaller volume of necrosis. Moreover, the effect of endothelial progenitor cells, regardless of their maturity level, was significantly more pronounced than that of mesenchymal stem cells, indicating the specificity of endothelial damage caused by bisphosphonates.

Data on the anti-angiogenic effect of bisphosphonates have also been obtained in clinical studies. Thus, a pronounced (approximately twofold) decrease in the level of vascular endothelial growth factor (VEGF) even after the first administration of zoledronic acid or pamidronate, in the authors' opinion, is a predictor of subsequent development of osteonecrosis. However, the decrease in VEGF levels cannot be considered a reliable indicator of osteonecrosis. In experimental work, K.L. Marino et al. showed that in rats with a model of osteonecrosis, the level of VEGF in the blood four weeks after tooth extraction was significantly higher than in the control group. The authors suggested that the blood supply to the healing area in the experimental group was insufficient, which is why VEGF expression continued to increase, and that this was caused by the absence of released cytokines that should form with normal osteoclastic activity. These data do not refute the role of impaired blood supply as a factor in the development of osteonecrosis, but raise questions about the role of VEGF as a marker of vascular disorders.

It is assumed that the anti-angiogenic mechanism of action of bisphosphonates is partly similar to the mechanism of their anti-resorptive action, namely — through the inhibition of the activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway, however, they are also capable of inhibiting the activity of endothelial cells through an FPPS-independent pathway. According to J. Lechner et al. (2021), although the anti-angiogenic effect of bisphosphonates is important in the treatment of bone metastases as well as malignant tumors in the bones themselves, the “flip side of the coin” is the fact that, similar to the action of glucocorticoids and estrogens, bisphosphonates are “ischemic and hypoxic stressors” for bones, causing a remodeling of the jawbone metabolism and leading to impaired microcirculation in the bone marrow compartment, primarily due to thrombosis and infarctions in the territory of individual branches of the supplying artery.

It should be noted that the anti-angiogenic effect of bisphosphonates manifests differently depending on age. Experiments on mice have shown that young mice (age 4 weeks) receiving bisphosphonates do not exhibit inhibition of angiogenesis; rather, an increase in the number of small vessels in the metaphysis of the tibia was observed. This was not seen in adult mice. Considering that bisphosphonates are primarily used in middle-aged and elderly people, the anti-angiogenic effect of bisphosphonates is significant for the older age group. Thus, current data indicate the important role of impaired regional blood circulation in the development of osteonecrosis. Although the anti-angiogenic theory cannot fully explain why bone necrosis associated with bisphosphonates is usually not observed in other bones except for the jaws.

Conclusion

Despite the fact that all mechanisms of osteonecrosis development studied in modern literature are not mutually exclusive, it is evident that microcirculation disturbance is an important link in the pathogenesis of BRONJ, and influencing this link allows for the prevention of BRONJ development. The dysfunction and damage of the endothelium under the influence of bisphosphonates play a special role in the damage to the vessels of the microcirculatory bed.

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