Bisphosphonates in bone cement inhibit PMMA particle induced bone resorption

OBJECTIVE—Wear particle induced bone resorption is thought to be one of the mechanisms that contribute to implant loosening. It has previously been shown that macrophages, in response to polymethylmethacrylate (PMMA) particles, differentiate into bone resorbing osteoclasts, and that this process is inhibited by a bisphosphonate, etidronate (EHDP). The aim of this study was to determine whether incorporating EHDP in bone cement could reduce PMMA associated bone resorption.
METHODS—Two concentrations of EHDP were mixed with PMMA monomer before polymerisation. Particles of PMMA (1-10 µm) were generated then added to mouse monocytes cocultured with UMR106 rat osteoblast-like cells and the extent of osteoclast differentiation was determined by assessing the extent of tartrate resistant acid phosphatase (TRAP) staining and measuring the amount of lacunar bone resorption.
RESULTS—The addition of PMMA to monocyte-UMR106 cocultures resulted in a marked increase in the number of TRAP positive osteoclast-like cells and a significant increase in the number of lacunar resorption pits compared with control cultures to which no particles had been added. After the addition of particles of PMMA + 20 mg EHDP, significantly fewer lacunar pits (p=0.00006) and fewer TRAP positive cells were noted compared with cocultures containing PMMA particles alone.
CONCLUSIONS—These results indicate that by mixing a bisphosphonate with bone cement, it is possible to inhibit PMMA particle induced bone resorption. This bisphosphonate inhibition of PMMA biomaterial wear particle containing macrophage-osteoclast differentiation and bone resorption may provide a possible therapeutic strategy to prevent or to control the osteolysis of aseptic loosening.

Keywords: bisphosphonate; bone resorption; aseptic loosening; macrophages     

Bisphosphonates

Osteoporosis is the result of bone loss due to an imbalance in bone turnover such that bone resorption exceeds bone formation. Bisphosphonates are potent inhibitors of osteoclast activity that reduce bone turnover and re-establish the balance between bone resorption and formation. In clinical studies, several bisphosphonates prevent bone loss, preserve bone structure, improve bone strength and, in patients with osteoporosis, substantially reduce fracture risk. They are effective in multiple clinical settings including postmenopausal osteoporosis, low bone mass in men and drug-induced bone loss. Intermittent oral dosing and intravenous administration are more convenient than the original daily dosing regimen. These drugs are generally well tolerated and have an excellent safety profile in that serious side effects are uncommon. Potent bisphosphonates are generally the preferred treatment option for most patients with or at risk for osteoporosis.     

Bisphosphonates

After the development of potent bisphosphonates including alendronate and risedronate, evidence has accumulated that not only vertebral but also non-vertebral fractures can be prevented by these agents. In addition, numbers needed to treat for both vertebral and non-vertebral fractures by alendronate and risedronate are around 30 to 90. Thus, these agents are expected to improve the socio-economical situation of osteoporosis treatment as well as the survival and quality of life of osteoporotic patients. Once-a-week oral bisphosphonates and long-acting intravenous formula that can successfully inhibit bone resorption for 3 months or longer are also under development. Although PTH and alendronate treatment in combination did not show much beneficial effects, there are results showing additive effect of sequential treatment with PTH followed by alendronate. From these studies, we can expect even better prospect for osteoporosis treatment by choosing from or sequentially combining these different modality of therapies.     

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双膦酸盐是治疗骨质疏松的主要药物,其有2个经典的药理作用:与骨骼的矿盐成分有很高的结合能力以及抑制破骨细胞活性。双膦酸盐的P-C-P化学基本结构相同,但因侧链联接不同化学基团而有不同的临床作用方式和效果,由于彼此化学结构、生化特点和药理作用的差异,各双膦酸盐在作用发挥的速度、时间、骨骼效用持续时间和降低骨折率方面也会有差异。含氮原子的作用强于不含氮原子的双膦酸盐,含氮原子双膦酸盐包括阿仑膦酸盐、利塞膦酸盐、依班膦酸盐、唑来膦酸盐等主要通过甲羟戊酸代谢途径,抑制法尼基焦磷酸盐合成酶,阻抑破骨细胞活性所需的小分子信号蛋白,抑制破骨细胞活性;非含氮原子双膦酸盐主要通过抑制能量代谢抑制破骨细胞活性。治疗骨质疏松应用双膦酸盐总体安全,副反应少,有些罕见的并发症是否有直接相关,仍需进一步观察。     

Metabolic bone disease and bone quality

On the progress of study concerned with pathology of metabolic bone disease such as osteoporosis, it has been known that most of bone strength can be explained by bone volume. As bone volume can be determine by bone mineral density (BMD) with dual-energy X-ray absorptiometry (DXA), it has been widely used for diagnosis of osteoporosis or efficacy of treatment. However, with the advance of bone morphometry, decrease of bone strength or existence of insufficiency fracture is influenced by not only loss of BMD but also deterioration of bone quality especially bone microstructure. In this chapter, we will give an outline of change of bone quality in metabolic bone disease.     

Bisphosphonates.

Bisphosphonates now occupy a prominent position among therapeutic options for the prevention and treatment of various forms of osteoporosis. Their clinical profile of bone-specific efficacy, rapid response, protection from both spine and hip fractures in patients with osteoporosis, and excellent tolerability is all that can be expected of an anti-remodeling drug. Even in the era of anabolic agents, bisphosphonates will continue to be important treatment options. It is not possible to compare or contrast the clinical effectiveness of the various bisphosphonates on the basis of existing data. Despite marked differences in the in vitro potency of drugs, the clinical responses to each of the bisphosphonates discussed above are similar. New bisphosphonates may not be more effective but will provide different tolerability profiles and different routes of administration, thereby increasing the number of patients in whom bisphosphonates can be used. Having these effective agents challenges clinicians to identify the most appropriate patients for bisphosphonate use and to develop strategies to improve acceptance of and adherence to these useful agents.     

Bisphosphonates and adhesion molecules

Bisphosphonates are highly effective inhibitors of osteoclastic bone resorption. They can be divided into two groups with distinct mechanisms of action. The nitrogen-containing bisphosphonates (pamidronate, alendronate, risedronate, incadronate etc) can inhibit the mevalonate pathway in osteoclasts and inhibit protein prenylation of small G proteins including Rho, which might lead to alter cytoskeletal organization and cell motility. Others, like etidronate and clodronate, do not inhibit protein prenylation and can be incorporated into ATP-containing compounds that may be cytotoxic to osteoclasts. Further studies would be required to elucidate the molecular mechanism of bisphosphonate actions.     

Microdamage and bone quality

Fatigue occurs in every material under repetitive loading. Because bone is also being loaded under physiological condition, fatigue also occurs in bone and it is observed as microdamages under light microscope. However, in vivo bone is different from that ex-vivo. It is strongly suggests that in vivo microdamage is repaired by bone remodeling. Once generation and repair of microdamage is imbalanced, microdamage accumulates in bone and causes fatigue fracture.     

Aging and bone quality

At the research level, various factors have been correlated with changes in bone quality that underlie age-associated fragility. On the other hand, biochemical markers and imaging technology that can faithfully assess bone quality and are applicable to clinical practice remain to be developed.     

Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption

The present experiments were carried out to test the hypothesis that artery calcification is linked to bone resorption by determining whether the selective inhibition of bone resorption with the bisphosphonates alendronate and ibandronate will inhibit artery calcification. Artery calcification was first induced by treatment of 42-day-old male rats with warfarin, a procedure that inhibits the gamma-carboxylation of matrix Gla protein and has been shown to cause extensive calcification of the artery media within 2 weeks. These experiments revealed that ibandronate (0.05 mg. kg(-1). d(-1)) and alendronate (0.1 mg x kg(-1) x d(-1)) completely inhibited calcification of all arteries and heart valves examined after 2 and 4 weeks of warfarin treatment. A 10-fold lower dose of alendronate reduced artery calcification by 50% (P<0.005). These bisphosphonate doses are comparable to those that inhibit bone resorption in rats of this age. More rapid artery calcification was induced by treatment with warfarin together with high doses of vitamin D, a procedure that causes extensive artery calcification by 84 hours. Alendronate and ibandronate again completely inhibited calcification of all arteries and heart valves examined. The subcutaneous doses of alendronate and ibandronate necessary to inhibit artery calcification are comparable to the daily subcutaneous doses of these drugs that have previously been shown to inhibit bone resorption in rats of the same age, with 50% inhibition of artery calcification at 20 microg alendronate x kg(-1) x d(-1) and at 1 microg ibandronate x kg(-1) x d(-1) x Bisphosphonate treatment did not affect serum calcium and phosphate, and so the inhibition of artery calcification cannot be due to a simple lowering of the serum calcium phosphate ion product. We conclude that bisphosphonates inhibit the calcification of arteries and heart valves at doses comparable to the doses that inhibit bone resorption. These results support the hypothesis that artery calcification is linked to bone resorption. The mechanism of this linkage remains to be established, however, and an alternative explanation for the present results is also considered.     

Bone structure and bone quality

Bone strength is determined by bone mineral density, geometry of bone, microarchitecture of bone and quality of bone material. Recent data have shown that the prediction of bone strength can be greatly improved by including parameters of bone structure in the analysis. However, the relative importance of bone density and architecture in the etiology of bone fractures, an issue referred to as bone quality, is poorly understood. The challenge for the future will be to evaluate bone quality in vivo with the same or better accuracy than the invasive methods in use today.     

Vitamin K and bone quality

Dietary vitamin K intakes becomes reduced with aging. Low vitamin K intakes are associated with an increased incidence of hip fractures and an increase of under carboxylated osteocalcin in elderly men and women. The increase of under carboxylated osteocalcin is a risk factor for fractures in osteoporosis. Vitamin K2 treatment is effective for the prevention of fractures, but not for the increase of bone mineral density in osteoporosis. Vitamin K2 administration could be a potential treatment to improve the bone quality.     

Raloxifene and bone quality issues

With advances in clinical research in osteoporosis management, there has occurred a shift in therapeutic endpoints in osteoporosis from enhancement of BMD (bone mineral density) to prevention of bone fractures. Of note in this connection is the observation that fluoride therapy was associated with significant increases in BMD but was not preventive of bone fractures;on the other hand, raloxifene, while not as effective as bisphosphonate in increasing BMD, was preventive of bone fractures to a degree comparable to bisphosphonate therapy. This finding suggested that there should be more factors implicated in preventing bone fractures than increasing BMD, pointing to the importance of bone quality, as had been speculated in earlier studies. Thus, raloxifene has contributed in no small way towards advancing osteoporosis management. But in the same breath, the issue of bone quality still remains to be further explored, and further advances in both basic and clinical research are required to elucidate what it is that constitutes bone quality, as well as to establish a methodology for the assessment of bone quality.     

Vitamin D and bone quality

Active vitamin D analogs such as alfacalcidol have been shown to reduce fracture risk in clinical trials in spite of its moderate effects on bone mass. It has been reported that active vitamin D analogs may improve bone quality, by amelioration of bone microarchitecture, by specific effect on cortical bones, by acceleration of calcification, and by effect on nature of bone matrix proteins. The bone quality assessments that clarify the effect on bone mechanical properties will become important for the positioning of osteoporosis drugs.     

Secondary osteoporosis and bone quality

In secondary osteoporosis, rheumatoid arthritis patients showed high bone turnover and the same cut-off value in bone mineral density as postmenopausal osteoporosis. On the other hand, Glucocorticoid-induced osteoporosis showed low bone turnover and the higher cut-off value compared with postmenopausal osteoporosis. Examination about secondary osteoporosis except these conditions is needed.