Use of Bisphosphonates for Early AVN

Edward J. Harvey M.D., MSc, FRCSC
Associate Professor, McGill University
Co-Director: J.T.N. Wong Labs for Bone Engineering

Chantal Sguin, M.D.
Assistant Professor, Division of Haematology
McGill University Health Centre

Montreal, QC

Recent reports in the orthopaedic literature have suggested that bisphosphonates (BSPs) may be used as treatment for AVN of the hip. Despite these reports there is much to consider before opting for the use of BSP. Certainly, there are several concerns with the use of this medication. The pathology of AVN of the hip is, at best, poorly understood. There is uncertainty as to the inciting factor in AVN: hematological or bone marrow etiologies have yet to be elucidated. The mechanism of action of BSPs is also poorly understood. The exact pathway of effect on the disease process in AVN therefore is difficult to pinpoint - as both are poorly understood. Also, there are definite and reported complications associated with BSP use - the most concerning for the orthopaedic surgeon is that of an increased incidence of osteonecrosis of the jaw. We will outline just a cursory explanation of what using BSP may mean for the disease process and the patient.

Some studies have shown good early results with the use of BSP for AVN. Agarwala et al reported on sixty patients, with varied follow-up, with AVN of the hip. The most common cause of AVN was steroids. All patients were treated with alendronate 10 mg/day (or 70 mg/week) along with 500-1000 mg of daily calcium and vitamin D supplements. NSAIDs and analgesics were permitted as needed. Significant reduction in pain and disability scores and significant increase in standing and walking time were observed. Radiologically, the hips either stabilized or progressed by one grade. They concluded that alendronate reduces pain, improves function and retards AVN progression. Lai et al looked at forty patients with Steinberg stage-II or III nontraumatic osteonecrosis. They were randomly divided into alendronate and control groups of twenty patients each. The patients were observed for a minimum of 24 months. During the study period, only two of 29 femoral heads in the alendronate group collapsed, whereas 19 of 25 femoral heads in the control group collapsed. They concluded that alendronate appeared to prevent early collapse of the femoral head in the hips with Steinberg stage-II or IIIC nontraumatic osteonecrosis.

How does the BSP affect bone turnover or AVN? There is evidence for both direct and indirect effects on osteoclasts. Cellular actions of BSP include but are not limited to: interference with osteoclast cytoskeleton, inhibition of mevalonate pathway enzymes, apoptosis of osteoclasts, inhibition of osteoclast attachment to bone and inhibition of multiple other chemical processes within the cells. The BSPs also act on the osteoblasts, to either increase inhibitors or decrease promoters of osteoclast action or recruitment. Some bisphosphonates may act by causing chemical changes to the mineral itself, inhibiting crystal formation and making the mineral resistant to resorption. These effects depend on the amount of drug given. There is no general consensus about which mechanism is predominant in vivo, and the mechanisms may be different for each BSP. With the newer BSPs, the dose is so small that the effects cannot be caused by physical-chemical changes in the mineral. Is it the mineral change that is important in AVN patients? Will the newer medications alter the course of AVN? That is difficult to predict.

This prediction is made even tougher by the fact that the actual etiology and pathological processes in AVN of the hip are poorly understood. Bone marrow or mineralization dysfunction may not even be the common pathway for AVN - and therefore the use of BSPs might be useless and perhaps dangerous. New vascular hypotheses provide compelling pathogenic mechanisms for the etiology of avascular necrosis. The endothelial cell monolayer constitutes the inner lining of the vascular wall and plays an essential role in the homeostasis of the blood vessel. Due to its unique localization, the endothelium is continuously exposed to inflammatory cells and circulating factors that could induce endothelial activation and/or endothelial injury. Several studies in human and animal models of AVN have shown microvascular thrombosis. Endothelial cell damage could be followed by abnormal blood coagulation and thrombus formation with any resulting degeneration distal to the site of vascular occlusion. Other studies suggest that thrombophilia, particularly impaired fibrinolysis, plays a potential role in thrombus formation in AVN. Changes in shear stress could lead to apoptosis of endothelial cells, which can ultimately contribute to plaque erosion and thrombus formation. Dysregulation of endothelial cell activating factors and stimulators of angiogenesis or repair processes could also affect the progression and outcome of AVN. Likewise, regional endothelium dysfunction, referred to as a potential defect in endothelial cells located in the feeding vessels of the femoral head itself, may also have a crucial role in the pathogenesis of the AVN. Certainly, if the etiology for AVN is hematological then the uncontrolled usage of NSAIDs in the clinical studies (admitted by the authors) further confounds the results. Efficacy of BSP in treating endothelial dysfunction is also suspect.

There also seems to be a risk of serious complications with the use of BSPs. Osteonecrosis of the jaw has been reported recently. It was first described in 2003, and hundreds of cases have been reported worldwide. Bamias et al amongst others, in reputable medical journals, have studied the incidence, characteristics, and risk factors for the development of ONJ among patients treated with bisphosphonates. The incidence of ONJ increased with time of exposure to the BSP. Certainly this is not a desirable or expected outcome if you are actually treating the patient for osteonecrosis.

BSPs may have a role in treatment of AVN in the future. Although recent reports in the orthopaedic literature have suggested that BSP may be used as treatment for AVN of the hip, we feel that there are several concerns. The pathology of AVN of the hip is poorly understood. The mechanism of action of BSPs is also poorly understood. Treatment with BSP has been shown to reproducibly cause osteonecrosis. Certainly, empirical treatment after clinical observation has been a mainstay of medical therapy since the 19th century - but that treatment model for this particular disease may be inadequate.

References

1. Fleisch H., Russell R.G., Francis M.D. Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science 1969;165:1262-4.

2. Sahni M., Guenther H.L., Fleisch H., et al. Bisphosphonates act on rat bone resorption through the mediation of osteoblasts. J Clin Invest 1993;91:2004-11.

3. Hughes D.E., Wright K.R., Uy H.L., et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 1995;10:1478-87.

4. Vadasz, Z., Misselevich,I., Norman, D., Peled,E., and Boss,J.H. (2004). Localization of vascular endothelial growth factor during the early reparative phase of the rats' vessels deprivation-induced osteonecrosis of the femoral heads. Exp. Mol. Pathol. 77, 145-148.

5. Agarwala S., Jain D., Joshi V.R., Sule A.Efficacy of alendronate, a bisphosphonate, in the treatment of AVN of the hip. A prospective open-label study. Rheumatology (Oxford). 2005 Mar;44(3):352-9.

6. Lai K.A., Shen W.J., Yang C.Y., et al. The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. A randomized clinical study. J Bone Joint Surg Am. 2005 Oct;87(10):2155-9.

7. Bamias A., Kastristis E.,et al, Anagnostopoulos A., Papadimitriou C., Terpos E., Dimopoulos M.A. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol. 2005 Dec 1;23(34):8580-7.

8. Kerachian M.A., Harvey E.J., Cournoyer D., Chow T.Y., Sguin C.. Avascular necrosis of the femoral head: vascular hypotheses Endothelium. 2006 Jul-Aug; 13(4): 237-44.

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