Biomarkers and pharmaceutical strategies in steroid-induced osteonecrosis of the femoral head: A literature review

Abstract

The underlying pathology of steroid-induced osteonecrosis of the femoral head (ONFH) is unclear but is known to be multifactorial. It is therefore difficult to find a single predictive biomarker for this disease, and multiple biomarkers are likely to contribute to ONFH progression. Investigation of protein–protein interactions is vital in order to elucidate fully the pathogenesis of this disease, and provide new treatment strategies. This review article discusses the known biomarkers and current treatment strategies for ONFH.

Introduction

The pathogenesis of steroid-induced osteonecrosis of the femoral head (ONFH; also known as avascular necrosis) is multifactorial, involving altered fat metabolism, fat emboli, intravascular coagulation, inhibition of angiogenesis and apoptosis.^1,3–9 There are several known biomarkers for ONFH^10–18 Multiple biomarkers are required for disease development, ¹⁰ but there is little information available regarding protein–protein interaction in this context.

Despite the general clinical success of total hip replacement, such surgery is not always the best choice for some younger patients (<60 years of age). ⁵ In vivo and in vitro studies have reported varying levels of success for pharmaceutical treatments. Combination therapy results in better outcomes than a single treatment, possibly due to the multifactorial nature of the disease.^8,19

This review article will provide an overview of ONFH biomarkers and pharmaceutical treatment strategies.

Materials and methods

A search of PubMed®(1950–May 2014) and Embase® (1950–May 2014)was performed independently by X.Q. and Y.Z. using the keywords ‘osteonecrosis’ OR ‘avascular necrosis’ AND ‘steroid’ AND ‘biomarker’ AND ‘proteomics’ AND ‘treatment’. There were no restrictions regarding publication date. Additional reports were obtained from the database of the library at Guangzhou University of Traditional Chinese Medicine, Guangzhou, China. The author and corresponding author discussed and decided the selected articles. The majority of articles were experimental studies, with some clinical observations and case studies.

Discussion

Pathogenesis

Steroid therapy is used to treat conditions including systemic lupus erythematosus, kidney transplantatopm, rheumatological diseases (including rheumatoid arthritis) and acute lymphoblastic leukaemia. ¹ Since it was first reported that the use of glucocorticoids may lead to osteonecrosis, ² several theories have been proposed regarding the underlying aetiological events leading to ONFH. These theories include vascular occlusion or ischaemia, altered fat metabolism, fat emboli and intravascular coagulation.^1,3–9

Biomarkers

Lipoprotein

Patients with ONFH were found to have lower serum apolipoprotein A-IV concentrations compared with healthy volunteers, and these concentrations increased with stage of disease. ¹⁰ It was concluded that apolipoprotein A-IV could be treated as a potential biomarker for early diagnosis of ONFH. In addition, patients with nontraumatic ONFH had significantly lower plasma adiponectin and high-density lipoprotein cholesterol (HDL-C) concentrations, and higher triglyceride concentrations, compared with healthy control subjects. ¹¹

A study in rabbits revealed that a high low-density lipoprotein cholesterol (LDL-C) to HDL-C ratio was significantly associated with the incidence of ONFH. ¹² It was hypothesized that the high LDL-C/HDL-C ratio may lead to local hyperlipidaemia, but there was no significant difference between control animals and those with ONFH in terms of cholesterol or triglyceride concentrations. ¹² This finding is in contrast with another study in rabbits, where total cholesterol and triglyceride concentrations were significantly higher in animals with ONFH compared with controls. ²⁰ Finally, patients with autoimmune disease who developed ONFH showed no increase in hepatic enzyme concentrations. ²¹

P-glycoprotein and zinc-α2-glycoprotein

P-glycoprotein (P-gp) activity may play an important role in the progression of ONFH, possibly via decreasing the intracellular availability of glucocorticoids.^22,23 The incidence of ONFH was decreased by a P-gp inducer (rifampicin) and increased by an inhibitor (verapamil), and P-gp activity was found to have a direct impact on both adipogenesis and apoptosis. ¹³

Zinc-α2-glycoprotein is implicated in lipid metabolism, regulation of cell cycling and cancer progression, and is a potential ONFH biomarker. ¹⁸ Studies have shown that chronic kidney disease and proliferative diabetic retinopathy are closely related to zinc-α2-glycoprotein concentrations.^24,25 Zinc-α2-glycoprotein is a lipid mobilizing factor^26,27and may play an important role in ONFH progression.

Vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) concentrations have been found to be significantly lower in rabbits with ONFH than in control animals. ¹⁴ VEGF plays a critical role in vascularization and vessel function, and may be implicated in the initial stages of ONFH, in addition to in the neovascularization observed in the penumbra of advanced stage ONFH. ²⁸

Other biomarkers

Human cartilage glycoprotein-39 (HC-gp39) may be a useful inflammatory marker in hip joint disease. ¹⁵ In addition, plasma interleukin 33 concentration is a possible biomarker for early ONFH diagnosis and progression. ¹⁶ Intramedullary concentrations and bioactivity of leptin have been shown to decrease significantly in patients with ONFH compared with controls, indicating that this molecule may play an important role in disease pathogenesis. ¹⁷

It has been shown that bone turnover markers and levels of certain hormones (including bone-specific alkaline phosphatase, osteocalcin, beta-crosslaps, 25-hydroxy-cholecalciferol and parathyroid hormone) failed to predict the occurrence of ONFH. ²⁹ The advent of proteomics has led to the hypothesis that multiple proteins are required for the development and progression of ONFH. Patients with ONFH were found to have higher concentrations of kininogen 1 variant, complement factor C3 precursor and complement factor H but lower antithrombin III chain B, apolipoprotein A–IV precursor and gelsolin isoform α precursor concentrations than control subjects. ¹⁰ A study in a rat model of ONFH indicated the presence of multiple biomarkers including fatty acid synthase, nonmuscle myosin heavy chain, heat shock protein and COP9. ¹⁸

An overview of the various biomarkers involved in the pathogenesis of ONFH is given in Table 1.

Table 1.

Biomarkers implicated in the pathogenesis of steroid-induced osteonecrosis of the femoral head.

Reference	Study type	n	Biomarker	Statistical significance
Wu et al 10	Clinical	11	Apolipoprotein A-IV	P < 0.01
Shuai et al 11	Clinical	52	Plasma adiponectin	P < 0.001
Miyanishi et al 12	Animal model	38	LDL/HDL cholesterol ratio	P = 0.026
Han et al 13	Animal model	60	P-glycoprotein	P < 0.01
Kawasaki et al 15	Clinical	21	Human cartilage glycoprotein-39	P = 0.0015
Zheng et al 16	Clinical	125	Interleukin 33	P < 0.001
Ma et al 18	Animal model	20	FASN, NMHC, HSP, COP9, ZAG	–

LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; FASN, fatty acid synthase; NMHC, nonmuscle myosin heavy chain; HSP, heat shock protein; ZAG, zinc-α2-glycoprotein.

Pharmaceutical strategies

Lipid-lowering and anticoagulant treatment

Treatment with statins (mean duration 7.5 years) has been shown to protect against the development of ONFH. ³⁰ Lovastatin significantly decreased serum lipid concentrations and bone fat volume in steroid-treated rabbits, resulting in a significant decrease in the incidence of osteonecrosis compared with control animals. ³¹ Another animal study found that lanolin (which contains lanosterol) significantly reduced the incidence of ONFH compared with control animals (10% vs 75%). ³²

Based on the theory that the abnormal coagulation associated with hyperlipidaemia contributes to ONFH progression, Motomura et al ¹⁹ combined anticoagulant and lipid-lowering treatments in animal models. The combined-drug group had a significantly lower incidence of osteonecrosis than both the anticoagulant and the lipid-lowering groups (5%, 33% and 38%, respectively). This finding was confirmed by a further animal study. ⁸ It is therefore possible that combined use of anticoagulant and lipid-lowering drugs may result in a better outcome than either treatment alone, although this remains to be confirmed.

Antioxidant treatment

Several studies have indicated that suppression of steroid-induced oxidative stress can prevent vascular endothelial injury and, by extension, osteonecrosis.^33–35 Vitamin E significantly inhibited steroid-induced oxidative stress and the incidence of osteonecrosis in animal models of ONFH.^9,36 Vitamin E may suppress vascular damage by reducing oxidative stress in the blood and blood vessels, thereby maintaining antiplatelet and anticoagulant effects.

Bisphosphonates

Bisphosphonates improve pain scores and clinical function in patients with ONFH,^37,38 but cannot halt the progression of joint destruction. In contrast, bisphosphonate-related osteonecrosis of the jaw has been reported in both in animal experiments and clinical research.^39,40 Further studies are therefore required to confirm the therapeutic efficacy of bisphosphonates for the treatment of ONFH.

Iloprost

Iloprost (a vasodilator) was shown to relieve hip pain and improve joint function in the early stages of osteonecrosis, but had little effect in the advanced stages of disease. ⁴¹ In addition, iloprost treatment resulted in a statistically significant decrease in oedema, visible in magnetic resonance images of patients with ONFH. ⁴²

Tissue repair protein

Transplantation of hypoxia inducible factor (HIF)-1α transgenic bone marrow cells improved bone regeneration in necrotic regions of ONFH by enhancing mRNA expression of osteogenic genes and osteogenic differentiation. ⁴³

Conclusions

The underlying pathology of ONFH is unclear but is known to be multifactorial. ¹ It is therefore difficult to find a single predictive biomarker for this disease, and multiple biomarkers are likely to contribute to the progression of ONFH. Investigation of protein–protein interactions is vital, in order to elucidate fully the pathogenesis of this disease, as well as provide new treatment strategies.