Methods. A literature review was performed on PubMed using the keywords “avascular necrosis,” “femoral

head,” and “osteonecrosis,” focusing on articles published in the last 12 years, excluding non-English and those

Cortisone-like drugs and excessive spiritis consumption were traditionally viewed as the primary contributing

factors for emerging avascular necrosis. Recent studies emphasize impaired angiogenesis, coagulopathy and

endothelial dysfunction as significant risk factors. Magnetic resonance imaging remains the gold standard for

diagnosis, while nuclear diagnostic methods are used for predicting prognosis. Biphosphonates, statins,

vasodilators prove to be effective but remain to be prescribed without guidelines. For patients with early disease,

Aseptic necrosis of the femoral head, clinically

known as avascular necrosis, is a progressive

degenerative disorder characterized by the gradual

deterioration of bone tissue, which is primarily

initiated by a significant reduction in blood flow to

the subchondral bone (1,2). Reduction of blood flow

without infection (2). The pathogenesis of AVN is

multifactorial and complex, with exact mechanisms

remaining unclear (3). Recognized risk factors for

avascular necrosis include chronic excessive spiritrs

consumption, long-term use of steroids, and a range

of underlying medical conditions such as systemic

lupus erythematosus, sickle cell disease,

coagulopathies, and malignancies (2,4). Additio-

nally, interventions like high-dose radiation therapy

and previous surgical procedures on the hip joint can

femoral neck fractures or hip dislocations, can

precipitate AVN by disrupting blood flow through

the lateral epiphyseal vessels (4). Displaced

fractures, which cause significant disruption to the

vascular supply of the femoral head, show more than

double the risk of developing avascular necrosis

(AVN) compared to non-displaced fractures, with

AVN occurring in approximately 15% of displaced

cases versus around 6% of non-displaced ones (5).

Non-traumatic AVN, on the other hand, is frequently

alcohol abuse (6). The increase in AVN cases during

the COVID-19 pandemic has been linked to the

widespread administration of high-dose

corticosteroids such as prednisolone (7). Research

has shown that corticosteroid doses exceeding 2

grams of prednisone equivalent per day are

associated with a prevalence of AVN in

30% of cases (1,7). Chronic alcohol consumption is

believed to contribute to AVN by increasing

intracellular triglyceride accumulation, leading to

osteocyte pyknosis and diminished bone formation

by promoting the differentiation of stromal cells into

adipocytes (8). Despite these identified risk factors,

approximately 30% of non-traumatic AVN cases

remain idiopathic (1). This uncertainty has led to

investigations into the molecular pathology of AVN,

revealing that impaired angiogenesis,

as potential treatments, although there are no

standardized guidelines for their use (8). Surgical

interventions for AVN vary based on the stage of the

disease. Joint-preserving procedures, such as core

decompression and osteotomy, are generally

recommended for younger patients in the pre-

collapse stage (2,8). These techniques aim to delay

the need for total joint replacement by slowing

disease progression (8). However, in advanced cases

where the femoral head has already collapsed and

arthroplasty (THA) remains the definitive treatment

A comprehensive literature review was performed

utilizing the PubMed database, employing the

search terms “avascular necrosis,” “femoral head,”

evaluation of the current understanding and

advancements in the pharmacological management

Avascular necrosis (AVN) of the femoral head is a

multifactorial condition, with its precise

pathomechanism still not fully elucidated (3). The

onset of AVN is believed to stem from various

arteria profunda femoris, branching from the arteria

femoralis (12). These vessels are crucial for

sustaining the subchondral bone and cartilage, with

the medial circumflex artery being particularly

important, as it supplies the majority of the femoral

head (3). Disruption of this delicate microvascular

network, whether due to trauma, thrombosis, or

other pathological mechanisms, can rapidly

compromise the oxygenation and nutrient delivery

to osteocytes, setting the stage for ischemic bone

obstruction of these subchondral microcirculatory

pathways, particularly the retinacular vessels, is

often responsible for ischemia and osteonecrosis

(11). If left untreated, AVN has been reported to

cause secondary degenerative osteoarthritis in

approximately 68-81% of patients, often resulting in

significant hip mobility limitations due to

other anemias, reduce the blood’s oxygen-carrying

efficiency, contributing to chronic bone ischemia

and subsequent necrosis (2,13,15). Non-traumatic

triggers of AVN, such as prolonged corticosteroid

use and chronic alcohol consumption, are linked to

dysregulated adipogenesis (6,7). This process

involves an increase in adipocyte size and number,

culminating in accumulation of lipids inside the

cells. The resulting rise in intramedullary pressure

compresses surrounding blood vessels and

challenged traditional views by proposing that these

three mechanisms—collectively referred to as the

"molecular troika"—are central to AVN

development (17). Normally, angiogenesis

compensates for ischemic events by promoting new

blood vessel formation to re-establish tissue

perfusion (18). However, in AVN patients, this

process is impaired, resulting in insufficient and

abnormal neovascularization. The newly formed

vessels are often leaky and structurally defective,

ischemia (18). The resultant failure to restore

adequate blood flow to the necrotic femoral head

initiates a cascade events that promotes joint to

collapse (18). Coagulopathy, another pivotal factor

in AVN, involves a disruption of the delicate balance

between procoagulant and anticoagulant factors.

This imbalance leads to excessive clot formation and

and exacerbates inflammation (2,4). Endothelial

cells fail to produce adequate amounts of vasoactive

molecules, leading to vascular dysregulation and

promoting a chronic pro-inflammatory state that

accelerates osteonecrosis (20). This triad of

angiogenesis impairment, coagulopathy, and

endothelial dysfunction has emerged as a critical

target for novel therapeutic approaches (1). Current

pharmacotherapy targets the restoration of

angiogenesis, improvement of anticoagulant

Diagnosis of AVN combines clinical examination

findings with imaging studies. Patients typically

report progressive hip pain, stiffness, and crepitus,

often following a phase of minimal or intermittent

symptoms (3,9). Physical examination frequently

reveals restricted hip motion, with pain notably

exacerbated during forced internal rotation (3).

however, standard X-rays often fail to detect early-

stage changes. (25). Conversely, magnetic

resonance imaging is recognized as the definitive

method for diagnosing osteonecrosis, providing

highest sensitivity (90-95%) and specificity (85-

95%) in identifying early-stage avascular necrosis

(26.27). MRI can detect subtle early indicators,

limited compared to MRI (27). In cases where joint

effusion or early marrow changes are suspected,

MRI is preferred due to its ability to visualize soft

tissue and early bone changes that precede

radiographic findings. Moreover, nuclear imaging

modalities such as single-photon emission

computerized tomography (SPECT/CT) have been

explored as diagnostic tools (25). A 2020 study

demonstrated that SPECT/CT is particularly useful

for determining AVN prognosis in patients over the

metabolic activity and predict the extent of necrosis.

However, their use remains secondary to MRI for

most clinical situations (27). Recent advancements

in imaging have focused on diffusion-weighted MRI

and dynamic contrast-enhanced MRI, which offer

deeper insights into tissue perfusion and necrotic

bone activity (30). These imaging techniques can

enhance early diagnostic accuracy and aid in

treatment planning by enabling real-time assessment

of ischemic damage. Recent studies indicate that

markers of bone turnover may improve diagnostic

Most AVN patients are middle-aged and lead active

lifestyles, which makes conservative treatment

options more favorable than surgical interventions

bisphosphonates, among others currently under

investigation (3). However, the efficacy of these

treatments remains limited, and no definitive

guidelines for their use have been established due to

the lack of robust evidence from clinical trials (34).

While bisphosphonates, which inhibit osteoclast

activity to reduce bone resorption, have been tested,

results from clinical trials have been inconsistent.

While some trials suggest that bisphosphonates may

slow down the progression of AVN by preventing

tested in AVN populations (34). Despite these

efforts, many patients eventually progress to the

point where surgical intervention becomes

necessary. An interesting area of research is

extracorporeal shockwave therapy (ESWT), which

has gained attention for its potential to promote

tissue regeneration and relieve pain. Several studies

published in 2015 demonstrated promising results,

with some subjects even showing complete

regression of MRI-detected necrotic changes after

findings, a large proportion of AVN patients treated

with pharmacotherapy eventually require surgical

intervention. Surgical management of AVN

typically involves joint-preserving procedures for

younger patients in the pre-collapse stages of the

disease, while total hip arthroplasty (THA) is

reserved for patients with advanced-stage AVN and

blood flow, and promotes healing within the necrotic

region. By facilitating better vascularization, core

decompression can slow the progression of AVN and

potentially delay or prevent the need for total joint

replacement (9). As a first-line treatment, it is

particularly effective when initiated during the early

stages of the disease, where intervention can lead to

favorable outcomes for patients (2). The principle

behind CD is to relieve intraosseous pressure within

the femoral head and restore blood flow by drilling

efficacy in reducing intraosseous pressure and

However, recent studies suggest that vascularized

bone grafts, particularly vascularized fibular grafts,

may offer superior outcomes compared to their

nonvascularized counterparts due to the enhanced

blood supply they provide to the affected area (13).

Osteotomies, which involve cutting and realigning

the bone to redistribute weight-bearing forces, are

generally not recommended in AVN treatment

accelerate the development of arthritis (3). For

patients with advanced disease and femoral head

collapse, THA remains the definitive treatment

option, offering significant improvements in pain

osteonecrosis. A 2023 meta-analysis of 18 studies

confirmed that MSC-based therapies support

revascularization and promote bone tissue

regeneration., as well as providing improved

functional outcomes and reduced pain, as measured

by functional scores and visual analog scales (18).

Due to their regenerative properties, MSCs present

a promising therapeutic option for early-stage AVN,

Moreover, advances in the understanding of MSC

potential can be augmented by manipulating their

microenvironment or priming them with specific

agents (18). In this context, angiotensin II may

boost the production of angiogenic factors like

VEGF, thereby promoting neovascularization and

These developments highlight the future potential of

MSC therapies in tissue engineering, suggesting that

recent advances are progressively moving toward a

clinically viable and effective solution for AVN.

evident, more extensive clinical trials are needed to

determine optimal cell delivery methods, dosages,

and the long-term safety of these interventions

before they can become a mainstream treatment

These mechanisms contribute to the ischemia and

subsequent bone necrosis that characterize the

disease. While conservative approaches like

pharmacotherapy and shockwave therapy show

promise for early-stage AVN, their success rates

vary, and many patients eventually require surgical

intervention. Core decompression and vascularized

bone grafting represent key surgical options aimed

at preserving joint function in earlier disease stages,

while total hip arthroplasty (THA) is the treatment

needed to optimize protocols and assess long-term

outcomes. The future of AVN management may

increasingly involve a combination of innovative

medical therapies and established surgical

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