**4. Rationale for using hyperbaric oxygen**

However, bone remodeling proceeds inefficiently because of dead trabeculae, where new living bone is placed. Moreover, osteolysis exceeds osteogenesis, and this results in loss of structural integrity of trabeculae, with subsequent subchondral fracture and joint incongruity [24].

Altered subchondral vascularity is the basic pathophysiological hallmark for FHN [9]. Kiaer and colleagues indicated that a blood supply drop of 60% will result in an intraosseous pO2 decrease, from 75 mmHg to 50 mmHg [25]. Consequently, it will cause evident ischemia.

Different pathogenic mechanisms can result in FHN. Cytotoxicity due to exposure to radiation, chemotherapy, or thermal injury causes direct death of marrow cells and osteocytes, though this was not shown in vivo yet [18]. Additionally, three main pathogenic mechanisms

**1.** Vascular interruption by fractures or dislocation (i.e., traumatic osteonecrosis). Femoral neck fractures or hip displacement usually result in extra-osseous arterial involvement. Specifically, when fracture occurs inside the joint capsule, vessels that oxygenate the subchondral bone suffer a direct trauma. A relatively high incidence of FHN in patients with

**2.** Intravascular coagulation and microcirculatory thrombosis. Different pathways can lead to the same vascular obstructions that mean sickle cell aggregations, clots, or lipid thrombi [6]. Thrombotic emboli can occur both in arteriosus and venous areas in samples of osteonecrotic tissue; in some animal models, they have been associated with osteocyte necrosis [3]. The prevalence of sickle cell anemia-induced osteonecrosis stands between 37 and 50%. The weak arterial network in the hip joint eases vascular occlusion by sickled cells [16]. In these patients, low oxygen tension environments are hypothesized to trigger hemoglobin precipitation which leads to erythrocyte sickling [6]. Moreover, the complication rate for patients with sickle cell disease undergoing orthopedic procedures is significantly higher than that for patients without sickle disease. Consequently, early and alternative interven-

Also, coagulation disorders are implicated in FHN. For example, genetic defects resulting in hypofibrinolysis or thrombophilia may lead to increased thrombi formation and blood flow obstruction in the bony tissues. Nevertheless, using a case-control methodology, elevated coagulation factor levels have been reported in patients with osteonecrosis showing the absence of known genetic defects [14]. Jarman et al. showed that coagulation abnormality-derived osteonecrosis is worsened by testosterone therapy, and its development may be slowed or stopped by discontinuation of therapy and, thereafter, anticoagulation [26]. Indeed, Guo and colleagues suggested the use of anticoagulant therapy for primary FHN. However, anticoagulants cannot play a protective role on secondary FHN [27]. Coagulation pathologies recognized before femoral head necrosis simplify therapeu-

**3.** Intraosseous extravascular compression from lipocyte hypertrophy or Gaucher cells. It can also result from hemorrhage, infection, high bone marrow pressure, marrow infiltration, and bone marrow edema [18]. Physiologically, since the pressure increases within

can lead to ischemic conditions and subsequent femoral head necrosis:

12 Hyperbaric Oxygen Treatment in Research and Clinical Practice - Mechanisms of Action in Focus

tions are critical to successfully delay total hip arthroplasty.

these fractures has been reported.

tic approach, preserving joints.

HBO2 therapeutic mechanisms of action are based on elevation both of the partial pressure of inspired O2 and of the hydrostatic pressure. The latter mechanism contributes to determine the compression of all gas-filled spaces in the body (Boyle's law), and it is fundamental to allow an effective treatment of those conditions where gas bubbles are present in the body and cause the disease (e.g., intravascular embolism or decompression illness with intravascular or intra-tissue bubbles) [35, 36]. However, most patients treated with HBO2 do not suffer from bubble-induced lesions, deriving their clinical improvements from the other mechanism of HBO2 therapy: the elevated O2 partial pressures achieved. High O2 partial pressures so obtainable in various tissues lead to the increase in the production of reactive O2 species (ROS) as well as of reactive nitrogen species (RNS), these last ones due to hyperoxia [37]. Controlled studies have already shown as the clinical efficacy from HBO<sup>2</sup> depends on modulation of intracellular transduction cascades, driving to synthesis of growth factors, promoting the wound healing, and ameliorating postischemic and post-inflammatory injuries [36].

at the present time, histological studies, scintigraphy, functional bone evaluation, radiography, magnetic resonance imaging (MRI), and computer-assisted tomography (CAT) are the most current diagnostic methods available. At an early stage, FHN is usually asymptomatic or

Therapeutic Mechanisms of Action for Hyperbaric Oxygen on Femoral Head Necrosis

http://dx.doi.org/10.5772/intechopen.75026

15

It may present with a limited range of hip movement as well as stabbing pain, especially during a forced intra-rotation. FHN should be considered if the patient feels pain in the hips and has no risk factors in his clinical history. In particular, plain radiographs can often appear as normal in the early stages of necrosis. Patients with a history of previous necrosis should be observed for bilateral FHN; this condition has been reported up to 70% of the observations [43]. Classification systems currently in use for FHN include the Ficat and Steinberg systems [15]. The Ficat classification substantially relies on standard radiographic presentations, where phase I shows normal images; phase II indicates a normal contour, with evidence of a bone remodeling; stage III is characterized by subchondral collapse or flattening of the femoral head; and phase IV indicates a narrowing of the joint space, with secondary degenerative changes in the acetabulum. The Ficat classification system is however based on radiographic imaging; therefore, the real size of the lesion cannot be quantified up to a more proper and

Steinberg expands the Ficat system into six stages, including quantification of involvement of the femoral head within stages I–VI, with three further subsets each: mild (less than 15% radiographic involvement of the head's articular surface), moderate (with a 15–30% involvement of the head's articular surface), and severe (greater than 30% involvement of the head's

Recently, the Association Research Circulation Osseous (ARCO) has recommended a third standardized classification system relying on an interpolated comparison of different procedure findings: radiographic, MRI, bone scan, and histologic findings [15]. Anyhow, not even this can eliminate completely the intrinsic operator-dependent variability, making Ficat and ARCO classification systems still not sufficiently reliable to assess FHN occurrence [44].

FHN is currently diagnosed by plain anterior-posterior and frog leg lateral radiographs of the hip, followed by MRI; this is considered the most accurate benchmark. Other existing tools for assessing the FHN presentation, such as venography, bone marrow pressure measurements,

Many therapeutic modalities have been proposed, and their effects were recently reviewed by

Where untreated, FHN is a progressive disease process in affected hip showing an intact articular survival rates of less than 60% in 5 years; furthermore, the survival rate in stage III

characterized by slight pain radiating to the knee and/or ipsilateral buttock.

accurate measure of the radiological appearance of the disease.

**6. Clinical management of femoral head necrosis**

articular surface) stages.

and core biopsy, are rarely used.

is less than 10% [10, 13].

Sen [45] and Zalavras and Lieberman [17].

The actual inability to establish which will be the correct dose of HBO2 to administer in each case is still depending on the lack in Level 1 evidence [1, 11]; as a matter of fact, the current scientific literature does not yet allow a clear identification of the optimal treatment protocol.

Nevertheless, HBO2 is positioned among the possible and feasible therapies which allow to provide a delay in undergoing hip arthroplasty surgery; it is a reasonable postulate that such therapy can show a beneficial effect without having the invasiveness of a surgical approach.

HBO2 increases extracellular oxygen concentration and reduces cellular ischemia and edema by inducing vasoconstriction [38]. Studies have already reported radiographic improvement in FHN at stage I according to the Steinberg classification, as well as a better pain control, compliance, and range of motion (ROM) in FHN at Ficat stages I–II [36]. Amid the possible effects of HBO2 , there is a reduced bone marrow pressure, leading to a significant pain relief, and an increased oxygen delivery to ischemic cells, thus relieving compartment syndrome so to prevent a progression in a further necrosis, stimulating angiogenesis and oxygen-dependent cells, and enhancing osteoclast and osteoblast function for remodeling and repair. Moreover, HBO2 is also able to stimulate the multipotent fibroblasts in the bone marrow with an additional aid in the osteogenesis process [37].

In FHN treatment HBO facilitates oxygenation of hypoxic tissue and reduces edema by creating a high concentration of dissolved oxygen and inducing vasoconstriction. This may explain the early pain relief noticed in patients treated with this modality; by saturating the extracellular fluid with diffused oxygen, HBO treatment will lead to a better oxygenation of the ischemic bone cells, independently of circulating hemoglobin and without the extra-energy requirement to provide for the dissociation of oxygen from hemoglobin. Late effects of HBO are bone resorption, revascularization, and osteogenesis [5, 36].

Yang et al. quantitatively evaluated the hemodynamic flow in animal models with steroidinduced FHN by using multi-slice CT perfusion imaging. Especially in the early stage, they assessed how HBO therapy resulted in regional blood flow improvement in the ischemic tissues. Additionally, they found high-grade new bone formation and a well-regenerated hematopoietic tissue [39]. Moreover, recent studies focusing among osteoblasts differentiation and suppression osteoclasts showed positive results due to hyperbaric oxygen treatment. In particular, HBO shifted the balance between bone formation and bone resorption promoting regeneration [40, 41].
