**3. Pathophysiology**

substantial clinical morbidity [1]. Osteonecrosis is characterized by the lack of or inadequate blood flow to the bony tissue that leads to death of the osteocytes and the bone marrow [2]. As reported by Parsons and colleagues, it is most common in the second to fifth decades of life, and the typical patient is a male, in his mid-30s [3]. Epidemiology reveals between 10,000 and 20,000 new cases of FHN diagnosed each year in the United States [4]. In the western countries, the prevalence of the disease is at a mean age of 39 years, and the 10% of hip replacements performed is due to FHN [5]. Femoral head collapse, hip joint degenerative lesions, and subsequent long-term disability represent possible adverse consequences of the untreated or nondiagnosed FHN [6]. In particular, it is estimated that more than 70% of femoral heads with osteonecrosis will proceed to collapse, requiring prosthetic joint replacement within 3–4 years of diagnosis [7]. About that, it is responsible for 5–18% of all hip replacements performed [4]. Moreover, similar pathophysiology can occur in other articular districts (i.e., the femoral condyle, the wrist, the head of the humerus, and the distal talus) caused by comparable avascular syndromes. Multifocal osteonecrosis is defined as a disease involving

Radiographic diagnosis is now possible at a former stage; thus, orthopedic physicians can

Hyperbaric oxygen (HBO) therapy is one of the proposed treatments. Indeed, tissue oxygenation promotes angiogenesis inducing edema reduction [1]. Moreover, by reducing intraosseous pressure, venous drainage is restored and the microcirculation is improved [10]. With restriction to the stage considered, Camporesi et al. showed that HBO should be considered the primary treatment modality in any patients and especially in young patients where the goal is to delay total hip arthroplasty as long as possible [5]. Therefore, the European Community accepted femoral head necrosis as an indication for hyperbaric oxygen therapy

Originally, the relation between femoral head necrosis and HBOT was deeply analyzed on a specific chapter published on Hyperbaric Medicine Practice [12]. It reported precise charts of patient results and a detailed review of the literature until 1997, as well as the different pathological outcomes and rationale for treatment [13]. Recently, an extended report on this topic has been proposed by Bosco and colleagues [1, 14]. They precisely updated the scientific literature until 2016 and summarized, for the paper's eligibility for the study, the number of patients, aim, inclusion/exclusion criteria, and obtained outcomes. Even though management, care, and therapeutic options are clearly stated for the pathology, available results differ from each other according to the stratification criteria and the particular stage of the disorder [15]. The present chapter aims to review more recent evidence from the scientific literature, outlining the physiology and the present status of pathology and therapy for femoral head necrosis. In particular, we focused on

In studying FHN, the absence of a bipedal mammalian model limits our knowledge among risk factors and pathogenesis of the disease. Additionally, completing longitudinal studies is

) on femoral head necrosis.

three or more separate anatomic sites concurrently or consecutively [8].

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

(HBOT) during the Consensus Conference in Lille, France [11].

therapeutic mechanisms of action for hyperbaric oxygen (HBO2

identify the disorder earlier [9].

**2. Etiology**

FHN physiopathology is characterized from a complex series of events that couple a usual pathway of cellular death and osteogenic processes [14]. Pathogenic course begins with two associated mechanisms: edema of interstitial marrow and necrosis of hematopoietic cells and adipocytes. Histological signs appear nearly 24–72 h following anoxia, even though osteocyte necrosis is evident after approximately 2–3 h of oxygen deprivation [22, 23]. These stimuli induce bone remodeling processes. Originally, inflammatory signs (i.e., reactive hyperemia and capillary revascularization) surround the necrotic area. Thus, this mechanism initiates bone repairing in which new bone hardly tries to remove and substitute dead tissues [9].

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].

the intraosseous extravascular region, microcirculation in vessels crossing the tissue decreases. Nevertheless, it is not a regular event. Many times, steroid consumption influences lipid metabolism leading to fat production in bone stem cells and drug-induced osteoporosis and osteonecrosis [3, 28]. This process will soon result in fat cell hypertrophy. Subsequently, intraosseous pressure will rise and ischemic condition will occur [29]. Though osteonecrosis is mostly associated with hypercholesterolemia and/or hypertriglyceridemia, the osteonecrosis-related lipid abnormalities have been well documented with the Gaucher disease (GD) [16]. Gaucher disease (GD) is a lysosomal storage disorder, caused by an impaired function of β-glucocerebrosidase, which results in accumulation of glucocerebroside in cells, and altered membrane ordering [30]. However, microcirculatory blood flow blockage is not necessarily the starting pathological event. Lysosomal contents released from Gaucher cells may damage vessel membrane, with localized osteonecrosis that may extend to bordering areas [31]. Skeletal involvement is typical in mature patients suffering from type 1 Gaucher disease, with a radiological evidence described in 93% of

Therapeutic Mechanisms of Action for Hyperbaric Oxygen on Femoral Head Necrosis

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

13

**4.** The fourth physiopathological mechanism is under investigation: extra-osseous venous obstruction. Although impairment of the extra-osseous veins happens, there is still an uncertainty whether it is a cause or effect. Additionally, it possibly has limited clinical meaning [6]. Recently, Shah et al. reviewed literature on this topic, and they investigated increased intraosseous pressure as a pathogenic process in FHN. In particular, bloodstream interruption or stasis in the venous side has been associated with increased pressure in

Since the seventies, scholars studied dysbaric osteonecrosis and explained radiographic features of this pathology [32]. It is an avascular bone necrosis induced by exposure to hyperbaric environments, typical for diverse and compressed air workers [33]. A literature review on dysbaric osteonecrosis evidenced that incomplete decompression procedures lead to blood supply decrease and subsequent osteonecrosis; this is due to the entry of nitrogen bubbles in the fatty marrow-containing shafts of long bones [34]. Studies clearly stated the approach to

therapeutic mechanisms of action are based on elevation both of the partial pressure of

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 intravascu-

from bubble-induced lesions, deriving their clinical improvements from the other mechanism

lar or intra-tissue bubbles) [35, 36]. However, most patients treated with HBO2

obtainable in various tissues lead to the increase in the production of reactive O2

and of the hydrostatic pressure. The latter mechanism contributes to determine

partial pressures achieved. High O2

do not suffer

species (ROS)

partial pressures so

cases. Among these, the 30% presents osteonecrosis [31].

be used, outlining diving decompression schedules [33].

**4. Rationale for using hyperbaric oxygen**

therapy: the elevated O2

osteonecrotic samples [6].

HBO2

inspired O2

of HBO2

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 can lead to ischemic conditions and subsequent femoral head necrosis:


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 therapeutic approach, preserving joints.

**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 the intraosseous extravascular region, microcirculation in vessels crossing the tissue decreases. Nevertheless, it is not a regular event. Many times, steroid consumption influences lipid metabolism leading to fat production in bone stem cells and drug-induced osteoporosis and osteonecrosis [3, 28]. This process will soon result in fat cell hypertrophy. Subsequently, intraosseous pressure will rise and ischemic condition will occur [29]. Though osteonecrosis is mostly associated with hypercholesterolemia and/or hypertriglyceridemia, the osteonecrosis-related lipid abnormalities have been well documented with the Gaucher disease (GD) [16]. Gaucher disease (GD) is a lysosomal storage disorder, caused by an impaired function of β-glucocerebrosidase, which results in accumulation of glucocerebroside in cells, and altered membrane ordering [30]. However, microcirculatory blood flow blockage is not necessarily the starting pathological event. Lysosomal contents released from Gaucher cells may damage vessel membrane, with localized osteonecrosis that may extend to bordering areas [31]. Skeletal involvement is typical in mature patients suffering from type 1 Gaucher disease, with a radiological evidence described in 93% of cases. Among these, the 30% presents osteonecrosis [31].

**4.** The fourth physiopathological mechanism is under investigation: extra-osseous venous obstruction. Although impairment of the extra-osseous veins happens, there is still an uncertainty whether it is a cause or effect. Additionally, it possibly has limited clinical meaning [6]. Recently, Shah et al. reviewed literature on this topic, and they investigated increased intraosseous pressure as a pathogenic process in FHN. In particular, bloodstream interruption or stasis in the venous side has been associated with increased pressure in osteonecrotic samples [6].

Since the seventies, scholars studied dysbaric osteonecrosis and explained radiographic features of this pathology [32]. It is an avascular bone necrosis induced by exposure to hyperbaric environments, typical for diverse and compressed air workers [33]. A literature review on dysbaric osteonecrosis evidenced that incomplete decompression procedures lead to blood supply decrease and subsequent osteonecrosis; this is due to the entry of nitrogen bubbles in the fatty marrow-containing shafts of long bones [34]. Studies clearly stated the approach to be used, outlining diving decompression schedules [33].
