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

Many therapeutic modalities have been proposed, and their effects were recently reviewed by Sen [45] and Zalavras and Lieberman [17].

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 is less than 10% [10, 13].

Actual clinical evidence clearly demonstrates that HBO is able to lead to an extended duration of the survival rate of the affected hips:


One of the first studies, proposed by Baixe and colleagues, affirmed that 20 HBO treatments were sufficient for pain reduction [48]. As previously reported, Camporesi and colleagues showed that after 20–30 treatments patients were substantially pain-free [5]. However, 20 HBO treatments are not sufficient for the complete hip healing.

Even though there are many evidences among beneficial effects of HBO, there is still no agreement on the number of HBO treatments required. The recent work by Bosco and colleagues generated a mean number of 83.3 ± 24.8 [47], while in the study by Koren et al., the average number of treatments was 78.3 ± 24.2: this in itself is remarkably close [10]. In other papers the number of treatments widely ranges from 20 to 120 [49].

**Figure 1.** MRI pictures of a patient treated with HBO. (A) A pretreatment MRI exhibiting bone defect. (B) A twelvemonth MRI showing near complete resolution of bone defect. (C) A seven-year follow-up MRI showing no change in

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bone defect [5].

Therapeutic Mechanisms of Action for Hyperbaric Oxygen on Femoral Head Necrosis http://dx.doi.org/10.5772/intechopen.75026 17

Actual clinical evidence clearly demonstrates that HBO is able to lead to an extended duration

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

• Reis et al. treated 12 patients with stage I ANFH, one daily HBO session, for a total of 100 HBO treatments. They reported that 81% of HBO-exposed patients returned to normal MRI

• A double-blind, randomized, controlled, prospective study evaluated hyperbaric oxygen therapy on a cohort of 20 patients with unilateral FHN (Ficat stage II) [5]. All patients were treated with either compressed oxygen or compressed air (HBA); each patient received 30 treatments of HBO or HBA for 6 weeks. After the initial 6-week treatment, the blind was broken: all HBA patients were then offered to undergo HBO treatment. From this point on, the study veers toward an observational design study. Range of motion (ROM), stabilometry, and pain were assessed at the beginning of the study and after 10, 20, and 30 treatments by a blinded physician. Resonance images were obtained at a pretreatment stage, at 12-month post-HBO, and at a final 7-year follow-up (**Figure 1**). There was a significant pain improvement after HBO, with significance after 20 treatments on average. ROM improved likewise during HBO, for all parameters, after 20–30 treatments. At 7-year follow-up, all patients remained substantially pain-free and none required hip arthroplasty; an almost complete radiographic healing of the osteonecrosis was observed in seven of nine hips. Hyperbaric oxygen therapy does appear to be a viable treatment modality in patients with Ficat II FHN [5].

• Koren et al. used HBO to treat 68 patients (78 joints) with stage I and II disease; these authors' HBO protocol involved breathing 100% oxygen at 2.0–2.4 ATA for 90 min, for a total of 20 treatments. They reported that 88% of the HBO treatment group had improvement on MRI and a 93% survival rate of the joints at 11.1 ± 5.1 year of follow-up of 54 patients

• Recently, the long-term effect of HBO in 217 patients with stage I, II, and III ANFH has been investigated [47]. These results validated previous findings: HBO shows itself to be able to significantly improve hip condition, alleviate pain, and, more importantly, avoid hip surgery in most of patients presenting a stage II disease. Moreover, this study further shows the beneficial effects of HBO in stage III patients, where hip pain is significantly reduced in most patients, hip surgery is avoided in approximately half of the patients, and

One of the first studies, proposed by Baixe and colleagues, affirmed that 20 HBO treatments were sufficient for pain reduction [48]. As previously reported, Camporesi and colleagues showed that after 20–30 treatments patients were substantially pain-free [5]. However, 20

Even though there are many evidences among beneficial effects of HBO, there is still no agreement on the number of HBO treatments required. The recent work by Bosco and colleagues generated a mean number of 83.3 ± 24.8 [47], while in the study by Koren et al., the average number of treatments was 78.3 ± 24.2: this in itself is remarkably close [10]. In other papers the

the obtained results are maintained for up to 4 years [47].

HBO treatments are not sufficient for the complete hip healing.

number of treatments widely ranges from 20 to 120 [49].

of the survival rate of the affected hips:

(58 joints) [10].

vs. only 17% in the untreated group [46].

**Figure 1.** MRI pictures of a patient treated with HBO. (A) A pretreatment MRI exhibiting bone defect. (B) A twelvemonth MRI showing near complete resolution of bone defect. (C) A seven-year follow-up MRI showing no change in bone defect [5].

A large number of sessions showed to be effective on pain relief and mobility improvement and avoided arthroplasty, in about 80% of cases. In particular, about 90% of Ficat I and II patients and half of Ficat III patients after HBOTs had no more need of surgery and all related complications for at least 4 years [47].

cytokines can synergistically stimulate osteoclast differentiation leading to a net increase in

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IL-6 has been demonstrated to exhibit a dual effect on osteoclastic differentiation. During the inflammatory process, monocytes/macrophages produce IL-6, which can directly stimulate pre-osteoclast cells to be differentiated and activated [56]. In addition, IL-6 can stimulate stromal/osteoblastic cells to produce certain effectors, namely, IL-6, which will then promote osteoclastic differentiation [56]. Thus, there is a dual contribution, direct and indirect interaction, in which IL-6 can upregulate bone turnover. In vivo studies of IL-6 found that in transgenic mice with overexpressed IL-6 there is a greater bone turnover, reduced osteoblasts, and increased osteoclasts leading to osteopenia [58]. Correspondingly, IL-6-deficient mice displayed reduced osteoclasts and lower levels of bone erosion [59]. Kurokouchi and colleagues found TNF-α to increase the expression of IL-6 and ICAM-1 genes [60]. Hence, lower levels of TNF-α resulting from HBOT exposure could explain the reduction in IL-6. This effect, in summation with the synergistic effects of TNF-α, IL-6, and RANKL, could ultimately lead to decreased levels of osteoclastogenesis and, hence, greater resolution for the patient [56]. In the case of FHN, HBOT results in a decreased amount of circulating TNF-α. We propose the following mechanism: HBOT leads to reduced levels of TNF-α leading to decreased binding of TNF-α to the p55r type 1 receptor and thus decreased levels of NF-kB activation [56]. This reduction in RANKL would

tip the balance of OPG/RANKL in the direction of osteoblast activation [50].

, Giuliano Vezzani1

2 Anesthesia, Tampa General Hospital, TEAM Health, Tampa, Florida, USA

**Author details**

Gerardo Bosco1

**References**

cine. 2017;**44**(6):497-508

of Radiology. 2007;**63**(1):16-28

\*, Alex Rizzato1

\*Address all correspondence to: gerardo.bosco@unipd.it

Biomedical Sciences, University of Padova, Padova, Italy

Understanding the HBOT's molecular mechanism of action remains the best approach in order to gain greater recognition for this treatment and to achieve earlier resolution for patients.

1 Master Level II in Diving and Hyperbaric Medicine and Physiological Lab, Department of

[1] Camporesi E, Vezzani G, Zanon V, Manelli D, Enten G, Quartesan S, et al. Review on hyperbaric oxygen treatment in femoral head necrosis. Undersea & Hyperbaric Medi-

[2] Malizos KN, Karantanas AH, Varitimidis SE, Dailiana ZH, Bargiotas K, Maris T. Osteonecrosis of the femoral head: Etiology, imaging and treatment. European Journal

, Vincenzo Zanon1

and Enrico Camporesi2

RANKL activity and control their own expression [56].
