Hyperbaric oxygen therapy for osteonecrosis
Health technology assessment|
We have summarized research on the clinical effect and safety of HBOT as a treatment for osteonecrosis. We have also examined the cost-effectiveness and budget consequences of HBOT.
Hyperbaric oxygen treatment (HBOT) has been suggested as an alternative or adjunct treatment that can prevent further development of osteonecrosis, a bone disease in which bone structure deteriorates. Patients receiving HBOT breathe pure oxygen in a high-pressure chamber. We have summarized research on the clinical effect and safety of HBOT as a treatment for osteonecrosis. We have also examined the cost-effectiveness and budget consequences of HBOT.
- We found two systematic reviews and two randomised controlled trials (RCT) on the effect and safety of HBOT for osteonecrosis, and 13 case studies of safety.
- HBOT can increase the number of patients with osteoradionecrosis of the jaw who achieve full mucosal coverage of the jaw bone.
- It is unclear whether HBOT is more effective than standard treatment results in complete healing of osteoradionecrosis, healing of medication-related osteonecrosis, or a variety of outcomes for ideopathic osteonecrosis of the femur head.
- HBOT-related adverse events appear to be few and transitory.
- Offering HBOT as an adjunct to standard treatment might be cost-effective for patients with osteoradionecrosis of the jaw if willingness-to-pay for an additional patient who achieves full mucosal coverage is greater than NOK 340 975 per patient who achieves full mucosal coverage of the jaw bone.
The five-year budget impact of HBOT for osteoradionecrosis of the jaw is approximately NOK 6 020 400. There is great uncertainty regarding budget impacts of HBOT for other indications.
Osteonecrosis is a bone disease caused by restricted blood supply to the bone tissue in one or more joints. Without adequate blood supply, the body will not be able to form new bone when old bone tissue dies. If this process continues without treatment, bone structure can collapse. Osteonecrosis is most common in the femoral head in the hip joint but may also occur in the shoulder, knee, ankle, hand, foot and jaw.
Osteonecrosis may occur spontaneously, without known cause (idiopathic osteonecrosis), as a complication of, for example, drug use, radiation therapy, high alcohol consumption or disease (secondary osteonecrosis) or following an injury (traumatic osteonecrosis).
The total incidence of osteonecrosis in Norway is unknown, but osteonecrosis was the primary cause of 226 of almost 9000 primary hip prosthesis surgeries in 2016.
The Norwegian health service has no clear guidelines for treatment strategies at early stages of osteonecrosis. Possible treatments are surgery or non-surgical measures such as drug treatment, rest, shockwave therapy, pulse electromagnetic fields and hyperbaric oxygen therapy.
Hyperbaric oxygen therapy (HBO) implies that the patient is sitting or lying in a pressure liner and breathes 100% oxygen while increasing the air pressure. This increase in oxygen content improves the oxygen supply to the bone tissue, reduces bone marrow oedema, and thus pressure. It also stimulates the resuscitation of blood vessels (angiogenesis), which is considered to be essential for stopping and reversing the development of osteonecrosis.
Effectiveness and safety
We searched for systematic overviews and primary studies in the following databases in March / April 2018: Cochrane Library, MEDLINE, PubMed, Embase, CEA Registry and Epistemonikos databases, Center for Reviews and Disseminations. In addition, we searched for studies on the websites of international publishers of guidelines, and in registers for controlled studies.
Two researchers made paired and independent assessments of the eligibility of the studies according to pre-specified inclusion and exclusion criteria, and methodological quality (risk of systematic bias) in included studies. We extracted data from all relevant studies and presented them in text and tables. We assessed our confidence in effect estimates using Grading of Recommendations, Assessment, Development and Evaluation (GRADE).
We included two systematic reviews, two RCTs and 13 case series in this health technology assessment. We considered the methodological quality of the systematic reviews as high. The risk of bias we considered unclear in one RCT and high in the other. Because case series are generally considered a poor research design, we did undertake our own quality assessment of this evidence.
One systematic review included three RCTs on effects of HBOT of radiation-related osteonecrosis in the jaw. More patients receiving HBOT achieved complete mucosal coverage at 12- to 18 months’ follow-up, than in control groups (RR 1.30; 95% CI 1.09 - 1.55; 3 studies / 246 participants). We had medium confidence in the effect estimate. The effect estimate of the absence of osteonecrosis after one year was RR 0.60 with 95% CI 0.25 to 1.41 (1 study). Our confidence in the effect rate was very low.
The other systematic review included one RCT that examined the effect of HBOT for drug-related osteoarthritis on healing, compared to standard treatment. The effect estimate was RR 1.56 with 95% CI 0.77 to 3.18 (1 study). Our confidence in the effect estimate was very low.
The two RCTs examined the effect of HBOT for osteonecrosis in the hip joint, but there was only one that reported data from which effect estimates could be calculated. The RCT compared a "cocktail treatment" that included HBO with shockwave treatment. The outcomes were joint survival (RR 1.00; 95% CI 0.88 to 1.15), radiological findings (RR 0.96; 95% CI 0.30 to 3.11), pain (MD 0.4; 95% CI -0.16 to 0.96) and quality of life (MD -3.35; 95% CI -6.14 to -0.56 and MD -2.03; 95% CI -4.30 to 0.24 for physical and mental health, respectively). Our confidence in all effect estimates was very low.
Results from 13 case studies and three RCTs (one of which was derived from a systematic review) indicated few or no complications or adverse effects from HBOT.
The strength of the clinical effect section of this report is that it is based on a recent and thorough literature search using an explicit search strategy and paired independent evaluations of the eligibility of the studies. We have conducted paired, independent assessments of the methodological quality (risk of bias) of the included studies, and our confidence in the effect estimates is based on GRADE methodology. These independent assessments reduce the risk of bias in our own work. We have quality assured the our analysis by consulting three experts on osteonecrosis and HBOT, and incorporating assessments from two external reviewers in the report.
Although the literature search and selection process was thorough, we cannot rule out having missed potentially relevant studies. An inherent weakness in systematic reviews is that they become outdated when new studies are published. This systematic overview was updated as of April 2018.
Results regarding adverse effects of HBOT were essentially based on data from case studies. It is not uncommon to include observational studies to investigate rare occurrences and events that occur in the long run, because these events are often not recorded in controlled trials. Case series involve a high risk of systematic error in the observations, so it is difficult to assess whether the incidence of adverse events is representative of the population or whether there is a causal connection between the intervention and outcomes.
The evidence is particularly weak for the patient group with idiopathic osteonecrosis, where we know little about the effect of HBOT per se and not as part of a combination treatment. We did not identify studies with comparative conditions similar to Norwegian standard treatment. However, as far as radiation and drug-related osteonecrosis is concerned, the studies are few and the impact estimates uncertain. We found no studies of children, and no long-term outcomes.
We developed a simple decision-tree model to assess cost-effectiveness of HBOT in addition to standard treatment compared to standard treatment alone for osteoradionecrosis of the jaw. The model’s outcome was an incremental cost-effectiveness ratio (ICER) where cost was measured in 2018 Norwegian kroner and effect was measured as the proportion of patients achieving complete mucosal coverage of the jawbone. We assumed no relapse among patients who achieved complete mucosal coverage. Patients who do not achieve full mucosal coverage receive surgical treatment. We assumed that 15% will require extensive surgical reconstruction of the jaw, while 85% require less extensive surgery. To take into account uncertainty, we ran a one-way sensitivity analysis on the effect of varying the proportion of patients who need surgical reconstruction. We used probabilistic sensitivity analysis to see the impact of uncertainty in effect estimate on results. We calculated budget impacts over five years.
The cost per additional patient who achieves complete mucosal coverage of the jawbone is approximately NOK 341 000 for patients treated with HBO in addition to standard treatment compared to patients receiving only standard treatment. Probabilistic sensitivity analysis shows that the cost per additional complete mucosal coverage may vary from approximately NOK 268,500 to NOK 491,000. When the proportion of patients requiring extensive surgical reconstruction of the jaw is varied from 5% to 85%, the cost per extra full mucosal coverage ranges from approximately NOK 382 500 to NOK 50 570. Budgetary implications for treatment of 17 patients per year are estimated at additional costs of approximately NOK 6 202 400 (4% discount rate). Cost per additional patient who achieves complete mucous membrane coverage is approx. NOK 341 000 among patients treated with HBO in addition to standard treatment compared to patients receiving standard treatment. Probabilistic sensitivity analysis shows that the cost per additional complete mucosal coverage may vary from approximately NOK 268,500 to NOK 491,000. When the proportion of patients requiring extensive surgical reconstruction of the jaw is varied from 5% to 85%, the cost per extra full mucous membrane coverage ranges from approx. NOK 382 500 to NOK 50 570. Budgetary implications for treatment of approximately 17 patients per year are estimated at additional costs of approx. NOK 6 202 400 (4% discount rate).
It was not possible to create a cost-effectiveness model of HBOT for either drug-related osteonecrosis of the jaw (ORNJ) or osteonecrosis of the hip. Five-year discounted costs for treatment of 50 ORNJ patients are approximately NOK 16,400 213. Treatment of 200 patients per year with osteonecrosis of the hip may cost NOK 18,446,000 discounted over five years. In both cases, it was not possible to calculate additional costs in relation to standard treatment.
The economic evidence about the use of HBOT for osteonecrosis is very limited. We were constrained to a very simplified cost-effectiveness model because of limited information about the natural history of the disease and quality of life among patients. The model can only be used to calculate cost per additional patient who achieves complete mucosal coverage but not to calculate cost per QALY for patients receiving HBOT. Without a calculation of cost per QALY, it is not possible to assess the severity of disease or to measure cost-effectiveness in a way that is easily comparable across other types of treatments or diseases.
HBOT for radiation-related osteonecrosis can lead to more patients achieving complete mucosal coverage of the jawbone than with standard treatment. For these patients HBOT could potentially be interpreted as cost effective if the willingness-to-pay for an additional patient who achieves complete mucosal coverage of the jaw is more than approximately NOK 341 000.
The evidence is too uncertain to answer the question of the efficacy and safety of HBOT for other outcomes, and in the case of other types of osteonecrosis. Thus, we do not know whether HBOT in addition to standard treatment gives better, poorer or identical effects on any of the outcomes, compared to other or no treatment.
In order to provide better research-based answers to questions about the effect of HBOT, future studies should be based on a controlled, prospective study design; and include relevant clinical outcomes, study populations of adequate size, and opportunities for long-term follow-up. Children should also be included in the studies.