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    Osteonecrosis: Is Conservative Management an Option?

    In this Evidence-Based Controversies article, the authors examine the literature on the viability of pharmacologic and biophysical modalities for non-operative treatment of patients with osteonecrosis of the hip or knee.

    Authors

    Feroz Osmani, BS; Savyasachi Thakkar, MD; and Jonathan Vigdorchik, MD

    Disclosures

    The authors have no disclosures relevant to this article.

    Introduction

    Osteonecrosis is an ischemic pathologic process associated with a number of conditions that affect patients across a range of ages. Two common pathologies seen in orthopaedics are hip and knee osteonecrosis.

    Hip osteonecrosis is generally seen in younger patients, those ages 20 to 40 years old. It affects 20,000 to 30,000 patients and contributes to 10% of the annual number of total hip arthroplasties (THA) in the United States. Spontaneous regression is rare, with a collapse rate of 67% in asymptomatic hips and 85% in symptomatic hips. [1] To date, the literature has not agreed on a uniform treatment algorithm. 

    Knee osteonecrosis is most commonly caused by ischemia to the watershed areas of the medial femoral condyle. Spontaneous osteonecrosis of the knee typically affects an older patient population, those ages 50 to 65 years old; secondary osteonecrosis is commonly seen in younger patients. Up to 4% patients have post-arthroscopic knee osteonecrosis. [2]

    Osteonecrosis is triggered by a variety of factors that disrupt blood flow to the osteocytes. This ischemia causes bone necrosis, which in turn stimulates an inflammatory response. The inflammation is followed by reabsorption and collapse of the affected areas. The pathology of osteonecrosis occurs via 2 principal pathways: the traumatic and the atraumatic.

    The traumatic pathway begins with an inciting event that results in interruption of blood flow. Without timely correction, this initial insult may lead to critical ischemia and resulting bone necrosis. [3]

    The atraumatic pathway is caused by a variety of factors that may decrease blood flow. These include:

    • Coaglulopathy (antiphospholipid antibody, inherited thrombrophilia, hypofibrinolysis)
    • Glucocorticoid use
    • Alcohol use
    • Sickle cell crisis
    • Decompression sickness
    • Gaucher’s disease
    • Drugs
    • Toxins
    • Radiation

    The final common pathway of this inciting episode may stimulate adipocyte hypertrophy, endothelial damage, and thrombus formation, leading to critical ischemia. [3]The classification of osteonecrosis is based on radiographic and magnetic resonance imaging (MRI) findings (Tables 1-3). The Ficat and Arlet classification is divided into categories from 0-normal radiographs to IV-femoral head collapse and osteoarthritis. [4] The Steinberg staging system expands on the Ficat and Arlet classification with more thorough categories and introduces mild, moderate, and severe sub-classifications. [5] The Association Research Circulation Osseous (ARCO) classification categorizes osteonecrosis as 0-no changes to IV-osteoarthritis, acetabular changes, joint destruction. [6]

    The Steinberg staging system is currently used to guide management, with stage I and II osteonecrosis handled more conservatively. At stage III osteonecrosis and beyond, subchondral collapse occurs and a more-aggressive management strategy must be considered.

    One of the issues in managing patients with osteonecrosis of the hip or knee is whether conservative treatment is a viable and effective option. Various conservative treatment modalities are available, and they attempt to target different pathologic pathways. [7]

    Methods

    To determine the appropriateness of conservative management for osteonecrosis of the hip or knee, we performed a systematic review based on electronic searches through the PubMed, Embase, CINAHL Plus, and Cochrane databases from January 2001 to November 2015 using combinations of the following keywords:

    • Osteonecrosis management
    • Avascular necrosis management
    • Hip osteonecrosis
    • Hip avascular necrosis
    • Knee osteonecrosis
    • Knee avascular necrosis

    Inclusion criteria were English-language studies that reported on hip and knee osteonecrosis management. Exclusion criteria were studies in other languages and studies that were not focused on hip or knee osteonecrosis.

    We identified 16 studies based on these criteria. The therapies we assessed for the conservative osteonecrosis management included:

    • Bisphosphonates
    • Prostaglandin agents
    • Enoxaparin
    • Statins
    • Hyperbaric oxygen
    • Extracorporeal shockwave therapy
    • Pulsed electromagnetic field therapy

    Results

    Bisphosphonates

    Agarwala et al [8] evaluated the efficacy of bisphosphonates in the treatment of avascular necrosis of the hip. The cohort included 100 patients who were taking 70 mg of oral alendronate once a week and 500 mg to 1000 mg of calcium plus 400 IU to 800 IU of vitamin D3. Patients were followed every 3 months for up to 1 year, then every 6 months thereafter. X-rays were obtained every 3 months; MRIs were obtained every 3 months for up to 1 year, then yearly thereafter 

    Walking time, standing time, and pain were shown to have improved at all time points. The intervention was most effective in the early stages of osteonecrosis (stages I and II). By extrapolating the data, 50 to 80 hips may need surgery by 3 to 4 years after diagnosis. Of the 10 hips that underwent replacement during the follow-up period, 8 had advanced osteonecrosis (stages III and IV). [8]

    A similar study by the same authors following the same methodology analyzed 395 hips in patients with osteonecrosis. At 4-year follow-up, 92.2% of hips did not need surgery, whereas 2% of stage I hips, 8% of stage II hips, and 33% of stage III hips needed arthroplasty. [9] 

    A randomized controlled trial conducted by Lai et al [10] analyzed 40 patients with Steinberg stage II or III non-traumatic osteonecrosis. Twenty patients (29 hips) received 70 mg of alendronate weekly for 25 weeks and 20 control patients (25 hips) received no drug/placebo. Radiographs were obtained every 10 weeks.

    On follow-up, only 2 of the 29 femoral heads in the alendronate group had collapsed and 1 hip had undergone THA. In the control group, 19 of the 26 hips collapsed and 16 hips underwent THA.

    Nishii et al [11] compared 14 patients (20 hips) who received 5 mg of alendronate daily to 8 control patients (13 hips). The alendronate group showed a reduced biochemical marker of bone reabsorption and lower frequency of collapse of the femoral head. They reported less pain than patients in the control group.

    With regard to spontaneous osteonecrosis of the knee, ibandronate, another bisphosphonate, was used in a retrospective double-blind study conducted by Meier et al. [12] Fourteen patients were treated with intravenous (IV) ibandronate and 16 patients received IV placebo for 3 months. All subjects received oral diclofenac with oral supplementation of calcium carbonate and vitamin D for 12 weeks. On follow-up at 48 weeks, the ibandronate treatment showed no significant beneficial effect.

    Although bisphosphonates may be useful in the management of osteonecrosis, limiting factors such as cost, treatment duration, and weight-bearing restrictions must be considered, as should identification of the role of this therapy in the treatment protocol for osteonecrosis.

    Prostaglandin Agents

    Disch et al [13] used a 5-day course of IV iloprost to treat 33 patients, 16 with isolated edema and 17 with necrosis, ARCO stages I to III. The Harris hip score (HHS), range of movement, extent of edema as measured by MRI, pain on a visual analog scale, and patient satisfaction were monitored and recorded. There was a significant improvement in these measures during the follow-up period.

    Regardless of the etiology, Disch et al explained that iloprost may be a feasible conservative treatment option to reduce pain and promote early mobilization. [13]

    Jager et al [14] reported on 50 patients affected by bone marrow edema or avascular necrosis who were given iloprost. Significant improvement was seen in pain and functional and radiological outcomes after administration. Mean pain level decreased from 5.36 on day 0 to 1.63 at 6 months, and both HHS and Knee Society Score (KSS) increased during follow up. 

    Jager et al [14] also described the complex intracellular interactions associated with iloprost, making it clear that we do not completely understand all the downstream pathways that can affect osteonecrosis.

    Enoxaparin

    A prospective study by Glueck et al [15] analyzed the effects of enoxaparin on patients with osteonecrosis related to thrombophilia/hypofibrinolysis (Ficat stages I/II). Twenty hips (13 patients) were treated with 60 mg of enoxaparin daily for 3 months. Fifteen hips (12 patients) with osteonecrosis from other causes were used as the control and did not receive the medication.

    At 2 years, only 1 hip in the enoxaparin group had progressed to THA, while 12 hips in the control group had progressed to THA. [15] 

    Enoxaparin may delay progression of hip osteonecrosis, reducing the need for THA. However, more studies are needed to bolster the case for enoxaparin as a medical therapy for osteonecrosis.

    Statins

    High-dose steroid use is a known cause of osteonecrosis. Pritchett et al [16] studied 284 patients taking statins at the time of high-dose steroid therapy, using MRI scans to verify if osteonecrosis had developed. After an average of 7.5 years of follow-up, only 1% of patients had developed osteonecrosis, compared with the 3% to 20% usually reported in patients taking high-dose steroids. [16]

    Another study analyzed whether statin usage reduces corticosteroid-related osteonecrosis in the renal transplant population. Ajman et al [17] looked at 2881 patients in the renal transplant database, of which 338 patients were taking statins. Fifteen (4.4%) developed osteonecrosis, compared with 180 of 2543 (7%) patients who were not taking statins. 

    These studies have provided evidence that statins may offer protection from osteonecrosis in patients who need high-dose steroids.

    Hyperbaric Oxygen

    A double-blind trial performed by Camopresi et al [18] included 19 patients with stage II osteonecrosis, and it compared 6 weeks of compressed oxygen (HBO) treatment with 6 weeks of compressed air (HBA) treatment. Significant reduction in pain was observed after 20 HBO treatments.

    Range of motion improved significantly during HBO for all parameters between 20 and 30 treatments. All patients remained pain free at 7-year follow-up, and none required THA. [18] 

    Reis et al [19] treated 12 patients (16 hips) with stage I osteonecrosis with HBO for 100 days, following up with an MRI at 2 years. At follow-up, 81% of hips had reversal of osteonecrosis.

    Extracorporeal Shock Wave Therapy

    Extracorporeal shock wave (ECSW) therapy was compared with core decompression by Wang et al [20] in a randomized controlled trial. Patients were identified as ARCO stage I to III, with 23 patients (29 hips) placed in the ECSW group and 25 patients (28 hips) placed in the core decompression group. Before treatment both groups shared similar pain and HHS scores.

    At 25 months of follow-up, the ECSW group showed significant improved in HHS and pain scores. In the ECSW group, 5 of the 13 lesions designated as stage I or II showed regression on imaging; 2 stage II and 2 stage III lesions had progressed. In the core decompression group, 4 lesions regressed and 15 progressed. ECSW was observed to be more effective than core decompression in stages I and II osteonecrosis. [20]

    Wang et al [21] compared ECSW therapy with ECSW plus alendronate (70 mg weekly for 1 year) in a 48-patient cohort. The ECSW-only group contained 25 patients (30 hips) and the ECSW plus alendronate group contained 23 patients (30 hips).

    On follow-up, both groups showed significant improvement in pain and function; however, there was no significant difference between groups. ECSW alone showed results comparable to those of ECSW plus alendronate, with both therapies proving to be effective treatments for osteonecrosis.[21]

    Pulsed Electromagnetic Field Therapy

    In a retrospective analysis by Massari et al, [22] 66 patients (76 hips) were treated with pulsed electromagnetic field stimulation of the femoral head for 8 hours per day for an average of 5 months. The pulsed electromagnetic field stimulation preserved 94% of Ficat stage I or stage II hips. Fifteen hips required THA, although 12 of these patients were Ficat stage III.

    Pain was present in all patients at the beginning of the treatment period, but disappeared after 60 days in 53% of patients. [22]

    Marcheggiani Mucciolo et al [23] followed 28 patients with MRI-confirmed Koshino stage 1 spontaneous osteonecrosis of the knee that were treated with pulsed electromagnetic fields therapy for 6 hours per day for 90 days. Significant reduction in knee pain and necrosis was observed at the 6-month follow-up, and 86% of knees had not undergone surgery at 23-month follow-up. 

    These studies suggest that pulsed electromagnetic field stimulation is a viable option for early-stage osteonecrosis of both knee and hip.

    Discussion

    As previously mentioned, atraumatic osteonecrosis of the hip traditionally affects younger patients, whereas osteonecrosis of the knee affects older patients. The atraumatic pathway is a complex interplay of multiple factors leading to bone death. These factors can be inhibited or reversed by the pharmacologic or biophysical management regimens investigated in this review.

    With no uniform treatment algorithm in place, the management of osteonecrosis seems difficult and open to interpretation. This may lead to poorer prognosis due to the time-sensitive nature of osteonecrosis.

    Ficat stages I and II may be effectively managed conservatively. When the severity progresses to stage IV or V, operative intervention is the only solution. Surgery, however, may be problematic in young patients, as the literature recommends delaying total joint replacement as long as possible to avoid the associated and downstream complications.

    In this systematic review, we investigated various non-operative treatment options, including pharmacologic management and biophysical modalities.

    Pharmacologic Modalities

    Bisphosphonates principally function by inhibiting osteoclasts, leading to decreased edema and remodeling to increase bone mineral density and delay collapse. They have proven to be effective in the management of osteonecrosis, with demonstrated improvements in walking time, standing time, and pain and delays in surgery.

    However, questions can legitimately be raised regarding cost, length of therapy, and use of bisphosphonates in combination with vitamin D and/or calcium. In addition, weight-bearing protocols be taken into consideration before initiating a regimen.

    Safety is always a concern with bisphosphonate use, with adverse events categorized by their frequency [24]. The most common of these include:

    • Gastrointestinal disturbances. Gastrointestinal irritation accounts for most of the adverse events associated with bisphosphonate use, affecting some 20% to 30% of users. It is a common reason for drug discontinuation.
    • Acute phase response. The development of an acute phase response, in the form of “flu-like” symptoms, has also been demonstrated to be a relatively common adverse event when compared with placebo. Within the first 15 days of zoledronate use, 42% of patients developed symptoms, compared with 12% of patients receiving placebo. Subsequent doses were associated with decreasing severity. [24]
    • Renal impairment. Caution must be taken in patients with known renal impairment. Although IV administration would not be common practice in this setting, a glomerular filtration rate less than 50 mL/min must be managed conservatively.
    • Hypocalcemia. Caution must also be taken in patients who have a predisposition for hypocalcemia, as bisphosphonates act as a trigger. This is much more of a concern with IV administration.
    • Atrial fibrillation. Atrial fibrillation is not considered a significant adverse effect of bisphosphonate use, as it was only demonstrated in 1 of the 2 phase III trials with zoledronate.
    • Osteonecrosis of the jaw. For the management of hip or knee osteonecrosis, osteonecrosis of the jaw is not a significant concern, as it is seen only at higher doses and with IV administration.
    • Atypical subtrochanteric femoral fractures. Although bisphosphonate use demonstrated reduction in the risk of classic subtrochanteric fractures, typical subtrochanteric fracture patterns have been seen in patients on long-term therapy. [24]

    Iloprost is a vasoactive synthetic prostacyclin analog that functions to dilate arterial and venous vascular beds, reduce capillary permeability, and inhibit platelet aggregation. Recent studies have also shown evidence of pain reduction in treated patients. [13]

    The most common adverse events include severe headaches and nausea. Others include flushing and hypotension, trismus and jaw pain, cough, and flu-like symptoms. Overall, the literature has shown the therapy to be effective and allows for increased range of motion, decreased pain, and improved HHS and KSS scores and patient satisfaction.

    A commonly used low-molecular weight heparin, enoxaparin has been shown to prevent the progression of Fiscat stage I and II of osteonecrosis of the hip. This could be especially beneficial in younger patients if it would delay or prevent the need for THA.

    However, the literature is scarce and further investigation is required to determine enoxaparin’s role, including the associated risks/benefits in osteonecrosis management. The most common adverse events with the use of enoxaparin include nausea, diarrhea, fever, mild swelling, bruising, and redness. 

    Statins have been well documented for use in cholesterol and heart disease management. For the treatment of osteonecrosis, statins increase expression of BMP-2 and decrease expression of the adipocyte gene, resulting in a reduction in intraosseous pressure.

    High-dose steroid use predisposes patients to osteonecrosis. The studies discussed above have shown evidence that the use of statins in patients on high-dose steroid therapy may prevent the development of osteonecrosis.

    The most serious adverse reaction to statin therapy is life-threatening rhabdomyolysis, leading to muscle pain, liver and kidney failure, and possibly death.

    Overall, the literature has demonstrated that pharmacologic treatment modalities generally reduce pain levels, improve HHS and KSS scores, and may delay or eliminate the need for surgical intervention. The risk/benefit profile must be further investigated when beginning these pharmaceutical regimens.

    Biophysical Modalities

    Pressurized oxygen supplementation increases extracellular oxygen levels, which reduces edema and reverses ischemia. The studies reviewed showed that patients who underwent hyperbaric oxygen therapy had improved range of motion and pain scores. Patients treated at early stages of osteonecrosis showed evidence of reversal on MRI.

    Unfortunately, the most significant downfall with this option is the substantial cost of therapy. [19] Serious adverse events have been observed with hyperbaric oxygen therapy, with 17% of patients reporting ear pain or discomfort. Otologic trauma was verified in 3.8% of patients. Other studies have demonstrated inner ear and lung pathology. Careful pre-treatment examination and intra-therapy monitoring are paramount. [25]

    Extracorporeal shock wave treatment up-regulates VEGF and BMP-2 expression, stimulating angiogenesis and osteogenesis to prevent osteonecrosis. Patients with stage I and II osteonecrosis have been observed to have improvements in HHS and pain scores, as well as regression in hip and knee necrosis. The adverse event profile is relatively mild, with the most common issues being pain and localized swelling and redness. [26]

    Similar to ECSW, pulsed electromagnetic field therapy uses up-regulation of VEGF and BMP-2 to promote angiogenesis and osteogenesis. For stage I and II osteonecrosis, pain was found to be the most significantly improved metric. KSS increased, the patient-reported outcome EQ-5D score improved, and MRI findings improved from baseline with pulsed electromagnetic field therapy. It is also noteworthy that a delay in THA was observed.

    There have not been any adverse events reported in the literature for this therapy.

    Similar in efficacy but generally much more costly that pharmacologic agents, biophysical therapy has been shown to improve outcomes in the osteonecrosis population. Interestingly, not only has the development of osteonecrosis decreased, but several studies have also shown that reversal of bone necrosis may be evident.

    As this systematic review has shown, conservative management is best reserved for Ficat stage I and II osteonecrosis, with no significant data demonstrating efficacy in the later stages. However, there is yet to be agreement on the role of conservative treatment modalities in the management algorithm for osteonecrosis of the hip and knee.

    Adverse event profiles and administration costs must be further investigated in this patient population to effectively determine the value of these interventions.

    Conclusion

    Osteonecrosis of the hip and knee can be effectively treated with conservative management early in its prognostic course.

    Generally, stage I and II osteonecrosis, prior to subchondral collapse, can be approached with pharmacologic and biophysical treatment modalities before more-invasive measures such as core decompression are considered. At stage III and beyond, however, conservative treatments are no longer viable treatment options.

    Although various conservative treatments are available, further research must be done to determine which modalities carry the best cost/risk/benefit ratio to establish a standard of care for the treatment of osteonecrosis.

    Author Information

    Feroz Osmani, BS; Savyasachi Thakkar, MD; and Jonathan Vigdorchik, MD, are from NYU Langone Medical Center’s Hospital for Joint Diseases, New York, New York.

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