Role of Orth Biologics in Core Decompression for Femoral Head Preservation in Early Avascular Necrosis of Hip

Head preserving procedures for Early Avasculathe Necrosis of hip are invariably effective in early stage. Core decompression (CD) is mostly performed modality for early stages of AVN having different success rates. Current review aims at determining efficiency of Bone marrow aspirate concentrate, Platelet rich Plasma, Bone morphogenic proteins and combining it with Core Decompression for early AVN stage, before femoral head collapse. To preserve a femur head damaged by osteonecrosis, treatment options should be applied early in the disease process for best results. When the articular cartilage becomes deficient to nutrients, it become more difficult to save a particular femur head, and eventually bone destruction occur, affecting hip biomechanics; articular changes eventually develop, necessitating arthroplasty or arthrodesis. Other early treatment techniques has been identified & improved to improve femur head survival & delay replacement. Analysis of 20 studies published between 2011 and 2020 was done of which 6 were retrospective & 14 were prospective. PRP showed better survival and functional outcome, however 3 studies showed inconclusive evidence for its regular usage. BMAC enhanced efficiency of CD & cell increment or combination of PRP for growth stimulation. Concluding, CD and BMAC worked effectively that CD only before femoral head collapse. But, PRP need more evidences for extensive utilization. Adding PRP to BMAC or culturing it would increase potency of CD with BMAC. Less data is available to assess efficiency of BMP-7 & role of Intraosseous bisphosphonate therapy could be studied for inexpensive & better alternate. Review Article Dadlani; JPRI, 33(60B): 938-952, 2021; Article no.JPRI.80198 939


INTRODUCTION
Femur head AVN is progressive intraosseous condition leading to limitation of function as condition progress [1]. There is subchondral damage radiologically, which leads to support loss to femoral head joint surface, further leading to subchondral collapse & femoral head distortion [2][3][4][5].
The etiology of atraumatic osteonecrosis hip includes steroid, alcohol, coagulopathies, and others resulting in decreasing mesenchymal stem cells & increasing quantity of adipose cells & apoptotic cells, according to studies conducted over the last decade and a half [6][7][8]. It causes a mismatch between bone synthesis & osteolysis, resulting in loss of bony trabeculae. As a result, the articular cartilage's subchondral support is compromised, resulting in subchondral collapse, head deformation, altered hip biomechanics, & arthritis.
The goal of core decompression is to relieve intraosseous pressure & enhance blood supply to femur head in order to slow/stop progression of osteonecrosis. It had shown promise for the early phases of osteonecrosis, allowing for blood vessel growth & restoration of vascularity. CD only has shown promising outcomes in FICAT Stage 1, the success of similar technique in succeeding stages falls [9][10][11]. As a result, adjuvants are required to boost efficiency in further stages.
Transtrochanteric rotational and varus or valgus osteotomies transfer sick region of head away from weight bearing area in early stages of disease process, allowing unaffected portion to take its place; they have previously been reported to preserve the damaged head [12,13]. The outcomes of these procedures have been mixed, and their use has fallen in recent years [13].
Fibular & vascular grafts have been added with CD with better results, however they're difficult operations to execute. Newer orthobiologics, are progressively investigated in last 10-12 years; CD has been augmented with BMAC, PRP, & BMP-7 to boost the success rates [14][15][16][17]. Less studies [18,19] had looked at them in the later stages.
Goal of systematic review is to evaluate efficiency of current orthobiologics to core decompression for head preserving in early stages of osteonecrosis & to search literature for any new therapy that might improve their survival chances in new century. In order to improve the findings, we looked into other ways to administer these adjuvants.

Study Design
According to the PRISMA standards [20], systematic evaluation of literature is conducted using specific search engine such as Pub-Med and scopus.

Inclusion and Exclusion Criteria
Surgical methods for preserving the femur head damaged by AVN were included in study. We focussed mostly on CD & adjuvants used in conjunction with CD that improve femoral head survival rates in pre-femur head collapse stages of AVN. PRP & BMAC orthobiologics were perfectly recognised & included in study describing their use. Excluded studies included patients with extensive head deformation & arthritis alterations. Any studies published before 2011 were eliminated, including cadaveric investigations. Articles written in other languages were also excluded.

Data Collection and Analysis
Data was plotted on a table that contained the authors' names, year of publication, pertinent demographic information, study type, & outcome measures of relevance.
In the studies covered, total 665 cases having 846 hips affected by AVN were included, with 295 cases being male & 195 being females. 3 studies [23,31,38] didn't divide patients by gender (n 1/4 93 patients), while three others [28,29,33] did so depending on number of hips performed (M 1/4 78; f 1/4 26). In general, there was a significant male preponderance in the research that were considered.
In individual research, lowest number of cases were four [23], but greatest were hundred [37]. Average age of patients in the study was 37 yrs, demonstrating frequency of early osteonecrosis in young people & need for procedures such as arthroplasties to prevent progression. The average age of the patients in two trials [23,28] was not mentioned. In the trials, the average follow-up length ranged from 9 months to 6 years.

Core Decompression + PRP
When compared to normal circulation, PRP is plasma with a higher number of platelets [41]. The platelets have many growth factors, that are released post treatment & aid in tissue growth and development. Theoretically, if CD lowers intraosseous pressure, growth factors may aid in growth & bone formation, reducing complains & potentially reversing/postponing disease progression. In current study, three studies looked at the impact of PRP with CD (Table I). While CD procedure differed from study to study, the therapy principle remained the same. In a randomised control experiment, Xian et al. used PRP with CD to treat 24 cases with early AVN. They compared them to 22 CD-only patients [21]. Both groups received autologous bone grafts, with a three-year minimum follow-up.
Despite the fact that both groups improved their HHS, PRP group had higher clinically important increase. At last follow-up, the HHS and VAS scores too favoured PRP group (P 1/4 0.024 and 0.0125, respectively). 3 cases in PRP group required THR, whereas 7 individuals in another group had to undergo procedure owing to arthritis. PRP is a successful adjuvant to CD for early stages of AVN, according to the authors' findings.
In 40 hips of 30 patients, Samy et al. used another procedure for decompression: they did anterior dislocation, and drilled several holes [22]. To keep the adjuvant in place, they injected bone graft combined with PRP & coated area with fibrin glue. At follow up, HHS became 90.3 as compared to preoperative HHS, with 36 patients having better score. THR was presented to the remaining four. In addition, the VAS score improved dramatically (P 0.0001).
Guadilla et al. studied CD using arthroscopy & under C arm, as well as the effects of CD using graft & PRP in 4 cases with AVN hips [23]. By the fifth month after surgery, all 4 cases had a sixty percent improve in pain intensity and were able to resume normal lives. Authors described a procedure that involved accessing femur head from base when hip was flexed to 10 to 15 degrees and the hip was in a neutral coronal plane with mild traction. A Steinmann pin (3.2mm) was used to drill numerous holes through anterior/accessory port. PRP was infiltrated into channel that had been formed.

Core Decompression + BMAC
Mono-nuclear stem cells, which are building blocks of hip's skeletal anatomy, are found in bone marrow aspiration concentrate (BMAC). They develop into bone-forming cells replacing old, faulty cells, preserving structural balance & integrity [16][17][18][19]. Introducing fresh pool of lineage cells capable of differentiating into cells required for hip's normal physiology appears to be promising therapy option for pre collapse phases of AVN. BMAC, MSCs, BMMCs had all be used to refer to the cells [24][25][26][27][28]. Several studies have looked into its use as a CD adjuvant, with great result (table II)   Houdek et al. [39],  [37]. They told considerably better HHS in BMAC group after a 5-year follow-up. In addition, ten hips in the CD-alone group deteriorated radiologically (necrotic volume), with five of them requiring arthroplasty; just two hips in the BMAC group deteriorated further. The scientists came to the conclusion that a larger BMAC delivers a better functional outcome and slower disease development, as well as a higher chance of survival. As a result, cultured BMAC in combination with CD may be a viable alternative in the future.
When administered as an adjuvant, BMAC with MMNCs had shown to improve CD effectiveness.
In the early stage of AVN, the vast majority of trials testing this combination showed excellent results, with symptomatic pain reduction & better functional outcome. Improving quality & quantity of these cells prior to infiltration could help achieve these therapeutic aims of hip survival even more.

CD + BMAC + PRP
By BMAC's mixed outcomes, the focus might be turning to increasing no. of bone formation cells. Aside from ex vivo cultivation of cells mentioned, adding growth agents to increase number of these cells could be viable option. Latter is accomplished by combining BMAC with PRP, which contain all of necessary growth factor (Table III).

CD + rh-BMP-7
MSCs are stimulated by bone morphogenetic proteins (BMPs), which help them proliferate and differentiate into bone-forming cells. BMP-7 is a available product that is tested in non-union situations. Papanagiotou  Overall, recombinant BMP-7 has been used sparingly as a CD adjuvant in the last decade, owing to its limited availability and expensive cost. Although the lone trial evaluating its efficacy found significant improvements in all seven hips, the data is insufficient to endorse it as a useful adjuvant. More research is required to determine the utility.

Other Adjuvants-Bisphosphonates
Such pricey therapies become inaccessible in countries with high percentage of the people living below poverty line & no comprehensive insurance coverage. As a result, there is demand for cheaper adjuvants that could be administered to large number of patients. Bisphosphonates prevent bone loss caused by osteoclasts by triggering osteoclast death [42]. In theory, their ability to prevent bone death in osteonecrosis may be critical, and studies utilising bisphosphonates with both subcutaneous & enteral routes have shown promising result in early AVN [43,44]. Therefore, it is necessary for targetting action of drugs to exact location where it is required; intraosseous route can be a viable approach for improving bisphosphonate effect in the diseased part [45][46][47].
To summarise, it is likely that, in addition to CD, which stimulates new bone formation, a bisphosphonate such as ibandronate, injected intraosseously, will limit bone resorption. They are substantially less expensive than the rest of adjuvants mentioned, so if they are proven to be beneficial in combination with CD, they can benefit a large number of patients. This therapy technique is already being tested by the authors of this review.

Miscellaneous-Combination and Routes of administration
Aside from intraosseous administration, BMMCs can also be administered intra-arterially via the femoral artery. In thirty patients (24 male; 6 female) having AVN, Cai et al. instilled BMMC coupled with allogenic umbilical cord derived MSC [48]. This approach was used to treat 49 hips with AVN at ARCO 2 or 3 stage. Procedure included Digital Subtraction Angiography(DSA) and identifying one of 3 arteries: MCFA, LCFA, or obturator artery, with major one in femur head cannulated and cells injected within thirty minutes. Patient's pain and function of joint improved as a result of the treatment. The HHS healed dramatically after a year, and forty four bone lesions on CT improved. They came to the conclusion that such treatment was safe option for AVN patients.
Chen et al. used solely MSC from cord for intraarterial injections in 9 ARCO II & III cases (4 male & 5 female). Their MRIs showed that between 1 & 2 years, necrotic volumes dropped dramatically (7.1660.73 to 5.8661.67 cm3); the approach was also effective in boosting the HHS as compared preoperatively at one year [49]. Daltro et al. proposed method for injecting BMAC into a femoral head lesion that involved a percutaneous technique and single puncture by a 3 mm trocar under fluoroscopic supervision [50]. 89 patients were observed for five years, & their complains and HHS improved significantly from 75.8 -93.2 (p 1/4 0.0005). 3 patients didn't improve to their satisfaction, but their radiological phases did not progress.
Sun et al. studied use of recombinant BMP-2 with the 'Light bulb operation' [51]. The study included forty two patients with seventy nine hips in ARCO stages 1, 2, and 3A, with a follow up of 6 year. BMP-2 was given to 36 hips together with curettage and bone graft, while forty three hips got simply curettage & bone graft . HHS in the 1st group was 82.3613, while in the non-BMP group it was 78.9612. Stage 2 disease produced better results than Stage 3. 2 groups had survival rate of 81.9 and 71.9 percent, respectively, with Stage 3a having only 34.5 percent overall. Few of the related studies were reviewed [52][53][54].

CONCLUSION
The high frequency of hip AVN in a younger group necessitates early intervention to save the afflicted hip & postpone THR as long as possible. Core Decompression, in combination with available adjuvants such as BMAC, PRP, or their combination, is better and effective than Core Decompression alone for getting this therapeutic goal; but, the associated cost necessitate evaluation of other adjuvants & appropriate selection of patients in determining best routes of administration of the ortho-biologics, in order to improve the outcomes.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.