Keywords femoral head osteonecrosis - core decompression - platelet-rich plasma - mesenchymal
stem cells - synthetic bone graft
Introduction
Osteonecrosis of the femoral head (ONFH) is a disorder with a wide-ranging etiology
and the pathogenesis is still unclear.[1 ] Estimates indicate that 10,000 to 20,000 new cases are diagnosed in the United States
each year.[2 ]
Glucocorticoid use and alcohol abuse are among the most recognized risk factors for
this disease. Different pathophysiological mechanisms have been postulated, including
fat emboli, increase of intraosseous pressure, and microfracture of the trabecular
bone.[2 ]
ONFH is commonly seen in patients between their third and sixth decades and it can
lead to destruction of the hip joint, with femoral head collapse and coxarthrosis.
Usually the symptom reported by these patients is pain, often localized to the groin;
this pain can limit range of motion (ROM), especially passive internal rotation, greatly
reducing the normal activities of daily living and therefore the quality of life.
The diagnosis is performed with a radiographic evaluation in association with magnetic
resonance imaging (MRI).[1 ]
[2 ]
[3 ] The most common method of staging the disease is Ficat classification, which recognizes
five different stages of bone necrosis from stage 0 to stage 4.[4 ]
The gold standard for end-stage osteonecrosis is total hip arthroplasty (THA).[5 ] Despite the clinical success of THA in this population, significant concerns persist
regarding the long-term outcomes of younger patients undergoing prosthetic joint arthroplasty.[5 ]
[6 ] These concerns lead to practice nonoperative management like physical therapy, or
a conservative surgical approach, like core decompression, with the goal of delaying
or preventing the need for THA. Even though this procedure has been used for more
than three decades, its efficacy remains controversial and there is still no consensus
in literature.[7 ]
[8 ] One of the possible reasons for its failure is that a single core decompression
does not induce an adequate osteogenic activity in the necrotic area. The development
of regenerative medicine has gone beyond this limit and in recent years core decompression
has been supplemented with additional procedures like an osteoinductive agent that
can enhance bone repair.[9 ] Bone healing is produced by a cellular mechanism including mesenchymal stem cells
(MSCs). The MSCs need to be recruited in the pathological area. These nonhematopoietic
progenitor cells are able to be differentiated in osteoblasts under the influence
of growth factors such as bone morphogenetic proteins, platelet-derived growth factor
(PDGF), transforming growth factor β (TGF-β), insulin-like growth factor, fibroblast
growth factor (FGF), and parathyroid hormone.[9 ]
[10 ]
For these reasons, we adopted a surgical approach that provides core decompression,
performed with an expandable reamer tool that allows optimal debridement of dead bone
through a small incision, in association with MSCs implantation and platelet-rich
plasma (PRP) injection. The association of MSCs and PRP induces an osteogenic activity
and stimulates bone repair. PRP is a fraction extracted by the centrifugation of whole
blood, which contains a high concentration of platelets; three to four times higher
than normal. The growth factors present in platelets, such as PDGF, TGF-β, basic FGF
(bFGF), endothelial growth factor (EGF), and vascular EGF (VEGF), play a critical
role in tissue repair, regeneration, and differentiation of MSCs.[9 ]
[10 ]
[11 ]
[12 ]
[13 ]
The procedure is completed with a synthetic bone graft (PRO-DENSE bone graft substitute;
Wright Medical Group, Memphis, Tennessee, United States) for backfilling the surgically
created defect. PRO-DENSE is a new CaSO4 /CaPO4 composite graft that provides a bone graft substitute that resorbs and is replaced
with bone during the healing process.
The aim of this study was to report the survivorship in patients with ONFH treated
with core decompression in association with MSCs implantation, PRP injection, and
synthetic bone graft substitute and to define the role of this procedure in avoiding
or delaying THA.
Our hypothesis was that a new CaSO4/CaPO4 synthetic composite graft, in association
with PRP and autologous mesenchymal cells during core decompression, could delay total
hip replacement in patients with OFNH, especially in patients with early stages of
the disease.
Methods
We prospectively evaluated the results of a series of 16 patients with ONFH, treated
by core decompression, injection of PRP and MSCs, and backfilling of the core tract
with PRO-DENSE.
The institutional review board approved the study protocol and all patients gave informed
consent for participation in the study.
The indication for the procedure was ONFH of all stages according to Ficat classification.[4 ]
Exclusion criteria included femoral head with advanced segmental collapse; patients
with post-traumatic ONFH; patients aged 65 years or more; presence of blood dyscrasias
or a history of vascular disease; chemotherapy anticancer therapies in progress or
drugs that inhibit bone marrow function; sepsis, septic arthritis, osteomyelitis,
or other ongoing infectious processes; other systemic infectious processes; previous
hip operations, both in open or arthroscopy; women who were pregnant; patients deemed
mentally incapable and/or for which it was reasonably foreseeable that they would
not adhere to the planned program of postoperative evaluation; preoperative platelet
count <175,000/µL and hemoglobin <11 g/dL.
There were 14 men (22 hips) and 2 women (4 hips). The mean age at the time of the
procedure described was 42 years (range 29–60 years; standard deviation ± 9.8). Right
hips were involved in 14 cases (53.8%), while left hips in the remaining 12 (46.2%).
We identified the following risk factors and associated conditions with ONFH: three
patients were on chronic therapy with steroids (defined as a dose >2 g prednisone
or its equivalent per month for 3 months minimum; underlying pathologies were rheumatoid
arthritis and Steinert dystrophy); two patients were HIV positive and three were alcohol
abusers. In the remaining eight patients, the necrosis was idiopathic.
The diagnosis of ONFH was made using anteroposterior radiographs and standard MRI.
The hip stage was classified according to Ficat classification.[4 ] We had two cases (7.7%) of stage I, eight cases (30.8%) of stage II, ten cases (38.5%)
of stage III, and six cases (23.1%) of stage IV ([Table 1 ]).
Table 1
Demographic and epidemiologic data
Sex
Male
14 (87.5%)
Female
2 (12.5%)
Etiology
Idiopathic
8 (50%)
Chronic therapy with steroids
3 (18.7%)
HIV positive
2 (12.6%)
Alcohol abusers
3 (18.7%)
Side
Right
14 (53.8%)
Left
12 (46.2%)
Age at surgery (y)
41.9 ± 9.8
Ficat classification
I
2 (7.7%)
II
8 (30.8%)
III
10 (38.4%)
IV
6 (23.1%)
Mean follow-up (y)
4.2 ± 1.8
Abbreviation: HIV, human immunodeficiency virus.
Among the patients with bilateral osteonecrosis, two had both hips in stage II, two
had a hip in stage II and stage III in the contralateral, and the other six had a
hip stage III and the contralateral stage IV. The average time elapsed between the
first surgery and surgery on the contralateral hip was 12.2 months, with a minimum
of 2 months and a maximum of 18 months. The interval minimum of 2 months was in the
two patients suffering from necrosis in stage III and IV.
Surgical Technique
The first step of the surgical procedure was taking a 60 cc venous blood sample; after
centrifugation, using the GPS III Platelet Separation System (Biomet Biologics, Warsaw,
Indiana, United States) a formulation of PRP was obtained with over 90% of the available
platelets.
With the patient under lumbar or general anesthesia, placed on the operating table
in a supine position on a radiolucent table, in a sterile surgical field, aspiration
of 60 cc of autologous bone marrow in the anterior superior iliac crest was performed.
The next step was isolation and concentration of aspirated marrow to obtain MSCs.
After centrifugation, red blood cells and plasma are removed to keep only the nucleated
cells, which are stem cells, monocytes, and lymphocytes. The concentrate of the mononucleated
component thus obtained has a volume of approximately 6 mL. The resulting transplant
material has a concentration of mononuclear cells 6.9 times greater than the concentration
present in the aspirated bone marrow starting.
The procedure was performed during the same surgery time of core decompression of
the femoral head. With the patient placed on the operating table, a 3 cm longitudinal
incision was made at the level of the greater trochanter and after the subcutaneous
diaeresis, the fascia lata and the vastus lateralis were dissected until the lateral
cortex of the proximal femur was reached. Under fluoroscopic guidance (both anteroposterior
and lateral views), a Kirschner wire was introduced, as a guide wire into the necrotic
lesion.
At this point, after the introduction of the tissue protector over the guide wire,
the decompression of the necrotic area was performed with a 9 mm drill bit, monitoring
the direction under fluoroscopic control. The tip of the trephine was stopped at a
distance of 5 mm from the endosteal surface of the femoral head.
Afterward, the necrotic zone was thoroughly cleared using a sharp curette and the
X-REAM (Wright Medical Group) percutaneous expandable reamer for advanced debridement.
Fluoroscopic guidance was very useful at this stage, helping to estimate how thoroughly
the necrotic zone had been cleared. Once debridement was complete, the suction tip
from the PRO-DENSE Core Decompression Procedure Kit was used to remove the debrided
tissue, and flushing with a combination of irrigation and suction was performed. At
this moment, pre-prepared PRP and MSCs were injected into the core. Then the bone
core, soaked in MSCs, was turned, and synthetic (PRO-DENSE) injectable graft was used
to completely fill the surgically created bone defect ([Fig. 1 ]). The last steps were the suture of tissue layers and the wound medication.
Fig. 1 Surgical main step of the procedure: (A ) Introduction of a Kirschner wire as a guide wire into the necrotic lesion; (B ) decompression of the necrotic area with a 9 mm drill bit and (C ) cleaning using a sharp curette and the X-REAM percutaneous expandable reamer for
advanced debridement; (D ) suction tip used to remove the debrided tissue and flushing with a combination of
irrigation and suction; (E ) injection of PRP and MSCs, in the core; (F ) postoperative radiographic control.
Postoperative Rehabilitation
Patients were given a physiotherapy protocol to strengthen the gluteal muscles and
quadriceps after surgery and began to walk with aids without loading on the side operated
on, by on average of 40 days. For the following 3 months, progressive tolerance loading
was recommended. The indications for the load were the same for all patients, regardless
of the stage of the disease at diagnosis.
Statistical Analysis
Longitudinal analysis using Kaplan–Meier estimates and a log-rank test was used to
compare survival curves of patients with different Ficat stages, where survival rate
refers to the intervention of total hip replacement. The association between the ONFH
stage and the failure rate of core decompression treatment in association with PRP
and MSCs injection and synthetic bone graft substitute was investigated by Fisher's
exact test. For data analysis, a dedicated statistical software was used (SPSS vs
19, Chicago, Illinois, United States).
Results
Two hips of grade IV, in patients with bilateral disease, were excluded from the study
because they underwent directly to prosthetic surgery. Twenty-four hips were enrolled
in the study.
The rate of failure was statistically significantly higher in patients with disease
at stage III and IV compared with patients at stage I and II (p < 0.05). The survivorship of core decompression in association with the procedure
is 50% at 75 months of follow-up ([Fig. 2 ]). The survival rate was 80% for patients in early stage and 28.6% for patients in
advanced stage at 75 months. From the 24 hips included in the study, in 12 cases (50%)
joint replacement was necessary: two patients in stage II (25%) were scheduled for
total hip replacement after 2.5 years from core decompression, six patients were in
stage III (60%), of which four patients underwent hip replacement after 2.4 years
and two patients scheduled for surgical procedure after 6 years from core decompression,
and four patients in stage IV underwent hip replacement after 1.4 years (100%). Overall
patients undergo THA at a mean of 2.7 years ([Table 2 ]). When we compared Kaplan–Meier survival curves of patients in stage III + IV and
patients in stage I + II, we noticed that the survival functions are statistically
different (p < 0.05, log rank test), particularly in stage I + II where we had a greater surviving
core decompression, in comparison to patients in stage III + IV ([Fig. 3 ]).
Fig. 2 Kaplan–Meier survival curves for all patients at 75 months for prosthesis, after
core decompression.
Fig. 3 Comparison of survival curves at 75 months for core decompression.
Table 2
Failure rate in 24 operated hips
Stage
Failure n (%)
I + II (n = 10 hips)
2 (20)
III + IV (n = 14 hips)
10 (71.4)[a ]
I (n = 2 hips)
0 (0)
II (n = 8 hips)
2(25)
III (n = 10 hips)
6 (60)[b ]
IV (n = 4 hips)
4 (100)
Note: Failure has been defined as if arthroplasty was performed after core decompression,
or the patient was scheduled for hip replacement.
a
p < 0.05 stage I + II versus stage III + IV.
b
p > 0.05 stage III versus stage I + II.
Discussion
This study investigates the effectiveness of core decompression treatment in association
with mesenchymal cell implantation, PRP injection and synthetic bone graft substitute
in avoiding or delaying THA in patients with ONFH.
It has been demonstrated that core decompression, managed in the early stage of osteonecrosis,
reduces the intraosseous pressure in the femoral head and promotes vascular invasion
and regeneration of the necrotic tissue.[14 ]
[15 ]
[16 ] Mont evaluated 42 studies in which a total of 1,206 hips were treated with core
decompression and 819 had various nonoperative treatments.[2 ] Seventy four percent of the hips treated prior to collapse resolved adequately after
core decompression, and only 22.2% of the hips treated nonoperatively had satisfactory
outcomes.
The core decompression alone does not induce an adequate osteogenic activity in the
necrotic area and it has been proven that subchondral mechanical support in the weight-bearing
segment of the femoral head is essential during the period of revascularization to
prevent femoral head collapse.[17 ] A meta-analysis that evaluated core decompression alone found that further surgical
intervention was necessary in 16, 37, and 71% of Steinberg stages I, II, and III,
respectively.[18 ]
In 2010, Bednarek evaluated 63 patients (72 hips) with aseptic osteonecrosis of the
femoral, and all patients were treated with core decompression, followed by filling
the bone defect with autologous or synthetic bone grafts (PRO-DENSE).[19 ] After 1 year of follow-up, pain relief with preservation of a spherical femoral
head was obtained in 45 hips (63%). Recently Yu evaluated 19 hips in 18 patients with
ONFH, 6 hips in stage II C and 13 hips in stage III A, graded according to the system
of the Association Research Circulation Osseous and estimated by the modified index
of necrosis, treated with core decompression combined with synthetic bone grafts (PRO-DENSE).
The average age of the patients at the time of surgery was 48 years.[8 ] The clinical failure was defined as conversion to THA or progression in head collapse.
At the conclusion of the study, three hips at stage IIC and eight hips at stage IIIA
were converted to THA in an average of 8.5 months postoperatively. Advanced collapse
of the femoral head while awaiting THA was observed in the other six hips. Of the
19 hips, only 2 hips (10.5%) survived without further collapse in the 5-year follow-up.
This resulted in an 89.5% failure rate with early resorption of the grafting in an
average of 5.3 months.
These results suggested that core decompression, combined with an injectable calcium
sulfate and calcium phosphate composite graft (PRO-DENSE), was associated with high
failure rates in the early postoperative period.
Recently surgeons have considered a core decompression associated with autologous
bone marrow aspirates, which contain osteoprogenitor cells, and growth factors with
osteoinductive (bone morphogenetic protein) or angiogenic potential (vascular endothelial
growth factor) to enhance bone repair in the femoral head.[20 ]
Hernigou and Beaujean did a prospective study of 189 hips in 116 patients treated
with autologous bone marrow grafting and core decompression.[21 ] Six percent of patients with precollapsed hips required a total hip replacement
(stage I and II); 57% of patients with radiological signs of collapse before the core
decompression needed an arthroplasty (stage III and IV). The success rate was higher
in patients that received increased numbers of progenitor cells.
Persiani et al analyzed the clinical outcome of a series of patients affected by avascular
necrosis (AVN) of the femoral head and treated with core-decompression technique and
autologous stromal cells of the bone marrow.[22 ] Twenty-nine patients with 31 hips were treated. The clinical and radiological outcome
has been assessed through self-administered questionnaires (Harris Hip Score, visual
analog score [VAS], and Short Form 12), X-ray, and magnetic resonance. Of all the
examined hips, 25 showed relief of the symptoms and a resolution of the osteonecrosis,
11 of these were at stage I and 14 at stage II. Progression of the disease occurred
in six hips (2 stage II, 2 stage III, and 2 stage IV).
Tabatabaee et al recently evaluated the effects of core decompression and concentrated
bone marrow implantation on ONFH, recruiting 28 hips with early ONFH, randomly assigned
into two groups of core decompression with (group A) and without (group B) bone marrow
injection.[23 ] The mean Western Ontario and McMaster Universities Arthritis Index (WOMAC) and VAS
scores in all patients improved significantly (p < 0.001). MRI showed a significant improvement in group A (p = 0.046) and significant worsening in group B (p < 0.001).
In 2012, Sen et al treated 51 osteonecrotic hips in 40 patients randomizing into two
treatment groups. Patients in group A (25 hips) were treated with core decompression,
and those in group B (26 hips) received autologous bone marrow mononuclear cell instillation
into the core tract after core decompression.[24 ] The clinical score and hip survival were significantly better in group B than in
group A (p < 0.05).
A review of four studies and 219 hips compared the use of core decompression alone
or in association with MSCs and highlighted that MSCs lead to better results in terms
of progressed vascularization and clinical results (Harris Hip score).[25 ]
A small prospective study conducted by Gangji et al compared core decompression with
implantation of autogenous bone marrow cells with core decompression alone.[26 ] Bone marrow implantation significantly reduced pain and disease progression at a
5-year follow-up. In the bone marrow group, 3 of 13 hips (23%) progressed, compared
with 8 of 11 hips (73%) in the control core decompression group. However, the need
for THA was not significantly reduced in the bone marrow group (2 of 13 hips [15%])
versus the control group (3 of 11 hips [27%]).
As regards use of PRP, in 2014 Pak et al reported a case of a 43-year-old man with
early stage (stage 1) AVN of the femoral head treated with adipose tissue-derived
stem cells and PRP.[11 ] Patient's severe hip pain was considerably improved at 3 months after treatment,
with pain scores, ROM, and MRI showing near complete resolution of necrosis. Pain
scores, ROM, and MRI at 18 and 21 months after treatment indicated complete resolution
of AVN.
Our hypothesis was that a new CaSO4 /CaPO4 synthetic composite graft, the PRO-DENSE, in association with PRP, and autologous
mesenchymal cells, could have several theoretical advantages in enhancing the success
rate of core decompression: the PRO-DENSE provides mechanical support, MSCs and PRP
induce an osteogenic activity and stimulate bone healing thanks to the platelets'
growth factors contained in α granules such as PDGF, TGF-B, bFGF, EGF, and VEGF that
play a critical role in tissue healing, and differentiation of MSCs.[9 ]
[10 ]
[11 ]
The cumulative survivorship at 6.3 years was 50%, but this was elevated to 80% considering
only patients in stage I and II.
The overall failure rate was 50% (12 hips): two patients were in stage II (25%), six
patients were in stage III (60%), and four patients were in stage IV (100%).
Our results were similar to those of Rajagopal who conducted a literature review of
three studies with isolated core decompression.[27 ] Stratification based on Ficat stages demonstrates failure of core decompression
in later stages. The incidence of conversion to THA with stage I and II disease was
0 to 16.7% and 17 to 43.8%, respectively. However, 66% of patients with stage III
needed a THA after a minimum 2-year follow-up. These results are comparable to our
findings but in shorter follow-up, confirming that biological supplementation can
enhance healing and delay hip replacements.
According to the literature data, best results were obtained for patients at early
stage of osteonecrosis, before the collapse of the femoral head.[1 ]
[2 ]
[3 ]
[7 ]
[18 ]
[27 ]
A significantly higher cumulative survival rate was found for patients in early stage
compared with patients in advanced stage (80% versus 28.6%). Although clinical outcomes
improved in early and advanced ONFH stage after the core decompression with biological
supplementation, patients in early stage had better results compared with patients
in advanced stage.
A significant association was found between ONFH stage and the rate of failure of
this procedure: patients in stage I + II had an inferior failure rate compared with
stage III + IV (p < 0.05). The risk of failure was higher in patients at stage III and IV, as an irreversible
damage of the joint is already in place. Despite the small number of patients studied
and lack of control group, this study has showed a positive effect of PRP and MSCs
supplementation in the treatment of ONFH.
This study has several limitations: first of all the limited number of patients; furthermore,
we mixed four different techniques (core decompression, PRP, MSCs, and synthetic bone
graft). In this way it is impossible to clearly know which of the procedures was truly
effective in improving outcomes.
In conclusion, our results suggest that the technique is safe and good preliminary
results were obtained in patients with early stages of the disease with no reported
complications.
