Copyright © 2007 by The Journal of Bone and Joint Surgery, Inc.
Commentary & Perspective
Commentary & Perspective by
Tom Minas MD, MS*,
Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Posted October 2007
This prospective randomized study compares multiple
endpoints after treatment of cartilage defects of the weight-bearing femoral
condyles with either autologous chondrocyte implantation or microfracture. This
methodologically sound study confirms the difficulty of treating articular
cartilage defects and the progressive osteoarthritis that can ensue despite
treatment with cartilage repair techniques. The results demonstrated good
clinical improvement in 77% of patients in both groups and equal failure rates
of 23% in both groups at five years. More alarming was the radiographic
progression of osteoarthritis in one-third of patients in this young patient
cohort by five years after treatment, which correlates with poorer clinical
outcome and persistent pain.
There were forty patients in each treatment group, which was
the number that the original sample-size estimation had shown was required to
demonstrate a difference in the Lysholm and SF-36 scores between the groups of
at least 0.75 standard deviation from the mean, with an alpha level of 0.05.
The patients were independently evaluated at two years and evaluated by the
author at five years with complete follow-up on all patients (although some
were only contacted by telephone and/or mail).
The characteristics of the patients were similar between the
autologous chondrocyte implantation and the microfracture group with regard to
age (mean, 33.3 and 31.1 years, respectively), defect size (mean, 5.1 and 4.5
cm2, respectively), prior surgery (mean, 1.6 and 1.4 procedures,
respectively), and body weight (mean, 81 and 82.1 kg, respectively).
Eighty-nine percent of lesions were located on the medial femoral condyle, and
11% were located on the lateral femoral condyle.
The outcome measures included the validated Short Form 36
[SF-36] as well as nonvalidated joint-specific scores, such as the Lysholm
score, the International Cartilage Repair Society (ICRS) form, the Tegner score,
and a visual analog scale. Secondary end points included a histological
evaluation of biopsy specimens at two years (as assessed with a
semiquantitative four-point grading system) and a radiographic evaluation with
use of the classification system of Kellgren and Lawrence.
The pain sensitive scores (the SF-36 physical component score
and the visual analog scores) demonstrated the greatest clinical and
statistical improvements. This result is not surprising considering that
patients present with painful chondral lesions and that relief of pain is the
primary objective of the treating surgeon, with a secondary objective of
halting osteoarthritic progression of disease in a chondral defect. Although
the SF-36 physical component score was superior in the microfracture group at
two years, no difference in those scores was seen between the two groups at five
years. There was significant clinical improvement (p < 0.05) in both groups
at five years (72% of the patients had less pain, and 80% had improvement in
the Lysholm score). Both groups had substantial improvement in the SF-36 and
Tegner scores, although, with the numbers available for study, the differences
were not significant. The autologous chondrocyte implantation group showed an
initial slow improvement (understandably so, as the implantation procedure
involves open arthrotomy) and scored lower than the microfracture group at two years
but then "caught up" and had equal scores at five years.
Subsequent surgical procedures were common after both autologous
chondrocyte implantation (25%) and microfracture (10%). Autologous chondrocyte
implantation is known to have periosteal-related problems of overgrowth, and
25% matches the results obtained in my own series. The 10% reoperation rate in
the microfracture group, however, included surgery for adhesions and overgrowth,
which is somewhat surprising.
Both treatments had a prevalence of failure of 23% (nine of
forty patients). Failure was defined as requiring reoperation because of
symptoms due to a lack of healing of the chondral defect. Autologous
chondrocyte implantation failure occurred earlier (26.2 months after the
implantation), and microfracture failure occurred later (37.8 months after
treatment). The modes of failure (graft edge, total delamination, or central
degeneration) were not elucidated. Were the failures in the largest defect
sizes, and did this pattern differ between the microfracture and autologous
chondrocyte implantation groups? Failures were treated with repeat cartilage
repair by microfracture, autologous chondrocyte implantation and osteochondral
grafting, high tibial valgus osteotomy, and, for one failure in each group,
total knee arthroplasty.
The best histological quality at the two-year assessment was
found in knees that did not fail. This is not surprising and validates our
efforts to produce hyaline articular cartilage and fill the defect with hard,
smooth tissue that is well integrated to adjacent native cartilage and
underlying bone, thereby stabilizing the defect and maintaining a congruent
joint.
The 23% failure rate in both groups is high, and the 33%
prevalence of osteoarthritis should be assessed further. Axial alignment radiographs
were not mentioned in the index article1 and are presumed not to have
been made. Clinical assessment of mechanical alignment is difficult, with mild
hip varus and tibial genu varum possibly accounting for a substantial amount of
mechanical varus. As little as 2° of mechanical varus or valgus malalignment
could predispose patients in either group to premature graft failure and
progression of disease2.We perform osteotomies in one-third of our patients
with tibiofemoral disease, thereby restoring the mechanical axis to neutral,
and neither we nor the Gothenburg group (personal communication) have seen
joint-space narrowing.
It has been documented, however, that chondral defects alone
have resulted in early osteoarthritis despite the presence of only mild or no
symptoms. Messner and Maletius3 reported on twenty-eight young
athletes who received minimal treatment for full-thickness articular defects of
the knee. Lesions were traumatic in origin in the majority of these patients. At
an average follow-up of fourteen years, twenty-two patients had excellent or
good function. Twelve patients (43%) had radiographic evidence of joint-space
narrowing, however, which, according to those authors, is a rate "twice as high
as in patients with partial meniscectomy with initially intact cartilage and
similar follow-up time." Axial alignment was not discussed in their series.
Intralesional osteophyte formation has been reported to occur
in up to 25% of knees that have undergone microfracture repairs4,5.
This may account for the biopsies that reveal type-4 histology (inadequate
biopsy or no repair tissue—predominantly bone).
We are currently reviewing our patients who had failure of autologous
chondrocyte implantation after marrow stimulation techniques and comparing them
with our patients who had chondral defects that remained untreated. Our
unpublished data suggest that the failure rate associated with autologous
chondrocyte implantation after marrow stimulation is 2.5 times higher than that
seen after autologous chondrocyte implantation without the use of marrow
stimulation techniques. Poor attachment and early delamination of well-formed autologous
chondrocyte implantation grafts has been observed.
In the current study by Knutsen et al., 93% of patients were
previously treated with operative procedures, including débridements (twenty-nine
patients), Pridie drilling (three patients), and drillings or fragment fixation
for the treatment of osteochondritis dissecans (thirteen patients). These
treatments may have altered the subchondral bone, creating unfavorable conditions
for autologous chondrocyte implantation or microfracture or both.
The results from the Gothenburg group differed from the
results of this study in that those authors achieved good-to-excellent results
for 90% of their patients when the problem was with the weight-bearing femoral
condyle and for 89% of their patients who had osteochondritis dissecans6.
Durability of the weight-bearing femoral condyles was reported to be 96% at ten
years7. Is this difference related to technique or to cell culture,
which, in the Gothenburg series, was autologous serum with no cryopreservation
of the chondrocytes?
Long-term follow-up of the cohort in the series of Knutsen
et al. will indeed be interesting. Persistent pain correlated best with
Kellgren and Lawrence osteoarthritis changes and visual analog scores. Do
chondral defects predispose to osteoarthritis, despite treatment? Does subtle malalignment
or genetic predisposition to osteoarthritis determine the eventual outcome?
This study does clearly show, however, that hyaline cartilage repairs are
durable and that a good repair fill relieves symptoms regardless of the type of
treatment. Important questions remain: Can we enhance marrow treatments to form
hyaline repair over bone or fibrocartilage? Can we optimize autologous
chondrocyte implantation cultures so that they will have no fibrous component
and will integrate to underlying bone? Is microfracture a site-specific repair
as has been suggested5? Is autologous chondrocyte implantation
effective throughout the knee? Does prior microfracture adversely affect autologous
chondrocyte implantation?
Additional well-controlled studies are needed. I
congratulate the authors for an excellent collaborative study and for setting
the standard for future comparative trials to evaluate new techniques. This
should continue to be our goal.
*The author did not receive any outside funding or grants in
support of his research for or preparation of this work. The author or a member
of his immediate family received, in any one year, payments or other benefits
in excess of $10,000 or a commitment or agreement to provide such benefits from
a commercial entity (Genzyme Biosurgery). Also, a commercial entity (Genzyme
Biosurgery) paid or directed in any one year, or agreed to pay or direct,
benefits in excess of $10,000 to a research fund, foundation, division, center,
clinical practice, or other charitable or nonprofit organization with which one
or more of the authors, or a member of his or her immediate family, is
affiliated or associated.
References
1. Knutsen G, Engebretsen L, Ludvigsen TC, Drogset JO, Grontvedt T, Solheim E, Strand T, Roberts S, Isaksen V, Johansen O. Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial. J Bone Joint Surg Am. 2004;86:455-64.
2. Sharma L, Song J, Felson DT, Cahue S, Shamiyeh E, Dunlop DD. The role of knee alignment in disease progression and functional decline in knee osteoarthritis. JAMA. 2001;286:188-95.
3. Messner K, Maletius W. The long-term prognosis for severe damage to weight-bearing cartilage in the knee: a 14-year clinical and radiographic follow-up in 28 young athletes. Acta Orthop Scand. 1996;67:165-8.
4. Mithoefer K, Williams RJ 3rd, Warren RF, Potter HG, Spock CR, Jones EC, Wickiewicz TL, Marx RG. The microfracture technique for the treatment of articular cartilage lesions in the knee. A prospective cohort study. J Bone Joint Surg Am. 2005;87:1911-20.
5. Kreuz PC, Steinwachs MR, Erggelet C, Krause SJ, Konrad G, Uhl M, Sudkamp N. Results after microfracture of full-thickness chondral defects in different compartments in the knee. Osteoarthritis Cartilage. 2006;14:1119-25.
6. Peterson L, Minas T, Brittberg M, Nilsson A, Sjögren-Jansson E, Lindahl A. Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clin Orthop Relat Res. 2000;374:212-34.
7. Peterson L, Brittberg M, Kiviranta I, Akerlund EL, Lindahl A. Autologous chondrocyte transplantation. Biomechanics and long-term durability. Am J Sports Med. 2002;30:2-12.
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