Misconceptions (1): epiphyseal fusion causes cessation of growth.

At the end of a growing long bone, the epiphysis adjacent to the articular cartilage is separated from the metaphysis and diaphysis by a cartilaginous disk—the growth plate. When the bone reaches its appointed, genetically determined, length, two things happen: longitudinal growth ceases, and the epiphysis fuses with the metaphysis as the growth plate disappears. Since the publication of Lawson Wilkins’ classic text it has been widely believed by endocrinologists and pediatricians that growth stops because the epiphysis fuses. For example “. . .the epiphyses all become engulfed in the process of forming bone. . .” “. . .leading to short adult stature due to early fusion of the epiphyseal growth plates. . .” and “. . .sustained linear growth through puberty as a consequence of failure of epiphyseal fusion. . .”. This belief probably reflects the obvious truism that once fusion has occurred further longitudinal growth is no longer possible. I argue that it is the other way around—the epiphysis fuses because growth stops. In other words, fusion is a marker of growth cessation but not a determinant of it. But, I also demonstrate that epiphyseal fusion is an active process that, although necessarily preceded by, does not automatically follow, cessation of growth. The width of the growth plate depends on the relationship between the rate of addition of new cartilage at the distal end and the lifespan of the cartilage before it is replaced by cancellous bone at the proximal end. Cartilage addition depends on the rate of recruitment of new chondroblasts, the amount of matrix synthesized by each cell during its brief lifespan, which is about twice its own volume, and the increase in cell volume, which is about tenfold. Changes in the longitudinal growth rate, however, are due mainly to changes in the frequency of cell proliferation rather than in the other two variables. It is the number of new chondroblasts added each day that is the primary engine of long bone growth. Cartilage replacement depends on cessation of matrix production by chondrocytes, maturation and provisional calcification of cartilage, vascular invasion from the marrow of the metaphysis, resorption of some calcified cartilage by new chondroclasts, deposition of bone on the remaining cartilage to form the primary spongiosa, and replacement of bone with cartilage cores by bone without cartilage to form the secondary spongiosa. During most of the growth period, the processes of cartilage addition and replacement are coupled, so that the width of the growth plate does not change, but toward the end of the growth period the growth plate becomes progressively narrower before it finally disappears. Endochondral ossification represents the culmination of a sequence of changes in the cartilage cells and their associated matrix that must always occur in the same order and that require a minimum period of time. There can be no vascular invasion before the cartilage is mineralized and no mineralization before the cartilage has matured. Consequently, the notion that epiphyseal closure is the result of ossification occurring earlier and earlier and eventually catching up with the still proliferating chondroblasts is intrinsically implausible, not to say absurd. Would the primary spongiosa, having come to rest adjacent to the proliferative zone, send out spicules of mineral like fingers to strangle the dividing cells? Clearly, nothing like this happens. The growth plate narrows, not because cartilage replacement occurs earlier, but because cartilage addition occurs more slowly as the rate of chondroblast proliferation declines, and the growth plate does not begin to disappear until proliferation has stopped altogether. In 1966, I first came to realize that what I had been taught must be wrong, not from considerations of this sort (which at that time I could not have formulated clearly), but from the study of serial hand radiographs in a patient with pseudohypoparathyroidism. In this disease, target cell resistance to parathyroid hormone is often accompanied by short metacarpals and metatarsals, which in accordance with the current dogma are commonly attributed to premature epiphyseal fusion. In my patient, retarded growth was observed in the affected bones several years before fusion occurred (Figure 1), and similar observations were later made in another patient in whom “the shortness was not caused by early obliteration of the growth plate.” Further support for the primacy of growth was provided by its temporal relationship to skeletal maturation. Based on the appearance, enlargement, and fusion of the epiphyses, a maturation score can be assigned. The rate of increase in the score is the maturation velocity, for which the peak value occurs 1 to 2 years later than the peak height velocity, in both sexes. The most direct evidence was the observation that, in each of the 15 phalanges studied, longitudinal growth invariably ceased about 3 months before the earliest radiographic sign of epiphyseal fusion. This study confirmed in human subjects the earlier observation in rats that cell proliferation and longitudinal growth ceased about 3 weeks before the earliest histologic evidence of epiphyseal fusion. Collectively, the data demonstrate that epiphyseal fusion does not precede, but rather follows, the cessation of growth. Nevertheless, fusion is not simply the result of continued cartilage replacement in the same manner with no further cartilage addition. Fusion is an active process with its own hormonal controls, cellular mechanisms, and structural features. The epiphyses can remain unfused long after growth has stopped, if there Address for correspondence and reprints: Dr. A. M. Parfitt, 4301 W. Markham, Slot 587, Little Rock, AR 72205-7199. E-mail: parfittalwynm@ uams.edu Bone Vol. 30, No. 2 February 2002:337–339