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Skeletal metabolism in paget's disease of bone.

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SKELETAL METABOLISM IN
PAGET’S DISEASE OF BONE
STEPHEN M. KRANE
Paget’s disease of bone is characterized by focal
resorption of existing bone followed by the deposition of
woven and lamellar bone in a characteristic pattern. GIthough bone turnover may be markedly increased, the
coupling between formation and resorption is maintained. Metabolically there is increased efflux and influx
of mineral ions in the involved areas. In addition, there
is a parallel increase in resorption of matrix components, particularly collagen, with increased excretion
of degradation products containing 4hydroxyproline,
hydroxylysine, and its glycosides. A portion of the urinary 4-hydroxyproline and hydroxylysine is in the form
of peptides of approximately 5,000 daltons which appear
to be related to collagen synthesis. Circulating levels of
other organic matrix components are also increased
such as procollagen fragments and the y-carboxyglutamic acid-bone protein. The increased levels of most of
these metabolites return toward normal with specific
therapy. The pattern of change suggests that bone resorption is decreased initially with therapy followed by a
coupled decrease in formation.
The primary event in Paget’s disease of bone is
generally assumed to be a focal, intense resorption of
existing bone (1,2). This is seen typically on histologic
specimens as scalloped resorption spaces filled with
osteoclasts which may assume bizarre shapes and conFrom the Department of Medicine, Harvard Medical School
and the Medical Services (Arthritis Unit), Massachusetts General
Hospital, Boston, Massachusetts 021 14.
Supported by USPHS grants AM03564, AM04501, and
AM07258. This is publication No. 821 of the Robert W. Lovett Memorial Group for The Study of Diseases Causing Deformities.
Address reprint requests to Dr. Stephen M. Krane, Massachusetts General Hospital, Boston, MA 021 14.
Arthritis and Rheumatism, Vol. 23, No. 10 (October 1980)
tain many more nuclei than normal. Even in biopsies
taken from the earliest lesions, however, there is some
evidence of osteoblastic response, most often characterized by the deposition of lamellar and/or woven bone
adjacent to areas of irregular resorption usually on opposing portions of the trabeculae. We have assumed
that the osteoblastic response is somehow coupled to the
resorption, but the mechanism of this coupling remains
undefined (3,4). In many instances the formation of new
bone seems to be excessive and not simply governed by
resorption in view of the occurrence of sclerotic bone
and remodeling that exceeds the normal dimensions of
the involved bone. The increase in the new bone formation is at the expense of hematopoietic marrow and fat.
CALCIUM METABOLISM
Despite the production of sclerotic and enlarged
bones, assumed to represent an exaggerated response to
resorption, under most circumstances in Paget’s disease
the formation/resorption coupling is extraordinary. It
can be calculated that mineral ions move in and out of
the skeleton occasionally at a rate over 20-fold normal
without alterations in the serum concentrations of these
ions. Estimation of these rates of ion movement has
been obtained largely from the analysis of the changes
in specific activity in urine and plasma as a function of
time following the administration of pulse tracer doses
of radioactive calcium, such as those illustrated in Figure 1. The calculations of the radiocalcium kinetics involve assumptions for which proof may not exist. However, if one also calculates the magnitude of matrix
resorption based on the excretion of collagen degradation products, the rates of bone turnover in Paget’s disease are extremely high and the estimates from the in-
KRANE
1088
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Figure 1. Change in specific activity after administration of a pulse
tracer dose of radiocalcium (45Ca) to a patient with Paget’s disease of
bone. The arrow indicates the slope of disappearance of radiocalcium
from serum and urine of a normal subject (Reproduced from Krane
SM et al: J Clin Invest 35:874-887, 1956, with permission). Since the
data for specific activity are on a logarithmic scale, the difference in
attained specific activity between the pagetic patients and the normal
subjects is marked.
terpretation of radiocalcium kinetics may not be that
inaccurate.
We have been impressed with the magnitude of
calcium turnover in the presence of only minimal
changes in calcium balance. This is illustrated by the
example shown in Table 1. When this patient with Paget’s disease was studied on a low calcium intake, she
was very nearly in calcium balance (5). However, instead of a normal bone formation (calcium deposition)
rate of approximately 500 mg/24 hr, the amount of calcium entering bone each day, her bone formation rate
was over 10 times normal, associated with a nearly
equal bone resorption rate (formation/resorption coupling).
It is extraordinary that despite the large amounts
of calcium removed from the skeleton every day, similar
amounts must be redeposited without altering plasma
calcium concentrations or resulting in marked changes
in urinary calcium excretion. It is possible, therefore,
that bone formation represents an important homeostatic mechanism for maintenance of the normal plasma
calcium concentration ( 6 ) . The organism could not
manage an influx into the extracellular fluid of approximately 5 gm of calcium daily except by routing the cal-
cium back into the skeleton, without marked depletion
of skeletal mineral mass or intolerable changes in the
plasma calcium concentration. As a consequence of
these large increases in calcium entry into the skeleton,
a pulse tracer dose of radiocalcium is rapidly cleared
from the plasma in patients with Paget’s disease (3), accounted for entirely by increased skeletal uptake. The
calcium that enters bone becomes “fixed” and no longer
available for short-term exchange. On the basis of
quantitation of the products of radiocalcium decay, it is
also apparent that once radiocalcium is “fixed” in the
skeleton, it appears to be insulated from the circulation
(3).
Long-term exchange reactions may explain these
observations, but alternatively, one can envision the formation of new bone with a rapid accumulation of the
mineral phase. As the level of plasma radiocalcium rapidly falls while the concentration of stable calcium remains constant, the new calcium-phosphate crystals are
rapidly covered by an outer surface of nonlabeled calcium. This increased rate of formation of the calciumphosphate mineral phase in bone as well as increased
blood flow to bone (7) accounts for the increased uptake
in Paget’s disease of other bone-seeking isotopic preparations (8) currently used in bone scanning procedures.
The maintenance of the equilibrium between influx and efflux of calcium and other mineral ions from
the skeleton as well as the high rate of ion exchange in
Paget’s disease depend upon local cellular events. The
function of the cells involved in this process can be perturbed by external influences in the same direction as
the cells of normal bone. For example, a fracture in pagetic bone markedly distorts the formation-resorption
equilibrium (1-3). This is manifested in part by an increase in urinary calcium excretion, which gradually returns to normal as the fracture heals, although this may
take many months or even years.
The equilibrium is also perturbed as a result of
immobilization of the whole skeleton or a portion
Table 1. Calcium metabolism in a patient* with Paget’s disease of
bone
Metabolic function
Calcium mg/24 hr
Intake
Urinary excretion
Fecal excretion
Bone formation
Bone resorption
120
129
68
5572
5657
* This woman with Paget’s disease was 67 years old at the time of
study (5). Alkaline phosphatase was 67 Bodansky units (normal <
4.5). Calcium kinetics were calculated (3) from data, some of which
are shown in Figure 1.
SKELETAL METABOLISM
thereof. Immobilization somehow results in increase in
the rate of resorption in pagetic as well as normal bone,
and decrease in the rate of bone formation. Thus, the
gap between formation and resorption is widened, resulting in loss of bone mass accompanied by a markedly
negative calcium balance, reflected mainly by increases
in urinary calcium excretion. Under unusual circumstances, these perturbations may be severe enough to
elevate the concentration of plasma calcium despite the
restraints imposed by homeostatic adjustments of parathyroid gland function. As a rule, however, the coupling
between bone formation and resorption is so complete
that the majority of patients with Paget’s disease of
bone have normal urinary calcium excretion, even when
their disease is extensive, as long as they are active and
have sustained no recent fracture.
COLLAGEN METABOLISM
When bone is resorbed, there is resorption not
only of the ions from the mineral phase, but components from the matrix as well. The major component
of the organic matrix of pagetic and normal bone is type
I collagen. Other substances are also found in normal
bone matrix such as sialoproteins, glycoproteins, phosphoproteins, and specific proteins containing y-carboxylated glutamic acid residues (9). Markers are available
for several of those components which also permit
quantitation of matrix resorption.
The collagen of normal bone is type I collagen
(10). Small amounts of type I11 collagen may also be
found, usually associated with blood vessels. The few
specimens of pagetic bone that we have examined by digestion of demineralized specimens with cyanogen bromide followed by chromatography (Byrne MH, Krane
SM; unpublished) have not shown the presence of detectable amounts of type I11 collagen peptides. Moreover, bone fragments from patients with Paget’s disease
synthesize only type I collagen in culture whereas skin
fibroblasts synthesize both types I and I11 collagens (1 1).
It has not been proved, however, that all of the collagen
in lamellar and woven pagetic bone is type I. The composition of the loose, fibrous stroma replacing the fatty
and hematopoietic marrow in areas of bone involved in
the pagetic process has not yet been determined. Although normal bone contains apparently the same type
I collagen as skin, it has not yet been proved in humans
that these type I collagens have identical amino acid sequences, although it is assumed that they do.
Normally, however, skin and bone collagens are
not identical from the point of view of posttranslational
1089
modifications (12,13). These modifications include the
pattern of glycosylation of the hydroxylysine residues
and the pattern of the reducible crosslinks analyzed after reaction with sodium borotritide (14-16). The helical
portions of the collagen molecules also contain unique
carbohydrate moieties in which some hydroxylysines
are linked glycosidically to galactose residues and some
of the galactose residues are also linked to glucose. In
normal bone the ratio of glucosyl/galactosyl hydroxylysine (Hyl[Glc-Gal]) to galactosyl hydroxylysine
(Hyl[Gal]) is 0.47 rf: 0.009, compared to 2.06 & 0.47 in
human skin (13). In 5 pagetic bone samples examined,
the ratio of Hyl[Glc-Gal]/Hyl[Gal] was 0.396 to 0.743,
not significantly different from normal (17). The reducible crosslinks of normal bone collagen involve predominantly the reduced Schiff base of hydroxylysine
and hydro x y 1y s i n e a Id e h y d e s (hydro x y 1y s in 0hydroxynorleucine) (14- 16). A minor crosslink, hydroxylysinonorleucine, has been found to be relatively
increased in pagetic bone compared to normal bone
(18), although the significance of this finding remains to
be established.
The resorption of bone collagen, presumably
carried out by osteoclasts in the resorption lacunae, is
probably accomplished by the release of collagenolytic
enzymes from the osteoclasts. These enzymes are incapable of resorbing collagen from mineralized bone
and can act only after the mineral phase is completed
(19,20). The collagen molecules fragmented and solubilized from the collagen fibers are then denatured and
can be cleaved by proteases present in the local environment. These proteases release peptides containing portions of the collagen molecules, which include marker
amino acids that result from posttranslational modifications and are unique for collagen-like sequences. These
markers include 4-hydroxyproline, hydroxylysine, and
hydroxylysine glycosides. Since the hydroxylation of
both lysyl and prolyl residues occurs after incorporation
of these amino acids into the growing polypeptide
chain, and the hydroxylated amino acids are not reutilized for collagen biosynthesis, measurement of their excretion provides reasonable quantitation of collagen resorption. Unfortunately, free 4-hydroxyproline released
from collagen peptides is rapidly metabolized by the hydroxyproline oxidase in the liver to yield degradation
products not readily measurable (21,22).
Therefore, although determination of the urinary
excretion of 4-hydroxyproline peptides can give a reasonable measure of the relative rates of matrix resorption, such rates are underestimated because of irregular
oxidation of the free amino acid. Although there are no
KRANE
1090
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Figure 2. Urinary excretion of total urinary 4-hydroxyproline peptides in patients with Paget’s disease of bone. (Reproduced from
Franck WA et a1 Am J Med 56592-603, 1974, with permission.) The
extent of the Paget’s disease was estimated from the radiologic survey
of the patient’s skeleton.
specific data in patients with Paget’s disease, based on
other studies (23), it is probable that the hydroxyproline
excreted represents only 10-20% of that actually released from the resorbing matrix. We presume that the
increased excretion of urinary 4-hydroxyproline in Paget’s disease is from bone, although such measurements
provide no direct information regarding the source of
collagen degradation products, since the content of hydroxyproline varies relatively little from one tissue collagen to another. Nevertheless, the excretion of 4-hydroxyprohe-containing peptides is markedly increased
in patients with Paget’s disease (24), and the increase
generally parallels the extent and “activity” of the skele:z! prcresa (2-5){Fig~re
2). 1xfi-3rsas.,?omd..dd
.hu
$ ..,..mans excrete less than 40 mg of 4-hydroxyproline peptides daily, patients with Paget’s disease occasionally
excrete in excess of 1 gm.
Despite the fact that measurement of 4-hydroxyproline-peptide excretion underestimates collagen resorption, it can be used to calculate a rate of bone resorption which averages approximately one third of the
value calculated on the basis of radiocalcium kinetics
(4). Since the rate of matrix resorption is probably underestimated by measuring 4-hydroxyproline excretion
and overestimated by determining radiocalcium kinetics, the true value probably rests somewhere between
but nevertheless indicates the extraordinary magnitude
of the process of bone turnover in Paget’s disease.
Measurement of hydroxylysine and its glycosides
provides further information about the source of collagen degradation since in human collagens these components are present in concentrations specific for the
different collagenous tissues. In pagetic subjects with total excretion of 4-hydroxyproline greater than 2
pmoles/mg creatinine, the pattern of urinary excretion
of hydroxylysine and its glycosides is consistent with the
interpretation that bone is the only or major source of
collagen degradation (17,26) (Figure 3). On the other
hand, in patients with inactive or limited disease and in
normal subjects, the pattern of excretion of hydroxylysine and its glycosides is most consistent with the interpretation that some other component contributes to
urinary collagen degradation products. This could involve skin collagen, as well as the first component of hemolytic complement, Clq (17).
Most of the 4-hydroxyproline in urine is present
in the form of dialyzable peptides which represent approximately 90% or more of the total. Urine, however,
also contains 4-hydroxyproline in a nondialyzable fraction with a molecular weight of approximately 5,000
daltons (6,27,28). These nondialyzable peptides, which
mole /mole
0
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I
2
1
1
1
4
Hyp /CreOlinine
I
6
I
I
8
1
I
0
I
40
p moles / mg
Figure 3. Urinary excretion of total urinary Chydroxyproline (Hyp)
as well as hydroxylysine (Hyl) and its glycosides, Hyl(GlcGa1) and
Hyl (Gal). (Reproduced from Krane SM et a1 J Clin Invest 59819827, 1977, with permission.) Note that at very high 4-hydroxyproline
excretion rates (-2 pmoles/mg creatinine), the ratio of Hyl (GlcGal)/
Hyl(Ga1) was approximately 0.5, a value similar to that in bone collagen. At low excretion rates, this ratio rose. The low excretion rates
were in normal subjects before and after calcitonin injection to decrease bone formation. The high excretion rates of 4-hydroxyproline
were obtained from patients with Paget’s disease.
SKELETAL METABOLISM
1,
I,
1091
proal
I proal
I
s-s’
S‘,
I
Amino
Extension
I 1
Short
Helix
I
I /
Major
Helix
Telopept ides
S,
I
I I
1
pfoQ2
4
Carboxy
Extension
- 1
Figure 4. Schematic representation of the structure of type I procollagen. Note the break in the major helix in
this illustration, necessitated by its considerably larger relative length compared with other portions of the molecule. Adapted from Prockop et al (29) and Morris et a1 (31).
have an amino acid composition similar to that of collagenous proteins in general and contain hydroxylysine as
well as 4-hydroxyproline, are excreted in increased
amounts in the urine of patients with Paget’s disease. It
has been observed that when tracer doses of I4C proline
are given to pagetic patients and the rate of incorporation into urinary “C hydroxyproline is measured, radioactivity appears within hours in the nondialyzable peptides, suggesting that they are related to collagen
synthesis rather than collagen degradation (27,28). It
has not been shown, however, which collagen molecules
are the source of these peptides or from where in the
structure they are derived. The peptides appear to be
heterogeneous and their composition did not correspond with known sequences of type I collagens.
It should be emphasized, however, that the entire
amino acid sequence of human type I collagen has not
been reported. Since there are many homologies so far
demonstrated in collagen sequences among several animal species, it is unlikely that marked differences would
be revealed in human type I bone collagen compared
with other animal type I collagens already sequenced.
We suggested that these rapidly labeled urinary
peptides could arise from a specific cleavage of certain
collagen molecules that never become mature (29-3 l),
as has been shown in other systems. Cleavage of a portion of the collagen molecule normally released prior to
assembly of collagen fibrils might also be a source of
these peptides. The amino terminal extension portions
of procollagen molecules have been shown to have collagen-like regions which are cleaved prior to deposition
of the collagen molecule in the fibril (29-32). These collagen-like regions are located in the carboxy terminal
portion of the amino terminal procollagen extensions
(Figure 4) and contain approximately 50 residues. The
peptide analyzed from the a1 chain of calf skin type I
collagen does not contain hydroxylysine and has a composition different from that of the human urinary polypeptides. The urinary peptides could be derived from
the a 2 chain or alternatively a different sequence might
be present in human type I procollagen, especially that
from bone. It is also possible that the fibrous stroma
that replaces the marrow in pagetic lesions contains
type I11 collagen, thus the urinary peptides could have
their source in the amino terminal extensions of type I11
procollagen.
Procollagens contain extensions at the carboxy
terminal end of the molecule, which are also cleaved
prior to deposition of the collagen fibril (Figure 4). A
radioimmunoassay has been developed which is specific
for the disulfide linked triple chain carboxy terminal extension of human type I procollagen (33). Sera from patients with Paget’s disease contain increased concentrations of this carboxy terminal fragment which averaged,
in a small series, 52 pg/dl, compared to a normal range
of 5-15 pg/dl (34). The concentrations in pagetic sera
correlated roughly with the level of alkaline phosphatase activity as well as with the urinary excretion of 4hydroxyproline peptides. The highest value approximated 200 pg/dl.
Treatment of Paget’s disease with calcitonin or
diphosphonates is accompanied by decreases in 4-hydroxyproline-peptide excretion as well as in the levels of
serum alkaline phosphatase activity. The levels of the
carboxy terminal procollagen peptides also return to
normal after treatment with disodium etidronate. It is
probable that the carboxy terminal procollagen type I
extension peptides are derived from portions of the
molecule not incorporated into the collagen matrix of
bone. It is also conceivable that small amounts of these
cleaved peptides are trapped in bone as the fibril is
formed and are released only when the bone matrix is
KRANE
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resorbed. The reported pattern of change in the procollagen peptides relative to that of alkaline phosphatase activity and urinary 4-hydroxyproline excretion
could not distinguish among these possibilities. The carboxy terminal portions of the procollagen molecules so
far analyzed do not contain collagen-like sequences and
therefore the approximately 5,000 dalton collagen-like
peptides present in the urine of patients with Paget’s
disease are probably not derived from the carboxy terminal extensions.
Examination of the amino terminal peptides has
revealed biological properties of considerable interest.
The addition of the amino terminal peptides prepared
from a collagenase digest of either calf pro al(1) chains
or pro aI(II1) chains inhibits collagen synthesis in cultured bovine or human dermal fibroblasts, with 50% inhibition observed at a concentration of 4-6 pM (35).
The peptides appear to inhibit the translation of messenger ribonucleic acid coding for type I procollagen,
which raises the possibility of a regulatory function in
collagen biosynthesis (36). How this information can be
integrated into the interpretation of the events in pagetic bone where both collagen resorption and formation are so enormously increased, however, remains for
the future.
Levels of alkaline phosphatase activity are char-
acteristically elevated in serum of patients with Paget’s
disease (1,3,37). Since most of the alkaline phosphatase
is found within osteoblasts, it is assumed that the levels
of alkaline phosphatase in serum of pagetic patients reflect the activity of the overall extent of the pagetic
process and the “activity” of the bone-forming cells.
Observations that the levels of alkaline phosphatase activity correlate with those of urinary 4-hydroxyproline
excretion provide further evidence for formatiodresorption coupling. When bone resorption is acutely decreased, for example, by the administration of calcitonin, one can observe a pattern of change in the
excretion of matrix markers (Figures 5 and 6) consistent
with a decrease specifically in the resorption of bone
collagen (6,17). In some individuals there may be acute
responses of bone formation to reductions in bone resorption.
CONCLUSION
In the future, it is likely there will be many more
markers available to evaluate bone metabolism in human subjects. Since Paget’s disease is among the disorders characterized by extraordinary perturbations in
bone turnover rates, such markers will be of considerable use in understanding pathophysiology as well as
--
p moles / mg
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HYD
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Hyl
HYP
Hyl (Glc G a l )
Hyl ( G a l )
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CALCITON IN
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1600
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Figure 5. Urinary excretion of urinary 4hydroxyproline (Hyp) as well as hydroxylysine (Hyl) and
its glycosides Hyl (GlcGal) and Hyl (Gal) after injection of salmon calcitonin in a patient with
Paget’s disease of bone. (Reproduced from Krane et a1 J Clin Invest 59:819-827, 1977, with permission.) Note the reciprocal rise in the ratio of Hyl(GlcGal)/Hyl(Gal) as total 4hydroxyproline
excreted fell. This change in the ratio of the glycosides plus the rise in the ratio of urinary Hyl/
Hyp are consistent with a decrease in resorption of bone collagen and relative increase in contribution from other sources of collagen.
SKELETAL, METABOLISM
1093
REFERENCES
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I
1
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-
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0600
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1200
i800
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T I M E O f DAY
Figure 6. Response of urinary 4hydroxyproline (Hypro) in diffusate
and retentate after dialysis, as well as plasma calcium concentration,
after intravenous infusion of porcine calcitonin (PCT) in patient GC
with Paget's disease of bone. The protocol is similar to those in studies
previously reported (6). Note that the fall in serum calcium concentration and total urinary 4-hydroxyproline excretion after calcitonin infusion was accompanied by a relatively greater fall in the diffusate
than the retentate fraction and a rise in the ratio of retentate/diffusate. This is consistent with a relatively greater decrease in bone resorption than formation.
evaluating therapy. The utilization of radioimmunoassays for the procollagen extensions are an example of
how these markers may be of value. A further illustration is the recent finding that the specific noncollagenous bone protein that contains y-carboxyglutamic acid (38,39) can also be identified by
radioimmunoassay in the serum of normal human subjects (40). The levels of this protein are also increased in
the serum of patients with Paget's disease, although it
has not yet been demonstrated whether this increase reflects increased resorption of existing matrix or the synthesis of new matrix.
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DISCUSSION
Dr. Avioli: Jane Lian has processed 22 urine samples of
patients with Paget’s disease and no difference was
noted in total GLA protein excretion.
Dr. Krane: Dr. Lian is measuring y-carboxyglutamic
acid or total GLA in urine, but the radioimmunoassay measures specific bone GLA protein, known as
osteocalcin. Since she is not measuring the specific
protein, she might not detect these increases.
GLA proteins are synthesized by chick bones in
organ culture. The sequence is probably different
from other GLA proteins. The chemical assays may
be misleading. The carboxy terminal pro 1 radioim-
munoassay looks interesting, but circulating levels
are low compared to the amounts of hydroxyproline
excreted in the urine; that is, they are still in terms of
micrograms/liter. Unless the carboxy terminal peptides have an extremely rapid turnover, collagen
turnover is not accounted for. A true biosynthetic
marker could enable us to distinguish formation
from resorption, but it is still conceivable that a small
amount of the carboxy terminal material is laid down
and never gets completely resorbed. Then when bone
is resorbed, the carboxy terminal peptides that were
residuals of formation are released.
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