REMARKS UPON THE

PHYSIOLOGY OF BONE IN RELATION TO BONE DISEASES*

EUGENE H. EISING, M.D., F.A.C.S.

NEW YORK

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HERE has been alIotted to me for discussion the group of bone tumors that are caIIed benign, together with

those borderIine growths which cIinica1 experience shows to have a tendency toward malignancy, in their reIation to some of the newer aspects of the physioIogy of bone.

In presenting this phase of the subject I have planned for the most part to avoid any descriptive detai1 of any one type of bone growth, or of entering upon any classification based upon histology, anat- omy, prognosis or malignancy; but to search behind this cIinica1 picture screen for the cause or causes of bone neopIasm of whatever histoIogica1 constituent.

consist of cartiIage aIone, and the other tumor cartiIage with a greater or lesser admixture of bone, and to concIude that they must be of an entireIy different nature; or, to reconciIe the histoIogica1 similari- ties between, for instance, Paget’s disease and bone syphilis, aIthough arising from totally different causes. It might be worth whiIe to search for some common stock or nature, residing in bone itself, fundamenta1 to a11 these pathoIogica1 processes and from which a11 take their origin.

I fee1 that it is within the scope of this assignment to present certain viewpoints which I have harbored in mind and which appear to me to be fundamental to a11 bone pathoIogy.

It has seemed to me that not onIy the benign tumors, but aIso the associated diseases to which bone is subject, incIuding the group of cystic disease, osteomaIacia, Paget’s disease and the inflammatory processes, aIthough resuIting from different etioIogic factors, represent in the main, differences in reactive tendencies towards invasion, in a tissue whose physioIogy is but poorIy understood.

From this aspect, in the light of our present knowledge, such an investigation wiI1 carry one away from a consideration of the bone ceI1, whose function is very littIe known, and lead to a consideration of the interceIIuIar materiaI of bone, spoken of as the caIc&ed matrix. It is this materia1 that is the finished product we caI1 bone, and it is here that we must seek the soIu- tion of those baflling problems presented in the pa.thoIogy of bone.

This thought necessariIy throws one back upon the embryology of bone, but with this phase I shaI1 burden you as IittIe as may be possible.

It seemed to me aIso that it was a fauIty starting point to assume a difference in etioIogy between, for instance, a chon- droma and an osteochondroma, and to ascribe for each a special presiding control determining that the one tumor shouId

Without disgressing too far, Iet me remind you that in 1873 AdoIph KijIIiker propounded his theory of the muItinucIeate ceIIs of deveIoping bone. These ceIIs he caIIed “osteocIasts” and considered them the direct agents of bone resorption.

Since that date, this theory of bone production and bone resorption has found its way into medica thought and firmIy established itseIf.

AI1 recent investigations tend to contro- *From the Hospital for Joint Diseases. Read before the Section of Orthopedic Surgery, New York Academy

of Medicine, May 20, 1927.1

367

368 American Journa.1 of 5urger.v Eising-Physiology of Bone OCTOBER, ,937

vert this theory and in fact attack the very foundations of our hitherto accepted ideas of the physioIogy of bone.

It is Iargely the resuIts of American research that have denied to the osteoclast and to the osteobIast the functions attrib- uted to them in the deveIopment of bone. Prominent among the names of workers in this field are Lewis, ShipIey, MackIin and Arey.

As stated by Arey’ : “The concIusions of Kolliker regarding the history and signif-

that “There seems to be no satisfactory evidence that the osteocIasts are the active causes of bone destruction. On the con- trary, they appear to be degenerating ce1Is.”

Con&ding this digression, I wouId add that this theory has greatIy retarded our search of the truth, and has stood as a barrier successfuIIy staying any scientific advance to the understanding of the physiologv of bone.

To me”it has been astonishing to find

FIG. I. AduIt rat skul1, fuII thickness, Bast method, showing Iacunar ceils and Haversian canaIs.

icance of the osteocIasts have gained great prominence. It shouId be kept cIearIy in mind, however, that his opinions were aImost whoIIy inferentia1. He neither offered direct proof of the origin of osteocIasts nor of their fate. The apparent reasonab1enes.s of these deductions, and the prestige of their originator doubtless account for their acceptance by numerous later investigators and for their wide- spread incIusion in texts.” And in his careful and elaborate study, he con- cIudes, “In working over this fieId and evaluating the tota evidence, the writer has become highIy sceptical concerning the potency of the osteocIasts in bone resorption.”

With Lewis, he wouId take the position

FIG. 2. FetaI guinea-pig skuI1, showing area of condensa- tion, rich in cells, chondromucoid substance and Haversian canaIs. Periphery shows interceIIuIar matrix in which Iime salts wiI1 be Iaid. Notice avascuIarity of large areas.

how tenaciousIy the authors of many recent textbooks and surgeons of the present day, fai1 to incorporate the prod- ucts of this newer research and appIy it to their daily probIems.

Approaching, therefore, the study of the structure of bone, it appeared to me that bone must be examined in its naturaI state and not after the introduction of the various artifices entaiIed in decaIc&ation and sectioning.

I have Iong maintained the point of view that it is the organic interceIIuIar matrix that is the eIement of bone structure that hoIds the key to the probIems of bone physioIogy and not the muItinucIente ceIIs.

NEW SERIES VOL. III, No. 4 Eising-PhysioJogy of Bone American Journal 01 Surgery 369

This organic intercellular matrix is a tribution is diffuse and shows no evidences collagenous material, the product of a of crystallization. DecaIciJication of such specialized differentiation of the mesen- bone sawdust shows the same organic thyme, and appears to possess the unique matrix seen in other preparations. biologic feature that I wouJd caJ1 for want PathoJogicaJ bone treated in the same of a better term “calcium coaguJation.” manner, shows the same caJc&ed units,

This collagenous material shows no but their contours are irreguJar, many are ceIJuIar structure but, after the ordinary bent or irreguIarly curved, the calcium is fixing methods, shows numerous Jong stria- irreguJarJy- distributed and they show a tions. Although, as just stated, there is no tendency to bizarre shapes. There are visibJe cellular structure in the organic Iocations where there looms into promi- matrix before caicification, after caIcifica- nence in the midst of such a unit, a well-

FIG. 3. Sawdust made from normal ox bone. Cakified FIG. 4. Bone sawdust, metastatic carcinoma. Trabec- trabecuIae lying in rows. ulae irregularly shaped, irreguIarly ossified.

tion a definite structure can be made stained bone ceI1 that is not seen in norma apparent. bone.

If sawdust is made from norma bone These bodies represent bone trabecuJae cortex, using a fairIy fine saw, and stained and demonstrate that caJc&cation is not by any method, the constitution and a diffuse process extending through a structure of the caJcified matrix can be homogeneous interceJJuJar materia1, but studied. Examinations have been made that there are definite and reguJar Iimita- of such sawdust from norma human bone, tions of the pre-osseous colJagenous pathoJogica1 human bone, and bone of substance which define the size and the ox and the rat. configuration of each trabecula.

In norma human, ox and rat bone there It wouJd be hazardous indeed, in our is practicaJIy an identica1 structure except present knowJedge, to caJ1 these bodies ceJIs, for some trifling variation in the size of even though their contours are not dissim- the calcified units. iIar to a connective-tissue cell, and

The genera1 contours of these units are though occasionaIJy in pathologica bone spindIe-shaped, sometimes lying singJy but a structure Iike a nucIeus has been seen. more frequentJy Iying in rows; their Iength and width are uniform. the caIcium dis-

In the attempt to study the bone matrix _ before caIc&cation, it was pJanned to

empIoy the agency of vita1 staining using into a fibriIIar network which later becomes pregnant rats. AIthough this appeared impregnated with the saIts of lime and to be a ready soIution to a diffrcuh probIem, produces bone. it was found that the parent anima1 became This colIoid material can be more readily deepIy stained and that the pIacenta studied in the vitaIly stained anima1 and successfuIIy filtered a11 of the excess dye can be seen before the fourth day. The and that not a particIe of the stain could neighboring structures are intenseIy stained be found in the fetus. The pIacenta pro- whiIe this bone juice remains colorless. vides compIete protection of the fetus This materia1 can be differentiated from from the diffusion of the dye. blood serum. The Iatter takes the coIor of

AIthough it is usuaIIy stated that vita1 the dye, whereas this bone juice remains staining stains the bones, in our experi- colorIess.

FIG. 5. Rat skuII, aduIt, vita1 staining, showing suture line. FIG. 6. Adult rat femur, cross section, vita1 stain. Mar-

row cavity and crest of femur, showing distribution of Haversian canaIs.

ments (using trypan bIue mostIy, but also aIizarin and Iitmus) the bone matrix did I beIieve that this geIatinous materia1 not take the dye, but the connective tissues represents an early form of pre-osseous of the periosteum and Iigamentous struc- materia1 and provides the framework for tures were deeply stained. The blood the structure that is destined to become vesseIs and Haversian canaIs could often caIIus and Iater bone. be seen stained. The origin of this materia1 is purely

Leriche and PoIicard2 in their recent conjectura1, but it is IikeIy to be a product book upon the physioIogy of bone, speak of the organic bone matrix, for if it came of a geIatinous Iiquid that occurs about from any other source, it wouId be Iikely the ends of fractured bones and that can to carry with it the coIor of the dye. be seen at about the fourth or fifth day A tremendous amount of labor has been after fracture. They refer to Gerdy who spent upon the probIem of the ossification in 1853 described this materia1, which was of the pre-osseous substance. In earIy spoken of by the older writers as “sue feta1 Iife the mesenchymatous structure, osseux” or bone juice. by a process of condensation, undergoes a

Leriche and PoIicard have watched the differentiation into transitory cartiIage. Fur- transformation of this gelatinous material ther condensation occurs, and nucIei appear. _ _

370 American Journal of Surgery Eising-Physiology of Bone OCTOBER, ,927

NEW SERIES VOL. III, No. 4 Eking-PhysioIogy of Bone American Journal of Surgcrv 371

This embryonic ceIIuIar cartiIage is composed of Iarge, vesicuIar, poIyhedra1 or irreguIarIy rounded ceIIs, among which is found a smaI1 amount of chondromucoid ground substance which surrounds the ceIIs.

This chondromucoid interceIIuIar sub- stance forms more or less compIete septa and represents the embryona1 matrix into which the bony material wiI1 eventuaIIy be laid.

A further differentiation, apparentIy

Here again, therefore, from an embryo- IogicaI standpoint we have a very definite statement that the caIcihcation of bone is not the product of the activity of the ceIIs of bone, but is a further differentiation of the organic matrix of bone.

From the purely inorganic chemica1 angIe al1 research into the probIem of bone production has signaIIy faiIed.

From this chemica1 angIe Watts” has made a series of microscopic investigations of the action of the two salts in aqueous

FIG. 7. Femur, one week-old guinea-pig, vita1 stain; incomplete ossification; open Haversian canals; bone ceIIs in pre-osseous tissue.

unaided by the ceIIuIar structure, occurs in this matrix producing a hyaline appear- ance, giving each celI the appearance of being surrounded by a distinct ceI1 membrane.

The carefu1 study by Carey3 of the mi- nute consecutive changes in the earIy stages of the deveIopment of bone Ieads him to the folIowing conclusions: “It is cIearIy demonstrated that degeneration of the parenchymatous cartilage ceIIs and calcifi- cation of the interceIIuIar cartiIaginous matrix are not processes intrinsic to the cells invoIved, as one is led to beIieve by reviewing the literature of these changes in early primary bone deveIopment, but are the natura1 resuItants of the differen- tiation of the fibroblastic perichondrium.”

FIG. 8. Rat femur three days old. IncompIete ossifica- tion of trabecuIae.

and coIIoid soIutions. His experiments would warrant no conclusion appIicabIe to the matrix except, perhaps, the negative one, that caIc&cation is not the resuIt of

On the other hand, the ihuminating experiments of Shipley, Kramer and How- Iand: demonstrate the avidity of the

direct precipitation.

decaIcified matrix for the saIts of bone. They pIaced pieces of cartilage and bone of rachitic rats in norma rat serum and caIcification occurred. The calcium phos- phate is deposited in the intercelIuIar matrix and never in the cytoplasm of the ceIIs themselves, just as is the case when heaIing occurs in vivo.

ShipIey found, furthermore, that, calci- fication does not begin on the surface of

372 American Journal of Surgery Eising-PhysioIogy of Bone OCTOBER, 1927

the shce of tissue as one might expect a priori, but the first deposits of Iime saIts are in the depths of the cartiIage and the process graduahy extends to the surface.

Numerous attempts have been made to produce caIcification in pieces of dead cartiIage, but these experiments fail to show calcification.

In summarizing, these authors concIude: “It is impossibIe to advance any theory to expIain the seIective deposit of the caIcium salts. The process is cIearIy not one of simple precipitation. It depends upon the activity of living tissue.”

From this survey of the pre-osseous materia1 and of the process of ossification, it seems demonstrated that the vita1 substance of bone structure is the coIIage- nous interceIIuIar materia1, and that the aberrations of bone, as presented in its pathoIogic states, must find their chief cause in this substance.

What theory, then, can be offered in the pIace of the one hitherto heId?

It must be understood at the outset that any theory of the physioIogy of bone must account not onIy for norma bone production but aIso, through aberrations of this normaI physiology, for the mani- festations presented in disease, including processes reactive to bacteria1 or other invasion, and tumors of bone.

In other words, the test of accuracy of any theory, is its II exibiIity to accommodate its appIication to a11 conditions that may properIy faI1 within its scope.

If we wiI1 accept, therefore, as a first premise, as stated above, that the vita1 substance of bone structure is the coIIage- nous interceIIuIar materia1, the probIem at once faIIs within the domain of the chemis- try of the cohoids.

A fact not mentioned before is the avascularity of the pre-osseous tissue. This substance is devoid of blood vesseIs to such a degree that it forces the infer- ence that the saIts of Iime, namely caI- cium phosphate and caIcium carbonate, aheady in the proper ratio, must be an inherent part of the coIIagenous matrix.

If we wiI1 concede that the interceIIuIar substance of bone consists of such a colloid body which contains in its sub- stance the specific elements of bone, it becomes easy to conceive how by bioIogica1 activity, which I have eIsewhere spoken of as “calcium coagmation, ” bone forma- tion might readily be established.

This conception does not involve any new or unknown action of coIIoid matter but is entirely paraIIe1 with the action of certain coIIoid substances both inside and outside of the Iiving organism. ExampIes of such bioIogica1 cohoid mutations occur, for instance, in the development of the teeth, the exoskeletons of various animaIs and, probably, in the formation of galI- stones and other concretions.

The property of reversibiIity which is pecuIiar to coIIoids wouId amply explain the destructive processes of bone absorp- tion and osteolysis.

This conception would, therefore, give the pIace of first importance to the cohag- enous interceIIuIar matrix, and regard it as a tissue that retains its vitaIity and hoIds in a reversibIe colIoida1 state the inorganic salts of bone. Any influence, be it chemica1, bacteriaI, vascular, nervous or gIanduIar, wouId exert its effect upon this substance, which in turn, wouId be reflected in a corresponding aIteration in the caIcified content.

An expIanation of the pathology of bone, however, rests not merely upon an expIanation of the mobiIization of the calcium content, but aIso upon the muta- tions of the organic matrix, reIeased from its caIcium saIts.

The decaIcified matrix, in view of its cIoseIy reIated functions and derivations from a common ancestra1 mesenchyme, might be converted into or repIaced by any form of connective tissue or cartilage, might degenerate into .cysts or might undergo malignant change.

This facility for changing the type of specialization is sometimes referred to as “plasticity ” and is especiaIIy pronounced in tissues of the connective tissue’ type.

Nr.u SERIFS VOL. III, No. 4 Ersing-PhysioIogy of Bone American Journal of Surgery 373

A mechanism such as the one described, would giv-e us, I believe, an explanation for a11 the various phenomena presented in the pathologic states of bone.

To be more specific, how, then, may this theory be applied to some of the common Iesions of bone?

In osteitis fibrosa cystica, the fibrotic change is paramount. The bony trabecuIae Iose their caIcium content. DecaIcification and caIcification are simuItaneous proc- esses. Areas of complete decaIcification are seen; in these regions the organic matrix appears to have undergone meta- pIastic changes and heahhy young con- nective tissue may be seen, or areas of new cartiIage formation.

The fibrosis may extend throughout the marrow cavity. DecaIcilication of the cortica1 bone occurs with fibrous repIace- ment involving the entire structure Ieaving only a she11 of IameIIar bone, covered by periosteum.

AIong with this librotic change is a strong tendency to the formation of cysts. The formation of cysts is most probabIy the resuIt of regressive changes of fibrous tissue, which compIetes its cycIe in the stage of Iiquefaction. Whether these cysts are primary or part of a more compIex bone lesion, their mechanism is probabIy the same.

The mechanism of the production of OsteomyeIitis affords a striking exampIe of this theory. Contrary to other lesion in which the decaIcihed matrix undergoes metapIastic changes, in osteomyelitis, owing to bacteria1 invasion or circuIatory dis- turbances, the organic matrix itseIf under- goes devitaIization and death. There foI- Iows, in consequence, an inhibition of further bioIogica1 inffuences upon the caIcilied coIIoid, resuIting in a mass of dead, inert caIcific materia1, destined to become sequestrum and dependent upon molecuIar disintegration for its remova1.

The reIationship between new bone formation and the organic matrix of bone in osteogenic sarcoma, has been discussed by me in a previous publication.6

REFERENCES

I. AREY, L. B. The origin, growth and fate of osteo- clasts and their reIation to bone resorption. Am. J. Amt., rgrg-zo, xxvi, 315-337.

2. LERICH. R.. and POLICARD. A. I-es nrobkmes de Ia I I

physiologic normaIe et pathoIogique de 1’0s. Paris, 1926.

3. CAREY, E. J. Direct observation on the transforma- tion of the mesenchyme in the thigh of the pig embryo. J. Morpbol., xxxvii, 1922, I--53.

4. WATTS, J. C. Behavior of caIcium phosphate and cat&m carbonate (bone satts) precipitated in various media, etc. Biolog. Bull., 1922, xliv, 280.

5. SHIPLEY, P. G., Kramer, B., and HOWLAND, J. Studies upon caIcification in vitro. Bio-&em. J., xx, 1926,

379-388. 6. EISIN~, E. H. Bone formation in osteogenic sarcoma.

Arch. Surg., 1926, xii, 867-886.

Discussion

DR. MAX A. GOLDZIEHER (by invitation): It is a very important point in the preceding paper that growth of bone tissue or destruction of bone is not a product of osteoblast or osteo- cIast activity, respectiveIy. For many years pathoIogy was and stiI1 is hampered by the conception of absoIute tissue and ceII specific- ity. The basic truth of the statement that every ceII derives from another cell of similar character is of course stiI1 to be maintained, particularly in the teaching of pathoIogy to medical students, but the exceptions from this ruIe are many and shouId not be overlooked. It is a fact that bone tissue and cartiIage are usuaIly formed in the fetus and Iater in life from a bone or cartiIage matrix, or from the specific periostea1 and perichondrial tissue. On the other hand, it cannot be denied that both cartiIage and bone can be formed quite independently as, for instance, in obsoIete tubercuIous foci in the Iungs. Bone formations in such foci contain a11 the features of real bone tissue and often include channels hIled with reguIar bone marrow. Similar observations in genera1 pathoIogy indicate that the formation of bone is not a specific property of specific cells or “OsteobIasts. ” It rather seems that connective tissue ceIIs of any kind may produce bone as a result of some, as yet unknown, st;muIation.

The question comes up whether the matrix of the bone tissue, which of course is not the prod- uct of the so-called osteoblasts, is an independ- ent Iiving substance as described in Dr. Eising’s paper, or whether it shouId be regarded as an interceIIuIar materia1 dependent on some ceIIs as to both nutrition and function. The

conception of an independent acelIuIar matrix tion and decaIcification, respectively, by far the is certaimy new and striking, but it is question- best materia1 avaiIabIe is that of bones with abIe that there is enough evidence to maintain osteomalacia or rickets. In such conditions, such a point which is in contradiction to our even better than in embryoIogica1 specimens, general knowIedge of Iive protoplasm. I wouId it can be demonstrated that caIcium content rather fee1 incIined to beIieve that the bone and formation of bone matrix are two totahy matrix is the product of some ceIIs and stil1 different processes, aIthough physioIogicaIIy remains under the inffuence of these ceIIs so constantIy combined. WhiIe in both pathologi- far as nutrition and function are concerned, caJ conditions there is a resorption of bone tissue similarly to the behavior of the coIIagenous including both the caIcium and the matrix, there connective tissue IibriIs. is SimuItaneousIy formation of matrix with-

Of utmost importance in Dr. Eising’s paper out calcium surrounding the bone trabecuIae is the emphasis laid upon the coIJoida1 chemical as a 1imeIess seam. It has been definiteIy shown aspects of bone pathoIogy, particuIarIy so far as that these osteoid seams are not due to decal- caIcification and decaIcification are concerned. cification, but to deposit of straight IimeIess It seems to me that the conception of osteoid. If the pathoIogica1 process tends decalcification on the basis of simpIe colIoida1 toward healing, the ostoid tissue, which is often chemica1 processes such as occur in vitro, can quite bulky, reveaIs intense caIcification. There be we11 maintained. On the other hand, I don’t is absoIuteIy no evidence to show that secondary fee1 confident that the process of caIcification caIciiication of osteoid has anything to do with wiJI be ever repeated in vitro experiments, as the activity of osteobIasts and there is no calcitication of bone seems to be dependent on better expIanation for this process than that of the action of Iiving celIs. I am purposeIy differ- some coIIoid chemica1 changes in the osteoid entiating here between the diffuse caIcification which, however, cannot be demonstrated but in of bone tissue as a vita1 process and the precipi- Jive bone tissue. It seems, therefore, that such tation of coarse granuIes of Iime in and about caIcihcation of osteoid tissue is dependent on necrotic tissues or exudates. In studying the the vita1 function of ceII eIements within the formation of bone and the processes of calcifica- bone matrix.

374 American Journa.1 of Surgery Eising-PhysioIogy of Bone OcroEm7, rg2,