Part 35

Osteitis deformans is a chronic constitutional affection characterized by the absorption of compact bone, chiefly in the cranium and long bones, and the laying down of fibro-osteoid tissue in such an excess as to enlarge the affected bones. This material, which is soft and cuts with reasonable ease, has calcareous matter in it as shown by Röntgen- ray examination. Paget described it in a classical article in 1876[48] since which time the reported cases have mounted to three hundred and fifty. Because it has only been recognized in its best developed stages, it may be that early mild or arrested cases have been overlooked. Judging by the instances claimed to have been found in museum collections of bones, it is probably an affection dating to antiquity. So far these remarks apply only to man but in lower animals the reports are very few and those are not available in the original. The abstracts and references show considerable confusion. The names osteitis deformans, osteoporosis, osteitis fibrocystica, osteodystrophia deformans and osteosarcoma, leontiasis ossei, etc., are used almost interchangeably. In 1901 Barthelemy[49] described a condition (_Maladie du Son_) in horses in which there was a marked enlargement of the head and of the epiphyses of the long bones. His cases were more allied to osteitis fibrosa cystica. Paget’s disease always attacks the diaphyses of the bones and not the epiphyses. Goldman[50] described typical examples of this condition in fowls. Jöst[51], in one communication, described a case in a horse which he says was identical with that condition described by Paget as osteitis deformans and by Virchow as leontiasis ossei; he also refers to similar cases in goats and monkeys. Rossweg[52] found it in goats. In wild animals the only suggestive article found was by Jöst but the description was probably of an osteoporosis and a craniosclerosis which occurred in a young lion and a monkey. All the communications deal with either domesticated animals or those in captivity.

The etiology of this condition is as obscure to-day as it was at the time of Paget’s first description. Prince thought it might be due to a defect in some peripheral nerve or nerve centre or to a tract degeneration. Cases have been reported in conjunction with a myelitis. There has been however little on which to base these suppositions. Paget felt that the process was at least upon an inflammatory basis and deduced this from the enlargement and the excessive production of an imperfectly developed structure with increased blood supply. Many felt that rickets, osteomalacia and osteitis deformans were all manifestations of the same disease. A bacterial cause was proposed by Arcangelli who claimed the discovery of diplococci and improvement from a vaccine. Lancereaux[53] and Richards felt that focal infection played a profound rôle in the etiology. However all other observers fail to isolate an organism from the bones or to get improvement from removal of infectious foci. Heredity has been held responsible in seven per cent. of the cases in human beings.

That some inflammatory factor is partly responsible seems plausible when one considers the active growth of fibrocellular tissue in the endo- and periosteum. The more interesting theories go back to perversions of internal secretions, pituitary, parathyroid etc., (Macallum & Vogtlein). Higbee and Ellis[54] say in relation to the neurotrophic theory that if the neurotrophic mechanism governs metabolism and is influenced by the activity of the ductless glands, there is considerable likelihood that its disturbance may possibly be found to be the cause.

Da Costa[55] believed the disease to be a disorder of bone metabolism probably dependent on the absence or perversion of some internal secretion. There is much evidence on hand to indicate that disorders of the ductless glands do influence bone metabolism, and changes in these glands have been reported in cases of Paget’s disease, although the findings and lesions have been far from uniform or distinctive or even confined to one gland. Eight cases were reported as possibly due to a hypothyroid condition; pituitary changes were found in three; adrenal changes in one; parathyroid reported missing in two; three had sclerotic thyroids. Many case reports make no mention whatever of the glands of internal secretion.

Da Costa interprets the retention of calcium, phosphorus and magnesium, with the sulphur loss found in these cases, as indicating a stimulated osseous or osseoid formation accompanying the resorption of a highly sulphurized organic matrix. In the course of this calcification procedure we suppose a certain quota of the sulphur of the matrix is replaced by other elements, a process which must entail retention of calcium, phosphorus and magnesium and increased elimination of sulphur. He shows the close parallelism between the mineral metabolism of a growing boy, a case after parathyroidectomy and a case of osteitis deformans, and suggests that this depends in some way either on the absence or perversion of some internal secretion, possibly of the parathyroids, which controls calcium exchange in the body. Substances from some cause arise which have the power to abstract calcium from the body tissues, the abstraction of these salts being the first step in the production of the disease.

The example which is reported in full was the first to be encountered in our 5,365 autopsies but shortly after this series was concluded two more came to autopsy and Dr. Corson-White’s studies were made to embrace these.

A reddish woolly monkey (_Lagothrix infumatus_) received November 25, 1919, was a particularly active specimen and as far as we could determine a perfectly healthy adult animal. He passed the tuberculin test and was placed on exhibition. In April, 1920, he was first reported as crippled and was removed to the laboratory in June, 1920. At that time the long bones of the legs and arms were bowed anteriorly and laterally, the degree of curvature making the hands and feet seem disconnected. The monkey could stand but made no voluntary effort to do so. There was evidently some pain although it could not have been at all severe. He resented handling, especially of his arms and legs. The head was rounded, resembling that of a baby, and the eyes were protuberant suggesting an exophthalmos. The maxillary bones were so excessively thick that the mouth could not close and the monkey drooled saliva. His blood on admission to the infirmary in May was—Hg eighty-nine per cent., R. B. C. 4,370,000, W. B. C. 5,800; one week before death it was Hg fifty-four per cent., R. B. C. 2,860,000, W. B. C. 6,000. Routine urine examination showed a constant trace of albumin, hyaline and granular casts. There was at no time a Bence-Jones protein reaction, excess of indican, indol, or diacetic acid. He had a constant slight diarrhœa with some flatulence, the semifluid, constantly acid feces presenting a preponderance of Gram-positive coccoid organisms. His appetite was fair and he showed marked craving for lime, eating plaster from the walls when he could get it. Because of this desire for lime he was given a salt mixture to see if it would have any effect on the bone condition. The mixture used was the following:

NaCl 0.874 grams KCl 0.548 grams CaH(PO) H_{2}O 3.608 grams Ca lactate 0.386 grams Mg citrate 0.848 grams K citrate 1.953 grams

This mixture the animal ate with avidity and seemed more comfortable; other than that no change was noted.

An inorganic metabolism examination was attempted on the ordinary diet and the diet plus the salt mixture. Under the circumstances at our disposal this was not entirely accurate but showed such marked variation from the control animals examined—normal and osteomalacic—and such marked correspondence on the four separate four-day periods of each intake that it seemed acceptable. The result of this investigation on the first series of four four-day periods was:

═══════════╤═════════╤═══════════════════╤═════════════════════════════ │ Intake │ Output │ Total ───────────┼─────────┼─────────┬─────────┼───────────────────────────── „ │ „ │ Feces │ Urine │ „ ───────────┼─────────┼─────────┼─────────┼───────────────────────────── Calcium │0.0280 │0.014 │0.0022 │0.0162 = 0.0118 retention Magnesium │0.0640 │0.034 │0.0123 │0.0463 = 0.0177 retention Phosphorus │0.1540 │0.027 │0.0430 │0.07 = 0.084 retention Sulphur │0.1440 │0.002 │0.1680 │0.17 = 0.026 loss ───────────┴─────────┴─────────┴─────────┴─────────────────────────────

The result on the higher salt content was practically the same, the retention being in proportion slightly less. The diet for these small monkeys is two apples, two bananas, six small sweet potatoes, with a lump of boiled rice about the size of an egg. The content of this diet has been found very low in calcium, phosphorus, sodium, chlorine and iron, while potassium, magnesium and sulphur were high. To this diet lime water was added to increase its inorganic content.

This Reddish Woolly Monkey died August 20, 1920, and was immediately posted. There was marked thickening of the frontal, occipital and parietal bones, upper and lower jaws. The increase in the size of the alveolar margins prevented the closing of the mouth; only the last four teeth could be brought into apposition. The enlargement of the mandibles reduced the capacity of the mouth cavity. The skull while decidedly thickened did not enlarge at the expense of the cranial cavity. There was a cervical and dorsal kyphosis. The chest was increased anteroposteriorly and contracted laterally. The long bones were thick, bulky and deformed. (Fig. 46.)

A Black Spider Monkey (_Ateles ater_) showed a general hyperplasia of the whole shaft of the long bones. She was much deformed by curvatures and swellings of the skeleton—head enlarged, face deformed by the swelling of the upper and lower alveolar processes, jaws do not close and the palatal bones were flattened, skull irregularly thickened, elastic but not soft, slight subperiosteal growth. Thickening of the long bones was largely due to subperiosteal growth; section of the ulna showed a subperiosteal osseoid layer surrounding the old shaft. This tissue seemed to be very poor in lime salts, cutting without any grit. Marrow cavity was filled with a fairly firm, deep red marrow which did not bleed on section. The third monkey, a Brown cebus (_Cebus fatuellus_) showed exactly the same general picture but was less severely affected than the other two.

“The more minute study of the bones of these monkeys shows a variety of pictures while preserving one general form. The skull was smooth, mottled by irregularly placed areas of congestion; it was asymmetrically thickened; differentiation between cortex and diploe, internal and external tables was lost; calcareous matter was absorbed and the resultant bone was soft, elastic and porous; lacunæ enlarged and lined with bone corpuscles and giant cells. Other areas show more dense bone, the reparative processes being more active in that the lamellæ are wide and the vascular spaces narrower. As a rule the compact bone is absorbed, the Haversian canals are more or less confluent and there is generally a marked increase of newly formed osseoid tissue. The ossifying periosteitis obliterates the depressions for the cranial arteries and the sutures. The skull cap becomes finely porous, cancellous and even cavernous. The spaces are filled with a soft, red marrow-like material. The bones at the base of the skull are much less involved; the pericranium, dura and brain are normal.

“The long bones show interlacing narrow strands which are in some regions wide, in others narrow or thin as in spongy bone. Large irregular cavities are present and there is a disappearance of the compact bone and an encroachment on the medullary canal of a relatively dense new bone with small irregular trabeculæ surrounded by osteoblasts and a fibrous connective tissue which fills the outer trabecular spaces. The new bone is often both subperiosteal and subendosteal, the latter often gaining on the former. It is always soft and irregularly calcified. The general arrangement of the strands in the deep layers is longitudinal but in the subperiosteal bone they are very irregular and almost at right angles with the central strands. In this new osseoid tissue cysts are frequent, varying in size from very small to rather large cavities filled with a cloudy gelatinous material. The picture here is very like osteitis fibrosa cystica. Endosteal cells proliferate and may fill up the marrow spaces so that solid masses of fibrous tissue result. Frequently the osteoid material shows fibrillæ. The compact bone may be irregular with well marked Haversian systems. Toward the periosteum the cells may become scanty, the bone dense in structure while toward the interior the cells are more numerous and in the more cancellous portions, the trabeculæ become slender and far apart; here they may be covered by a single row of osteoblastic cells. The intertrabecular spaces are large, irregular and filled with a delicate alveolar tissue containing only a minimal number of normal bone marrow cells, large capillaries and no giant cells. Periosteum may be of usual thickness; the bone immediately beneath is spongy. The sclerosis of the bone in its densest areas is entirely due to the ossification of spindle cells which have remained in the place of the original marrow of the bone. As a whole the bone is nowhere normal in amount or proportion but the small Haversian systems are properly made, the abnormality being chiefly due to cellular and fibrous growth around the large lamellæ which at times is normal in amount but usually much in excess. In places this consists wholly of fibroblasts, at others of giant and round cells very suggestive of sarcoma. All histologists apparently agree that Paget’s disease starts as a resorption of already calcified bone.”

These data seem to supply ample evidence that the autopsy diagnosis of Paget’s osteitis deformans was correct. While the anatomy and course and chemical changes presented by these monkeys do not settle the causation of the disease, they offer very definite suggestions which Dr. Corson- White summarizes in the following cautious conclusions.

“Many of the cases of Paget’s disease first came under the observation for fractures, accidents common in osteomalacia but very rare in developed cases of osteitis deformans. Early cases all presented diarrhœa, which was present in all the early human cases seen, and in all the cases reported in monkeys. This symptom was mentioned in fourteen of the cases from the literature. It was also a constant symptom in primate osteomalacia. The diet of these monkeys was exceedingly low in those substances essential to bone development, and Sherman has shown that the calcium balance is regulated to a certain extent by the calcium ingested, and that when the diet was poor in this element, the output materially exceeds the intake, a fact which is immediately changed where the animal is put on a diet high in calcium. So far as we could find there are no studies on the mineral metabolism of beginning cases of Paget’s disease. It seems possible from the osteomalacic animals previously studied, that the low mineral and otherwise faulty content of the diet might so disturb the chemical equilibrium directly, through the neurotrophic mechanism or through the perversion of the ductless glands, that the mere addition of lime water might entirely change the pathological picture. This is in accord with the histology. The initial histological picture is always resorption of bone, a general decalcification which later presents an irregular proliferation. The disease then progresses along different lines ending as osteitis fibrosa cystica, Paget’s or Von Recklinghausen’s diseases, etc., dependent upon the strength of the reparative stimulus and the organism upon which it acts.

“These cases are of interest (1) because they are typical examples of Paget’s disease as it has been described in man both clinically and pathologically, (2) because the disease shows the same general type of inorganic metabolism that was exhibited in man, (3) because of the alkali hunger shown by one monkey, and by two human cases, a hunger which was severe, which preceded the deformity and disappeared after the deformity was established, (4) because the disease developed in animals fed on a diet insufficient in its inorganic and vitamine content to which an excess of calcium was added.

“From this study it seems possible that Paget’s disease may be just one stage in a deficiency disease, a reparative response through a neurotrophic mechanism or through the perversion of the glands governing calcium metabolism which has been perverted by an improperly balanced diet.”

TUMORS.

Neoplastic diseases of the bones have yet to be classified to everyone’s satisfaction. All gradations of hyperplasia of osteogenetic cells and fibres and of the marrow elements, from simple inflammation to true sarcoma, are recognized. As one reviews a large series of lesions, clearly defined types may be found, but there are transition stages to which an exact name is difficult or impossible to apply. Nor does the pathological diagnosis always fit with the clinical course. Thus, for example, the giant cell tumor of bones looks malignant, and is not, and its structure may be simulated in such diseases as fibrous osteitis and Paget’s disease. As we have seen in the discussion of the latter of these two, abnormalities of fibre and cell growth simulate neoplasms very closely. In addition it might be mentioned here that actinomycosis may produce bony growths resembling sarcoma. When osteitis deformans affects the facial bones especially, it has been called leontiasis ossium, and it is then a more nodular, tumor-forming process, the enlargement consisting of fleshy masses occupying the whole bone, but especially the marrow cavity. Histologically the lesion is fibrocellular, frequently with numerous giant cells; accumulations of small sarcoma-like alveoli may be found. We have encountered four cases among common opossums (_Didelphys virginiana_) and one in an Isabelline Gazelle (_Gazella isabella_) and, because of the localization and fleshy consistency of the tumor, we have called them osteosarcomata for descriptive purpose, but not for classification among neoplasms (where they will not be found). Two of the opossums had osteoporosis and gelatinous marrow in the ribs. All these animals had been in the exhibition under a year, and as far as known are not related. Figure 47 shows the gross character, while the following is the description from one protocol.

Common Opossum (_Didelphys virginiana_) ♀ . Osteosarcoma of alveolus, rarefying osteitis deformans of skull, hypertrophy of thyroid, acute catarrhal enteritis, acute hyperplasia of spleen. About the middle of both lower rami and involving the posterior half of each upper maxilla is a uniform elliptical growth apparently emanating from alveolus. Teeth not loose, but can be moved in tumor to be described. On section a white glistening homogeneous growth is seen apparently originating in the body of the alveolus and around the teeth. The shaft of bone is soft and easily broken. What remains of marrow is irregularly injected. In upper jaw there is a distinct porosis of facial bones; they and the enclosed sinuses are deeply injected. Lower four ribs on both sides show distinct nodulations of pale color along a bluish bone. All ribs are very soft and section shows osteoporosis of shaft with injected marrow and distinct cartilaginous periosteal bone formation. The skull is everywhere soft and the bone is apparently increased in thickness, rich in blood, but porotic. Rest of skeleton seems well calcified. Microscopic section of tumor shows practically the same picture. Bone is nowhere normal in amount and proportion but the Haversian systems seem properly made, the abnormality consisting chiefly of cellular and fibrous growth around larger lamellæ, which at times is normal in amount but usually much in excess. In places this consists wholly of fibroblasts, at others of giant and round cells very suggestive of sarcoma; indeed all areas must be called giant cell sarcoma. There is an attempt to lay down osteoid tissue at places particularly beneath periosteum. The giant cells are in great numbers and some seem osteoclastic. As the lamellæ disappear young connective tissue seems to take their place but giant cells do not remain numerous at such places. Despite its atypical nature it must probably be looked upon as an osteosarcoma. The tooth socket is not much involved save for hyalinization of root matrix immediately about dentinal zone.

In another Isabelline Gazelle (_Gazella isabella_) there was a fibro- osteoma localized to one side of the superior maxilla (Fig. 48); this has been included among the tumors, while the above mentioned cases have not been so grouped.

True osteosarcoma seems not to have occurred. One tumor was seen upon the wing of a Cuvier’s Toucan (_Rhamphastos cuvieri_) which was formerly diagnosed as sarcoma, but later examination reveals some giant cells in arrangement suggestive of tuberculous osteitis; since this is the only case and not unequivocally a tumor its record is hardly warranted. Osteomata of the hard variety have been seen on the ribs of a pigeon and a pheasant as small rounded compact well outlined tumors. It is thought that they represent products of healing after osteomalacia or rickets. An osteochondroma growing from the nasal cartilage was found in a caracal (_Felis caracal_), a fibro-osteoma was found on the vertebra and clavicle of a Beechy’s spermophile (_Citellus grammurus beecheyi_) and a fibroma occurred on the clavicle of a lesser snow goose (_Chen hyperboreus hyperboreus_). The only other tumor from a bone was an endothelioma from the periosteum of the clavicle in a moorhen (_Gallinula chloropus_). It corresponds to the usual idea of this tumor. It probably caused death by cachexia, and by its size, interference with respiration. The only secondary tumor was a metastasis in the tibia from a spindle cell sarcoma of the kidney in a scaly ground dove (_Scardapella squamosa_).

THE MUSCLES.