Massive Osteolysis An Unusual Cause of Bone Destruction JANE L. ROSS, M.D. ROGER SCHINELLA, M.D. LOUIS SHENKMAN, M.D. New York, New York A patlent who presented with multiple lytic lesions of bone was found to have massive osteolysis. The clinical course of this patient Is described and the literature on massive osteolysls reviewed. Thls disease of uncertain etiology Is pathologkally marked by resorption of bone, and replacement by angiomas and flbrosls. X-ray flndlngs are usually more severe than expected from the patients’ cllnlcal presentatlon. Laboratory studles, including attempts at biopsy, are generally unrevealing. Drug therapy is of no value, and success of surgical attempts at bone union are unpredictable. Massive osteo- lysis should be considered in the differential diagnosis of osteolytic lesions, particularly since this disorder can result In serious mor- bldlty. Osteolysis is a common abnormality of bone which can be caused by a variety of decalcifying processes. A rare type of osteolysis, first described by Jackson [l] in 1838, is massive osteolysis. This disorder is usually progressive and marked by spontaneous dissolution and disappearance on roentgenograms of one or more bones. Known also by a variety of eponyms, including Gorham’s disease, disappearing bone disease, essential osteolysis, progressive atrophy of bone, he- mangiomatosis-lymphangiomatosis of bone, phantom bone and pro- gressive osteolysis [l-7], this entity was clearly .defined as a specific pathologic disorder only in 1954 by Wham and Stout [ 21. Less than 80 cases of this disease have been reported and, except for the original descriptions and Gorham’s classic paper [ 1,2,8], this disorder has not been reviewed recently in the general medical journals. Since most internists are not familiar with this syndrome, which should be included in the differential diagnosis of osteolytic lesions, we here report a case of this disease and review the literature on this unusual disorder. CASE REPORT FromthsDeperbmwrtsofMsdlclnsandpethdogy, New York Unlverslty Medical Center,New York, New York. Requests far reprints should be ad- dressedto Dr. Louis Shenkman, New York Uni- verslty Medical CenterSchool of Medicine, 550 First Avenue, New York, New York 10016. Man- uscrlpt accepted January 31, 1978. A 60 year old men of Man origin was admitted to the neurosurgicai service of Bellevus Hospital Center with signs of spinal cctrdccmpression. The patient had been in good health until five years prior to admission when he entered another hospital with pains in the chest and beck. Multiple fractures and lytic lesions of his ribs were found. Bone scan revealed increased uptake of 994echnetium pyrophosphate In the lower lumbar spine and sacrum. Biopsy of one of the lytic bone lesions was reported as “nondiagnostic,” and the patient was treatedsymptomatically with salicyiates. Because of a hematocrit value of 55 per cent, blood volume and red cell mass determinations were performed. They were found to be increased, but no therapy was instituted. One year prior to admission he noted pain in both arms and in the distribution of the sixth and seventh cervical nerves. X-ray films showed collapse of the Auguel 1975 The American Journal of Medlclne Volume 65 367
Transcript
Massive Osteolysis
An Unusual Cause of Bone Destruction
JANE L. ROSS, M.D. ROGER SCHINELLA, M.D. LOUIS SHENKMAN, M.D.
New York, New York
A patlent who presented with multiple lytic lesions of bone was found to have massive osteolysis. The clinical course of this patient Is described and the literature on massive osteolysls reviewed. Thls disease of uncertain etiology Is pathologkally marked by resorption of bone, and replacement by angiomas and flbrosls. X-ray flndlngs are usually more severe than expected from the patients’ cllnlcal presentatlon. Laboratory studles, including attempts at biopsy, are generally unrevealing. Drug therapy is of no value, and success of surgical attempts at bone union are unpredictable. Massive osteo- lysis should be considered in the differential diagnosis of osteolytic lesions, particularly since this disorder can result In serious mor- bldlty.
Osteolysis is a common abnormality of bone which can be caused by a variety of decalcifying processes. A rare type of osteolysis, first described by Jackson [l] in 1838, is massive osteolysis. This disorder is usually progressive and marked by spontaneous dissolution and disappearance on roentgenograms of one or more bones. Known also by a variety of eponyms, including Gorham’s disease, disappearing bone disease, essential osteolysis, progressive atrophy of bone, he- mangiomatosis-lymphangiomatosis of bone, phantom bone and pro- gressive osteolysis [l-7], this entity was clearly .defined as a specific pathologic disorder only in 1954 by Wham and Stout [ 21. Less than 80 cases of this disease have been reported and, except for the original descriptions and Gorham’s classic paper [ 1,2,8], this disorder has not been reviewed recently in the general medical journals. Since most internists are not familiar with this syndrome, which should be included in the differential diagnosis of osteolytic lesions, we here report a case of this disease and review the literature on this unusual disorder.
CASE REPORT
FromthsDeperbmwrtsofMsdlclnsandpethdogy, New York Unlverslty Medical Center, New York, New York. Requests far reprints should be ad- dressed to Dr. Louis Shenkman, New York Uni- verslty Medical Center School of Medicine, 550 First Avenue, New York, New York 10016. Man- uscrlpt accepted January 31, 1978.
A 60 year old men of Man origin was admitted to the neurosurgicai service of Bellevus Hospital Center with signs of spinal cctrd ccmpression. The patient had been in good health until five years prior to admission when he entered another hospital with pains in the chest and beck. Multiple fractures and lytic lesions of his ribs were found. Bone scan revealed increased uptake of 994echnetium pyrophosphate In the lower lumbar spine and sacrum. Biopsy of one of the lytic bone lesions was reported as “nondiagnostic,” and the patient was treated symptomatically with salicyiates. Because of a hematocrit value of 55 per cent, blood volume and red cell mass determinations were performed. They were found to be increased, but no therapy was instituted. One year prior to admission he noted pain in both arms and in the distribution of the sixth and seventh cervical nerves. X-ray films showed collapse of the
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MASSIVE OSTEOLYSIS-ROSS ET AL.
fifth and sixth’cervical vertebrae with destruction of intervening disc spaces.
fifth cervical vertebra and partial collapse of the fourth and sixth cervical vertebrae. Bone scan at this time revealed in- creased uptake in the cervical spine, ribs, lumbar spine and sacrum. Electromyographic studies demonstrated neurologic involvement of the nerve roots of the fifth and sixth cervical vertebrae. He was treated with cervical traction and showed symptomatic improvement. Three weeks prior to admission he was seen at another hospltal wlth increasing arm and neck pains. At this time roentgenograms showed angulation at the old cervical fracture sites, and a myelogram revealed com- pression of the cord at the level of the fifth and sixth cervical vertebrae. He was transferred to this hospital for further work-up and management.
Past medical and surgical history included a cholecys- tectomy, appendectomy, pilonidal cyst repair, and hyper- tension and atrial fibrillation. Medications included digoxin, Aldomete, furosemide and Talwine. He denied any past or recent trauma.
Physical examination revealed a welldeveloped man with a blood pressure of 170190 mm Hg and an irregular pulse rate of 70 to 80/min. Pertinent findings included tenderness to palpation over the lower cervical vertebrae, weakness of the left arm and leg, and a palpable liver edge 3 cm below the right costal margin.
Complete blood count, urinalysis, blood urea nitrogen, electrolytes and liver function studies were all within the normal range. Serum calcium was 10 mg/dl and phosphorus 3.7 ng/dl. The 24 hour urinary excretion of calcium was 100 mg and of phosphorus 960 mg. Serum alkaline phosphatase was normal. Latex fixation was negative, and ANA titer was positive at a 1: 10 dilution in a speckled pattern. Serum thy- roxine was 7.9 pg/dl and triiodothyronine (Ts) resin was 32 per cent, both in the normal range.
Roentgenograms of the spine revealed collapse of the fourth, fifth and sixth cervical vertebrae with destruction of the intervening disk spaces (Figure 1). A compression frac- ture of the 10th thoracic vertebra was also noted. Osteolytic lesions were evident in the sacrum, left pubic ramus and left second and fifth metatarsals (Figures 2 and 3). Multiple rib fractures were noted on the chest film. All of the fractures appeared to be of the same age, with blurring of the fracture sites and early callus formation. A bone scan showed multiple areas of increased uptake in the cervical spine, 11 th and 12th thoracic, and fourth and fifth lumbar vertebrae, the left foot, left sternoclavicular area and several ribs.
Bone marrow examination revealed a normoblastic mar- row with increased cellularity, a slight increase in mega- karyocytes and erythroid hyperplasia. No tumor cells were seen. Biopsy of the sacral lesion and the second left meta- tarsal was performed.
Review of the slides from the biopsies of the pubic sym- physis, second metatarsal and sacrum showed crush artefact of bone. Considerable fibrosis but no excessive vascularity was seen in the bone marrow, and no definitive diagnosis could be made from these specimens.
The biopsy specimen taken from the compression fracture of fourth through sixth cervical vertebrae revealed large patulous, mostly empty, endothelial lined channels with very thin walls (Figure 4). These channels were within bony tissue, did not invade through the cortex and occasionally impinged upon and even surrounded bony trabeculas. No excessive osteoclastic activity was noted, but a mild increase in os- teoblastic activity was present adjacent to the expanded vascular channels. The osteoblast:osteoclast ratio was 40-5011. p small number of the vascular channels contained red cells. These findings indicated a hemangioma of cav- ernous type.
Cultures of the biopsy material were negative for fungus, acid-fast organisms and bacteria.
The patient was initially treated with a “halo brace” for three weeks; he then underwent cervical laminectomy and posterior cervical fusion using ilial bone chips. He was dis-
Figure 2. Note &tic lesions in left pubic ramus and sa- crum.
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charged after two and a half weeks to be followed in the clinic
COMMENTS
Massive osteolysis must be distinguished from the many local and systemic diseases which are associated with bone resorption. These include disuse atrophy, acute inflammatory atrophy associated with trauma (Sudek’s atrophy), primary and metastatic tumors, hyperpara- thyroidism, granulomatous diseases, rheumatoid ar- thritis and congenital pseudoarthrosis. Other osteolytic processes that must be considered include progressive osteolysis of progeria [9], hereditary osteolysis [lo--121 and acroosteolysis [ 131. Partial bone de- struction can also be seen with bony aneurysms, chronic infections of bone and aseptic necrosis. An- other rare entity known as cystic angiomatosis of bone can present in a fashion similar to massive osteolysis. Although attempts have been made to separate these entities on the basis of site of bony involvement and size of vascular channels [ 141 considerable variation exists and cystic angiomatosis may well be a form of massive osteolysis. Presentation. In most patients with massive osteolysis, the disease develops before the third decade, but it has been described in patients ranging in age from one and a half to 60 years. There is no sex or racial predilection, and no associated endocrinologic or metabolic abnor- malities have been found. The disease does not appear to have a genetic basis. It is a chronic disorder which begins insidiously without pain [ 151 and is characterized
Figure 4. A, low power view of bone biopsy specimen (vertebra). Note the widely dilated vascular channels which are closely approximated. The bony trabeculas at the upper left and in the center show reactive fibrosis and new bone formation. B, high power of a bony trabeculum from another area showing the endothelial lining of one of the dilated vascular channels and new bone formation in the adjacent trabeculum. Hematoxylin and eosin stain, magnification X40 (A) and X400 (B), reduced by 30 per cent.
Figure 3. Osteolytic lesions are present in left second and fifth metatarsal bones.
by a progressive regional loss of bone with resultant deformity, atrophy or limitation of motion of the involved part. Gorham et al. [l] noted that a long interval usually elapses before the pathologic process progresses far enough to produce symptoms, and then the dramatic x-ray findings come as a surprise. After a variable time course, the process usually arrests spontaneously. The disease may also present with pain in the area of in- volvement, although some investigators [ 16,171 suggest that pain is not present unless an associated pathologic fracture is present. Although not a consistent finding, many reports describe a preceding history of trauma to the affected area [ 2,181.
Although involvement of the pelvis and shoulder girdle predominates, all bones, including the skull, may
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be involved. Despite the often massive bony resorption, patients are frequently left with little disability. Dense fibrous tissue may replace lost bone and contribute to the maintenance of internal rigidity of the affected areas [ 171. It has been suggested that the fibrous tissue may be derived from or represent residual periosteum overlying the involved bone [2,3,19-211. After spon- taneous arrest of the disease, reossification does not occur, although reossification has been described in a few cases after external irradiation [ 18,221.
Physical examination may reveal tenderness, de- formity or muscle weakness of the involved area, but no systemic findings [23]. Some soft tissue swelling may be seen initially, but inflammation is not present and the overlying skin is unaffected [24]. Laboratory and X-ray Flndings. Except for slight el- evation of the alkaline phosphatase level associated with fractures, laboratory studies are usually within normal limits. In one reported case a low serum mag- nesium level was found [25], but corrective therapy did not result in clinical improvement. Slight eosinophilia was noted in one additional patient [26]. Although blood and urinary calcium and phosphorus levels have been reported to be in the normal range in these patients, Thompson and Schurman [27] found an increased 47-calcium turnover rate, but this was not of diagnostic value. Angiography has been employed in an attempt to demonstrate the lesions [28] but unlike angiomatous malformations, arteriovenous fistulas and vascular tu- mors in which abnormal vessels are seen, no connec- tion between the abnormal tissue and the vascular circulation have been demonstrated. Similarly, veno- graphy has been attempted [29] but found to be of no diagnostic value [27]. Bone scans usually show de- creased isotope uptake in affected areas [27], although our patient and the patient described by Sancristen et al. [26] had increased uptake of 99 technetium pyro- phosphate. In addition, a brain scan in a patient with skull involvement demonstrated increased uptake by the affected bone [30]. Fornasier [30] noted that bone regeneration can occur in massive osteolysis and our patient’s pathologic slides showed slight increase in osteoblastic activity. It may be that this histologic finding correlates with the increased uptake noted on bone scan. Thompson and Schurman [ 271 also reported in- creased skin temperature by thermography in areas overlying bony involvement.
Roentgenographically, massive osteolysis is char- acterized by bone destruction with progressive osteo- lysis that partially or completely resorbs bone without respect for joint boundaries [ 161. Generally no evidence of reossification can be seen. According to Johnson and McQure [23], a diagnostic sign is tapering-down of bone to a cone-like spicule at the edges of lesions. This is the result of intraosseous involvement which removes medullary support and extraosseous involvement that
compresses bone externally. A detailed description Of the chronologic x-ray changes depicted by these workers include: (1) early intramedullary and subcortical radiolucent foci resembling “patchy osteoporosis”; (2) concentric shrinkage of the shaft of bones by tapering of the involved end; (3) complete resorption of the in- volved structure unless spontaneous arrest occurs; and (4) progression of osteolysis to involve nearby bones. Osteolysis at two distinct anatomical sites with normal bone intervening may also be seen [31]. Morbidity and Mortality. Although many of the patients described were able to function well despite extensive bone involvement, the disease may result in severe deformity or disability. The most serious sequelae are usually seen in patients with rib and vertebral involve- ment. Complications have included spinal cord com- pression (as in our patient) and paraplegia [24], and collapse of the rib cage with resultant thoracic deformity and respiratory impairment. The development of a chylous or serosanguinous pleural effusion has been noted in some instances. A recent case report [32] described invasion of the thoracic duct by angiomatous tissue which had spread from involved upper thoracic vertebrae, thereby causing a chylothorax. Although this complication had previously proved fatal in six patients [ 2,3,19,23,33], operative obliteration of the chylous leak was successful in this case. Pathology. Although clinical presentation and x-ray findings may suggest a diagnosis of massive osteolysis, the ultimate diagnosis lies in the histologic examination. An important point which should be stressed is the need for a large specimen of bone for pathologic examina- tion. Bone fragments have often been inadequate for diagnosis. On gross examination, the bone is soft and weak with a spongy texture [3]. Gorham [l] noted that on incision, bloody or serous fluid exudes from the ab- normal bone, and occasionally severe hemorrhage is noted. The cortex is markedly thinned and the marrow brown: After a review of the slides in eight of the original cases, Gorham defined a specific pathologic progres- sion. An increase in the number of dilated capillaries filled with red cells is seen first in affected bone. A point which Gorham and others emphasized [3,X,27,31] and others disputed [28,34,35] was the conspicuous ab- sence of increased number of osteoclasts. The large number of capillaries form hemangiomas which replace bone and are capable of spreading into soft tissues [2]. The process continues causing disintegration of cortical and cancellous bony elements until all the bone is re- sorbed and only a fibrous band remains. It is generally thought that this fibrotic tissue represents periosteum. It has been previously noted that the course of this disease is uncertain and usually self-limited so that the amount of bony resorption is variable. Gorham et al. [3] noted that this process does not resemble the formation of ordinary hemangiomas in bones which are localized
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and do not spread. The latter may destroy bone but never totally dissolve it and usually show regeneration. It has been emphasized that a characteristic feature of massive osteolysis is the complete lack of new bone formation [ 16,24,36] although others [31] dispute this.
The etiology of massive osteolysis is not known. King [ 181, in 1946, introduced the term “hemangiomatosis” when he observed the non-neoplastic proliferation of blood vessels. Many investigators believe that the pri- mary angiomatosis in the osseous tissue is the basis for the massive osteolysis [3,19,33,37]. Histochemical studies by Heyden et al. [22] showed strong acid phosphatase and leucine aminopeptidase activity in perivascular mononuclear cells, suggesting that these cells participate in bone resorption. Gorham et al. [2] proposed that the active hyperemia caused an abnormal balance between osteoblast and osteoclast activity so that the latter was favored. This theory was supported in later studies showing that high oxygen concentration stimulated osteoclastic resorption of bone in mice and low oxygen levels favored bone formation [38,39]. Oxygen deprivation blocked osteogenesis and favored chondrogenesis. This concept that venous stasis pro- moted bone formation and arterial hyperoxygenation promoted bone resorption [40-421 was later demon- strated by Gorham [43,44] and experimentally sup- ported in rat studies [45]. Several patients with asso- ciated skin hemangiomas have been described [ 16,19,31,33] causing Halliday et al. [16] and Fornasier [30] to suggest a congenital vascular defect as a pos- sible etiology. Thompson et al. [27] recently suggested that the disease is a primary aberration of vascular tissue in bone related to unchecked granulation-like tissue. As noted previously, many patients have pre- sented with a history of trauma, and several investiga- tors believe that this either causes or triggers the dis- ease [ 18,271. In addition, inflammatory processes [2], neurologic abnormalities [46] and simple bone cysts [47] have been suggested etiologies. Earlier papers reported lymphangiomatous tissue on histologic ex- amination; however, Jaffe [48] noted that lymphangi- omas of bone characteristically have soft tissue in- volvement that is not usually seen with massive os- teolysis. Several investigators [47-521 have speculated on a causative relationship between massive osteolysis and multicentric cyst-like zones of bone resorption due to lymphangiomas. The proposed mechanism is that congenital nests of lymphatic tissue in bone and soft tissue increase in size and cause destruction by pres- sure [16].
MASSIVE OSTEOLYSIS--ROSS ET AL.
An interesting speculation that has not as yet been tested is a possible etiologic role for prostaglandins. In vitro, these fatty acids, especially of the E series, are potent stimulators of bone resorption [ 531. Tashjian’s group [54,55] proposed that prostaglandin E2 may be the agent responsible for the hypercalcemia in certain mouse and rabbit tumors. Prostaglandin E 1 and E2 have been implicated as causing bone resorption in rheu- matoid arthritis [56] and as the cause of hypercalcemia in various solid tumors, notably renal cell carcinoma [57,60]. It has recently been suggested that elevated prostaglandin E levels may be used as a marker to identify patients whose hypercalcemia will respond to indomethacin therapy, an agent which inhibits prosta- glandin synthesis [59]. If elevated levels of prosta- glandin E were found in patients with massive osteol- ysis, then therapy with inhibitors of prostaglandin syn- thesis might be warranted. Another possible etiology for this disease, also untested, would be the production of other factors favoring osteolysis, such as the os- teoclast stimulating factors noted by Mundy et al. [60] in multiple myeloma. Therapy and Management. The correct therapy for massive osteolysis is even more uncertain than the etiology. In most cases bone resorption stops sponta- neously. Attempts at bone grafting have met with vari- able success [ 15,16,29,61], and there are several re- ports showing involvement of grafts by the osteolytic process [ 611. The most persistent effort at therapy seems to have been made in 1958 by Branco et al. [25] who tried estrogen, androgen (testosterone propionate), magnesium, calcium fluoride, adrenal extracts, vitamin D, aluminum acetate solution, ultraviolet radiation, ionized calcium, somato trophic hormone, placental extracts, vitamin B12, amino acids, and transfusions of placental blood and blood from growing young children. None of these modalities had any beneficial effect on this disease. The lack of efficacy of some of these agents has been confirmed [ 15,25,62]. Others have resorted to amputation of severely involved extremities [24,61]. The best approach seems to be good con- servative management, hoping for early spontaneous arrest of the disease. As noted earlier, heroic surgery may be of value in some cases [ 321.
ACKNOWLEDGMENT
We would like to thank Dr. Anthony loppolo for referring this patient to us. Dr. Shenkman is an Irma T. Hirsch1 Scientist.
REFERENCES
1. Jackson JBS: A singular case of absorption of bone (a bone- 3. r&rkm LW, Stout AP: Massive osteolysis. J. Bone Joint SUrg less arm). Boston Med Surg J 18: 388, 1838. 37A: 985, 1955.
2. Gorham LW, Wright AW, Shultz HH, et al,: A rare form of 4. Branch HF: Acute spontaneous absorption of bone. J Bone massive osteolysis. Am J Med 17: 674, 1954. Joint Surg 27: 706. 1946.
August 1979 The American Journal of Medlclne Volume 65 371
MASSIVE OSTEOLYSIS-ROSS ET AL.
5.
6.
7.
6.
9.
10.
11.
12.
13.
14.
15.
16.
17.
16.
19.
20.
21.
22.
23.
24.
25.
26.
27.
26.
29.
30.
31.
32.
33.
34.
35.
Thoma KH: A case of progressive atrophy of the facial bones with complete atrophy of the mandible. J Bone Joint Surg 15: 494,1933.
Jackman WA: A case of spontaneous absorption of bone. Br J Surg 26: 944, 1930.
Vitali M: The prosthetic management of a case of essential osteolysis. J Bone Joint Surg 448: 652, 1962.
Jackson JBS: Absorption of the humerus after fracture. Boston Med Surg J 10: 245, 1872.
Ozonoff MB, Clemett AR: Progressive osteolysis in progeria. Am J Roentgen01 100: 75, 1967.
Shurtleff DB, Sparkes RS, Clawson DK, et al: Hereditary os- teolysis with hypertension and nephropathy. JAMA 188: 363, 1964.
Gluck J, Miller JJ: Familial osteolysis of the carpal and tarsal bones. J Pediatr 81: 506, 1972.
Kohler E, Babbitt D, Huizenga B, et al.: Hereditary osteolysis: a clinical, radiological and chemical study. Radiology 108: 99, 1973.
Cheney WD: Acro-osteolysis. Am J Roentgen01 94: 595, 1965.
Brower AC, Culver JE. Keats TE: Diffuse cystic angiomatosis of bone: report of 2 cases. Am J Roentgen01 118: 456, 1973.
Butler RW, McCance RA, Barrett AM, et al.: Unexplained de- struction of the shaft of the femur in a child. J Bone Joint Surg 408: 487, 1958.
Halliday DR, Dahlin DC, Pugh DG. et al.: Massive osteolysis and angiomatosis. Radiology 82: 837, 1964.
Castleman B, M&Jelly BU: Case records of the Massachusetts General Hospital. N Engl J Med 270: 731, 1964.
Henderson MS: Acute atrophy of bone-report of an unusual case involving the radius and ulna. Mlnn Med 19: 214, 1936.
57.
58.
Fine RD. Gonski A: Massive osteolysis of the skull. J Neurosurg 43: 92, 1975. 59.
Fornasier VL: Hemangiomatosis with massive osteolysis. J Bone Joint Surg 528: 444, 1970.
Patrick JH: Massive osteolysis complicated by chylothorax successfully treated by pleurodesis. J Bone Joint Swg 568: 347, 1976.
60.
Hambach R, Pujrnan J, Maly V, et al.: Massive osteolysis due 61. to hemangiomatosis. Radiology 71: 43, 1958.
Milner SM. Baker SL: Disappearing bones. J Bone Joint Surg 408: 502, 1958.
Coley BL: Neoplasms of Bone and Related Conditions, New
36.
37. 38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
62.
York, Paul B. Hoeber, 1960, p 783. Edeiken J, Hodes PJ: Roentgen Diagnosis of Diseases of Bone,
Baltimore, Williams & Wilkins Co., 1967, p 539. Stout AP: Masslve osteolysis. Radiology 73: 435, 1959. Goldhaber P: The effect of hyperoxia on bone resorption in
teogenesis in vitro. Anat Ret 149: 57, 1964. Geiser M, Trueta J: Muscle action, bone rarefaction and bone
formation experimental study. J Bone Joint Surg 408: 282, 1958.
Jee WS, Arnold JS: Structural changes in dog skeleton con- tained plutonium. J Bone Joint Surg 41A: 771, 1959.
DeValderrama JF, Trueta J: The effect of muscle action on the intraosseous circulation. J Pathol 89: 179, 1965.
Gorham LW: Circulatory changes associated with osteolytic and osteoblastic reactions in bones. Possible mechanism involved in massive osteolysis; An experimental study. Arch Intern Med 105: 199, 1960.
Gorham LW, West WT: Circulatory changes in osteolytic and osteoblastic reactions. Arch Pathol 78: 673, 1964.
Anderson CE, Parker J: Invasion and resorption in enchondral ossification. J Bone Joint Surg 48A: 899, 1966.
Leger L. Ducroquet R, Leger H, et al.: Osteolyse dite essen- tielle. Maladies du Squelette, Paris, Masson et Cie, 1949, p 190.
Jacobs JE, Kimmelstiel P: Cystic angiomatosis of the skeletal system. J Bone Joint Surg 35A: 409, 1953.
Jaffe HL: Tumors and Tumorous Conditions of the Bones and Joints, Philadelphia, Lea 8 Febiger, 1959.
Harris R, Prandoni AG: Generalized primary lymphangiomas of bone. Report of a case associated with congenital lym phedema of the forearm. Ann Intern Med 33: 1302, 1950.
Hayes JT, Brady GL: Cystic lymphangiectasis of bone. A case report. J Bone Joint Surg 43A: 107, 1961.
Koblenzer PG, Bukowski MJ: Angiomatosis (Hamartoma- tosis-Hem-Lymphangiomatosis). Report of a case with diffuse involvement. Pediatrics 28: 65, 1961.
Shopfner CE, Allen RP: Lymphangioma of bone. Radiology 76: 449, 1961.
Klein DC, Raisz LG: Prostaglandins: stimulation of bone re- sorption in tissue culture. Endocrinology 86: 1436, 1970.
Voelkel EF, Tashjian AH Jr., Franklin R, et al.: Hypercalcemia and tumor prostaglandlns. The VXp carcinoma model in the rabbit. Metabolism 24: 973, 1975.
Tashjian AH Jr., Voelkel EF, Levine L, et al.: Evidence that the bone resorption stimulating factor produced by mouse fi- brosarcoma cells in prostaglandin E2. A new model for the hypercalcemia of cancer. J Exp Med 136: 1329, 1972.
Robinson DR, Tashjian AH Jr., Levine L, et al.: Prostaglandin stimulated bone resorption by rheumatoid synovia. A possible mechanism for bone destruction in rheumatoid arthritis. J Clin Invest 56: 1181, 1975.
Powell D, Singer FR, Murray TM, et al.: Nonparathyroid hu- moral hypercalcemia in patients with neoplastic diseases. N Engl J Med 289: 176, 1973.
Seyberth HW, Segre GV, Morgan JL, et al.: Prostagfandins as mediators of hypercalcemia associated with certain types of cancer. N Engl J Med 293: 1278, 1975.
Robertson RP, Bayllnk DJ, Metz SA, et al.: Plasma prosta- glandin E. In patients with cancer with and without hyper- calcemia. J Clin Endocrinol Metab 43: 1330, 1976.
Mundy GR, Raisz LG, Cooper RA, et al.: Evidence for the se- cretion of an osteoclast stimulating factor in myeloma. N Engl J Med 291: 1041,1974.
Aston JN: A case of massive osteolysis of the femur. J Bone Joint Surg 408: 514, 1958.
Phillips RM, Bush OB Jr., Hall HD, et al.: Massive osteolysis (phantom bone, disappearing bone). Report of a case with mandibular involvement. Oral Surg 34: 886, 1972.
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