Henry Ford Hospital Medical Journal Henry Ford Hospital Medical Journal

Volume 31 Number 1 Article 2

3-1983

The Regional Acceleratory Phenomenon: A Review The Regional Acceleratory Phenomenon: A Review

Harold M. Frost

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Recommended Citation Recommended Citation Frost, Harold M. (1983) "The Regional Acceleratory Phenomenon: A Review," Henry Ford Hospital Medical Journal : Vol. 31 : No. 1 , 3-9. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol31/iss1/2

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Henry Ford Hosp Med J Vol 31, No 1,1983

FeatuiFe Articles The Regional Acceleratory Phenomenon: A Review

Harold M. Frost, MD'

Tbe regional acceleratory phenomenon (RAP) is a com­plex reaction of mammaUan tissues to diverse noxious stimuli. The phenomenon occurs regionally in the ana­tomical sense, involves both soft and hard tissues, and is characterized by an acceleration and domination of most ongoing normal vital tissue processes. It may represent an "SOS" mechanism which evolved to poten­

tiate tissue heaUng and local tissue defensive reactions. When a RAP is obtunded, retarded healing and lowered resistance to infection and mechanical abuse may ensue.

When ignored in experimental design, the phenomenon can seriously perturb studies of metabolic bone disease and of the effects of mechanical, endocrinologic, and biochemical factors on skeletal physiology.

This review concerns an entity which affects both skele­tal and soft tissues and may explain certain features of some diseases. It can also perturb experimental studies of metabolic bone disease and of mechanical and other effects on skeletal physiology; if unrecognized, its fea­tures may be assigned to other causes. While physicians have long known many of its manifestations, it was first recognized and proposed as a general entity by the author. Of necessity, this review reflects his experience, biases, and limitations (1-4).

characteristics of the Regional Acceleratory Phenomenon (RAP)

Causes In a normal body any regional noxious stimulus of suffi­cient magnitude seems to evoke a RAP. It appears that the size of the affected region and the intensity of its response varies directly wi th the magnitude of that stim­ulus, although to different degrees in different individuals.

The effective noxious stimuli include crushing injury, fracture (5,6), bone operations of any kind (7-9), arthrot-omy, ar ter iotomy, burns, acute denervat ion, acute paralysis (10,11), infarcts, soft tissue and bone infections (12-15), and most noninfectious inflammatory joint pro­cesses including rheumatoid arthritis, rheumatic fever, pseudogout and Reiter's disease (10,16).

Nature

Once evoked, many ongoing regional soft and hard tissue vital processes accelerate above normal values. Collectively, those accelerated processes represent the RAP, and they include: perfusion (17); growth of skin.

bone, cartilage, and hair (6,18-20); turnover of bone, cartilage, synovial f lu id, connective and fibrous tissue (18,21,22); chondral and bone modeling including cor­rection of malunions in chi ldren; skin epithelialization; cicatrization; soft tissue and bone healing (23); and cel­lular metabolism.

Consequently, an affected region develops erythema and edema and becomes warm on thermography as well as to touch. The accelerated local bone turnover increases the uptake by bone-seeking isotopic agents, which causes the hot regions often found in acute and chronic osteomyelitis, in actively healing fractures, in the pres­ence of joint inflammation of any cause, in Sudeck's atrophy, and in the presence of some bone metastases (24). Photon absorption studies and routine x-rays can reveal decreased regional bonedensity duetoan increased remodel ing space. A joint contracture, which was pre­viously too rigid to respond to wedging casts or traction, can respond more readily during the three months or so fol lowing a major local bone operat ion, a phenomenon which suggests that the RAP rendered the capsular and related tissues more plastic for a t ime.

Clinically, as well as histologically, the particular cause of a RAP can imprint its own features on the concomitant general features of the RAP, so that their combination can appear characteristic or even diagnostic. Such char-

Submit led for pub l ica t ion : November 24,1982

Accepted for pub l icat ion: January 24,1983

'Sou thern Colorado Cl inic, 2002 Lake Avenue, Pueblo, C O 81004

Address repr int requests to Dr. Frost, 2002 Lake Avenue, Pueblo, CO 81004

Frost

acteristic imprints (such as necrosis, pus, eosinophil ia, Langhan's giant cells, hemosiderin, or scar) usually allow one to distinguish between trauma, acute pyogenic infection, immune reactions, chronic infections, necro­sis, and metastasis as examples.

Among the above clinical manifestations, physicians wil l recognize some of the classical signs of inflammation (26,27), which this writer suggests represent an early recognized manifestation of a stereotyped, more gen­eral phenomenon.

Anatomical distribution

The RAP involves the region where its stimulus arose, such as a knee, wrist, leg, foot or hip, including soft and hard tissue components. Following an acute paraplegia, hemiplegia, or monoplegia, whether due to trauma, poliomyelitis or other acute disease, or whether due to lower motor neuron or central lesions, the RAP can affect the whole paralyzed part of the body (28,29). The transition from involved to uninvolved regions seems gradual, rather than abrupt, and the distribution of the RAP seems to reflect regional vascular anatomy and innervation. Given severe stimuli, abscopic involvement can occur, meaning that accelerations of ongoing tissue turnover and perfusion can occur in the contralateral regions of the body.

Duration

In healthy humans, and fol lowing a single stimulus such as a Colles' fracture, pyarthrosis or gunshot wound, cl in­ical evidence of the RAP typically lasts about four months in bone, somewhat less in soft tissues, and longer for severe than for mild stimuli. But fo l lowing acute paralysis as f rom a brachial plexus injury, orafter a severe burn, the RAP can last f rom six months to over two years. Thus, for commensurate periods, it can accel­erate the bone loss caused separately by mechanical deloading, and thereby can predispose to hypercalciuria and genitourinary tract lithiasis (25,30). When the causa­tive stimulus persists for prolonged periods, as it can in active rheumatoid arthritis, osteomyelitis, Paget's dis­ease of bone or in the presence of an osteoid osteoma, the RAP persists similarly wi thout any known evidence of a natural limit to its duration.

The "SOS" Role of the RAP

The RAP may have evolved to accelerate healing of injuries and tissue defense reactions to local infect ion, infarction, mechanical abuse, and other noxious pro­cesses. Such a role suggests an "SOS" type phenomenon which would potentiate the survival of a species during evolution in a physically competit ive environment. Once

begun, it tends to dominate other ongoing processes and those endocrine, drug, and mechanical effects which tend to depress or potentiate those activities in healthy subjects.

Two different groups of clinical situations illustrate the postulated "SOS" role for the RAP. One reflects its posi­tive effects, the second its impairment.

Clinical Examples of RAP Effects

Potentiated bone healing

In the type of fracture nonunion, termed a "biological fa i lure" (31) or an atrophic or ol igotrophic nonunion (32), fracture callus arises too slowly and too scantily for satisfactory union but not f rom any known flaw in treat­ment. Dr. Robert Schenk and a group of Swiss orthopae­dists, who developed a highly efficient system of internal fixation of fractures that has come into wide use in devel­oped nations, taught the orthopaedic community that such nonunions can heal, given intimate apposition fixed rigidly enough to allow less than about 50 microns of interfragment mot ion (23). Such union occurs not by callus production but by BMU-based remodeling, which knits the fragments together with numerous secondary osteons crossing the fracture interface (23,33). BMU-based remodeling refers to the quantized or pocket-type turnover of adult human lamellar bone. It occurs in discrete units and involves an activating stimulus that causes an initial focal resorption process fol lowed by a bone formation process. That A-R-F sequence normally consumes about three months (1,21,23,30,33), and the secondary haversian system represents one of its wel l -known products.

Normally, such remodeling turns over less than 5% of the adult human tibial compacta annually (34,35). If no other factor acts after such fixation, less than 5% of a tibial fracture interface would bridge in the first year. About twenty years would be required for complete bridging. Yet union typically occurs wi th in six months because the operation itself (whether intermedullary nailing, compression plating, or a securely fixed sliding bone graft) accelerates the local bone turnover ten to f i f ty-fold above normal for more than a year. That reac­t ion accelerates the healing process (23) in the soft tissues as well as in the bone.

Such observations suggest that normal fracture healing may routinely require an accompanying RAP. If so, a delayed union not due to inadequate treatment could reflect an obtunded RAP, and the often beneficial effects of bone grafting or electrical stimulation could, in part at least, result f rom a newly evoked RAP. Signifi-

Rapid Acceleratory Phenomenon

cantly, studies by Takahashi, et al have shown exactly such effects of electrical bone stimulation (36).

The pathological RAP

Two clinical entities seem to illustrate pathological or " runaway" RAPs. In Sudeck's atrophy, an acute injury originally evokes a typical RAP, but the local accelera­tions characteristic of that RAP persist long after the original injury has healed. Sympathetic nerve blocks often cure this condit ion, but corticosteroids and related agents may not. The other entity, regional migratory osteoporosis, also may fol low a local injury, although it can occur spontaneously. When due to injury, this dis­order also persists long after the injury has healed; and it is intr iguing that sympathetic blocks are not beneficial, but corticosteroids and some other prostaglandin inhib­itors often help (37,38).

Arthrofibrosis

Joint stiffening due to diffuse fibrosis can fol low regional surgery, trauma, infection, noninfectious inflammation as in rheumatoid arthritis, and the development of a regional osteoid osteoma. All of these can evoke a RAP which, among other effects, increases collagen produc­t ion in the regional connective, fascial, capsular, and ligamentous tissues. Lacking frequent range-of-motion exercises, that fibrosis binds the regional gliding mechan­isms together.

The next examples illustrate proposed clinical examples of obtunded or absent RAPs.

Neuropathic soft tissue problems

In diabetics with significant peripheral neuropathy but good perfusion,and in nondiabet icpat ientswithdener-vated limbs or severe peripheral neuropathy of other origin (biochemical, mechanical, post-frostbite, nutr i ­t ional), the affected tissues respond poorly to wounds, mechanical abuse, and/or infections (27). In healthy tissues, such lesions promptly evoke a RAP (which includes the classical signs of inflammation plus acceler­ated turnover and metabolism of local skin and underly­ing soft tissues). Local healing is thus accelerated. But in these neuropathic affections, those accelerations are either obtunded or absent, whi le erythema, increased perfusion, or edema develop slowly, healing is pro­longed, and local resistance to infection, mechanical abrasion, and pressure declines. Proof of the regional rather than systemic origin of those phenomena lies in the fact that in the same individual no such problems arise in uninvolved body parts.

The Charcot joint

Whether due to diabetes, lues, syrinx, other central

nervous system disease or traumatic lesions, typical Charcot joint signs include considerable local bone and joint destruction and gross instability (3) but relatively mild edema, heat, swelling, and discomfort. Static histo­logic examination of Charcot joints reveals typical kinds of tissue responses to those stimuli, including fibrosis, dilatation of capillaries, product ion of new woven bone, low grade in f lammat ion, resorpt ion of debris, and edema (12,26,40).

However, the static histology misses an important but quite consistent dynamic feature. That is, given equal destruction, daily usage, and instability, the Charcot joint tissues develop far less tissue response per week than would normal joints, in which equivalent abuse would promptly evoke pronounced swelling, edema, and erythema, greatly increased local perfusion, fibrosis, and reactive bone formation.

This observation suggests that an obtunded RAP plays a major role in the pathophysiology of Charcot joints. In addi t ion, the associated impairment of deep pain sensa­tion (41,42) allows daily activity to cause new damage faster than the lethargic, obtunded repair processes can react to and heal it, so destruction is progressive. Similar phenomena can occur in subjects with congenital absence of pain (43).

Clinically, an obtunded RAP accompanies local sensory but not motor denervation; it was rarely observed in victims of anterior poliomyelitis. Sensory impairment may be due to central or peripheral trauma, to central nervous system disease or peripheral neuropathy. Var­ied observations and experimental data support the concept. For example, in patients with paralysis due to spinal cord injury at the cervical or thoracic levels, in whom lower l imb innervation remains intact, lower limb wounds and fractures heal normally and infect ion responds satisfactorily to treatment (44). In contrast, after regional peripheral denervation, reduced perios­teal and longitudinal overgrowth occur in amputation stumps (45), and impaired healing in denervated tissues is well known.

Rheumatoid phenomena

The tendency of excessive local collagen product ion, postulated to be a positive RAP effect, to cause joint stiffness typically occurs early and dur ing active and severe rheumatoid arthritis inflammation. However, in late cases of rheumatoid arthritis and in some of its variants, opposite effects can occur: ligaments and cap­sules stretch, joints become lax and subluxated, and microscopic tendon damage accumulates, so poorly repaired that spontaneous rupture finally occurs. Never-

Frost

theless, the classical external evidence of inflammation and other RAP manifestations is often unimpressive. Considerable internal damage may occur with minimal external signs of local tissue reaction, a state interpreted to indicate an impaired RAP. In addition to the disease process, therapeutic agents may play a role in that impairment. Paradoxically, in these same patients, skin and bone lesions may heal properly, and a ruptured rheumatoid tendon usually heals normally after surgical repair.

The RAP in Research

Histomorphometric bone studies

I first suspected that the RAP was a general entity about 1960 when the sixth and seventh ribs were removed at autopsy from a patient who had undergone a thoracot­omy seven years earlier. Histomorphometric measure­ments o f the originally resected sixth rib disclosed much higher bone turnover than was present in the uninjured adjacent rib. Numerous subsequent observations in human subjects have shown that any type of significant injury to a bone usually accelerates its turnover for a year or more.

This phenomenon suggests that repeated biopsy of the same bone before and after some treatment may pro­duce effects on bone remodeling which yield pro­foundly perturbed data (25,30,46-49). The techniques of serial rib biopsies (50-53) and of obtaining a biopsy first f rom one and then f rom the opposite i l ium (33,54-57) have been developed to minimize that error. Most his-tomorphometrists now realize that serial biopsies of the same bone cannot provide useful pre- to post-treatment bone turnover parameters (1). These potentially per­turbing effects of the RAP on experimental data are often overlooked by investigators interested in other kinds of skeletal problems, as indicated below.

Longitudinal bone growth

In chi ldren, bone growth often accelerates for some time after a major fracture or surgical procedure (58). With variable success surgeons have also tr ied to stimu­late bone growth by periosteal stripping, or by implant­ing beef bone or ivory pegs (8,19). The ensuing growth accelerations represent typical positive RAP effects.

Growth acceleration may also fo l low acute paralysis, whether due to trauma, poliomyelit is (11,28,29) oro ther affections, as well as local irritants such as chronic osteomyelitis, an osteoid osteoma, juvenile rheumatoid arthritis, or an irritating foreign body (12,19). Some observers have attr ibuted the unpredictable growth increases which can fol low such affections to an effect

of mechanical deloading. However, the invariable result of deloading without any complicating RAP, which appears in chi ldren paralyzed early in life [e.g., myelomeningo­cele (11)] is a short l imb (2,3,59). On the other hand, acute paralysis can produce the bony and soft tissue phenomena of a RAP in both laboratory animals and humans. In those situations, I suggest that the RAP tran­siently stimulated growth, i.e., for about a year, which dominated the concurrent growth depression caused by mechanical deloading. When thetransient dominat­ing RAP subsided, the persisting depressive effect became apparent.

Similar opposing forces may explain the confusing results observed when experimental forces are applied across growing epiphyseal plates (2,3). The surgical implantation of the hardware applying those forces evoked a RAP which tended to accelerate growth, whi le the mechanical forces exerted their own effects (2,3), and investigators observed the variable net results (60,61).

Bone loading experiments

The interest of the orthopaedic community in mechani­cal effects on bone architecture has made "Wolf f 's law" a password (62). In the last two decades of the 19th century Julius Wolf f proposed in essence that living bone can occasionally change its internal architecture in response to a change in the mechanical loads it carries, and that such changes made it better equipped mechan­ically to support those altered loads. Accordingly, he proposed that the mechanical usage of a bone can inf lu­ence its architecture. A representative experiment involves surgically implanting to each end of a bone hardware which is connected by restraints in order to compress the bone uniaxially. Some investigators attrib­uted the resulting increased outside bone diameter and porosity to increased mechanical compression. How­ever, they usually omitted the necessary control : i.e., identical devices implanted identically in the opposite l imb but wi th the restraint disconnected. Such surgical procedures certainly cause a RAP, and the reported bone reactions are typical RAP manifestations (3,7). Such experiments combine compression effects with unrec­ognized RAP effects.

The same problems occur in studies of mechanically deloading long bones by plate fixation (63,64). To distin­guish RAP from stress-strain effects, it is necessary to implant identical screw-plate devices on each femur, one of which has loosened screws. However, investiga­tors have usually omitted this control. Although compar­ison of the effects of rigid to flexible plates involves the use of different materials, many investigators have not

Rapid Acceleratory Phenomenon

compared the effects o f the materials independently for either the RAP or the mechanical bones (65,66), so con­clusions based on such experiments are diff icult to defend (67).

Discussion

Experimental studies of the RAP

High, et al have provided the only published experimen­tal data specifically applicable to RAP effects (51-53). Evoked in adult canine rib by periosteal stripping, dynamic histomorphometric analyses (47,56,68) of the stripped as well as of the uninjured ribs revealed signifi­cantly accelerated turnover in the stripped ribs six weeks later, apparently unmodif ied by concurrent treatment with other agents. The design of those experiments el im­inates mechanical deloading as a significant factor in the results, indicatingthat bone RAP effects need not neces­sarily reflect mechanical effects. On the other hand, other experiments reveal that a RAP can also result f rom acute deloading and, furthermore, can differ in kind and anatomical location according to the subject's age (14,22,69).

Mechanisms underlying the RAP

Although understanding isfarfrom complete, the causes of the RAP are many and depend on the anatomy and

competence and autonomic innervation of the regional blood supply, regional sensory innervation and mechan­ical loading, as well as the gamut of local biochemical and biological factors already known to be associated with injury, repair, metastasis, and inflammation, e.g., prostaglandins, leukotr ienes, lysozymes, and other leukocyte activities. Takahashi, et al produced typical bone RAPs by electrical stimulation of bone with com­mercial equipment used to treat fractures, and control studies revealed that surgical implantation alone also caused unequivocal but less severe RAPs (36). Basic differences in some causative factors, both in kind and magnitude, may characterize soft and hard tissue RAPs, accounting for the differences in their microscopic features.

Similar to the features of the lower motor neuron or BMU-based bone remodeling (1), the RAP may repre­sent a final common pathway for an appropriate physio­logic expression of diverse stimuli. Its particular clinical, biochemical, and histologic features may accompany the specific features of the causative stimulus, such as trauma, infection, an immune reaction, or necrosis. The RAP is a process of the intermediary organization of tissues and organs and is not revealed in the properties of isolated cells, so effective study cannot utilize ex vivo systems but wil l require the use of intact subjects.

References

1. Frost FHM. Bone remodel ing and its relationship to metabolic bone disease. Springfield, IL: Charles C. Thomas, 1973.

2. Frost H M . A chondral model ing theory. Calcif Tissue Int 1979;

28:181-200.

3. FrostFHM. A theory of lamellar bone model ing. In : Physiology and pathology of bone and cartilage metabol ism: Proceedings, Japan O r t h o p a e d i c Research Soc ie ty . C h u g a k u , T o k y o , 1980: 571-628.

4. Frost H M . The regional acceleratory phenomenon. O r thop Clin North Am 1981;12:725-6.

5. Lacroix P. Remarques sur I'ost^oporose post-traumatique. In : DJ FHioco, ed. L'Ost^oporose. Paris: Masson & Cie, 1964:34-41.

6. Simmons DJ, Cohen M . Postfracture linear bone growth in rats. Clin Or thop 1980;149:240-8.

7. Goodman AE, Lanyon LE, McFie F-l. Functional adaptation of bone to increased stress. J Bone Joint Surg 1979;61 A:539-46.

8. Jenkins DHR, Cheng DHF, Hodgson AR. Stimulation of bone growth by periosteal str ipping. J Bone Joint Surg 1975;57B:482-4.

9. KhouryS,Si lbermanFS,CabriniRL. Stimulation o f t he longitudinal growth of long bone by periosteal str ipping. J Bone Joint Surg 1963;45A:1679-87.

10. Goodman CR. Osteoporosis as an early compl icat ion of hemiple­gia. NY State M e d J 1971;71:1943-5.

11. Ring PA. Shor ten ing and paralysis in po l iomye l i t i s . Lancet 1957;2:980-3.

12. Jaffe HL. Metabol ic , degenerative and inf lammatory diseases of bones and joints. Philadelphia: Lea and Febiger, 1972.

13. Johnson LC. Morpho log ic analysis in pathology. In: Frost H M , ed. Bone biodynamics. Boston: Little Brown and Co, 1964:543-654.

14. Uhthof f H, Jaworski ZFG. Bone loss in response to long-term immobi l izat ion. J Bone Joint Surg 1978;60B:420-9.

15. Kazarian L, Cann L, Parfitt A M , Simmons D, Morey-Ho l ton E. A 14-day ground-based hypokinesia study in nonhuman primates— A compi lat ion of results. NASA T M 1981:41268.

16. Zanzi F, Roginsky MS, Ellis KJ, Blau S, Cohn SH. Skeletal mass in rheumatoid arthrit is: A comparison wi th forearm bone mineral content. A m J Roentgenol 1976;726:1305-6.

17. Paadis GR, Kelley PJ. Blood f low and mineral deposit ion in canine tibial fractures. J Bone Joint Surg 1975;57A:220-6.

18. Beckman J, Rodegerdts U, Buddecke E. "C-glucose and ^ss-metabol ism of pig epiphyseal cartilage and its variations after osteotomy. J Bone Joint Surg 1975:578:507-10.

Frost

19. Ferguson AB, Jr. Or thoped ic surgery in infancy and ch i ldhood. 4th ed. Balt imore: Wil l iams and Wilkins, 1975.

20. Karaharju E, RyoppySA,Makinen RJ. Remodel ing by asymmetrical epiphyseal growth. J Bone Joint Surg 1976:588:122-6.

21. Jaworski ZFG. Physiology and pathology of bone remodel ing. O r thop Clin Nor th Am 1981;12:485-512.

22. Klein L, Dawson M D , Heiple KG.Turnover of col lagen in the adult rat after denervat ion. J Bone Joint Surg 1977;59A:1065-7.

23. Schenk RK. Die histologieder pr imaren knochenhei lung in Lichte neuer Konzept ionen Uber den Knochenumbau. Unfal lhei lkunde 1978;31:219-27.

24. Hughes S, Khan R, Davies R, Laender P. The uptake by the canine tibia of the bone scanning agent ' ' ' " 'Tc-MDP before and after an osteotomy. J Bone Joint Surg 1978;608:578-82.

25. Minaire P. L'Ost^oporose d ' immobi l izat ion. In : Donn^es bio lo-giques et histologiques quantitatives. Lyon: Epidirm, 1973.

26. Anderson W A D , Kissane JM. Pathology. 7th ed. St. Louis: CV Mosby, 1977.

27. Rhoads JE, Al len JG, Harkins H M , Moyer CA. Surgery: Principles and practice. Toronto: JB Lippincott Co, 1970.

28. Ring PA. The inf luence of the nervous system on the growth of bones. J Bone Joint Surg 1961;43B:121-40.

29. Ring PA, Ward BCH. Paralytic bone lengthening fo l lowing pol io­myelitis. Lancet 1958;2:551-3.

30. Minai re P, Meun ie r PJ, Edouard C, Bernard J, Courpron P, Bourret H. Quanti tat ive histological data on disuse osteoporosis. Calcif Tissue Res 1974;17:57-73.

31. Frost H M . Or thoped ic biomechanics. Springf ield: Charles C. Thomas, 1973.

32. Connol ly JD. Selection, evaluation and indications for electrical st imulation of ununi ted fractures. Cl in O r thop Rei Res 1981; 151:39-53.

33. Courpron P. Bone tissue mechanisms under ly ing osteoporoses. Or thop Clin North Am 1981;12:513-45.

34. Frost H M . Measurement of human bone format ion by means of tetracycline labell ing. Can J Biochem 1963;41:31-42.

35. Rowland RE. Resorption and bone physiology. In: Frost H M , ed. Bone biodynamics. Boston: Little Brown and Co, 1964:335-52.

36. Takahashi H, Watanabe G,Togawa Y, HanaokaT, KonnoT, Saito Y, Suzuki H. The effect of various types of microelectrical current on internal remodel ing of bone in dogs. Trans Or thop Res Soc 1982; 7:369.

37. Duncan H, Frame B, Frost H M , Arnstein AR. Migratory osteolysis of the lower extremities. Ann Int M e d 1967;66:1165-73.

38. Langloly ND, Hunder GG, Riggs BL, Kelley PJ. Transient painful os teoporos is of the l ower ex t remi t ies . J Bone Joint Surg 1973;55A:1186-96.

39. Charcot JM. Sur quelques arthropathies qui paraissent d^pendre d'une lesion du cerveau ou de la moelle ^pin ie re. Arch Physiol Norm Pathol 1863;1:161-229.

40. Aegerter E, Kirkpatrick J A, Jr. Orthopaedic diseases. Philadelphia: WB Saunders Co, 1975.

41. Duncan CP, Shim S. The autonomic nerve supply of bone. J Bone Joint Surg 1977;59B:323-4.

42. Mi l le r MR, Kasahara M . Observations on the innervat ion of human long bones. Anat Rec 1963;145:13-23.

43. D r u m m o n d RP, Rose GK. A twenty-one year review of a case of congenital indi f ference to pain. J Bone Joint Surg 1975;57B:241-3.

44. Aaro H, Eerola F, Aho AJ, Penttinent R. Spinal cord trauma and fracture healing. In: DeLuca HF, Frost H M , Jee WSS, Johnston CC, Jr, Parfitt A M , eds. Osteoporosis. Balt imore: University Park Press, 1981:497.

45. Bunch W H , Deck JD, Romer J. The effect of denervation on bony growth after below knee amputat ion in rats. Cl in O r thop Rei Res 1977;122:333-9.

46. Frost H M . Mathematical elements of lamellar bone remodel ing. Springf ield: Charles C. Thomas, 1964.

47. Jee WSS, Parfitt A M . Bone histomorphometry. A rmour -Mon tagu , Levallois, eds. 1981.

48. Parfitt A M . Morpho log ic basis of treatment in osteoporosis. M i n ­eral Elect Metabol 1980;4:273-87.

49. Parfitt A M , Duncan H. Metabol ic bone disease affecting the spine. In : Rothman RH, Simeone FA, eds. The spine. Philadelphia: WB Saunders Co, 1975:599-720.

50. Jett S, Duncan H, Frost H M . Adrenal cort icoid and salicylate actions on human and canine haversian bone remodel ing. Cl in Or thop 1970;68:301-15.

51. High WB, Capen CC, Black HE. His tomorphometr ic evaluation of the effects of intermit tent 1,25-dihydroxy cholecalciferol adminis­t rat ion on cortical bone remodel ing in adult dogs. A m J Pathol 1981;104:41-9.

52. High WB, Capen CC, Black HE. His tomorphometr ic evaluation of the effects of low dose parathyroid hormone administration on cortical bone remodel ing in adult dogs. Lab lnvest1981;44:449-54.

53. High WB, Capen CC, Black HE. Effects of thyroxine on cortical bone remodel ing in adult dogs. Am J Pathol 1981;102:438-46.

54. Coindre CJ, Meun ie r PJ. Etude h is tomorphom^t r ique de I 'osnon-Pag6tique chez le Pag^tique. Lyon: Faculty Alexis Carrel, 1980.

55. Melsen F. His tomorphometr ic ana lysis of iliac bone in normal and pathological condit ions. Aarhus: Aarhus Amtssygehus, 1978.

56. Melsen F, Moseki lde L. The role of bone biopsy in the diagnosis of metabolic disease. Or thop Clin Nor th Am 1981;12:571-602.

57. Rasmussen H. Theoretical considerations in the treatment of osteoporosis. In : DeLuca H, Frost H M , Jee WSS, Johnston CC, Jr, Parfitt A M , eds. Osteoporosis. Balt imore: University Park Press, 1981:383-92.

58. W u YK, Mi l tner LA. A procedure for st imulation of longitudinal growth of bone. J Bone Joint Surg 1937;19:909-21.

59. Epker BN, O'Ryan F. Effects of early surgical advancement of the mandible on subsequent growth. In : Effects of early surgery on growth. Ann Arbor : University of Michigan Press, 1982.

60. Porter RW. The effect of tension across a growing epiphysis. J Bone jo in t Surg 1978;60B:242-55.

61. Strobino LJ, French GO, Colonna PC. The effect of increasing tensions on the growth of epiphyseal bone. Surg Gynecol Obstet 1952;95:694-700.

62. Wol f f J. Das Gesetz der Transformation der Knochen. Berl in: Hirschwald, 1892.

R a p i d A c c e l e r a t o r y P h e n o m e n o n

63. Akeson W H , Woo SLY, Couits RO, Matthews JD, Gonsalves M , Amie l D. Quant i tat ive histological evaluation of early fracture healing of cortical bones immobi l ized by stainless steel and com­posite plates. Calcif Tissue Res 1975;19:27-38.

64. M o y e n BJL, Lahey PJ, Winberg EH, Harris W H . Effects on intact femora of dogs of the application and removal of plates. J Bone Joint Surg 1978;60A:940-7.

65. Bradley GW, McKenna GB, Dunn HK, Daniels A U , Statton W O . J Bone Joint Surg. 1979;61A:866-72.

66. Tonino AJ, Davidson CL, Klopper PJ, Linclau LA. Protection f rom stress in bone and its effects. Experiments with stainless steel and plastic plates. J Bone Joint Surg 1976;58B:107-13.

67. Rabischong R, Bonnel F, Oonishi H, Asaada P, Micalef f JP. Com-portement b iom^canique du bassin a I'^tat normal et avec pros-t h s e totale de la hanche. Ref Chir Or thop 1977;63(Supp ll):95.

68. Meunier PJ. Bone histomorphometry. Paris: A rmour -Montagu , 1977.

69. Jaworski ZFG, Liskova-kiar M , Uhthof f H. Effect of long-term immobi l izat ion on the pattern of bone loss in older dogs. J Bone Joint Surg 1980;62B: 104-10.