Henry Ford Hospital Medical Journal

Volume 31 Number 1 Article 2

3-1983

The Regional Acceleratory Phenomenon: A Review

Harold M. Frost

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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

This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. 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 com­ tiate tissue heaUng and local tissue defensive reactions. plex reaction of mammaUan tissues to diverse noxious When a RAP is obtunded, retarded healing and lowered stimuli. The phenomenon occurs regionally in the ana­ resistance to infection and mechanical abuse may ensue. tomical sense, involves both soft and hard tissues, and is When ignored in experimental design, the phenomenon characterized by an acceleration and domination of can seriously perturb studies of metabolic bone disease most ongoing normal vital tissue processes. It may and of the effects of mechanical, endocrinologic, and represent an "SOS" mechanism which evolved to poten­ biochemical factors on skeletal physiology.

This review concerns an entity which affects both skele­ bone, cartilage, and hair (6,18-20); turnover of bone, tal and soft tissues and may explain certain features of cartilage, synovial fluid, connective and fibrous tissue some diseases. It can also perturb experimental studies (18,21,22); chondral and bone modeling including cor­ of metabolic bone disease and of mechanical and other rection of malunions in children; skin epithelialization; effects on skeletal physiology; if unrecognized, its fea­ cicatrization; soft tissue and bone healing (23); and cel­ tures may be assigned to other causes. While physicians lular metabolism. have long known many of its manifestations, it was first Consequently, an affected region develops erythema recognized and proposed as a general entity by the and edema and becomes warm on thermography as well author. Of necessity, this review reflects his experience, as to touch. The accelerated local bone turnover increases biases, and limitations (1-4). the uptake by bone-seeking isotopic agents, which characteristics of the Regional Acceleratory causes the hot regions often found in acute and chronic Phenomenon (RAP) osteomyelitis, in actively healing fractures, in the pres­ ence of joint inflammation of any cause, in Sudeck's Causes atrophy, and in the presence of some bone metastases In a normal body any regional noxious stimulus of suffi­ (24). Photon absorption studies and routine x-rays can cient magnitude seems to evoke a RAP. It appears that reveal decreased regional bonedensity duetoan increased the size of the affected region and the intensity of its remodeling space. A joint contracture, which was pre­ response varies directly with the magnitude of that stim­ viously too rigid to respond to wedging casts or traction, ulus, although to different degrees in different individuals. can respond more readily during the three months or so following a major local bone operation, a phenomenon The effective noxious stimuli include crushing injury, which suggests that the RAP rendered the capsular and fracture (5,6), bone operations of any kind (7-9), arthrot- related tissues more plastic for a time. omy, arteriotomy, burns, acute denervation, acute paralysis (10,11), infarcts, soft tissue and bone infections Clinically, as well as histologically, the particular cause of (12-15), and most noninfectious inflammatory joint pro­ a RAP can imprint its own features on the concomitant cesses including rheumatoid arthritis, rheumatic fever, general features of the RAP, so that their combination pseudogout and Reiter's disease (10,16). can appear characteristic or even diagnostic. Such char- Nature

Once evoked, many ongoing regional soft and hard Submitled for publication: November 24,1982 tissue vital processes accelerate above normal values. Accepted for publication: January 24,1983 Collectively, those accelerated processes represent the 'Southern Colorado Clinic, 2002 Lake Avenue, Pueblo, CO 81004 RAP, and they include: perfusion (17); growth of skin. Address reprint requests to Dr. Frost, 2002 Lake Avenue, Pueblo, CO 81004 Frost

acteristic imprints (such as necrosis, pus, eosinophilia, begun, it tends to dominate other ongoing processes Langhan's giant cells, hemosiderin, or scar) usually allow and those endocrine, drug, and mechanical effects one to distinguish between trauma, acute pyogenic which tend to depress or potentiate those activities in infection, immune reactions, chronic infections, necro­ healthy subjects. sis, and metastasis as examples. Two different groups of clinical situations illustrate the Among the above clinical manifestations, physicians will postulated "SOS" role for the RAP. One reflects its posi­ recognize some of the classical signs of inflammation tive effects, the second its impairment. (26,27), which this writer suggests represent an early recognized manifestation of a stereotyped, more gen­ Clinical Examples of RAP Effects eral phenomenon. Potentiated bone healing Anatomical distribution In the type of fracture nonunion, termed a "biological The RAP involves the region where its stimulus arose, failure" (31) or an atrophic or oligotrophic nonunion such as a knee, wrist, leg, foot or hip, including soft and (32), fracture callus arises too slowly and too scantily for hard tissue components. Following an acute paraplegia, satisfactory union but not from any known flaw in treat­ hemiplegia, or monoplegia, whether due to trauma, ment. Dr. Robert Schenk and a group of Swiss orthopae­ poliomyelitis or other acute disease, or whether due to dists, who developed a highly efficient system of internal lower motor neuron or central lesions, the RAP can fixation of fractures that has come into wide use in devel­ affect the whole paralyzed part of the body (28,29). The oped nations, taught the orthopaedic community that transition from involved to uninvolved regions seems such nonunions can heal, given intimate apposition gradual, rather than abrupt, and the distribution of the fixed rigidly enough to allow less than about 50 microns RAP seems to reflect regional vascular anatomy and of interfragment motion (23). Such union occurs not by innervation. Given severe stimuli, abscopic involvement callus production but by BMU-based remodeling, which can occur, meaning that accelerations of ongoing tissue knits the fragments together with numerous secondary turnover and perfusion can occur in the contralateral osteons crossing the fracture interface (23,33). BMU- regions of the body. based remodeling refers to the quantized or pocket- type turnover of adult human lamellar bone. It occurs in Duration discrete units and involves an activating stimulus that In healthy humans, and following a single stimulus such causes an initial focal resorption process followed by a as a Colles' fracture, pyarthrosis or gunshot wound, clin­ bone formation process. That A-R-F sequence normally ical evidence of the RAP typically lasts about four consumes about three months (1,21,23,30,33), and the months in bone, somewhat less in soft tissues, and secondary haversian system represents one of its well- longer for severe than for mild stimuli. But following known products. acute paralysis as from a brachial plexus injury, orafter a Normally, such remodeling turns over less than 5% of severe burn, the RAP can last from six months to over the adult human tibial compacta annually (34,35). If no two years. Thus, for commensurate periods, it can accel­ other factor acts after such fixation, less than 5% of a erate the bone loss caused separately by mechanical tibial fracture interface would bridge in the first year. deloading, and thereby can predispose to hypercalciuria About twenty years would be required for complete and genitourinary tract lithiasis (25,30). When the causa­ bridging. Yet union typically occurs within six months tive stimulus persists for prolonged periods, as it can in because the operation itself (whether intermedullary active rheumatoid arthritis, osteomyelitis, Paget's dis­ nailing, compression plating, or a securely fixed sliding ease of bone or in the presence of an osteoid osteoma, bone graft) accelerates the local bone turnover ten to the RAP persists similarly without any known evidence fifty-fold above normal for more than a year. That reac­ of a natural limit to its duration. tion accelerates the healing process (23) in the soft The "SOS" Role of the RAP tissues as well as in the bone. The RAP may have evolved to accelerate healing of Such observations suggest that normal fracture healing injuries and tissue defense reactions to local infection, may routinely require an accompanying RAP. If so, a infarction, mechanical abuse, and other noxious pro­ delayed union not due to inadequate treatment could cesses. Such a role suggests an "SOS" type phenomenon reflect an obtunded RAP, and the often beneficial which would potentiate the survival of a species during effects of bone grafting or electrical stimulation could, evolution in a physically competitive environment. Once in part at least, result from a newly evoked RAP. Signifi- Rapid Acceleratory Phenomenon

cantly, studies by Takahashi, et al have shown exactly nervous system disease or traumatic lesions, typical such effects of electrical bone stimulation (36). Charcot joint signs include considerable local bone and joint destruction and gross instability (3) but relatively The pathological RAP mild edema, heat, swelling, and discomfort. Static histo­ Two clinical entities seem to illustrate pathological or logic examination of Charcot joints reveals typical kinds "runaway" RAPs. In Sudeck's atrophy, an acute injury of tissue responses to those stimuli, including fibrosis, originally evokes a typical RAP, but the local accelera­ dilatation of capillaries, production of new woven bone, tions characteristic of that RAP persist long after the low grade inflammation, resorption of debris, and original injury has healed. Sympathetic nerve blocks edema (12,26,40). often cure this condition, but corticosteroids and related agents may not. The other entity, regional migratory However, the static histology misses an important but osteoporosis, also may follow a local injury, although it quite consistent dynamic feature. That is, given equal can occur spontaneously. When due to injury, this dis­ destruction, daily usage, and instability, the Charcot order also persists long after the injury has healed; and it joint tissues develop far less tissue response per week is intriguing that sympathetic blocks are not beneficial, than would normal joints, in which equivalent abuse but corticosteroids and some other prostaglandin inhib­ would promptly evoke pronounced swelling, edema, itors often help (37,38). and erythema, greatly increased local perfusion, fibrosis, and reactive bone formation. Arthrofibrosis This observation suggests that an obtunded RAP plays a Joint stiffening dueto diffuse fibrosis can follow regional major role in the pathophysiology of Charcot joints. In surgery, trauma, infection, noninfectious inflammation addition, the associated impairment of deep pain sensa­ as in rheumatoid arthritis, and the development of a tion (41,42) allows daily activity to cause new damage regional osteoid osteoma. All of these can evoke a RAP faster than the lethargic, obtunded repair processes can which, among other effects, increases collagen produc­ react to and heal it, so destruction is progressive. Similar tion in the regional connective, fascial, capsular, and phenomena can occur in subjects with congenital absence ligamentous tissues. Lacking frequent range-of-motion of pain (43). exercises, that fibrosis binds the regional gliding mechan­ isms together. Clinically, an obtunded RAP accompanies local sensory but not motor denervation; it was rarely observed in The next examples illustrate proposed clinical examples victims of anterior poliomyelitis. Sensory impairment of obtunded or absent RAPs. may be due to central or peripheral trauma, to central Neuropathic soft tissue problems nervous system disease or peripheral neuropathy. Var­ ied observations and experimental data support the In diabetics with significant peripheral neuropathy but concept. For example, in patients with paralysis due to good perfusion,and in nondiabeticpatientswithdener- spinal cord injury at the cervical or thoracic levels, in vated limbs or severe peripheral neuropathy of other whom lower limb innervation remains intact, lower limb origin (biochemical, mechanical, post-frostbite, nutri­ wounds and fractures heal normally and infection tional), the affected tissues respond poorly to wounds, responds satisfactorily to treatment (44). In contrast, mechanical abuse, and/or infections (27). In healthy after regional peripheral denervation, reduced perios­ tissues, such lesions promptly evoke a RAP (which teal and longitudinal overgrowth occur in amputation includes the classical signs of inflammation plus acceler­ stumps (45), and impaired healing in denervated tissues ated turnover and metabolism of local skin and underly­ is well known. ing soft tissues). Local healing is thus accelerated. But in these neuropathic affections, those accelerations are Rheumatoid phenomena either obtunded or absent, while erythema, increased The tendency of excessive local collagen production, perfusion, or edema develop slowly, healing is pro­ postulated to be a positive RAP effect, to cause joint longed, and local resistance to infection, mechanical stiffness typically occurs early and during active and abrasion, and pressure declines. Proof of the regional severe rheumatoid arthritis inflammation. However, in rather than systemic origin of those phenomena lies in late cases of rheumatoid arthritis and in some of its the fact that in the same individual no such problems variants, opposite effects can occur: ligaments and cap­ arise in uninvolved body parts. sules stretch, joints become lax and subluxated, and The Charcot joint microscopic tendon damage accumulates, so poorly repaired that spontaneous rupture finally occurs. Never- Whether due to diabetes, lues, syrinx, other central Frost

theless, the classical external evidence of inflammation of mechanical deloading. However, the invariable result and other RAP manifestations is often unimpressive. of deloading without any complicating RAP, which appears Considerable internal damage may occur with minimal in children paralyzed early in life [e.g., myelomeningo­ external signs of local tissue reaction, a state interpreted cele (11)] is a short limb (2,3,59). On the other hand, to indicate an impaired RAP. In addition to the disease acute paralysis can produce the bony and soft tissue process, therapeutic agents may play a role in that phenomena of a RAP in both laboratory animals and impairment. Paradoxically, in these same patients, skin humans. In those situations, I suggest thatthe RAP tran­ and bone lesions may heal properly, and a ruptured siently stimulated growth, i.e., for about a year, which rheumatoid tendon usually heals normally after surgical dominated the concurrent growth depression caused repair. by mechanical deloading. When thetransient dominat­ ing RAP subsided, the persisting depressive effect The RAP in Research became apparent.

Histomorphometric bone studies Similar opposing forces may explain the confusing I first suspected that the RAP was a general entity about results observed when experimental forces are applied 1960 when the sixth and seventh ribs were removed at across growing epiphyseal plates (2,3). The surgical autopsy from a patient who had undergone a thoracot­ implantation of the hardware applying those forces omy seven years earlier. Histomorphometric measure­ evoked a RAP which tended to accelerate growth, while ments ofthe originally resected sixth rib disclosed much the mechanical forces exerted their own effects (2,3), higher bone turnover than was present in the uninjured and investigators observed the variable net results (60,61). adjacent rib. Numerous subsequent observations in Bone loading experiments human subjects have shown that any type of significant injury to a bone usually accelerates its turnover for a year The interest of the orthopaedic community in mechani­ or more. cal effects on bone architecture has made "Wolff's law" a password (62). In the last two decades of the 19th This phenomenon suggests that repeated biopsy of the century Julius Wolff proposed in essence that living same bone before and after some treatment may pro­ bone can occasionally change its internal architecture in duce effects on bone remodeling which yield pro­ response to a change in the mechanical loads it carries, foundly perturbed data (25,30,46-49). The techniques of and that such changes made it better equipped mechan­ serial rib biopsies (50-53) and of obtaining a biopsy first ically to support those altered loads. Accordingly, he from one and then from the opposite ilium (33,54-57) proposed that the mechanical usage of a bone can influ­ have been developed to minimize that error. Most his- ence its architecture. A representative experiment tomorphometrists now realize that serial biopsies of the involves surgically implanting to each end of a bone same bone cannot provide useful pre- to post-treatment hardware which is connected by restraints in order to bone turnover parameters (1). These potentially per­ compress the bone uniaxially. Some investigators attrib­ turbing effects of the RAP on experimental data are uted the resulting increased outside bone diameter and often overlooked by investigators interested in other porosity to increased mechanical compression. How­ kinds of skeletal problems, as indicated below. ever, they usually omitted the necessary control: i.e., identical devices implanted identically in the opposite Longitudinal bone growth limb but with the restraint disconnected. Such surgical In children, bone growth often accelerates for some procedures certainly cause a RAP, and the reported time after a major fracture or surgical procedure (58). bone reactions are typical RAP manifestations (3,7). Such With variable success surgeons have also tried to stimu­ experiments combine compression effects with unrec­ late bone growth by periosteal stripping, or by implant­ ognized RAP effects. ing beef bone or ivory pegs (8,19). The ensuing growth accelerations represent typical positive RAP effects. The same problems occur in studies of mechanically Growth acceleration may also follow acute paralysis, deloading long bones by plate fixation (63,64). To distin­ whether due to trauma, poliomyelitis (11,28,29) orother guish RAP from stress-strain effects, it is necessary to affections, as well as local irritants such as chronic implant identical screw-plate devices on each femur, osteomyelitis, an osteoid osteoma, juvenile rheumatoid one of which has loosened screws. However, investiga­ arthritis, or an irritating foreign body (12,19). Some tors have usually omitted this control. Although compar­ observers have attributed the unpredictable growth ison of the effects of rigid to flexible plates involves the increases which can follow such affections to an effect use of different materials, many investigators have not Rapid Acceleratory Phenomenon

compared the effects ofthe materials independently for competence and autonomic innervation of the regional either the RAP or the mechanical bones (65,66), so con­ blood supply, regional sensory innervation and mechan­ clusions based on such experiments are difficult to ical loading, as well as the gamut of local biochemical defend (67). and biological factors already known to be associated with injury, repair, metastasis, and inflammation, e.g., Discussion prostaglandins, leukotrienes, lysozymes, and other Experimental studies of the RAP leukocyte activities. Takahashi, et al produced typical bone RAPs by electrical stimulation of bone with com­ High, et al have provided the only published experimen­ mercial equipment used to treat fractures, and control tal data specifically applicable to RAP effects (51-53). studies revealed that surgical implantation alone also Evoked in adult canine rib by periosteal stripping, caused unequivocal but less severe RAPs (36). Basic dynamic histomorphometric analyses (47,56,68) of the differences in some causative factors, both in kind and stripped as well as of the uninjured ribs revealed signifi­ magnitude, may characterize soft and hard tissue RAPs, cantly accelerated turnover in the stripped ribs six weeks accounting for the differences in their microscopic later, apparently unmodified by concurrent treatment features. with other agents. The design of those experiments elim­ inates mechanical deloading as a significant factor in the Similar to the features of the lower motor neuron or results, indicatingthat bone RAP effects need not neces­ BMU-based bone remodeling (1), the RAP may repre­ sarily reflect mechanical effects. On the other hand, sent a final common pathway for an appropriate physio­ other experiments reveal that a RAP can also result from logic expression of diverse stimuli. Its particular clinical, acute deloading and, furthermore, can differ in kind and biochemical, and histologic features may accompany anatomical location according to the subject's age the specific features of the causative stimulus, such as (14,22,69). trauma, infection, an immune reaction, or necrosis. The RAP is a process of the intermediary organization of Mechanisms underlying the RAP tissues and organs and is not revealed in the properties Although understanding isfarfrom complete, the causes of isolated cells, so effective study cannot utilize ex vivo of the RAP are many and depend on the anatomy and systems but will require the use of intact subjects.

References

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