Henry Ford Hospital Medical Journal

Volume 31 Number 1 Article 2

3-1983

The Regional Acceleratory Phenomenon: A Review

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Frost, Harold M. (1983) "The Regional Acceleratory Phenomenon: A Review," Henry Ford Hospital Medical
Journal : Vol. 31 : No. 1 , 3-9.
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Henry Ford Hosp M e d J
Vol 31, No 1,1983

FeatuiFe A r t i c l e s
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.

T h i s review concerns an entity which affects both skele- b o n e , cartilage, and hair (6,18-20); turnover of bone,
tal and soft tissues and may explain certain features of cartilage, synovial f l u i d , 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 d u e t o a n increased
the size of the affected region and the intensity of its remodeling space. A joint contracture, which was pre-
response varies directly w i t h 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.
o m y , a r t e r i o t o m y , burns, acute d e n e r v a t i o n , 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 o w n 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 S u b m i t l e d for p u b l i c a t i o n : N o v e m b e r 24,1982
tissue vital processes accelerate above normal values. A c c e p t e d for p u b l i c a t i o n : January 24,1983

Collectively, those accelerated processes represent the ' S o u t h e r n C o l o r a d o Clinic, 2002 Lake A v e n u e , Pueblo, C O 81004
Address reprint requests to Dr. Frost, 2002 Lake A v e n u e , Pueblo, C O 81004
RAP, and they include: perfusion (17); growth of skin.
 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, d r u g , 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
A m o n g the above clinical manifestations, physicians will postulated " S O S " role for the RAP. O n e 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 n o n u n i o n , termed a "biological
The RAP involves the region where its stimulus arose, f a i l u r e " (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, w h o 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). B M U -
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 w o u n d , 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 k n o w n products.
acute paralysis as f r o m 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 w o u l d bridge in the first year.
deloading, and thereby can predispose to hypercalciuria
About twenty years w o u l d be required for complete
and genitourinary tract lithiasis (25,30). W h e n 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 w i t h o u t any k n o w n 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 " S O S " 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 " S O S " type phenomenon reflect an o b t u n d e d RAP, and the often beneficial
which w o u l d potentiate the survival of a species during effects of bone grafting or electrical stimulation c o u l d ,
evolution in a physically competitive environment. Once in part at least, result f r o m 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
" r u n a w a y " 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 i n f l a m m a t i o n , 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 w o u l d normal joints, in which equivalent abuse
but corticosteroids and some other prostaglandin inhib- w o u l d 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 o b t u n d e d RAP plays a
Joint stiffening d u e t o 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
w h i c h , 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 w h o m lower limb innervation remains intact, lower limb
origin (biochemical, mechanical, post-frostbite, nutri- w o u n d s and fractures heal normally and infection
tional), the affected tissues respond poorly to wounds, responds satisfactorily to treatment (44). In contrast,
mechanical abuse, a n d / o r 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 p r o d u c t i o n ,
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 l i m b (2,3,59). O n 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 t h a t t h e RAP tran-
and bone lesions may heal properly, and a ruptured siently stimulated g r o w t h , i.e., for about a year, which
rheumatoid tendon usually heals normally after surgical dominated the concurrent g r o w t h 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 w h o had undergone a thoracot- implantation of the hardware applying those forces
omy seven years earlier. Histomorphometric measure- evoked a RAP which tended to accelerate g r o w t h , while
ments o f t h e originally resected sixth rib disclosed much the mechanical forces exerted their o w n 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 p r o - 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
f r o m one and then f r o m 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 f o l l o w acute paralysis, deloading long bones by plate fixation (63,64). To distin-
whether due to trauma, poliomyelitis (11,28,29) o r o t h e r guish RAP f r o m 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 o f t h e 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 k n o w n 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. O n the other hand, sent a final c o m m o n pathway for an appropriate physio-
other experiments reveal that a RAP can also result f r o m 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.

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