J Child Orthop (2016) 10:487–492

DOI 10.1007/s11832-016-0780-2

CURRENT CONCEPT REVIEW

The biology of bone lengthening

Ivan Hvid1 • Joachim Horn1 • Stefan Huhnstock1 • Harald Steen1

Received: 19 October 2016 / Accepted: 19 October 2016 / Published online: 12 November 2016
Ó The Author(s) 2016. This article is published with open access at Springerlink.com

Abstract Distraction osteogenesis biologically resembles The regenerate bone can be manipulated when needed by
fracture healing with distinctive characteristics notably in using injection of mesenchymal stem cells and platelets,
the distraction phase of osteogenesis. In the latency phase growth factors (BMP-2 and -7), and systemic medications
of bone lengthening, like in the inflammatory phase of (bisphosphonates and parathyroid hormone). Growth fac-
fracture repair, interleukines are released and act with tors and systemic anabolic and antiresorptive drugs are
growth factors released from platelets in the local haema- prescribed on special indications, while distraction osteo-
toma, leading to attraction, proliferation and differentiation genesis is not an authorized indication. To some extent,
of mesenchymal stem cells into osteoblasts and other dif- however, these compounds can be used off-label. Use in
ferentiated mesenchymal cells. These in turn produce children presents special problems since growth factors and
matrix, collagen fibers and growth factors. A callus con- specific anabolic medications may involve a risk of
taining cells, collagen fibers, osteoid and cartilage matrix is inducing cancer.
formed. Provided stable fixation, distraction will trigger
intramembranous bone formation. As distraction proceeds, Keywords Bone
Lengthening
Biology
Stem cells

the distraction gap develops five distinctive zones with Platelets
Growth factors
unmineralized bone in the middle, remodelling bone
peripherally, and mineralizing bone in between. During
consolidation, the high concentration of anabolic growth Introduction
factors in the regenerate diminishes with time as remod-
elling takes over to form mature cortical and cancellous Optimal conditions for the lengthening of long bones are
bone. Systemic disease, congenital bone deficiencies, well established. The basic requirements for an optimal
medications and substance abuse can influence the quality result of bone lengthening are minimally traumatic osteo-
and quantity of regenerate bone, usually in a negative way. tomies preferably located in a metaphysis, solid mechani-
cal fixation across osteotomies, an adequate latency period
before lengthening to establish repair processes, suit-
Additional information: A vast array of other GF’s are available for
experimental and laboratory use (see for instance: https://www.
able rhythm and amplitude of lengthening, a realistic goal
thermofisher.com/no/en/home/life-science/cell-culture/mammalian- regarding the extent of lengthening, and sufficient time for
cell-culture/recombinant-proteins/growth-factors.html). An online callus to mature before frame or nail removal [1]. Despite
independent encyclopedia on cells and cytokines is available (http:// observation of all these requirements, in some instances
www.cells-talk.com).
bone formation can be insufficient, and additional proce-
& Ivan Hvid dures may be required to obtain a stable regenerate.
[email protected] Knowledge of the biological processes involved in dis-
1
traction osteogenesis, and of diseases influencing these
Section of Pediatric and Reconstructive Orthopaedic Surgery,
processes (e.g. diabetes mellitus), provides the clinician
Department of Orthopaedic Surgery, Oslo University
Hospital, Rikshospitalet, Sognsvannsveien 20, 0372 Oslo, with tools to deal with the relatively infrequent problems
Norway related to underlying disease, and to problems related to the

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quantity and quality of bone formed during and after

distraction.

Distraction osteogenesis

The clinical method of bone lengthening is often referred to

as distraction osteogenesis or callus distraction (callotasis),
a term suggesting that fracture repair mechanisms are
fundamental to initiate bone formation, and that distraction
of the osteotomies will maintain these mechanisms for
some time [2]. The initial phase of fracture healing, the
inflammatory phase, is biologically identical to the initial
phase of distraction osteogenesis, the latency phase [3].
The distraction phase of bone lengthening has distin- Fig. 1 IGF-1 in periosteum as a function of time after osteotomy of
guishing features from fracture healing, notably in the the tibial shaft in a rabbit model. Mean data for non-osteotomized
mode of ossification, intramembranous bone formation control tibiae (filled diamond), osteotomized control tibiae (filled
square), and lengthened tibiae (filled circle) are shown. Phases of
being predominant [3]. The final stage of fracture healing lengthening are indicated. Osteotomy and lengthening values differ-
involving consolidation of the fracture and remodelling of ent from control values at 2 weeks, lengthening values different from
the callus again is similar to the consolidation phase in osteotomy and control values at 4 weeks (P \ 0.05) Data obtained
distraction osteogenesis. from [2], tables 1–3

The latency phase osteoblasts. In fracture repair, bone formation proceeds

through callus formation, bone being formed mostly
The minimally invasive, low energy osteotomy can be through endochondral bone formation when there is some
compared to a closed low energy fracture. Secure fixation instability across the fracture site, and mostly through
using an external fixator system or, in the older child or intramembranous bone formation when there is a more
adult, an intramedullary lengthening device, should ensure stable fixation across a minimal fracture gap.
an optimal local environment for the initial healing
response. The length of the latency chosen is usually from The distraction phase
3 to 10 days, depending on the age of the patient, the site of
lengthening (e.g. proximal tibial lengthening will benefit After latency, the osteotomy gap is distracted using a set
from a longer latency period compared to a distal femur), rhythm and amplitude. The amount of lengthening per day
underlying disease and diagnosis [e.g. lengthening in is usually set at 1 mm at increments of 0.25 mm 4 times
congenital limb length discrepancy (LLD) may benefit per day. This has proved a practical compromise.
from a longer latency period compared to acquired LLD], Increasing the rhythm (decreasing increments) leads to
local factors such as previous infection, irradiation or a better bone formation [6].
poor soft tissue envelope, ongoing pharmacotherapy such Distraction modifies the fracture healing process influ-
as NSAID’s or steroids, and environmental factors such as encing mainly the level and timing of expression of growth
smoking (parental smoking could be an issue). factors and other mediators [3]. This mechanotransduction
The local trauma of osteotomy induces an inflammatory creates an ordered network of bone collagen. Initially, this
response causing release of cytokines, notably interleuki- collagen tends to be a mixture of collagen type I (bone
nes (IL-1, IL-6), leading to the recruitment, proliferation collagen) and type II (cartilage collagen), but soon after
and differentiation of mesenchymal stem cells (MSCs or distraction is commenced, collagen type I predominates
osteoprogenitor cells differentiate into osteoblasts) from entirely. Bone matrix proteins are secreted, and mineral is
bone marrow, periosteum and endosteum. These cells incorporated to produce bone [7]. Mineralisation can usu-
produce a variety of growth factors (GF) including bone ally be seen on ordinary radiographs after 1–2 weeks of
morphogenetic proteins (BMPs, notably BMP-2, BMP-4 distraction. Collagen fibers and cells align themselves
and BMP-6), transforming growth factor b (TGF-b), pla- along the direction of tensile strain. Typically, five zones
telet derived growth factor (PDGF), and insulin-like can be distinguished between the native bone ends: a
growth factor (IGF-1) (Fig. 1) [2–5]. The haematoma central fibrous zone, two peripheral mineralized zones, and
formed in the osteotomy gap and its immediate surround- two intermediate zones containing mineralizing micro-
ings will be inhabited by fibroblasts, chondroblasts and columns [3].

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The growth factors appearing during the latency phase maintaining bone mass of the regenerate bone during this
are still in play, their amounts peaking during the distrac- phase of active remodelling, underscoring the importance
tion phase. Other growth factors appear. Vascular of keeping patients mobile and weightbearing. Active
endothelial growth factor (VEGF) and angiopoitin 1 and 2 weightbearing also has a positive effect during the dis-
promote the establishment of a capillary network. traction phase, and it serves to minimize loss of bone
Remodelling is initiated quite early on, reflected by an mineral in the native bone being lengthened [14].
increasing ratio of RANK/OPG [RANK is receptor acti-
vator of nuclear factor-kappab that will recruit osteoclasts,
OPG is osteoprotegerin which protects bone from exces- Influence of disease, medication and substance
sive resorption by binding to RANKL (RANK ligand)]. An abuse
increased ratio means that more osteoclasts are formed and
activated thus setting the stage for the well known cyclus of Diabetes mellitus is reported to have a negative effect on
bone remodelling [8]. bone regeneration, more so in type I than in type II dia-
Parathyroid hormone (PTH) plays a central role in the betes. Insulin has a direct effect on osteogenesis through
process of mineralisation which is also dependent on the stimulation of osteoblast differentiation, an effect not to
availability of vitamin D and calcium. It also influences the be confused with that of IGF-1, although the two are
RANKL/RANK/OPG signalling system as a systemic phylogenetically related and may have some interactions
regulator of bone remodelling [9]. It interplays with the [15]. Diabetes significantly affects fracture repair, and it
Wnt signalling pathway (read ‘‘wint’’, the name refers to its may have negative effects on new bone formation in dis-
primary discovery in fruit flies—wingless) [10, 11] which traction osteogenesis. The treatment of type II diabetes
profoundly influences bone formation and remodelling with Rosiglitazone may have further negative effect on
throughout embryonic and postnatal life. IGF-1 is essential bone formation [16], while treatment with Metformin may
to the actions of PTH on the skeleton, including the effects have positive effects [17].
it might have in bone regenerative interventions [2, 12, 13]. Disorders affecting general nutrition and intestinal
IGF-1 regulates osteoblast function in endocrine (produced absorption, such as anorexia [18] and celiac disease [19] can
in the liver through growth hormone stimulation, acting on profoundly affect bone health, and negatively influence
many tissues including bone), paracrine (influencing cells osteogenesis.
in the local environment) and autocrine (modifying the Several medications can negatively affect bone repair.
metabolism of the cell in which it is produced) fashions. It This does not automatically imply that bone formation in
is part of a complicated system including 6 IGF binding distraction osteogenesis is reduced, because the details of
proteins (BPs), some of which stimulate IGF-1 actions fracture repair and distraction osteogenesis are not iden-
(IGFBP 3 and 5), and some of which inhibits its actions. tical. Corticosteroids have not shown consistent negative
The upper limit of length gain in distraction osteogen- effects on fracture repair, although most studies point in
esis of long bones is related to complications including soft that direction. In rats, endochondral bone formation was
tissue problems. There is no absolute consensus on this negatively effected, but intramembranous bone formation
issue, but most authors would agree on 7–8 cm in the was not. It may be, therefore, that the negative effect on
femur and 6–7 cm in the lower leg. We are unaware of bone formed during distraction osteogenesis is minor [20].
specific biological restraints to indicate an upper limit to Chemotherapeutic agents in general may have some
the gain in length that might be achieved. negative effects on bone healing, but in experimental and
clinical studies on distraction osteogenesis to reconstruct
The consolidation phase surgical defects, mostly positive results have been repor-
ted [20, 21]. The antibiotics mostly used in conjunction
By the end of the distraction phase, the regenerate bone with distraction osteogenesis appear to be harmless with
features a central unmineralized zone, neighbouring zones regards to bone formation [20]. Prophylactic use of low
of mineralizing tissue, and peripheral zones consisting of molecular weight heparins appear to have no negative
wowen bone already influenced by the remodelling pro- effect on fracture healing, but antithrombotic therapy
cesses. As the central parts of the regenerate evolves into using heparin decreases bone formation and increases
bone, the growth factors peaking during the distraction resorption [20]. The effect of NSAIDs is still somewhat
phase are downregulated, and remodelling takes over. PTH controversial. However, drugs with a short serum half-
and the Wnt signalling pathways are important in this life, e.g. ibuprofen, appear to have little negative effect on
phase. The RANK/OPG ratio decreases, and TNF-a (tumor fracture healing and osteogenesis when given short term
necrosis factor, induces apoptosis) is upregulated. Inter- and in moderate dose. Indomethacin appears to be an
mittent mechanical stimulation is likely to play a role in exception [20, 22].

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For a variety of reasons, patients exhibiting chronic being used in older children and adults and may reduce the
substance abuse are considered poor candidates for com- problem of delayed mineralization to some extent.
plicated orthopaedic procedures. Chronic alcoholism is Lengthening over one or two flexible nails may be con-
known to be associated with osteoporosis and impaired sidered, and has been shown to reduce the time on external
fracture repair. Distraction osteogenesis in this setting has fixation [27].
not been studied clinically, but animal experiments show a Bone transport procedures add the challenge of healing
profound negative effect of chronical alcohol intake [23]. of the docking site. In some instances, this may be cir-
Smoking has a negative influence on bone healing, cumvented by acute shortening after bone resection, then
including bone formation in distraction osteogenesis [24]. lengthening. Docking would usually involve planned
autologous bone grafting, or other means of stimulation of
local repair.
Treatment of deficient bone formation Mechanotransduction, i.e. the promotion of bone for-
mation by mechanical means, can possibly be applied
Prior to lengthening procedures, it is advisable to investi- effectively by other means than weight bearing and frame
gate serum 25-OH vitamin D which should not be below manipulations. Low intensity pulsed ultrasound and pulsed
25 nmol/l, and preferably be 75–150 nmol/l. An adequate electromagnetic fields can deliver strains in the micro-
daily supply of mineral, primarily calcium, should be range to the regenerate during and after distraction. The
ensured. In general, it is better to anticipate problems with efficacy of pulsed ultrasound in shortening the treatment
bone formation than to have to manage a deficient regen- time in tibial lengthening is documented in randomized
erate or an atrophic non-union later on. clinical trials [28]. Femoral lengthening would not appear
Patients with congenital shortenings are at higher risk of to be a target, since the soft tissue envelope does not
deficient bone formation, reflected in a higher risk of transmit the ultrasound waves effectively. There is some
fracture after fixator removal. The fracture risk was higher documentation that pulsed electromagnetic fields may have
in these patients when lengthening was [15% of initial clinical value, including an internally controlled study
segment length (except for patients with achondroplasia), (bilateral lengthening, one side treated) in 30 patients, most
and when the latency period was less than 7 days [25]. of them achondroplasia patients. The treated side showed
Bone fragility is present in more than 100 different genetic earlier callus formation and maturation, and the frame
disorders including skeletal dysplasias [26]. Among these, could be removed about 1 month earlier on the treated side
achondroplasia patients are by far the most common can- [29].
didates for limb lengthening procedures, and they are
known to tolerate these procedures relatively well.
Another, much more difficult patient group is neurofibro- Stem cells and platelets
matosis (and congenital pseudarthrosis not related to this
disorder). Other osteochondrodysplasias are relatively rare There is no doubt that MSCs are important for successful
candidates for limb lengthening procedures, and clinical fracture healing and distraction osteogenesis. Platelets
experience accordingly limited. contain multiple growth factors important in bone regen-
Bone formation may be deficient in terms of volume and eration. Both are relatively readily available for autologous
quality. If volume is insufficient, a change of the length- use, and may be concentrated by centrifugation during
ening protol, reducing the number of increments per day surgery. The cell and platelet contents in the crude aspirate
(and thus the amount of daily lengthening), and in more and after centrifugation may vary. This may be of minor
severe cases intermittent compression–distraction (accor- importance for the individual patients, but cell (platelet)
dion maneuvre), can be attempted. If volume is still defi- counts and cell characterization are of importance in clin-
cient by the end of the lengthening procedure, the first line ical research, since success or failure may depend on the
of treatment would be autologous bone grafting. If quality number and types of cells injected. Failure to provide such
is deficient reflecting reduced mineral content of the newly information may jeopardize the conclusions made, and
formed bone, vitamin D status should be checked. This makes comparison of studies difficult or impossible. The
condition of protracted consolidation will postpone frame procedures involved in collecting marrow and blood during
removal beyond the average. The patient should be phys- a surgical procedure and the following centrifugation and
ically active and bear full weight on the limb [14]. Sub- aspiration of cell concentrates are relatively safe with little
muscular plating or intramedullary nailing may be risk involved of contamination or other potential danger to
considered to reduce time in fixator, but these measures the patient. More sophisticated procedures, involving iso-
involve a significant risk of infection when performed after lation and cultivation of cells outside the operating room
a period of external fixation. Motorized nailing is now obviously present considerably more risks.

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While there is abundant literature on experimental ani- predominant. Short term treatment does not have long-
mal research to document the potential of marrow derived term effects on remodelling, and therefore the risk of
stem cells and platelets to enhance bone formation in dis- complications related to long-term and high-dose use
traction osteogenesis, the clinical literature is sparse. A (atypical long-bone fracture, osteonecrosis of the jaw) can
recent randomized clinical trial with ten patients in each be considered minimal.
group reports on bilateral tibial lengthening for familial PTH is used clinically to treat osteoporosis in a prepa-
short stature. The treatment group had injection locally in ration known as teriparatid [PTH (1–34)], the N-terminal of
the osteotomy of a mixture of centrifugated marrow aspi- the native human hormone (ForsteoÒ). It has not been used
rate and platelet rich plasma obtained and injected during clinically in distraction osteogenesis, and only sporadic use
the index surgical procedure. There was no difference in in orthopaedic conditions have been reported. In animal
the time in external fixator between the groups, but the studies on distraction osteogenesis, PTH has shown sig-
cortical healing index was about 15% less in the treatment nificant anabolic effects. Since the effect is almost as large
group as was the time to full weight bearing [30]. These when given during the consolidation phase as compared to
cells were injected into the osteotomy at the time of sur- the distraction and consolidation phases, it holds promise
gery. Cells may be injected later in the process of length- as a rescue medication for the anabolic insufficient regen-
ening, e.g. to boost an insufficient regenerate during or erate [33]. The use in orthopaedic conditions is off-label.
after distraction. Due to possible cancer risk with long-term use (animal
studies), the duration of treatment should not exceeded
24 months over a patients life time. It should not be given
Growth factors during pregnancy, and it should not be given to children or
adolescents with open epiphyses.
Two growth factors are commercially available, BMP-2
(InductOsÒ, InfuseÒ) and BMP-7 (also known as osteo- Acknowlegements No funding was granted for this review.
genic protein-1 (OsigraftÒ). These GF’s are approved for
Compliance with ethical standards
use in lumbar spondylodeses and tibial fractures, and tibial
non-unions, respectively. They are not approved for use in This is a current concepts review paper, and contains no new material
children due to concerns about cancer risk. Large cohort in need of Review Board Approval.
studies conclude that the use of BMP-2 in lumbar
Conflict of interest Ivan Hvid, Joachim Horn, Stefan Huhnstock and
spondylodeses in an elderly population is not associated Harald Steen declare that they have no conflict of interest.
with increased cancer risk, but the issue remains contro-
versial [31]. Off-label use in children is possible. BMP-2 Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://crea
has been used in children undergoing scolioses surgery and
tivecommons.org/licenses/by/4.0/), which permits unrestricted use,
lower extremity surgery. Such use should be cleared with distribution, and reproduction in any medium, provided you give
national health authorities. The use of growth factors in appropriate credit to the original author(s) and the source, provide a
connection with distraction osteogenesis would mostly be link to the Creative Commons license, and indicate if changes were
made.
indicated to augment healing potential of bone grafting in
deficient callus and docking site non-union.
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