Review

Endocrine & Metabolic

Enhancement of fracture healing

1. Introduction
2. Evaluation of research so far
3. Expert opinion
Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by York University Libraries on 11/14/14
with parathyroid hormone:
preclinical studies and potential
clinical applications
Byron Chalidis, Christopher Tzioupis, Eleftherios Tsiridis &
Peter V Giannoudis†
†University

of Leeds, Academic Unit, Clarendon Wing, Leeds Teaching Hospitals NHS Trust,
Great George Street, Leeds, LS1 3EX, UK

Parathyroid hormone (PTH) has become the most widely studied hormone
with regard to its administration to various species and their respective skele-
tal responses. Beyond its affirmative effect in osteoporosis treatment, sys-
temic PTH administration seems to stimulate bone formation in the fracture
healing process. According to preclinical experimental studies, once-daily
administration of PTH enhances the morphometric and mechanical pro-
perties of fracture calluses and accelerates the normal fracture healing. Its
anabolic effect is obvious even in low doses, as well as in cases of implant fix-
ation and distraction osteogenesis. There is little evidence of toxic effects and
For personal use only.

there are only a few reports of adverse events related to its use. The inci-
dence of bone neoplasms in animal studies depends on the dose and dura-
tion of treatment. However, it is not prognostic of an equivalent risk
potential of carcinogenesis in humans. In summary, the clinical promise of
parathyroid hormone is very high and a positive effect in fracture healing
should be anticipated.

Keywords: fracture callus, IGF-I, mesenchymal cells, osteoblast, osteosarcoma, teriparatide

Expert Opin. Investig. Drugs (2007) 16(4):441-449

1. Introduction

Parathyroid hormone (PTH), an 84 amino acid polypeptide, is secreted by the para-

thyroid glands and it is a major regulator of Ca2+ and phosphate homeostasis [1]. The
main function of PTH is to maintain the Ca2+ ion concentration of the extracellular
fluids within physiologic limits [1]. Although high, sustained levels of PTH are cata-
bolic to bone tissue, intermittent low-dose administration is potentially anabolic
and leads to increased osteoblastic activity and recovery of bone mass [2-4].
Recent animal experimental studies have demonstrated that intermittent treat-
ment with recombinant human PTH (hPTH [1-34] and hPTH (1-84)) promotes
osteogenesis in fracture healing and enhances the size and the mechanical properties
of calluses [5-19].
At present, no published clinical trials have investigated the effects of PTH
treatment on human fractures. Based on the anabolic effect of PTH on osteoporotic
bone [2,3] and the encouraging preclinical results in fracture healing [5-20], it is
subsequently hypothesized that PTH may be successfully used in selected human
fracture cases.
This review primarily aims to summarize the present preclinical evidence on
the effects of PTH in fracture healing, its safety and the potential efficacy in
clinical practice.

10.1517/13543784.16.4.441 © 2007 Informa UK Ltd ISSN 1354-3784 441

 Enhancement of fracture healing with parathyroid hormone: preclinical studies and potential clinical applications
2. Evaluation of research so far
2.1 Mechanism of action
The cellular mechanism that is responsible for the anabolic
impact of intermittent PTH treatment on fracture healing is
not fully known. The mitogenic effect of PTH may be medi-
ated by regulators of bone remodeling such as TGF-β [21],
which is a known potent mitogen for osteoprogenitor cells
and it is regulated partly through PTH [21-23]. PTH may also
enhance the synthesis of IGF-I and the secretion of
IGF-I-binding proteins in osteoblast-like cells [24,25]. This
hypothesis was also suggested by an experiment from
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Watson et al. [26] in PTH-treated rats. In situ hybridization
techniques have demonstrated that the anabolic effect of PTH
is associated with increased IGF-I gene expression in
trabecular osteoblasts [23].
β-Catenin is thought to be a further important factor in
osteogenic activity of PTH [27]. It collaborates with endothelial
(E)-cadherin at the bone cell surface to keep the cell attached
to its neighbours as it can also modulate gene expression when
inserting into the nucleus. PTH operates via the β-cat-
enin-sparing mechanism that is driven by the paracrine Wnt
glycoprotein that promotes osteogenesis and bone growth [28].
In addition, Nakazawa et al. [5] have shown that PTH has
For personal use only.
an additional key effect on mesenchymal (chondroprogenitor)
cells by stimulating their proliferation and increasing their
recruitment into the chondrocyte lineage. As a result, a higher
proportion of progenitor cells achieve full osteoblast
differentiation [29].
In general terms, it is postulated that inflammatory media-
tors may stimulate IGF-I expression by periosteal cells follow-
ing a fracture. In turn, IGF-I stimulates chondrogenesis but
PTH enhances ossification in an autocrine (PTH) or para-
crine (PTH-related protein [PTHrP]) fashion [30]. It is consid-
ered that IGF-I mediates the effect of PTH on
osteoblast-induced bone formation and mesenchymal cells
proliferation [5].
2.2 Efficacy in fracture calluses
Several preclinical investigations have described the
enhancement of fracture healing and osteointegration in
animals after systemic [5-19] and local [13,20] administration
of PTH (Table 1). Andreassen et al. [9] studied the results of
intermittent administration of teriparatide (PTH [1-34])
200 µg/kg/day on the density and mechanical strength of
callus in a 27-month-old rat tibial fracture model during
the third and the eighth week of healing process. During
weeks 3 – 8, the increase of the bone mineral content
(BMC) of the callus was 169% in the PTH-treated animal
compared with 60% in the vehicle-injected animals. At
3 weeks, PTH increased maximum load and external callus
volume by 160 and 208%; at 8 weeks, these were increased
by 270 and 135%, respectively. In the contralateral intact
tibia, PTH treatment increased BMC by 18 and 21% at 3
and 8 weeks, respectively.
442 Expert Opin. Investig. Drugs (2007) 16(4)
Local delivery of PTH at the fracture site using the
gene-activated matrix technology has been shown to promote
bone regeneration [13,20]. Chen et al. [13] compared the results
of local, systemic and combined (both systemic and local)
application of PTH (1-34) in a rat osteotomized model. The
combination treatment group, when compared with the other
groups, showed significantly higher bone mineral density,
BMC and a trend for greater bone area in microradiographic
analysis. The authors concluded that there is an additive effect
of systemic intermittent PTH subcutaneous injection and
local PTH application in promoting bone regeneration in rat
femurs and hypothesized that the above combination may be
considered a powerful adjunct in treating local bony defects
such as non-union fractures.
Regarding the safety and tolerability of various PTH doses,
Alkhiary et al. [15] recorded the skeletal effect of daily sub-
cutaneous injection of PTH (1-34) 5 or 30 µg/kg of in
Sprague-Dawley rats. A significant increase was found over
the vehicle group with respect to torsional strength, stiffness,
BMC, bone mineral density and cartilage volume. The
authors stated that even low doses of PTH have an anabolic
effect throughout the remodeling phase of fracture healing
process without inducing bone resorption at low doses.
The duration of intermittent treatment of PTH on fracture
healing has been investigated by Komatsubara et al. [6] in a rat
model experimental study. Subcutaneous injection of
hPTH (1-34) 10 or 30 µg/kg/day improved the mechanical
strength of fractured bone by accelerating the remodeling of
woven bone to lamellar bone and the formation of a new cor-
tical shell without increasing callus size. Moreover, it was evi-
dent that 3 weeks pre-treatment with PTH prior to fracture
alone did not affect fracture healing. However, the healing
process was accelerated when PTH was administered 3 weeks
before and 12 weeks after the fracture. According to the data,
PTH application should be continued when fragility fracture
occurs in osteoporotic patients under PTH treatment.
Recently, evidence has been proposed that low-dose
hPTH (1-34) could enhance chondrogenesis and accelerate
cartilage differentiation. Nakazawa et al. [5] found that inter-
mittent low-dose treatment with recombinant hPTH (1-34)
increased the proliferation of chondroprogenitor cells and the
synthesis of type II collagen, resulting in the formation of a
larger cartilaginous callus. The PTH-induced cartilaginous
callus was then rapidly replaced with bone. The latter effect
was speculated by the authors to be a potential important
advantage to support the future clinical application of this
peptide in the treatment of skeletal injuries.
2.3 Efficacy in implant fixation
Addressing the issue of PTH administration and ortho-
pedic implant fixation, Skripitz et al. [18,19] compared the
effects of PTH in the implant–bone fixation of stainless
steel screws in terms of new bone formation and normal
baseline remodeling in rats. Histologic examination
revealed that PTH increased the density of surrounding
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For personal use only.

Table 1. Preclinical studies of PTH application in fracture healing process .

Study Year Animal Fracture model PTH dose: treatment duration Major findings
[20] 1996 Sprague-Dawley rats Mid-diaphyseal femoral Local PTH (1-34) and/or BMP-4 delivery Implantation of a gene-activated matrix containing either BMP-4 or
fracture PTH (1-34) resulted in a biologic response of new bone filling the
gap
Implantation of a two-plasmid gene-activated matrix encoding
BMP-4 and PTH (1-34) fragment acted synergistically
[8] 1999 3-month-old male Mid-diaphyseal femoral Daily subcutaneous injection injection of In the PTH-treated fractures, statistically significant increase in callus
Sprague-Dawley rats fracture PTH (1-34) 80 µg/kg versus saline vehicle area and strength
for 21 days Histologic examination of the calluses: increase in the amount of
new bone formed
Statistically significant increase in callus area and strength after
21 days of treatment of PTH-treated group (p < 0.05)
[10] 1999 3-month-old female Wistar Tibial fracture Daily subcutaneous injection of either 60-µg group: significant increase in BMC, external callus volume
rats PTH (1-34) 60 or 200 µg/kg for 20 or and ultimate load after 40 days
40 days versus vehicle control 200-µg group: significant increase in BMC, external callus volume
and ultimate load after 20 and 40 days
Both PTH groups: greater increases in contralateral intact tibia BMC
compared with vehicle after 40 days
[17] 2000 Adult male New Zealand Standard osteotomy in Daily injections of prednisone At 6 weeks, all of the animals treated with both PTHrP and
white rabbits both ulna of each rabbit (0.15 mg/kg) beginning 2 months prior prednisone showed complete union at the osteotomy site bilaterally.
to surgery and continuing until killing In contrast, no control osteotomies achieved union at 6 weeks
Daily injection of PTHrP analog RS-66271 Ulna in the PTHrP analog-treated rabbits showed greater
(0.01 mg/kg s.c.) starting 1 day after radiographic intensity (20 – 40%), larger callus area (209%

Expert Opin. Investig. Drugs (2007) 16(4)

surgery for 6 weeks anteroposterior view; 417% lateral view), greater stiffness (64%)
Control animals received subcutaneous and torque (87%) when compared with controls
normal saline
Study at 6 and 10 weeks
[11] 2000 4-month-old ovariectomized Bilateral tibial shaft Daily subcutaneous injection of either Increase in mechanical and morphometric fracture callus parameters
Sprague-Dawley rats fracture PTH (1-84) 15 or 150 µg/kg for 30 days (dose dependent) in the PTH-treated group
versus 17 β-estradiol No advantages in 17 β-estradiol-treated group
[18] 2000 Adult male Sprague-Dawley Implantation of bone Daily subcutaneous injection of human Cancellous density was increased by 90, 132 and 173% in the
rats conduction chamber at PTH (1-34) 15, 60 or 240 µg/kg for groups given PTH in a dose of 15, 60 or 240 µg/kg/day, respectively
the proximal tibial 6 weeks versus vehicle Linear correlation between bone density and the log PTH doses
metaphysis (r2 = 0.6)
BMP: Bone morphogenetic protein; BMC: Bone mineral content; BMD: Bone mineral density; C10: PTH 10 µg/kg before and after surgery; C30: PTH 30 µg/kg before and after surgery; CNT: Vehicle control; hPTH: Human PTH;
P10: PTH 10 µg/kg before surgery; P30: PTH 30 µg/kg before surgery; PTH: Parathyroid hormone.
Chalidis, Tzioupis, Tsiridis & Giannoudis

443
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444
Table 1. Preclinical studies of PTH application in fracture healing process (continued).

Study Year Animal Fracture model PTH dose: treatment duration Major findings
[9] 2001 27-month-old female Wistar Tibial fracture Daily subcutaneous injection of At 3 weeks: increased maximum load, external callus volume,
rats PTH (1-34) 200 µg/kg for 3 or 8 weeks BMC by 160, 208 and 190%, respectively, in the PTH group
versus vehicle At 8 weeks: increased maximum load, external callus volume,
BMC by 270, 135 and 388%, respectively, in the PTH group
Week 3 to week 8: callus BMC increased by 60% in the
vehicle-injected animals and by 169% in the PTH-treated animals
Contralateral intact tibia: PTH treatment increased BMC by 18 and
21% (3 and 8 weeks)
[19] 2001 Sprague-Dawley rats Implantation of one Daily subcutaneous injection of human PTH increased the screw mean removal torque from 1.1 to 3.5 Ncm
screw in either one or in PTH (1-34) 60 µg/kg/day over a period of (p = 0.001) and the mean pull-out strength from 66 to 145 N
both proximal tibia 4 weeks versus vehicle (p = 0.002)
Histologic examination: higher density of trabecular bone around
the implant in the PTH group
[12] 2002 2-month-old male Closed mid-diaphyseal Daily subcutaneous injection of On day 28 after fracture: BMC, BMD and ultimate load to failure of
Sprague-Dawley rats femur fracture PTH (1-34) 10 µg/kg for 4 or 6 weeks the calluses were significantly increased in the PTH-treated group by
versus vehicle 61, 46 and 32%, respectively, compared with the control group
On day 42 after fracture: similar increases of 119, 74 and 55%,
respectively
PTH (1-34) increases production of bone matrix proteins and
enhances osteoclastogenesis during the phase of callus remodeling

Expert Opin. Investig. Drugs (2007) 16(4)

[13] 2003 Adult male rats Bilateral femoral Daily subcutaneous injections of Combination of systemic and local PTH administration leads to
segmental osteotomy 40 µg/kg or local PTH (1-34) delivery or higher bone mineral density and mineral content
combination of the 2 for 6 weeks versus Local PTH gene therapy enhances the anabolic activity of systemic
vehicle PTH administration during fracture healing
[14] 2004 3-month-old male Mid-diaphyseal femoral Every second day: 60 µg/kg of human In 20 days: PTH (1-34) increased ultimate load (56%), stiffness
Sprague-Dawley rats osteotomy and PTH (1-34)/kg versus vehicle until (117%), total regenerate callus volume (58%), callus BMC (24%)
lengthening of the right consolidation occurs (20 or 40 days after and histologic bone density (35%) compared with untreated
femur using an external distraction was completed) distraction osteogenesis specimens
fixator In 40 days: PTH (1-34) increased ultimate load (54%), stiffness
(55%), callus BMC (33%) and bone density (23%) compared with
untreated distraction osteogenesis specimens
BMP: Bone morphogenetic protein; BMC: Bone mineral content; BMD: Bone mineral density; C10: PTH 10 µg/kg before and after surgery; C30: PTH 30 µg/kg before and after surgery; CNT: Vehicle control; hPTH: Human PTH;
P10: PTH 10 µg/kg before surgery; P30: PTH 30 µg/kg before surgery; PTH: Parathyroid hormone.
Enhancement of fracture healing with parathyroid hormone: preclinical studies and potential clinical applications
 Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by York University Libraries on 11/14/14
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Table 1. Preclinical studies of PTH application in fracture healing process (continued).

Study Year Animal Fracture model PTH dose: treatment duration Major findings
[7] 2004 3-month-old female Wistar Closed fracture above Daily subcutaneous injection of 60 µg/kg After 8 weeks: increased fracture strength and callus volume in
rats tibiofibular junction in intermittent hPTH or vehicle PTH-treated rats (ultimate load 66%, ultimate stiffness 58%, callus
the right tibia Duration of PTH application is 8 weeks volume 28%)
and rats investigated in 8 or 16 weeks After 16 weeks: no differences in fracture strength, callus volume or
callus tissue mechanical quality between PTH and vehicle
Comparing PTH-treated animals at 8 and 16 weeks: fracture
strength and callus tissue mechanical quality continued to increase
after the withdrawal of PTH (ultimate load 23%, ultimate stress
88%, elastic modulus 87%) and external callus volume declined
during this period (27%)
[6] 2005 Female Sprague-Dawley rats Transverse fracture in Daily subcutaneous injection of PTH for New cortical shell significantly higher in C10 and C30 groups
bilateral femur 3, 6 and 12 weeks in four groups versus compared with the other groups
vehicle Ultimate load in mechanical testing significantly higher in C30
Group I: P10 group than in CNT, P10 and P30 groups
Group II: C10 Intermittent PTH treatment at 30 µg/kg before and after osteotomy
Group III: P30 accelerated the healing process (earlier replacement of woven bone
Group IV: C30 to lamellar bone, increased new cortical shell formation, increased
the ultimate load up to 12 weeks after osteotomy)
[5] 2005 2-month-old male Closed mid-diaphyseal Daily subcutaneous of PTH (1-34) Low-dose treatment with PTH (1-34) increased the recruitment of
Sprague-Dawley rats fracture in the right 10 µg/kg for 2, 4, 7, 14, 21 and 28 days mesenchymal cells into the chondrocyte lineage
femur versus vehicle Proliferation of mesenchymal (chondroprogenitor) cells and

Expert Opin. Investig. Drugs (2007) 16(4)

synthesis of type II collagen
Formation of a larger cartilaginous callus
The PTH-induced cartilaginous callus was then rapidly replaced with
bone
[15] 2005 Male Sprague-Dawley rats Standard, closed femoral Daily subcutaneous injections of PTH Day 21: the 30-mg group had a significant increase over the
fracture (1-34) 5 or 30 µg/kg in 3 groups for controls with respect to torsional strength, stiffness, BMC, BMD and
35 days versus vehicle cartilage volume
Further PTH group division into 3 groups, Day 35: both groups treated with PTH showed significant increase in
killed on days 21, 35 and 84 after the bone BMC, density total osseous tissue volume and significant
fracture decrease in void space and cartilage volume
Day 84: the 30-mg group had significant increase over the controls
with respect to torsional strength and bone mineral density
BMP: Bone morphogenetic protein; BMC: Bone mineral content; BMD: Bone mineral density; C10: PTH 10 µg/kg before and after surgery; C30: PTH 30 µg/kg before and after surgery; CNT: Vehicle control; hPTH: Human PTH;
P10: PTH 10 µg/kg before surgery; P30: PTH 30 µg/kg before surgery; PTH: Parathyroid hormone.
Chalidis, Tzioupis, Tsiridis & Giannoudis

445
 Enhancement of fracture healing with parathyroid hormone: preclinical studies and potential clinical applications
bone and mounted the implant–bone contact. The results
of these studies indicate that intermittent PTH treatment
may be helpful in the augmentation of early fixation of
orthopedic implants.
2.4 Distraction osteogenesis
The act of PTH (1-34) treatment was also examined in dis-
traction osteogenesis [14]. Distraction osteogenesis is used for
both leg lengthening and bone transportation for the
treatment of fractures and non-unions. Using this method,
the time needed for the new formed bone to consolidate and
become strong enough for weight bearing can be
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≤ 12 months.
Seebach et al. [14] performed an experimental study on rats
investigating whether intermittent PTH (1-34) admin-
istration could accelerate the consolidation of new formed
bone after distraction osteogenesis. The results indicated a sig-
nificant increase in BMC and histologic bone density of the
femoral distraction callus in treated models. The contralateral
femur became stiffer and denser as well, but to a lesser degree.
The authors concluded that PTH (1-34) may be useful as a
stimulator of bone formation to improve regenerated bone
stability when consolidation occurs.
For personal use only.
2.5 Safety
The published data from the systematic application of PTH
in osteoporosis treatment, or from cases with long-standing
hyperparathyroidism [31], are reassuring regarding the fre-
quency and intensity of the side effects of the drug. The
described symptoms are usually mild and transient in most of
the cases and termination or discontinuation of treatment is
not a common incident (Table 2) [2,3,32-44].
However, some questions have been raised regarding the
potential PTH carcinogenicity and its effect in inducing
bone proliferative lesions [2,42,45,46]. Vahle et al. [46] noticed
that there is a dose of the peptide that is strongly osteogenic
but not carcinogenic in an oncogenicity long-term study in
female Fischer rats. PTH has not been proven to be
genotoxic and, therefore, it is virtually certain not to be
carcinogenic when applied for the very few times needed to
enhance fracture healing [15]. Furthermore, there is enough
ambiguity whether tumor-related studies in rat models could
be connected to human physiology [47,48] as there are several
differences in the osteon remodeling system between human
and rat skeletons. Nevertheless, the same limitations regard-
ing the appropriate selection of the patients must be followed
in a potential application of PTH in fracture cases. Paget’s
disease, previous bone radiation, history of cancer, bone
metabolic diseases, use in children, high levels of Ca2+ and
alkaline phosphatase, nursing and allergic reactions to PTH
or to its ingredients must be considered as contraindications
of teriparatide treatment. Patients at high risk should be
excluded from any therapeutic fracture protocol until
long-term safety data will re-establish the inclusion and
exclusion criteria [33,48].
446 Expert Opin. Investig. Drugs (2007) 16(4)
2.6 Clinical relevance
There is a very significant and continually growing interest in
the therapeutic efficacy and safety of PTH on human bone heal-
ing [25,35]. PTH seems to enhance both the mechanical strength
and the bone mass of the calluses, producing a sustained ana-
bolic effect throughout the remodeling phase of fracture heal-
ing. According to the experimental studies, it seems that the
effect of PTH is strongest on repairing, cancellous, loaded bone
with hematopoietic marrow [49]. As such, conditions are more
abundant in fracture sites (hematoma formation, angiogenesis
and cell proliferation) than the rest of the skeleton: one could
expect PTH to have an even stronger effect in orthopedic and
trauma surgery than in the treatment of osteoporosis. However,
some considerations exist regarding how the potential frac-
ture-healing effects of PTH in humans can be examined. As nei-
ther morphologic appearance nor mineral content correlate with
mechanical bone strength, it is conspicuous that clinical trials
will be designed with relevant end points.
Skripitz et al. [49] stated that PTH cannot induce bone for-
mation from uncommitted cells in comparison with other
anabolic agents (such as bone morphogenetic proteins) and,
therefore, it cannot be expected to be useful in non-unions.
Conversely, Whitfield [25] noted that clinical application of
such bone-building peptides will speed up the mending of
severe non-union fractures and the installation of artificial hip
and knees, expanding their potential targets far beyond osteo-
porosis. Recent evidence that PTH increases recruitment of
mesenchymal cells into the chondrocyte lineage, resulting in
formation of a larger cartilaginous callus supports this
hypothesis and the potential use of the PTH peptide beyond
the acute fracture-repairing processes [5,25].
Alternative delivery systems and greater patient tolerance
will enlarge the efficacy of PTH clinical application. Many
efforts have been made during the last years for the devel-
opment of non-injectable routes of PTH delivery including
oral (buccal, sublingual and enteric–gastrointestinal),
transdermal, nasal and pulmonary approaches [50]. If equiva-
lent bioavailability and anabolic action are achieved in com-
parison with standard injection methods, patient acceptance
and compliance will be increased. In particular, after the
trauma period, the aversion for self-injection could be over-
come and the duration of treatment may be extended to offer
the optimal result.
3. Expert opinion
PTH constitutes a promising skeletal anabolic agent, which
has largely changed the mainstay of osteoporosis treatment.
Since the FDA approval in 1992, several studies have taken
place to assess the therapeutic effect of PTH in post-
menopausal women and to compare its anabolic effect
against or along with previous well-known antiresorptive
agents such as bisphosponates and calcitonin. PTH seems
not only to be effective in increasing the bone density, but it
also has the potential to improve the microarchitecture of the
 Chalidis, Tzioupis, Tsiridis & Giannoudis

In addition to PTH studies, there has also been a constant

Table 2. Adverse effects of parathyroid hormone
influx of new information from all of the relevant disciplines
injection in humans.
of fracture healing. The contribution of many local and sys-
Adverse effect Studies temic regulatory factors such as hormones, cytokines,
Hypercalcemia [2,33,38,40,41,43,44]
growth factors and stem cells in bone regeneration is known
to be substantial and undisputable. The ability to visualize
Hypercalciuria [2,35,38,40,41]
and manipulate matters at the nanoscale, dealing with struc-
Serum creatinine increase [38] tures and devices with length scales in the range of
Creatinine clearance increase [37] 1 – 100 nm offers a new prospective of delivering bioactive
Headache [2,35] regulators (such as PTH) in a more accurate fashion. Drugs
such as PTH could be encapsulated into nanoparticles and
Dizziness [2]
be delivered to fracture site in a time-dependent fashion.
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Hyperuricemia [2,35,40]
New bone formation in the fracture site after implantation
Allergic events [34] of a degradable gene-activated collagen matrix sponge
Injection site reaction [34] loaded with plasmid DNA encoding hPTH (1-34) or bone
Nausea [34] morphogenetic protein-4 has already been accomplished on
an experimental basis. Gene therapy is an attractive method
Leg cramps [2,40]
for drug delivery as it could be associated with efficient tar-
geting to cell surface receptors and less protein is necessary
bone. On the other hand, long-term results are still unknown to achieve a clinically useful effect.
and close monitoring of patients for potential late adverse In the next 10 years, more data will be revealed regarding
events is obvious and imperative as the use of PTH is still a the precise cellular and biologic pathways of bone-healing
new protocol. processes and the appropriate manner to intervene with safety
The concept of an anabolic skeletal agent that could in fracture environment. Cross-disciplinary research will eval-
For personal use only.

provoke new bone formation and the promising results of the
initial studies in the treatment of osteoporosis may extend the
indications of PTH in trauma cases and especially in bone
fractures. In the last 10 years, many experimental trials have
been made with the purpose of testifying the role of the
intermittent PTH in the fracture environment. Accelerating
bone healing, stimulation of osteogenesis (hard callus
formation) and improvement of the mechanical strength of
callus mass have been documented with histologic and
histomorphometric analyses in animal models.
Despite the fact that the results were in favor of using the
PTH as an anabolic agent in the fracture-healing process in all
the animal trials, many questions regarding the safety, the
appropriate dose, the duration of therapy and the cost-effec-
tiveness are pending. Therefore, enthusiasm for widespread use
of PTH in orthopedic trauma cases must be tempered. Clini-
cal prospective blinded and randomized studies in different age
and gender groups will allow generation of adequate evidence
regarding the efficacy and safety of PTH in fracture repair.
uate the interaction and sequence of all of the aforementioned
anabolic factors and will radically change the prospects for
regenerative medicine.
So far, no systemic pharmacologic agent has been proven to
have undoubted clear benefits in fracture healing and, if PTH
confirmed to be effective in human bone callus formation, it
will offer optimum benefits.
In clinical practice, PTH could be a feasible therapeutic
agent in well-selected trauma conditions, such as fragility frac-
tures in osteoporotic patients. Acceleration of the healing
response and solid implant–bone consolidation will minimize
the risks of re-operation and prolong immobilization and
mortality.
Disclosure
This work is attributed to the Academic Unit, Trauma and
Orthopaedic Surgery, Clarendon Wing, Leeds General
Infirmary, Great George Street, Leeds, LS1 3EX, UK.

Expert Opin. Investig. Drugs (2007) 16(4) 447

 Enhancement of fracture healing with parathyroid hormone: preclinical studies and potential clinical applications
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Affiliation
Byron Chalidis1 MD, Trauma Fellow,
Christopher Tzioupis1 MD, Research Fellow,
Eleftherios Tsiridis1 FRCS PhD, Consultant
Orthopaedic Surgeon &
Peter V Giannoudis†1 BSc MB MD EEC
(Ortho), Professor of Trauma and
Orthopaedic Surgery
†Author for correspondence
1University of Leeds, Academic Unit, Clarendon
Wing, Leeds Teaching Hospitals NHS Trust,
Great George Street, Leeds, LS1 3EX, UK
Tel: +44 (0)113 392 2611;
E-mail: pgiannoudi@aol.com
449