Parathyroid Hormone for Bone Regeneration

Samantha J. Wojda,1 Seth W. Donahue2

1
Department of Mechanical Engineering, Colorado State University, Fort Collins, Colorado, 2Department of Biomedical Engineering, University of
Massachusetts, Amherst, Massachusetts
Received 22 February 2018; accepted 18 June 2018
Published online 21 June 2018 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jor.24075

ABSTRACT: Delayed healing and/or non-union occur in approximately 5–10% of the fractures that occur annually in the United States.
Segmental bone loss increases the probability of non-union. Though grafting can be an effective treatment for segmental bone loss,
autografting is limited for large defects since a limited amount of bone is available for harvest. Parathyroid hormone (PTH) is a key
regulator of calcium homeostasis in the body and plays an important role in bone metabolism. Presently PTH is FDA approved for use
as an anabolic treatment for osteoporosis. The anabolic effect PTH has on bone has led to research on its use for bone regeneration
applications. Numerous studies in animal models have indicated enhanced fracture healing as a result of once daily injections of PTH.
Similarly, in a human case study, non-union persisted despite treatment attempts with internal fixation, external fixation, and
autograft in combination with BMP-7, until off label use of PTH1-84 was utilized. Use of a biomaterial scaffold to locally deliver PTH to
a defect site has also been shown to improve bone formation and healing around dental implants in dogs and drill defects in sheep.
Thus, PTH may be used to promote bone regeneration and provide an alternative to autograft and BMP for the treatment of large
segmental defects and non-unions. This review briefly summarizes the unmet clinical need for improved bone regeneration techniques
and how PTH may help fill that void by both systemically and locally delivered PTH for bone regeneration applications. ß 2018
Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2586–2594, 2018.

Keywords: bone tissue engineering and repair; bone/bone biology; bone fracture; repair/therapeutics

Bone generally has effective capacity to heal and, due
to continuous remodeling of bone throughout adult
life, healing often occurs with no scar.1 However,
delayed healing and/or non-union occur in an esti-
mated 5–10% of the approximately 7.9 million frac-
tures that occur annually in the United States.2,3 If
the bone fracture healing process exceeds 3 months,
healing is considered to be delayed. If healing is not
achieved by 9 months with no evidence of new healing
in the previous 3 months, the fracture is considered to
be a non-union. Non-union incidence varies (ranging
from 1.9% to 30%) depending on fracture location,
configuration, and associated soft tissue damage, as
well as other treatment and lifestyle factors.4,5 Factors
that may disrupt healing and put patients at higher
risk for non-union include, but are not limited to,
inadequate immobilization, obesity, smoking, age, mal-
nutrition, and multiple injury.6–10 Segmental bone
loss, infection, and complications from previous sur-
geries may also contribute to non-union. Open frac-
tures, like those potentially caused by high energy
trauma, or large bone defects caused by trauma or
tumor resection have a higher relative risk for non-
union.11–14 Indirect costs, like productivity losses due
to the injury, account for more than half of the total
cost of long bone non-union.15 Average cost for treat-
ment of a long bone non-union was reported as US
$11,333.16
Current treatment options are dependent on loca-
tion and type of non-union. For those complicated by
segmental bone loss options include, but are not
Grant sponsor: NIH/NCRR Colorado CTSI; Grant number: UL1
RR025780.
Correspondence to: Seth W. Donahue (T: 413-545-6366;
F: 413-545-0724; E-mail: swdonahue@umass.edu)
# 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
limited to; bone grafting, distraction osteogenesis, and
bone transport, Masquelete technique, low intensity
pulsed ultrasound (LIPUS) and pulsed electromagnetic
field therapy (PEMF). Open fractures, non-unions
complicated by segmental defects, or cases where
removal of tissue at a site of non-union is necessary
for treatment,17 are typically addressed by shortening
the bone or filling the defect.18 Shortening the bone
has a limit of 3 cm in the upper limb and 1 cm in the
lower limb before inducing a functional deficit for that
limb. Filling the gap is traditionally achieved via bone
graft or bone transport.18 The gold standard for bone
grafting is autograft. Autograft has the major down-
falls of donor site pain and morbidity as well as limited
availability,19–21 as it is impractical to harvest a
sufficient amount of bone for repairing a critical size
defect. As a result, allografts are a common alterna-
tive. However, allografts have a higher rate of failure
(delayed or non-union, infection, or fracture) compared
to autograft as well as potential for immunogenicity
problems.18,22–25 Regardless of the downfalls, grafting
is presently the most effective option and approxi-
mately 2.2 million orthopaedic procedures utilize auto-
graft or allograft each year to treat large orthopaedic
defects.26
The limitations of grafting, and other currently
FDA approved methods, have led to progress in the
exploration of bioactive molecules for promotion of
bone regeneration. The cellular mechanisms behind
bone regeneration are not completely understood,
presenting challenges in optimizing alternatives to
bone grafts. However, the components that are under-
stood can be expanded upon as potential treatments.
For example, stem cells, gene therapy, and growth and
differentiation factors may all have potential for
complex healing applications. Thus far, bone morpho-
genetic proteins (BMPs) have shown the most promise.

2586 JOURNAL OF ORTHOPAEDIC RESEARCH1 OCTOBER 2018


PARATHYROID HORMONE FOR BONE REGENERATION
BMPs plays a role in bone regeneration and are known
to robustly promote osteogenic differentiation. BMPs
have, therefore, been combined with materials like
hydroxyapatite, Di-calcium phosphate dehydrate
(DCPD), collagen, PLGA, and poly(propylene fuma-
rate) (PPF), many others in order to create an implant
to promote bone healing.27–30 In 2001 the FDA
approved OP-1TM, a BMP-7 implant, as a potential
alternative to autograft in recalcitrant long bone non-
union situations. A short time later, InfuseTM, bovine
collagen with BMP-2, was FDA approved. Since then
BMP-2 has become a prominent treatment option for
spinal fusion applications, tibial fractures, and sinus
repair. BMP- 2 and BMP-7 have been shown to
perform as well as iliac crest bone grafts (ICBG) for
spinal fusion applications as well as long bone non-
union applications. BMP has also been effectively used
to enhance chances of union after failed grafting in
both tibial and femur non-unions,31,32 and in upper
limb-non unions when used in conjunction with autolo-
gous bone graft.33 BMP use may also be efficacious for
some trauma applications.34–37 However, BMP use
comes with the possibility of an increased risk of
cancer at 24 months.38 When BMP is used in non-
spinal orthopaedic procedures, serious adverse events
may lead to additional surgeries.39 Like ICBG, the
success of BMP is somewhat dependent on the type of
fracture as well as other patient predispositions to
non-union and is similarly, if not more, financially
burdensome than ICBG.40,41 Thus, there is a need for
additional alternative biologics to promote bone regen-
eration when complications arise.
Parathyroid hormone (PTH) is a molecule that has
good potential for enhancing bone regeneration in
large bone defects. This potential lies in the anabolic
effect PTH has on bone. Daily injections of PTH are an
effective FDA approved treatment for osteoporosis that
results in increases in both bone mineral density and
bone volume. Thus, PTH may promote bone regenera-
tion and provide an alternative to autograft and BMP
use for the treatment of large segmental defects and
non-unions. In a case study, treatment attempts with
internal fixation, external fixation, and autograft in
combination with BMP-7, non-union persisted until off
label use of PTH1-84 was utilized.3 This review briefly
summarizes how PTH may help fill the clinical need
for improved bone regeneration techniques.
BIOLOGICAL MECHANISMS OF PTH MEDIATED
BONE FORMATION
Parathyroid hormone, an 84 amino acid protein, is a
key regulator of calcium homeostasis in the body.
Normal secretion (from the parathyroid gland) is an
ultradian rhythm with tonic and pulsatile components
(70% tonic, 30% pulsatile), and is dependent on serum
calcium and phosphorous. The half-life of PTH in
humans is approximately 2–5 min and the pulsatile
component is in low amplitude high frequency
bursts every 10–20 min superimposed on the tonic
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2587
secretion.42,43 The pulsatile component is highly sensi-
tive to changes in ionized calcium and calcitrol levels.
When extracellular calcium concentrations are outside
of the normal range the parathyroid glands change
secretion of PTH to return serum calcium levels to
normal (using the skeleton as a calcium reservoir).
The classic actions of PTH, including stimulating bone
resorption and increasing calcium reabsorption, reside
in the N-terminal 1–34 region of the protein.44 PTH
acts through a g-protein coupled receptor, type 1 PTH
receptor (PTHR1). When PTH binds to the receptor,
adenylate cyclase, or phospholipase C is activated
starting a cascade that activates protein kinase A
(PKA) or protein kinase C (PKC), respectively.45
Activation of the PKA pathway is mediated by the Gas
part of the receptor, this cascade stimulates cAMP
production, and subsequently PKA. Activation of the
PKC pathway is a Gaq mediated response. PKC is
activated through phospholipase C dependent and
independent pathways, which leads to activation of
osteoblastic bone formation.46 Through these pathways
PTH can mediate both bone formation and bone
resorption. Thus, these pathways are generally cred-
ited with control of the classic actions of PTH.47
However, the evidence suggesting PTH induces MSC
differentiation to the osteoblast lineage is not neces-
sarily explained through the traditional pathway.
Anabolic effects may also stem from the effect PTH
has on local factors like BMPs, Wnts, or TGFb through
recruitment of their receptors to PTHR1 and/or endo-
cytosis.46,48,49 PTH has been shown to induce MSC
differentiation to the osteoblast lineage through a
signaling cascade that enhances BMP signaling.50
Similarly, T lymphocytes express functional PTHR1
and PTH has been shown to increase the production of
Wnt10b by bone marrow CD8þ T cells and induce
lymphocytes to activate canonical Wnt signaling in
preosteoblasts.51,52 Further supporting the role of T
cells role in increasing capacity of stromal cells to
support PTH induced effects, continuous infusion of
PTH (mimicking hyperparathyroidism) fails to induce
bone resorption and cortical bone loss in mice lacking
T cells.53 However, as the receptor for PTH is not
found in osteoclasts osteoclast response to PTH is
mediated through osteoblasts.54,55 The overall re-
sponse of osteoblasts to PTH stimulation, however, is
dependent on concentration and timing. Both tonic
and pulsatile secretions play a role in normal bone
maintenance, though it is not fully clear what role
each plays. In glucocorticoid induced osteoporosis
endogenous tonic PTH levels are decreased, and the
amount released in pulsatile fashion is increased.42 It
has been proposed that the increase in pulsatile
release is perhaps an attempt at compensation for the
decrease in tonic release, however an osteoporotic
state still develops. This raises the possibility of an
underappreciated role of tonic (continuous) PTH secre-
tions in normal bone maintenance that could be used
to develop novel bone regeneration strategies.
JOURNAL OF ORTHOPAEDIC RESEARCH1 OCTOBER 2018

2588 WOJDA AND DONAHUE
Generally, continuously elevated serum PTH levels
have catabolic effects in bone and intermittently
elevated PTH is anabolic. This effect is observed in
both animal and human models. Treatment of rats
with continuous infusion of PTH 1–84 resulted in an
increase in bone formation comparable to that associ-
ated with intermittent injection, but a more marked
calcemic effect and thus a net decrease in trabecular
bone.56 Similarly, continuously administered PTH 1–
34 caused a dose dependent decrease in dry weight of
the femur and a hyperparathyroidism-like condition in
the highest administered dose (214 ng/kg/h) in rats.57
This effect is also observed at the cellular level.
Continuous PTH 1–84 treatment for 7 days in mice
resulted in an increase in osteoclast number at day 2
followed by an increase in osteoblast number at day 4.
Whereas daily injections of PTH 1–84 did not affect
osteoclast number and the increase in osteoblast
number was significantly larger than that of continu-
ous treatment.58 Interestingly, in male Sprague Daw-
ley rats continuous infusion of PTH 1–34 for 12 days
(4 mg/100 g/day) had an inconsistent effect. Upon re-
peating the experiment three times, one of the three
experiments showed bone formation was increased
with continuous PTH treatment (n ¼ 7 per group) over
that of vehicle treated animals. However, the other
two experiments showed no difference between ani-
mals receiving vehicle treatment versus continuous
PTH 1–34 treatment.59 This variable response is
somewhat consistent with what is observed in humans
with primary hyperparathyroidism (PHPT). Cortical
bone loss is characteristic of primary hyperparathy-
roidism, however trabecular bone may be preserved or
even enhanced.60,61
In the classic presentation of PHPT, transiliac
biopsies exhibit increased cortical porosity as well as
reduced cortical width, but preservation, or enhance-
ment, of trabecular bone architecture.61 These find-
ings have been corroborated by studies in, post-
menopausal women with mild primary hyperparathy-
roidism (PTH levels: 116 þ/ 19 pg/ml, normal: 10–
65 pg/ml). Post-menopausal women with mild PHPT
showed preservation of trabecular bone whereas
postmenopausal women without PHPT exhibited tra-
becular bone loss.62,63 Similarly, a study in patients
with asymptomatic PHPT indicated bone mineral
density was reduced at cortical sites, but at more
cancellous sites (like the lumbar spine) it was
preserved.64 Other studies showed no correlation
between mild asymptomatic PHPT and risk factor for
vertebral fractures.65 However, more recent studies
indicated even if bone mineral density was preserved,
the risk of vertebral fracture was higher in postmen-
opausal patients with mild PHPT. The risk of verte-
bral fracture appears independent of severity of
PHPT. These observations on PHPT indicate there is
some inconsistency in response to continuously ele-
vated PTH. The reason for this is unclear. Studies
have examined the correlation of demographic factors
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as well as co-existing deficiencies (like serum 25-
hydroxyvitamin D (25OHD)) with severity of PHPT
as well as the impact on BMD and bone
turnover.66–70 However, no clear explanation stands
out. Perhaps there is a threshold above which
continuously elevated PTH is catabolic and below
which it is anabolic. As the preservative effects seem
limited to sites of higher remodeling (like trabecular
bone), continuously elevated PTH may also play a
role in bone regeneration. Thus, it is possible that
local delivery of PTH to a bone defect may promote
bone healing while minimizing potential negative
systemic effects.
Contrary to continuously elevated PTH, when inter-
mittently administered, both PTH 1–34 and 1–84 have
a consistent anabolic effect on bone.59,71–76 When PTH
1–34 and PTH 1–84 were administered intermittently
(as once daily injections) at an equivalent molar dose,
no difference in the anabolic effect on bone was
observed.73 Presently, recombinant PTH 1–34 is FDA
approved in the United States for the use of osteoporo-
sis treatment (administered as daily injections), as
FORTEO1 (Eli Lilly). Recombinant PTH 1–84 was
approved in Europe in 2006 for the treatment of
osteoporosis (but was withdrawn in 2014), as Preo-
tact1. Recombinant PTH 1–84 is also approved in the
United States for treatment of hypocalcemia in per-
sons with hyperparathyroidism (Natpara1). Intermit-
tently administered PTH decreases the risk of fragility
fractures, increases cortical thickness and improves
trabecular bone architecture in the ilium of post-
menopausal women,74,77 and increases bone mineral
density (BMD) in the lumbar spine in both men and
women.78 In osteoporotic women, bone mineral density
of the lumbar spine increases 6.3% with PTH treat-
ment compared to an increase of 4.6% with alendro-
nate (an anti-resorptive) treatment.79 Similarly, a 14%
increase in bone volume was observed in women with
osteoporosis that received daily injections of PTH 1–34
compared to the 24% loss in bone volume in women
with osteoporosis who were not treated with PTH.77
These changes occur due to an unbalance in remodel-
ing, favoring formation, caused by intermittent PTH
(daily subcutaneous injection) therapy.46,80
It is important to note PTH treatment in humans is
limited to 2 years and is associated with a “black box”
warning for potential tumorigenic effects. Surveillance
of human osteosarcoma patients has not yet detected a
causal association between PTH therapy and osteosar-
coma.81 However, studies in F344 rats indicated a
significant percentage of subjects developed osteosar-
coma following two years of PTH 1–34 treatment.82
Interestingly, in F344 rats, PTH 1–84 has an osteosar-
coma incidence curve shifted to the right of PTH 1–34
indicating a lower incidence of osteosarcoma in rats
given PTH 1–84 than 1–34.83 Low dose (5–10 mg/kg)
PTH resulted in no neoplastic changes, however high
dose (>30 mg/kg) administered for 20–24 months (70–
80% of lifespan) resulted in significant increases in

PARATHYROID HORMONE FOR BONE REGENERATION
osteosarcoma incidence.83,84 Similar studies in cyno-
molgus macaques indicated PTH 1–34 treatment (5 mg/
kg/d) for 18 months did not result in neoplastic
changes over the course of the 18 months of treatment
or the 3-year follow-up observation.85 Though there is
the potential tumorigenic effect with long-term high
doses of PTH, the ability of PTH to increase bone
formation makes it a molecule of interest for short-
term low dose bone regeneration applications.
EFFICACY OF SYSTEMIC PTH FOR BONE
REGENERATION AND DEFECT REPAIR
Based on the success of PTH as an anabolic osteoporo-
sis treatment, it follows that there may also be
implications for its use for promoting bone regenera-
tion in large bone defects. Though it may seem the
benefits of utilizing PTH for bone regeneration are
limited to intermittent administration, some of the
aforementioned findings suggest continuously elevated
PTH may be anabolic in certain circumstances, such
as in mild PHPT64 and tonic PTH secretions.42,43 The
ability of PTH to increase remodeling in bone gives it
great potential in the realm of fracture healing.86
Incorporation of PTH into a treatment process for
segmental defects could enhance healing. Research
thus far has examined the potential of systemically
administered PTH and PTH delivered locally (directly
to the defect site).
Daily injections of PTH seem to have a consistently
beneficial impact on healing of fractures, graft incorpo-
ration, implant fixation, distraction osteogenesis, and
spinal fusion in animal models.87–91 Treatment of rats
with PTH 1–34 (60 mg/kg/day) resulted in a dense
network of trabeculae in bone chambers as compared
to control.86 Similarly, treatment with PTH 35 mg/kg/
day or 105 mg/kg 3 per week resulted in a dose
dependent increase in bone ingrowth into bone cham-
bers in rat calvaria.89 Studies in mice examining
treatment with 10, 40, and 200 mg/kg/day show similar
dose dependent increases in bone formation in the
fracture callus.92 In male rats, 75 mg/kg/day PTH 1–84
for 12 weeks increased the healing of a femoral
defect.90 Daily injections of PTH 1–34 (15 nmol/kg/day)
and PTH 1–31 (15 nmol/kg/day) have been shown to
increase the external volume and strength of closed
fracture calluses.91 Similarly, closed fractures in rats
treated with daily injections of PTH showed an
increase in bone mineral content, bone mineral den-
sity, and cartilage volume.93 Accelerated healing was
observed with PTH treatment in a closed fracture
model in female cynomolgus monkeys.94 Systemic
intermittent injections of PTH have a consistently
anabolic effect on healing of closed fractures, indicat-
ing similar effects may be observed in more complex
healing scenarios like open fractures or segmental
bone defects.
An increase in union rate has not been observed as
a result of PTH treatment for open fractures in animal
models. However, like with closed fractures, treatment
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2589
did increase callus volume, bone mineral content, and
bone volume fraction.95 Intermittent injections of PTH
1–34 have also been shown to enhance guided bone
healing in rat calvarial defects.96 And more recently,
treatment with 100 mg/kg 3 per week for 8 weeks
increased union rate and accelerated healing in a
refractory fracture model in rats.97 Subcutaneous
injections of 40 mg/kg/day PTH in mice resulted in
enhanced healing (increased bone volume and BMC)
in an open defect reconstructed with a PLA/bTCP
scaffold.98 Likewise, rats treated with injections of
PTH 1–34 every other day during distraction osteogen-
esis showed increased callus volume and mechanical
strength.99 Bone graft healing in spinal fusion models
is also enhanced by intermittently administered PTH
1–34.100–102 Daily systemic injections of PTH 1–34
(40 mg/kg) enhance osseointegration of devitalized fem-
oral allografts in a critical size femoral defect model in
mice.103 Daily injections of PTH 1–34 (5 mg/kg/day)
also enhanced allograft incorporation in adult female
mongrel hounds.104
Though it is clear that PTH has positive impacts on
bone regeneration, the ideal administration regime is
yet to be determined. When the duration of PTH
treatment (as daily injections) was investigated in
mice, it was found that immediate treatment for only
2 weeks was sufficient to increase the ultimate torque
of femurs with diaphyseal allografts, but 4 weeks of
treatment showed no increased benefit in terms of
bone strength.105 Delaying the initiation of PTH
treatment until 4 weeks after surgery was completely
ineffective, whereas delaying only 1 or 2 weeks
resulted in equivalent biomechanical properties as
immediate treatment.105 When PTH was administered
at 15 mg/kg daily, 35 mg/kg 3 days/week, or 105 mg/kg
once per week, all PTH treatments resulted in more
bone formation than controls; however, PTH 105 mg/kg
once per week resulted in greater bone formation than
the other PTH groups.106 Four weeks of PTH treat-
ment in mice examining differences in low dose/high
frequency (3 mg/kg, 3 times/day), low dose/low fre-
quency (9 mg/kg, once/day), high dose/high frequency
(9 mg/kg, 3 times/day), and high dose/low frequency
(27 mg/kg, once/day) indicated high dose and/or high
frequency treatment increased callus bone volume but
did not have a significant impact on biomechanical
recovery whereas low dose/low-frequency therapy
resulted in a lesser increase in callus bone volume but
significant increases in biomechanical recovery mea-
sures.107 Likewise, studies by Sheyn et al.108 indicate
0.4 mg/kg was more successful in accelerating and
maintaining repair of bone defects in ostoportic rats
than higher doses. Current FDA approved treatment
is 20 mg/day (0.3–0.5 mg/kg) for up to 2 years when
used in humans for treatment of osteoporosis. The
dosages used in animal studies range from 0.4 to
40 mg/kg. Some studies show a dose response to PTH
and some do not, however it should be acknowledging
the higher doses in rodent studies are necessarily less
JOURNAL OF ORTHOPAEDIC RESEARCH1 OCTOBER 2018

2590 WOJDA AND DONAHUE
clinically relevant. Still, the high dose may be utilized
for studies ranging from 4 to 12 weeks in duration as
opposed to up to 2 years of treatment in clinical
applications.
PTH mediated enhancement of closed fracture repair
has been associated with a larger cartilaginous cal-
lus,109 amplified chondrocyte recruitment, and matura-
tion in early fracture callus, as well as an increase in
canonical Wnt signaling.110,111 Intermittent PTH
(10 mg/kg/day) enhanced closed fracture healing in rats
by stimulating proliferation and differentiation of osteo-
progenitor cells, increased production of bone matrix
proteins, and enhanced osteoclastogenesis during callus
remodeling.112 In a closed fracture model in female
cynomolgus monkeys PTH accelerated fracture healing
by shrinking callus size and increasing the degree of
mineralization of the fracture callus (accelerating callus
remodeling).94 However, when used in conjunction with
devitalized allografts, PTH 1–34 (40 mg/kg/day) in-
creased callus volume and mineral content, but did not
affect allograft bone volume, osteoclasts, or resorption
surfaces suggesting no increase in graft resorption.103
PTH administration can also influence endothelial
cells and stem cells which may aid in bone heal-
ing.113 The impact PTH has on vascular regeneration
as well as proliferation may aid in its anabolic
capabilities for bone regeneration applications. Not
only are bone endothelial cells capable of responding
to PTH,114 PTH enhances migration of CD45þ/
CD34þ (angiogenic progenitor cells) stem cells,115
and increases the number of hematopoietic stem cells
in the bone marrow that can be mobilized into the
peripheral circulation.116 Patients with primary hy-
perparathyroidism (PHPT) show an increased num-
ber of circulating CD45/CD34 stem cells in the
peripheral blood.117 Similarly, PTH levels in patients
with untreated PHPT are correlated with elevated
levels of circulating bone marrow-derived progenitor
cells.117 The ability of PTH to facilitate stem cell
mobilization was corroborated by a phase 1 clinical
trial where PTH enhanced CD34 cells in patients
with inadequate CD34þ cell counts.118 PTH also has
been shown to increase proliferation of bone marrow
stem cells and facilitate homing to sites of therapeu-
tic need.119,120 In both athymic rats and pigs PTH
significantly enhanced mesenchymal stem cell (MSC)
migration to the lumbar region (location of cylindri-
cal drill defects in two vertebral bodies) where they
differentiated into bone forming cells.108 There also
is evidence for a synergistic effect of treatment with
exogenous MSCs and PTH concomitantly when used
to treat rib defects in athymic rats.121 The impact
PTH has on homing of cells to injury sites could be
controlled outside of the already well-established
pathways resulting in the anabolic effect of PTH.
Though classic actions are generally accepted to
occur through the aforementioned PKA and PKC
signaling resulting from binding to PTHR1, there are
other possibilities.
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EFFECT OF LOCALLY DELIVERED PTH ON
FRACTURE HEALING AND BONE DEFECT
REGENERATION
Local delivery of PTH may allow for complete union in
what would otherwise be non-union scenarios while
reducing the costs and logistics associated with sys-
temic delivery. The effect of locally delivered PTH on
fracture healing and bone regeneration has not been
as extensively investigated as systemically delivered
PTH. However, there are some promising results. PTH
delivered via polyethylene glycol (PEG) matrix
resulted in a 1.9-fold increase in mineralized bone and
2.3-fold increase in the area of regeneration in bone
chambers in rabbit calvaria.122 Similarly, PEG matri-
ces with PTH 1–34 (20 mg/ml) were used to fill a
cylindrical defect around a titanium implant in the
mandible between the first premolar and second molar
in dogs. After 12 weeks, matrices infused with PTH
had a significantly greater area fraction of newly
formed bone within the defect compared to empty
defects or defects filled with the PEG matrix alone.
The PEG matrix with PTH was as effective as an
autogeneous bone graft when comparing newly formed
bone volume between groups.123 PTH 1–34 linked to a
fibrin hydrogel with a plasmin sensitive link has also
been investigated as a method for enhanced bone
healing. Cylindrical drill defects in the femur of sheep
(8 mm diameter, 13 mm depth) were filled with the
hydrogel containing PTH at 50, 100, 400, or 1000 mg/
ml. After 8 weeks the defects containing the hydrogel
with 100 mg/ml exhibited an increased bone volume
fraction as compared to the hydrogel control.124 Simi-
larly implantation of a gene-activated matrix contain-
ing a plasmid coding for PTH fragment 1–34 resulted
in new bone filling a segmental defect in a rat.125 PTH
1–34 covalently linked to a fibrin hydrogel (1 mg/ml)
has also been shown to improve postoperative progno-
sis of subchondral bone cysts in the distal aspect of the
proximal phalanx in horses.126 Local delivery of PTH
treatment has also been achieved through use of gene-
activated matrices (GAM) which induce local produc-
tion of PTH at the defect site. Treatment with PTH-
GAM and a collagen matrix has been shown to
promote bone regeneration in a craniomaxillofacial
bone defect.127 Though pulsatile release of PTH from
biomaterial scaffolds has been explored, they have not
been tested extensively in vivo for bone regeneration
applications.128,129 One study showed PTH delivered
via a cell free biomimetic nanofibrous scaffold designed
to deliver a daily pulse of PTH for 21 days. This
treatment resulted in improved regeneration of a
critical-size calvarial defect with negligible systemic
side effects in a mouse model.130 These studies indi-
cate that locally delivered PTH may prove to be
effective and affordable substitutes for bone grafts for
procedures such as the repair of critical size bone
defects. Though studies indicate locally delivered PTH
is a promising method for enhancing bone regenera-
tion, much research is still needed to determine the

PARATHYROID HORMONE FOR BONE REGENERATION
delivery materials, PTH concentrations, and PTH
delivery profiles that most efficaciously promote bone
regeneration.
SUMM ARY, CONCLUSION , AND FUTURE
DIRECTIONS
Parathyroid hormone is an effective anabolic agent used
in the treatment of osteoporosis. The evidence indicating
beneficial effects of systemic administration of PTH on
fracture healing are difficult to dispute. However, the
timing and dose of PTH treatment have yet to be
optimized. At least two studies have shown that PTH
injections administered once to three times a week (as
opposed to daily) may be sufficient to promote heal-
ing.97,106 However, the ideal window for PTH administra-
tion is unknown;105 for example, is PTH treatment
necessary during the entire healing process or could it be
limited to healing phases that are most responsive to
PTH? Though positive outcomes result from systemically
administered PTH, can the same (or better) anabolic
effect be achieved with locally delivered PTH for bone
regeneration applications? Studies thus far indicate prom-
ising outcomes for locally delivered PTH for bone regener-
ation applications. However, it is unclear whether or not
continuous or intermittent release is more efficacious. The
findings that tonic PTH secretion plays a role in normal
bone metabolism,42 and post-menopausal women with
mild primary hyperparathyroidism have a protective
effect against osteoporosis62 support the idea that low
levels of continuously delivered PTH can be used to
promote bone regeneration. Thus, future studies that
more closely examine the efficacy of locally delivered PTH
for bone regeneration applications could lead to improved
treatments for segmental defects in bone.
AUTHORS’ CONTRIBUTION
SJW: substantial contribution; completed literature
search, reviewed articles, wrote, and revised paper.
SWD: substantial contribution; reviewed articles,
edited, and revised paper. Both authors approved the
submission and final version of this manuscript.
ACKNOWLEDGMENTS
We thank Dr. Michael Yaszemski and Dr. Kristi Anseth for
helpful discussions on the clinical aspects of bone regenera-
tion and approaches for local PTH delivery to large bone
defects. This publication was supported in part by funding
from NIH/NCRR Colorado CTSI Grant Number UL1
RR025780. The content is solely the responsibility of the
authors and does not necessarily represent the official views
of the National Institutes of Health.
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