strontium ranelate enhances callus strength more than pth 1-34 in an osteoporotic rat model of fract

Strontium Ranelate Enhances Callus Strength More ThanPTH 1-34 in an Osteoporotic Rat Model of Fracture Healing

Bjoern Habermann • Konstantinos Kafchitsas •

Gavin Olender • Peter Augat • Andreas Kurth

Received: 6 May 2009 / Accepted: 26 October 2009 / Published online: 4 December 2009

� Springer Science+Business Media, LLC 2009

Abstract Treatment of an underlying disease is often

initiated after the occurrence of an osteoporotic fracture.

Our aim was to investigate whether teriparatide (PTH 1-34)

and strontium ranelate affect fracture healing in ovariec-

tomized (OVX) rats when provided for the first time after

the occurrence of an osteoporotic fracture. We combined

the model of an OVX rat with a closed diaphyseal fracture.

Sixty Sprague Dawley rats were randomly assigned to four

groups. Fracture healing in OVX rats after treatment with

pharmacological doses of strontium ranelate and PTH 1-34

was compared with OVX and sham-treated control groups.

After 28 days, the femur was excised and scanned by micro

computed tomography and the callus evaluated, after which

biomechanical torsional testing was performed and torque

and toughness until reaching the yield point were analyzed.

Only treatment with strontium ranelate led to a significant

increase in callus resistance compared to the OVX control

rats, whereas both PTH 1-34 and strontium ranelate

increased the bone volume/tissue volume ratio of the

callus. The PTH 1-34–increased trabecular bone volume

within the callus was even higher compared to sham. As for

the callus tissue volume, the increase induced by strontium

ranelate was significant, contrary to the changes induced by

PTH. Callus in strontium ranelate–treated animals is more

resistant to torsion compared with OVX control rats. To

our knowledge, this is the first report of the enhancement of

fracture healing by strontium ranelate. Because both

treatments enhance bone and tissue volume within the

callus, there may be a qualitative difference between the

calluses of PTH 1-34– and strontium ranelate–treated OVX

rats. The superior results obtained with strontium ranelate

compared to PTH in terms of callus resistance could be the

consequence of a better quality of the new bone formed

within the callus.

Keywords OVX rats � Osteoporosis � Fracture healing �PTH � Strontium ranelate

Osteoporosis leads to a reduction of the trabecular structure

in cancellous bone and to an increase in bone fragility. As a

result of these structural changes, a higher incidence of

bone fractures after inadequate trauma occurs in those

patients. In addition to the treatment of the fracture, it is

essential to initiate adequate treatment of the underlying

disease, i.e., osteoporosis. Because in most cases osteopo-

rosis is diagnosed at the time of fracture occurrence,

information on the influence of antiosteoporotic drugs on

fracture healing is essential.

Strontium ranelate has proven its efficacy in reducing

the risk of vertebral, nonvertebral, and hip fracture in

women with postmenopausal osteoporosis [1, 2]. This

efficacy of strontium ranelate is independent of baseline

risk factors [3] and is maintained during 5 [4] and even

B. Habermann (&) � K. Kafchitsas � A. Kurth

Department of Orthopaedics and Orthopaedic Surgery,

University Medical Center of the Johannes Gutenberg University

Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany

e-mail: [email protected]

K. Kafchitsas


A. Kurth


G. Olender � P. Augat

Biomechanical Research Laboratory, Traumacenter Murnau,

Murnau, Germany


P. Augat


123

Calcif Tissue Int (2010) 86:82–89

DOI 10.1007/s00223-009-9317-8

8 years [5]. Strontium ranelate has a dual mode of action

[6, 7]. In vitro, it increases bone formation by enhancing

preosteoblast replication, differentiation, and activity [8–

10] and decreases bone resorption by inhibiting osteoclast

differentiation, activity and stimulating osteoclast apopto-

sis [10–13]. In vivo, strontium ranelate increases bone

strength in intact rats or totally prevents its decrease in

ovariectomized (OVX) rats as a result of its positive effects

on microarchitecture and intrinsic bone quality [14, 15].

Teriparatide (PTH 1-34) has anabolic effects on bone

and increases bone strength [16–19]. A continuous infusion

of PTH 1-34 has catabolic effects, whereas its intermittent

administration has anabolic effects on bone formation. In

osteoporotic women, its intermittent administration leads to

an increase in bone mineral density (BMD) and a reduction

in vertebral and nonvertebral fracture incidence [20]. It was

shown in nonosteoporotic rats that daily administration of

PTH 1-34 enhances fracture healing [21]. Furthermore,

PTH 1-34 enhances callus formation in young, aged, and

OVX rats [22–25].

As the population ages, the prevalence of osteoporotic

fractures increases. Although most fractures heal, approx-

imately 5 to 10% are associated with impaired healing,

including delayed healing or nonunion. Fracture healing is

a long and difficult process, which includes a first phase of

inflammation and resorption and a second phase of bone

formation. Considering the poor quality and quantity of

bone in the elderly, there is a potential for the use of

pharmaceutical agents to enhance fracture healing.

The purpose of the present study was to determine the

effect of two antiosteoporotic treatments on fracture heal-

ing in osteoporotic OVX rats 28 days after fracture

occurrence. PTH, which has been proven to influence

fracture healing in OVX rats [24], was taken as a control

treatment. Strontium ranelate, which acts on both resorp-

tion and formation, is a good candidate to enhance fracture

healing. We combined the rat model of a closed, stan-

dardized diaphyseal fracture of the femur, as introduced by

Bonnarens and Einhorn [26], with the model of a post-

ovariectomy osteopenic rat, mimicking postmenopausal

bone loss [27].

Materials and Methods

Forty-five animals were ovariectomized at the age of

12 weeks, and a further 15 underwent sham operation. At

the age of 24 weeks, osteopenia in the OVX rats was

diagnosed by means of dual-energy x-ray absorptiometry

(DXA). Then, in all animals, a standardized mid-diaphy-

seal fracture was induced. Under general anesthesia

(100 mg ketanest [Ketavet], 1 mg midazolam [Dormicum],

and 10 mg xylazine [Rompun], i.p.), a 0.8-mm Kirschner

wire was introduced into the left femoral canal through a

medial parapatellar incision and arthrotomy of the knee.

After closing the wound, a mid-diaphyseal fracture was

produced by using a falling weight of 650 g over a three-

point bending mechanism. In all groups, the drop height of

the weight was 14 cm and induced by lateral loading. The

fracture was radiographically documented. In all cases, a

straight mid-diaphyseal fracture was induced. The animal

experiments were approved by the Regierungspraesidium

Darmstadt, Germany.

At the time of fracture, the animals were divided into

four groups. Group 1 was the sham control group, and

groups 2, 3, and 4 were the OVX treatment groups. Groups

1 and 2 were treated with NaCl 0.9% s.c. daily, group 3

was treated with 600 mg/kg/d strontium ranelate (pur-

chased from Servier Deutschland GmbH) p.o. daily, and

group 4 received 20 lg PTH 1-34 (purchased from Lilly

Deutschland GmbH) three times a weeks.c. (equivalent to a

dose of 20 lg/kg/d). The fracture was radiographically

documented. The dose of 600 mg/kg/d of strontium rane-

late leads to a blood strontium concentration close to the

human exposure after a therapeutic dose of 2 g/d [15]. The

dose of 20 lg/kg/d PTH 1-34 leads to higher human

therapeutic exposure but is a pharmacological dose used in

rats. The rats were liberated to calcium-reduced food and

water ad libitum (EF R/M, Sniff GmbH). They were killed

after 28 days and the left femurs were immediately

excised, wrapped in NaCl-soaked gauze, and frozen at

-80�C.

The samples were then scanned by MicroCT 80 by

Scanco Medical, Zurich, Switzerland. The whole bone

was scanned, and 600 slices 40 lm in thickness were

placed through the former fracture area. The center of

the fracture callus was defined manually as the point

where the previous organization of the cortical bone in

the fracture area was nearly inexistent. One hundred

slices of 40 lm were placed above and below. The

threshold for calluses was 155–320, whereas it was 320–

1000 for cortical bone and 155–210 for bone marrow.

The evaluation of the data focused on outer callus con-

tour, cortical contour, and marrow contour, as well as

cortical thickness and polar moment of inertia. BMD,

tissue volume (TV), bone volume (BV), and the BV/TV

ratio were recorded. BMD was achieved by measuring

mean voxel values. Mean voxel values (1/mm) could be

equalized to the bone mineral content when the scan was

calibrated for bone. The manufacturer’s software package

was used for image processing and data evaluation

(version 4.04).

After embedding the samples in methylmethacrylate

cement (Technovit, Heraeus Sulzer, Wehrheim, Germany),

torsion testing on the bones was carried out with the axial-

torsional 8874 system by Instron (Darmstadt, Germany).

B. Habermann et al.: Strontium Ranelate Enhances Callus Strength 83

123

Between the different steps of preparation, each specimen

was kept immersed in physiological solution to avoid

drying of the bone that could affect the biomechanical

properties. The speed of torsional testing was 1 degree per

second. Biomechanical testing recorded the modulus of

rigidity and torque until failure. The torque was expressed

in Nm. The yield point indicated the point between the

elastic and plastic phase. At this point, initial microfrac-

tures could be seen. The toughness in terms of the bone’s

resistance to fracture was measured in J/m3. Before anal-

ysis of the biomechanical data, the values were normalized

by combining them with the lower body weight of the sham

group [28].

Data were collected in Excel (Microsoft). All data were

expressed as the mean ± standard deviation. For statistical

analysis, we used one-way analysis of variance, and

P \ 0.05 was considered significant. Sigma Stat (SPSS)

was used.

Results

DXA

Ovariectomy led to a significant reduction in BMD in the

lumbar spine after 12 weeks (-22.07%, P \ 0.05).

Biomechanical Testing

In the OVX group, a huge and significant decrease in

resistance to torsional load was observed compared to the

sham group (OVX -33.16%, P \ 0.001) (Fig. 1; Table 1).

Treatment with strontium ranelate significantly

improved the mechanical properties of the callus when

compared to the OVX control group, while the improve-

ment induced by the treatment with PTH 1-34 did not reach

significance (strontium ranelate ?43.8%, P \ 0.05; PTH

?20.2%, P [ 0.05). Treatment with strontium ranelate or

PTH 1-34 also improved the mechanical properties of the

callus compared to the sham control group but did not

reach significance (strontium ranelate ?30.19%, P [ 0.05;

PTH 1-34 ?7.01%, P [ 0.05).

In all groups, mechanical testing to the yield point

showed no significant differences.

Micro Computed Tomography of the Fracture Callus

Ovariectomy led to a nonsignificant increase in the callus

tissue volume (mm3) when compared to the sham group

(?11.7%; P [ 0.05) and to a nonsignificant decrease in the

callus bone volume (mm3) (-1%, P [ 0.05). As for the

BV/TV ratio, ovariectomy significantly decreased the rel-

ative content of bone in callus (-7.7%; P \ 0.05) (Fig. 2).

The OVX rats showed a significant decrease in BMD

compared to the sham rats (-19.6%; P \ 0.05), which can

be interpreted as a lower BMD (Table 2 and Fig. 3).

PTH 1-34 and strontium ranelate both showed a sig-

nificant increase in bone volume of the callus when com-

pared to OVX control rats (strontium ranelate ?46.3%,

P \ 0,01; PTH 1-34 ?31.9%, P \ 0.05) with no signifi-

cant difference between the two treatments. As for the

callus tissue volume, the increase induced by strontium

ranelate was significant compared to OVX, whereas PTH

induced no change (strontium ranelate ?32.4%, P \ 0.01,

PTH 1-34 ?6.1%, P [ 0.05); the difference between both

drugs was significant (strontium ranelate vs. PTH, ?24.8%,

P \ 0.01). In both the PTH 1-34– and strontium ranelate–

treated animals, BV/TV was significantly increased com-

pared to the OVX control rats (strontium ranelate ?12.2%,

P \ 0.05; PTH 1-34 ?25.6%, P \ 0.001) (Fig. 2). The

BV/TV of the PTH-treated rats was even higher than in the

sham rats (?10.2%, P \ 0.05). Strontium ranelate and

PTH 1-34 both showed a nonsignificant increase in the

bone mineral content (strontium ranelate ?2.5%, P [ 0.05;

PTH 1-34 ?9.8%, P [ 0.05). The difference between them

was also not significant.

Discussion

Osteoporotic fractures in formerly untreated patients

mostly lead to increased morbidity and mortality. The risk

of being bedridden and experiencing further fractures is

increased. Adequate and evidence-based medication for

osteoporosis needs to be initiated. It is unknown whether

certain osteoporotic drugs impair fracture healing or

enhance it, so that patients may experience earlier mobility.

Besides vitamin D and calcium administration, bisphos-

phonates, estrogen, raloxifen, strontium ranelate, and PTH

1-34 are commonly used antiosteoporotic drugs. Up to

now, only preclinical data provided information on the

0

1

2

3

4

5

6

7

8

*

#

SHAM OVX OVX+ PTH 1-34 OVX +Strontium

Ranelate

Fig. 1 Torsion to bone fracture (J/m3). * P \ 0.05 compared to

sham. # P \ 0.05 compared to ovariectomy (OVX)

84 B. Habermann et al.: Strontium Ranelate Enhances Callus Strength

123

impact of the therapeutic agents on fracture healing.

Clinical trials with antiosteoporotic agents focusing on the

outcome of the fracture healing and not on the incidence of

osteoporotic fractures will be necessary.

The OVX rat is a model commonly used to mimic

osteoporosis-induced bone loss. Shortly after ovariectomy,

the changes in bone are close to those observed in human

postmenopausal bone loss. Bonnarens and Einhorn [26]

introduced the model of a standardized closed diaphyseal

fracture, which has been used in many studies since. The

advantage of a closed fracture is that the initial environ-

ment is unchanged and not influenced, as it would be after

an open osteotomy. Combining both models is interesting

to study the impact of an agent on fracture healing in an

osteoporotic environment.

Many previous publications have studied fracture heal-

ing in osteoporotic rats, with diverse outcomes [29–34].

One reason for these diverse outcomes is most certainly the

type of fracture used. These can be differentiated as closed

and open fractures, as well as the type of fixation and the

location, i.e. tibia, femur, or mandibula. Furthermore, there

have been recent reports on fracture models that use the

metaphysis [35, 36]. Such models are interesting because

metaphyseal fractures are probably the most common

fractures encountered in a clinical osteoporosis situation.

The problem with such fractures is the mechanical evalu-

ation of their stability and the reproducibility. The diaph-

yseal fracture in animal experiments is also a well-

established method, easy to standardize, and, after ex-

planting the bone, is suited to mechanical testing. However,

the advantage of a closed fracture as it was used in our

study is that the initial environment is unchanged and not

influenced, as it would be after an open osteotomy. Nev-

ertheless, another reason for a diverse outcome is the use of

different endpoints. Endpoints in the literature vary

between 3 and 18 weeks [21, 22, 29–33, 37]. As described

by Schmidmaier et al. [38], fracture healing in rats runs

through the same phases as it does in any other mammal.

At day 21, the endochondral ossification phase is almost

complete, and the remodeling phase has started [38, 39].

Therefore, we were of the opinion that any impact on

healing would be detectable at day 28.

Table 1 Biomechanical data of fracture callusa

Characteristic Sham OVX OVX ? PTH OVX ? strontium ranelate

Torsional load (J/m3) 5.31 ± 0.96 4.02 ± 1.46* 4.44 ± 1.26 5.39 ± 1.68#

Yield point 0.06 ± 0.06 0.26 ± 0.48 0.11 ± 0.06 0.05 ± 0.04

OVX ovariectomized, PTH teriparatidea Data are presented as mean ± SD

* P \ 0.05 compared to sham# P \ 0.05 compared to OVX

0

0.1

0.2

0.3

0.4

0.5

0.6

SHAM OVX OVX+ PTH 1-34 OVX + Strontium Ranelate

*#

###*

Fig. 2 Callus bone volume/tissue volume. * P \ 0.05 compared to

sham. # P \ 0.05 compared to ovariectomy (OVX). ### P \ 0.01

Table 2 Micro computed tomography data of fracture callusa

Characteristic Sham OVX OVX ? PTH OVX ? strontium ranelate

Callus tissue volume (mm3) 210.19 ± 46.38 234.87 ± 60.46 249.2 ± 4332* 311.18 ± 607***,##,$$

Callus bone volume (mm3) 83.77 ± 27.24 82.95 ± 29.68 109.43 ± 30.89 *,# 121.37 ± 31.04*,##

Callus bone volume/tissue volume 0.39 ± 0.05 0.35 ± 0.05* 0.43 ± 0.06*,### 0.39 ± 0.043#

Bone mineral content of the callus 546.72 ± 57.62 457.27 ± 74.12*** 501.96 ± 45.6* 468.63 ± 59.24*

OVX ovariectomized, PTH teriparatidea Data are presented as mean ± SD

* P \ 0.05; ** P \ 0.01; *** P \ 0.001 compared to sham# P \ 0.05; ## P \ 0.01; ### P \ 0.001 compared to OVX$$ P \ 0.01 compared to PTH


123

The primary question addressed in this study was whe-

ther PTH 1-34 and strontium ranelate impact on fracture

healing at endpoint. An impact on fracture healing, be it

either an enhancement or a decrease, is evaluated by

assessing the biomechanical properties of the callus.

Whereas many authors use a three-point bending test [29–

32, 34], there are some reports on the torsional testing [40,

41] that we used. In torsional testing, the initial collapse of

the bony structure is not so much influenced by where the

main load is applied but by the structure of the whole bone

itself. The fracture callus is not homogenous, and a three-

point bending test cannot be representative of the whole

callus biomechanical competence. In addition to mechan-

ical testing, micro computed tomography (lCT) has the

ability to reconstruct the fracture site in 3D and provide

information on remodeling status.

The present results confirm those of previous studies

showing that ovariectomy impairs fracture healing in rats

[24, 42–44], affecting trabecular bone formation and min-

eralization. The OVX group showed a significant decrease

in callus resistance to torsional testing, reflecting a weaker

callus strength and thus validating the model. The lCT

data in our study clearly show that ovariectomy affects the

callus, as previously demonstrated [24, 42–44]. Although

there were no significant differences in the volume of the

callus between the sham and OVX rats, ovariectomy led to

a larger callus. Furthermore, the bone and mineral content

of this callus were considerably and significantly reduced

Fig. 3 a Horizontal slice through fracture callus of an ovariecto-

mized (OVX) Sprague Dawley (SD) rat treated with placebo. bHorizontal slice through fracture callus of an OVX SD rat treated with

strontium ranelate. c Horizontal slice through fracture callus of an

OVX SD rat treated with teriparatide


123

in the OVX rats. A significant reduction in BMD 12 weeks

after ovariectomy was confirmed by the DXA data. These

results reflect the inhibition of trabecular bone formation

and the reduction of mineralization in the later stages of

fracture healing in the OVX rat model.

PTH 1-34 (20 lg/kg/d) OVX-treated rats did not show a

significant increase in their callus resistance compared to

the OVX control rats. It had been previously demonstrated

that PTH enhances bone repair in rats. Preclinical studies

have shown a dose-response relationship from 10 to

800 lg/kg/d in the administration of PTH, with higher

doses being more potent for enhancement of fracture

healing by increasing BV/TV, bone callus volume, and

finally callus resistance [45]. But the doses used in many of

these studies were much higher than the recommended

equivalent human doses. Many studies in normal and old

rats have now clearly shown that even at dosages more in

line with those corresponding to clinical exposure (5 to

10 lg/kg/d), PTH enhances fracture healing. Only one

study in OVX rats with low-dose PTH 1-84 (15 lg/kg/d)

showed that this agent is effective in enhancing fracture

healing, improving both callus formation and resistance as

assessed by a three-point bending test, whereas we used

torsional testing [24]. A recent report in a rat cortical defect

model showed that PTH at a clinically relevant dose is not

sufficient to substantially enhance cortical bone repair over

5 weeks [46]. The dose of 20 lg/kg/d used in our study is

an intermediate one when considering previous published

studies. Even if in the present study PTH did not signifi-

cantly increase the resistance of the callus, it significantly

influenced its remodeling. The callus volume tended to

increase, and the within-callus BV/TV was significantly

enhanced. Indeed, as an anabolic agent, PTH has been

shown to enhance callus formation by the early stimulation

of proliferation and differentiation of osteoprogenitor cells

[47].

Treatment with strontium ranelate (600 mg/kg/d leading

to a blood strontium concentration close to the human

therapeutic exposure) led to a significant increase in callus

resistance compared to the OVX control rats. The increase

in stability even exceeded the results of the sham group,

although not significantly. The strontium ranelate effects

on callus remodeling were expressed by a significant

increase in BV/TV and volume of the callus. The BV/TV

of the callus in strontium ranelate OVX-treated rats was

identical to that of the sham rats, suggesting that strontium

ranelate is able to restore a level of bone remodeling

approaching that of a normal rat. Strontium ranelate has

been proven to have a dual mechanism of action in vitro,

acting on both osteoclasts and osteoblasts. It can be thus be

hypothesized that this drug could decrease the first phase of

bone resorption while improving the second phase of bone

formation by promoting the differentiation of bone marrow

cells present at the callus site. Indeed, strontium ranelate

was shown to promote stromal cell differentiation at the

very first stage, but also during latter stages, during

osteoblast differentiation [9, 10].

Whereas both PTH 1-34 and strontium ranelate

increased the volume of trabecular bone within the callus,

only strontium ranelate improved the resistance to torsional

testing. The BV/TV of the PTH-treated rats was even

higher compared to sham rats, but with no subsequent

increase in mechanical resistance. As a consequence, there

may be a qualitative difference between the calluses of

PTH 1-34 and strontium ranelate-treated OVX rats. Indeed,

in an OVX fracture rat model, the callus of PTH-treated

OVX rats remained more porous than in the sham rats,

showing that even if PTH treatment induced increased

amounts of bone tissue in the callus, this bone has still the

altered mechanical properties induced by ovariectomy [24].

As an anabolic agent, PTH increases bone remodeling and

improves microarchitecture. However, the relatively huge

increase in bone remodeling induced by such an agent

could induce an overall decrease in the maturation of

collagen fibers and lead to a poorer intrinsic bone quality.

This has been shown recently in OVX rats receiving PTH

by a decrease in trabecular bone hardness [48]. Strontium

ranelate has been shown to improve bone remodeling,

leading to better microarchitecture and intrinsic tissue

quality in intact and OVX rats [14, 15]. This difference of

effect of both drugs on intrinsic bone quality associated

with a higher callus volume primarily after treatment with

strontium ranelate could explain the better resistance of the

callus after treatment with strontium ranelate compared to

PTH 1-34. A histology study would be required to establish

the exact mechanism of action of both drugs in this model.

Moreover, this study is limited by the fact that analysis was

performed only at endpoint. Nevertheless, the aim was to

study and compare the enhancement of fracture healing

between two drugs at a defined time point and not to study

the acceleration or delay of healing, which would have

required the assessment of different time points.

In conclusion, this is the first report on the enhancement

of fracture healing with strontium ranelate. The callus in

strontium ranelate–treated animals is even more resistant to

torsion in comparison to OVX and sham-untreated animals

and even to those treated with PTH 1-34. PTH did not

significantly enhance the resistance of the callus vs. OVX,

despite a significant increase in the BV/TV ratio within the

callus. The superior results obtained with strontium rane-

late compared to PTH could be the consequence of a better

quality of the new bone formed within the callus. Stron-

tium ranelate might be taken into consideration in order to

enhance fracture repair.


123

Acknowledgments The study was supported by Elsbeth Bonhoff

Stiftung. No direct funding from any pharmaceutical company was

received.

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strontium ranelate enhances callus strength more than pth 1-34 in an osteoporotic rat model of fract

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