Abstract
Background:
Parathyroid hormone (PTH) has been shown to increase bone mineral density and to reduce the rate of fractures in patients with osteoporosis and also to improve fracture-healing. The purpose of the present prospective, randomized, controlled study was to evaluate the effect of PTH 1-84 on the course of pelvic fracture-healing and functional outcome in postmenopausal women.
Methods:
Sixty-five patients had a dual x-ray absorptiometry scan, radiographs, and a computed tomography scan to document pelvic fractures. Twenty-one patients received a once-daily injection of 100 μg of PTH 1-84 starting within two days after admission to the hospital, and forty-four patients served as the control group. All patients received 1000 mg of calcium and 800 IU of vitamin D. Computed tomography scans were repeated every fourth week until radiographic evidence of cortical bridging at the fracture site was confirmed. Functional outcome was assessed with use of a visual analog scale for pain and a Timed "Up and Go" test.
Results:
The mean time to fracture healing was 7.8 weeks for the treatment group, compared with 12.6 weeks for the control group (p < 0.001). At eight weeks, all fractures in the treatment group were healed and four fractures in the control group were healed (healing rate, 100% compared with 9.1%; p < 0.001). Both the visual analog scale score for pain and the result of the Timed "Up and Go" test improved in the study group as compared with the control group (p < 0.001).
Conclusions:
In elderly patients with osteoporosis, PTH 1-84 accelerates fracture-healing in pelvic fractures and improves functional outcome.
Level of Evidence:
Therapeutic Level II. See Instructions to Authors for a complete description of levels of evidence.
Fractures in patients with osteoporosis are a global burden for both individuals and health-care systems. The estimated lifetime risk of an osteoporotic fracture is between 40% and 50% for women and between 13% and 22% for men1. Worldwide, about nine million fractures associated with osteoporosis occur annually2. Fractures in the elderly are associated with high morbidity and mortality; pain and immobility lead to a loss of quality of life and an increase in general frailty.
The most frequent fractures associated with osteoporosis (vertebral fractures, fractures of the distal part of the radius, and fractures of the hip) receive the most attention. Less-frequent fractures such as pelvic fractures now account for large numbers1,3 as life expectancy increases4,5.
Pelvic fractures account for about 30% of the number of hip fractures6-9 but have increased in recent years4,5. One-third of pelvic fractures occur in patients older than sixty-five years of age10, with a clear predominance in women.
The most common cause of pelvic fractures is low-energy trauma10. Almost all patients have severe pain.
The primary strategy in the treatment of osteoporotic pelvic fractures is pain management, patient mobilization, and the prevention of problems associated with comorbid conditions11. Only exceptional cases require treatment with internal or external fixation8.
In general, about 5% to 20% of pelvic fractures in this patient population result in delayed or impaired healing12,13, but only a limited number of adjunctive therapies are available to accelerate fracture-healing. Low-intensity ultrasound14 and local application of recombinant bone morphogenetic protein-215 have been tested in patients with fractures. No other successful pharmacological treatment for fracture repair has been described in humans, to our knowledge.
In preclinical and clinical studies, treatments that are used for osteoporosis (e.g., bisphosphonates, parathyroid hormone [PTH], and strontium ranelate) have shown effects on fracture-healing. The purpose of the present study was to determine the effects of PTH 1-84 on the time of radiographic and clinical fracture-healing and reduction of pain in a group of patients with osteoporosis and pelvic fractures who received PTH 1-84 for the treatment of osteoporosis and to compare them with a control group without PTH treatment.
The primary objective of the present study was to compare two groups of patients with osteoporosis who sustained pelvic fractures, with one group receiving once-daily subcutaneous treatment with 100 μg of PTH 1-84 and the other group of patients receiving no PTH treatment, in order to test the potential effect of PTH 1-84 on the time of radiographic and clinical fracture-healing.
Standard screening procedures for all older patients suspected of having osteoporosis were applied routinely at participating hospitals, which specialized in orthopaedic surgery and rheumatology. Bone markers as well as bone mineral density as determined with dual x-ray absorptiometry (DXA) were assessed. For patients with pelvic fractures, an initial radiograph was made and then a computed tomography (CT) scan was routinely performed to verify and confirm the diagnosis. For patients with pelvic fractures, the CT scan was repeated and the functional progression was assessed every four weeks.
Women were admitted to the hospital with severe acute pain in the pelvic area. Radiographs that were made immediately after admission revealed fractures of the pubic bones and/or ischial rami of the pelvis (OTA/AO [Orthopaedic Trauma Association/Arbeitsgemeinschaft für Osteosynthesefragen] classification 61-A2.2). Fractures were confirmed with CT scanning within two days after admission. Patients were concurrently screened for osteoporosis with use of DXA (Lunar Prodigy; GE Healthcare, Little Chalfont, United Kingdom). Routine laboratory examination and additional bone-turnover markers, such as alkaline phosphatase, bone-specific alkaline phosphatase, parathyroid hormone, 25 OH vitamin D, collagen cross-links, and sexual and thyroid hormone levels were determined. No patient was excluded because of abnormal laboratory tests.
The inclusion criteria for this randomized controlled study were a unilateral pelvic fracture, an age of more than seventy years, and the presence of osteoporosis according to the World Health Organization (WHO) DXA definition, with a T-score of below −2.5 at the lumbar spine or the proximal part of the femur. Patients with a history of tumors or chemotherapy and bone metastases were excluded from the study to avoid the inclusion of patients with pathological fractures. The use of treatments for osteoporosis within six months prior to the start of PTH 1-84 treatment was an exclusion criterion. No other concomitant treatment for osteoporosis (except calcium and vitamin D) was given during the time of the study.
Sixty-five centers were recruited chronologically, with every third patient being assigned to the treatment of osteoporosis with PTH 1-84. Patient allocation was communicated by phone to the doctors participating in the study on an individual basis. The twenty-one patients who were allocated to the treatment group received 100 μg of PTH 1-84, administered as a once-daily subcutaneous injection in the abdomen (Fig. 1). PTH 1-84 was manufactured with use of a strain of Escherichia coli modified by means of recombinant DNA technology. PTH 1-84 treatment was started within two days after admission to the hospital. Forty-four patients without PTH 1-84 treatment served as the control group. Because patients were managed for severe osteoporosis, the treatment was continued for twenty-four months after the fracture had healed. All patients received a daily supplementation consisting of 1000 mg of calcium and 800 international units (IU) vitamin D3 for the entire study period. The two groups were well matched (Table I). There were no differences in terms of medical management between the treatment and control groups.
Assessment of Fracture-Healing with Imaging Studies
Fracture healing was assessed on CT scans at Weeks 0 (at least two days after the fracture), 4, 8, 12, and later until evidence of fracture-healing (defined as cortical bridging) was confirmed. The percentage of fractures that had healed at Week 8 was considered to be the primary end point of interest. The assessment of the CT scans was done independently by a trauma surgeon (R.M.) and an orthopaedic surgeon (G.H.). All assessments were blinded.
Assessment of Clinical Fracture-Healing and Functional Outcome
Functional outcome was defined as a reduction in pain and an improvement in mobility and was assessed with use of a numeric visual analog scale (VAS) for pain (with 0 representing no pain and 10 representing the greatest imaginable pain) at Weeks 0, 4, 8, and 12 and a Timed "Up and Go" (TUG) test to determine functional outcome on the basis of weight-bearing at Week 816. The TUG test measures the time in which someone rises from a standard chair, walks 3 m, turns around, walks back, and sits in the chair again. A normal adult should complete the test in less than ten seconds; those who are dependent for most activities of daily life take more than thirty seconds.
Statistical Methods
Data are expressed as the mean and the standard deviation or as numbers and percentages.
The significance level (alpha) was set to 0.05. The chi-square test was used to compare the groups in terms of categorical variables. The Mann-Whitney U-test was used to compare the groups in terms of continuous and ordinal variables. Ninety-five percent confidence intervals (95% CI) were derived for categorical as well as for continuous and ordinal variables. Sample sizes were calculated with use of the chi-square test to compare two proportions. With an expected healing rate of 100% versus 40% at Week 8, it was determined that twelve patients in each group would be needed to reach a power of 80%.
Source of Funding
There was no external funding source.
Data were collected between January 2008 and March 2010. A total of seventy-five women were screened, and sixty-five patients were included in the study. Ten patients were excluded because of a history of tumors within the preceding five years, multiple fractures, other injuries at the time of pelvic fracture, and/or previous PTH treatment.
The median time from the fracture to the first sign of complete cortical bridging of the pelvic fracture as verified with CT scanning was 7.8 weeks for the treatment group, compared with 12.6 weeks for the control group (p < 0.001).
At Week 8, which was the primary end point, all fractures in the treatment group and four fractures in the control group had healed (healing rate, 100% [95% CI, 86.7% to 100.0%] compared with 9.1% [95% CI, 2.5% to 21.7%]). The treatment group demonstrated significant improvement in comparison with the control group in terms of functional outcome (as assessed with both the VAS score and the TUG test). From Week 0 to Week 8, the mean VAS score improved from 7.6 (95% CI, 7.0 to 8.1) to 3.2 (95% CI, 2.7 to 3.7) in the treatment group and from 7.7 (95% CI, 7.1 to 8.3) to 6.5 (95% CI, 6.0 to 7.0) in the control group (p < 0.001). At Week 8, the mean TUG test result was 22.9 seconds for the treatment group, compared with 54.3 seconds for the control group (p < 0.001).
At Week 12, all fractures in the treatment group and thirty fractures in the control group had healed (healing rate, 100% [95% CI, 86.7% to 100.0%] compared with 68.2% [95% CI, 52.4% to 81.4%]). Fourteen fractures in the control group had not healed by Week 12. The mean time to healing for these fractures was 14.9 weeks (range, thirteen to eighteen weeks). At the time of the latest follow-up, all fractures had healed (Table II).
All patients in the treatment group continued the PTH 1-84 treatment for twenty-four months. During the study period, no adverse events or deaths were recorded. In the treatment group, the latest visit (at which time fracture-healing was confirmed with CT scanning) was at Week 4 for one patient and at Week 8 for twenty patients. In the control group, the latest visit was at Week 8 for four patients and at Week 12 for thirty patients. In the remaining fourteen patients in the control group, the latest visit was at a mean of 14.9 weeks. No nonunion was detected at the time of the latest visit.
During the study, the patients in both groups had routine laboratory serum studies (blood cell count, creatinine, urea, serum glutamate oxaloacetate transaminase [SGOT], serum glutamate pyruvate transaminase [SGPT], gamma glutamyl transpeptidase [GGT], c-reactive protein, electrolytes) every four weeks. No laboratory abnormalities, including hypocalcemia or hypercalcemia, were noted. Levels of sexual and thyroid hormones were normal for postmenopausal women.
Pelvic fractures in the elderly are associated with delayed fracture-healing due to impaired bone quality, causing long-term pain and long-term immobilization leading to greater morbidity and mortality6,9. The primary strategy in treatment of pelvic fractures in patients with osteoporosis is pain management, patient mobilization, and the prevention of complications associated with comorbid conditions11.
In a number of studies, PTH has demonstrated an effect in terms of improving bone mineral density (BMD) and reducing the rate of future fractures in patients with osteoporosis17-19 while also improving fracture-healing20-22.
We analyzed the effect of PTH 1-84 on fracture-healing in patients with osteoporosis who had sustained pelvic fractures and found that PTH 1-84 significantly accelerated the time to healing of recent fractures as compared with that in a control group of patients without such treatment. This reduction in healing time may be important for elderly patients, especially those with pelvic fractures and long-term immobilization. To our knowledge, this is the first report on the effects of PTH 1-84 on the course of healing of pelvic fractures in elderly women with osteoporosis.
In animal studies involving intermittent administration of systemic PTH20 and in dose-response studies, teriparatide (PTH 1-34) was associated with enhanced mechanical properties in fracture callus and accelerated fracture-healing in young and old rats23,24. In a rat model, stimulatory effects were also found for implant fixation, bone-implant contact, and callus distraction osteogenesis25.
Animal as well as clinical data suggest that the main clinical advantages of using PTH are the acceleration of fracture-healing and enhanced bone formation20,21,23-25. Recently, acceleration of fracture-healing in association with teriparatide (PTH 1-34) was reported in a study of 102 postmenopausal women with distal radial fractures22.
Two different PTH compounds (PTH 1-34 and PTH 1-84) are approved for the treatment of severe osteoporosis in Europe. PTH 1-34 (teriparatide) consists of the first thirty-four amino acids of the human parathormone (the "active" part of this hormone). The other fifty amino acids are known as the "inactive" part of the parathormone. PTH 1-84, on the other hand, consists of eighty-four amino acids, the "complete" parathormone. Both substances are synthesized with use of recombinant technology, and both are administered by means of astandardized daily injection. We are not aware of any comparative studies of the two drugs, both of which have a strong anabolic action26.
Patients with nonoperatively treated pelvic fractures were chosen to support the concept that fracture-healing and functional outcome are accelerated by PTH 1-84. We considered this fracture type to be relevant and practical for a study of fracture-healing in humans because most of these fractures are accompanied by severe pain and almost all patients require bed rest. Immobilization can cause high morbidity and mortality in older patients.
In the present study, there was no time limit for the PTH treatment. Patients were primarily managed for osteoporosis, and, in all cases, treatment was continued after fracture-healing had been confirmed. The present study was more informative in terms of the rate of healing as compared with a recently published study22 in which teriparatide treatment was discontinued before radiographic fracture-healing was reached in all patients.
The present study had some limitations. Although the study was prospectively designed, the information was abstracted after the study was finished. Other limitations were the sample size and the patient-allocation process.
Patients in the PTH 1-84 treatment group were treated at a single center, and patients from this center and another center served as controls (no PTH 1-84 treatment). At both these institutions, the diagnostic and therapeutic procedures were the same. Demographic data demonstrated no significant differences between the patients in the two groups (Table I).
In conclusion, the present study showed acceleration in terms of both imaging and clinical fracture-healing in elderly patients with osteoporosis who were managed with PTH 1-84. For patients in this population who have pelvic fractures, PTH 1-84 treatment may reduce healing time, improve clinical outcomes, and reduce the time of immobilization and the risk of complications.
Note: The authors thank I. Wagner for typing parts of the manuscript, E. Kvas for help with the statistical analysis, and B. Eschweiler for reading the manuscript.
Johnell
O;
Kanis
J. Epidemiology of osteoporotic fractures. Osteoporos Int.
2005;
16 Suppl2:S3-7.[CrossRef]
Johnell
O;
Kanis
JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int.
2006;17:1726-33.[CrossRef][PubMed]
Kannus
P;
Palvanen
M;
Niemi
S;
Parkkari
J;
Järvinen
M. Epidemiology of osteoporotic pelvic fractures in elderly people in Finland: sharp increase in 1970-1997 and alarming projections for the new millennium. Osteoporos Int.
2000;11:443-8.[CrossRef][PubMed]
Kannus
P;
Palvanen
M;
Parkkari
J;
Niemi
S;
Järvinen
M. Osteoporotic pelvic fractures in elderly women. Osteoporos Int.
2005;16:1304-5.[CrossRef][PubMed]
Melton
LJ
3rd;
Sampson
JM;
Morrey
BF;
Ilstrup
DM. Epidemiologic features of pelvic fractures. Clin Orthop Relat Res.
1981;155:43-7.[PubMed]
Pohlemann
T;
Tscherne
H;
Baumgärtel
F;
Egbers
HJ;
Euler
E;
Maurer
F;
Fell
M;
Mayr
E;
Quirini
WW;
Schlickewei
W;
Weinberg
A. [Pelvic fractures: epidemiology, therapy and long-term outcome. Overview of the multicenter study of the Pelvis Study Group]. Unfallchirurg.
1996;99:160-7. .[CrossRef][PubMed]
Morris
RO;
Sonibare
A;
Green
DJ;
Masud
T. Closed pelvic fractures: characteristics and outcomes in older patients admitted to medical and geriatric wards. Postgrad Med J.
2000;76:646-50.[CrossRef][PubMed]
Culemann
U;
Beckenverletzungen
Pohlemann T. : Raschke
MJ;
Stange
R, . Alterstraumatologie. München: 2008; Urban & Fischer Verlag. p 286-304.
Krappinger
D;
Kammerlander
C;
Hak
DJ;
Blauth
M. Low-energy osteoporotic pelvic fractures. Arch Orthop Trauma Surg.
2010;130:1167-75.[CrossRef][PubMed]
Axelrad
TW;
Kakar
S;
Einhorn
TA. New technologies for the enhancement of skeletal repair. Injury.
2007;
38 Suppl1:S49-62.[CrossRef]
Bishop
GB;
Einhorn
TA. Current and future clinical applications of bone morphogenetic proteins in orthopaedic trauma surgery. Int Orthop.
2007;31:721-7.[CrossRef][PubMed]
Kristiansen
TK;
Ryaby
JP;
McCabe
J;
Frey
JJ;
Roe
LR. Accelerated healing of distal radial fractures with the use of specific, low-intensity ultrasound. A multicenter, prospective, randomized, double-blind, placebo-controlled study. J Bone Joint Surg Am.
1997;79:961-73.[PubMed]
Govender
S;
Csimma
C;
Genant
HK;
Valentin-Opran
A;
Amit
Y;
Arbel
R;
Aro
H;
Atar
D;
Bishay
M;
Börner
MG;
Chiron
P;
Choong
P;
Cinats
J;
Courtenay
B;
Feibel
R;
Geulette
B;
Gravel
C;
Haas
N;
Raschke
M;
Hammacher
E;
van der Velde
D;
Hardy
P;
Holt
M;
Josten
C;
Ketterl
RL;
Lindeque
B;
Lob
G;
Mathevon
H;
McCoy
G;
Marsh
D;
Miller
R;
Munting
E;
Oevre
S;
Nordsletten
L;
Patel
A;
Pohl
A;
Rennie
W;
Reynders
P;
Rommens
PM;
Rondia
J;
Rossouw
WC;
Daneel
PJ;
Ruff
S;
Rüter
A;
Santavirta
S;
Schildhauer
TA;
Gekle
C;
Schnettler
R;
Segal
D;
Seiler
H;
Snowdowne
RB;
Stapert
J;
Taglang
G;
Verdonk
R;
Vogels
L;
Weckbach
A;
Wentzensen
A;
Wisniewski
T; BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am.
2002;84:2123-34.[CrossRef][PubMed]
Podsiadlo
D;
Richardson
S. The timed "Up & Go": a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc.
1991;2:142-8.
Black
DM;
Bilezikian
JP;
Ensrud
KE;
Greenspan
SL;
Palermo
L;
Hue
T;
Lang
TF;
McGowan
JA;
Rosen
CJ; PaTH Study Investigators. One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med.
2005;353:555-65.[CrossRef][PubMed]
Greenspan
SL;
Bone
HG;
Ettinger
MP;
Hanley
DA;
Lindsay
R;
Zanchetta
JR;
Blosch
CM;
Mathisen
AL;
Morris
SA;
Marriott
TB; Treatment of Osteoporosis with Parathyroid Hormone Study Group. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med.
2007;146:326-39.[PubMed]
Hosking
D;
Alonso
CG;
Brandi
ML. Management of osteoporosis with PTH: treatment and prescription patterns in Europe. Curr Med Res Opin.
2009;1:263-70.[CrossRef]
Holzer
G;
Majeska
RJ;
Lundy
MW;
Hartke
JR;
Einhorn
TA. Parathyroid hormone enhances fracture healing. A preliminary report. Clin Orthop Relat Res.
1999;366:258-63.[CrossRef][PubMed]
Ellegaard
M;
Jørgensen
NR;
Schwarz
P. Parathyroid hormone and bone healing. Calcif Tissue Int.
2010;87:1-13.[CrossRef][PubMed]
Aspenberg
P;
Genant
HK;
Johansson
T;
Nino
AJ;
See
K;
Krohn
K;
García-Hernández
PA;
Recknor
CP;
Einhorn
TA;
Dalsky
GP;
Mitlak
BH;
Fierlinger
A;
Lakshmanan
MC. Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J Bone Miner Res.
2010;25:404-14.[CrossRef][PubMed]
Nakazawa
T;
Nakajima
A;
Shiomi
K;
Moriya
H;
Einhorn
TA;
Yamazaki
M. Effects of low-dose, intermittent treatment with recombinant human parathyroid hormone (1-34) on chondrogenesis in a model of experimental fracture healing. Bone.
2005;37:711-9.[CrossRef][PubMed]
Skripitz
R;
Andreassen
TT;
Aspenberg
P. Strong effect of PTH (1-34) on regenerating bone: a time sequence study in rats. Acta Orthop Scand.
2000;71:619-24.[CrossRef][PubMed]
Seebach
C;
Skripitz
R;
Andreassen
TT;
Aspenberg
P. Intermittent parathyroid hormone (1-34) enhances mechanical strength and density of new bone after distraction osteogenesis in rats. J Orthop Res.
2004;22:472-8.[CrossRef][PubMed]
Verhaar
HJ;
Lems
WF. PTH-analogs: comparable or different?Arch Gerontol Geriatr.
2009;49:e130-2.[CrossRef][PubMed]