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545
Bone Fractures Associated with Luteinizing Hormone–
Releasing Hormone Agonists Used in the Treatment of
Prostate Carcinoma
Murphy F. Townsend, M.D.
W. Holt Sanders, M.D.
Robert O. Northway, M.D.
Sam D. Graham, Jr., M.D.
BACKGROUND. Luteinizing hormone-releasing hormone agonists (LHRH-a) have
become an established treatment for certain patients with prostate carcinoma.
LHRH-a are known to decrease bone mineral density. The purpose of this study
Division of Urology, Department of Surgery,
Emory University School of Medicine, Atlanta,
Georgia.
was to determine the risk of bone fracture in men receiving LHRH-a for prostate
carcinoma.
METHODS. A retrospective chart review and phone interviews were conducted to
determine the incidence of bone fractures occurring in patients receiving LHRHa for the treatment of prostate carcinoma. Abstracted data included the number
of monthly LHRH-a injections, age, clinical stage of disease, sites of metastases,
and bone fracture history.
RESULTS. Twenty of the 224 patients (9%) treated with LHRH-a for prostate carcinoma between 1988 and 1995 at 3 teaching hospitals had at least 1 bone fracture
during treatment with LHRH-a. The duration of treatment to the time of fracture
ranged from 1 to 96 months (mean, 22.2 months). Seven fractures (32%) were
osteoporotic in nature (i.e., vertebral compression fractures or hip fractures after
a fall from standing), whereas 8 fractures (36%) were associated with a significant
traumatic event (i.e., a motor vehicle accident, boxing, etc.) and 5 were of mixed
etiology. Two of 22 fractures (9%) were pathologic.
CONCLUSIONS. This study demonstrated a 9% fracture incidence in a cohort of
patients receiving LHRH-a for prostate carcinoma for up to 96 months. The incidence of osteoporotic fractures was 5%. Cancer 1997; 79:545–50.
q 1997 American Cancer Society.
KEYWORDS: prostate carcinoma, hormonal therapy, osteoporosis.
L
The information in this article was presented
in scientific poster format at the Southeastern
Section of the American Urologic Association,
Puerto Rico, April 1996.
Address for reprints: W. Holt Sanders, M.D.,
Emory University School of Medicine, Emory
Central Clinic, Division of Urology, 1365 Clifton
Road, N.E., Atlanta, GA 30322.
Received April 17, 1996; revision received October 7, 1996; accepted October 11, 1996.
uteinizing hormone – releasing hormone agonists (LHRH-a) have
become a common palliative therapy for certain patients with
prostate carcinoma. By down-regulating anterior pituitary LHRH receptors, LHRH-a decrease circulating testosterone to castration levels.
Androgens play an important role in bone metabolism.1 – 7 The hypogonadism induced by LHRH-a, as well as hypogonadism from other
etiologies, has been shown to decrease bone mineral density in men.8–19
In females, LHRH-a therapy for endometriosis is limited to 6 months
of therapy due to a decrease in bone mineral density.20 Osteoporosis
(or a decrease in bone mass) leads to an increased risk of bone fractures.21 Osteoporotic bone fractures, especially of the hip and spine,
have become a major public health issue. They result in significant
morbidity and mortality and are projected to become increasingly
prevalent as our elderly population grows.22 – 24 There is no recommended time limit to LHRH-a therapy for prostate carcinoma patients. Despite the known decrease in bone density associ-
q 1997 American Cancer Society
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W: Cancer
546
CANCER February 1, 1997 / Volume 79 / Number 3
ated with their use, it is not known whether LHRH-a
cause a clinically significant increase in the incidence
of fracture. This investigation establishes the incidence of bone fractures in our population of patients
receiving LHRH-a.
MATERIALS AND METHODS
All prostate carcinoma patients treated between 1988
and 1995 with any number of monthly LHRH-a injections (specifically, leuprolide acetate, 7.5 mg intramuscular injection, or goserelin acetate implant, 3.6 mg
subcutaneous injection) at one of three teaching hospitals, the University Hospital, The Veterans Administration Hospital, and the county hospital, were identified. Medical records were reviewed and phone interviews were conducted. Patients were excluded from
the study group if they, their families, or their caretakers could not be contacted by telephone. Previous
treatment with radical prostatectomy, radiation therapy, and antiandrogens did not exclude patients from
enrollment in the study.
During telephone interviews, patients (or an adult
family member) were asked if they had suffered a bone
fracture any time after their first intramuscular injection of LHRH-a. The phone contact was reminded or
informed of the first injection date. If knowledge of
a fracture was recalled, further questions were asked
concerning the bone(s) involved, the circumstances of
the fracture episode (e.g., a motor vehicle accident, a
simple fall from standing or some other event), the
date of the fracture, and the hospital at which the
fracture was initially evaluated. Radiology records
from outside institutions were obtained to document
fractures. Defining a fracture as pathologic was based
on radiographic findings consistent with this diagnosis
and was therefore dependent on the radiologist’s interpretation.
Medical records of all study patients were reviewed. The data abstracted included each patient’s
date of birth, the clinical stage of prostate carcinoma
(based on the Whitmore – Jewett system), the total
number of monthly LHRH-a injections administered,
and the date of the first injection. Radiology reports
on all patients were reviewed in search of documented
occult/asymptomatic fractures about which the patient may have been unaware (e.g., vertebral compression fracture). Nuclear bone scan reports were reviewed to assist in disease staging as well as to compare fracture sites with metastatic foci.
The Student’s t test was used to compare the mean
number of injections of LHRH-a given to patients with
fractures and patients without fractures. Fisher’s exact
test was used to compare the frequency of fracture in
patients with early stage prostate carcinoma (classified
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TABLE 1
Patients Categorized by Stage of Disease
Stage
(TNM classification)
Total no.
of patients
Patients with
no fxr
A1 (T1a)
A2 (T1b)
B0 (T1c)
B1 (T2a)
B2 (T2b)
C (T3)
D0 (a)
D1 (TxN1-3Mx)
D2 (TxNxM2)
No stage
1
3
1
2
15
20
48
13
78
43 (19%)
1
1
1
2
13
20
47
12
65
42
Patients with
fxr
2
2
1
1
13
1
Fxr: bone fractures.
a
Patients with a rising prostate specific antigen and no evidence of metastases on bone scan after
definitive local therapy (radiation or prostatectomy) were designated Stage D0. There was no analogous
TNM classification for this group of patients.
as T1 and T2) with the frequency in those with metastatic carcinoma.
RESULTS
Three hundred two patients who received LHRH-a for
the treatment of prostate carcinoma between 1988 and
1995 were identified. Telephone contact was successful in 224 cases (74%). The 78 patients (26%) who could
not be contacted were excluded from the study. The
mean age of the patients was 73.1 years (range, 45 –
96 years). Clinical cancer stage could be determined
in 181 patients (81%). Four patients were Stage A
(T1N0M0), 18 (10%) were Stage B (T2N0M0), 20 (11%)
were Stage C (T3N0M0), and 139 (77%) were Stage D
(TXN1-3MX or TXNXM2). Patients with rising prostate
specific antigen and no evidence of metastases on
bone scan after definitive local therapy (radiation or
prostatectomy) were designated Stage D0. There was
no analogous TNM classification for this group of patients. More detailed staging is summarized in Table
1.
Twenty patients (9%) fractured at least one bone
at some time after their first LHRH-a injection. Two
hundred four patients (91%) were fracture free. In order to determine which fractures were most likely related to LHRH-a, we censored those patients who had
fractures (1) within 12 months of starting LHRH-a, (2)
associated with trauma or motor vehicle accidents, or
(3) considered to be pathologic, that is, associated with
blastic bone lesions. Nine patients were censored. The
resulting rate of fracture was 11 of 224 patients, or 5%.
The mean number of monthly LHRH-a injections for
all patients was 22.2 (range, 1 – 96). The fracture group
W: Cancer
Bone Fractures and LHRH Agonists/Townsend et al.
547
TABLE 2
Summary of Patients with Bone Fractures
Patient no.
Age
Mos received LHRH
Fxr
Fxr episode
Stage of disease
1
2
3
4a
4b
4c
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
72
78
84
75
75
75
71
79
80
78
80
59
72
74
75
78
72
88
52
69
67
75
6
16
21
12
13
13
27
45
36
28
26
23
4
22
23
18
14
19
4
31
2
14
R humerusa
L 3rd rib
Middle TS CF
L hipa
L maxillary sinus
Mid TS CF
R radius
L hip
L foot/ankle
L hip
R hip
R wrist
L hip
L ankle
L middle finger
R hip
Finger
T5, T7 CF
L middle finger
R proximal fibula
R clavicle
R rib
Fall
Thorocotomy
None
Fall
Fall
None
Tennis injury
Fall
Lawn mower injury
Fall
Fall
Fall
Fall
Trip/fall
MVA
Fall
Flight
None
Boxing injury
Tractor injury
Seizure
Fight
D2
D0
D2
D2
D2
D2
D1
A2
D2
D2
D2
D2
D2
D2
D2
Not known
D2
D2
B2
D2
B2
A2
LHRH: luteinizing hormone–releasing hormone; Fxr: bone fracture; L: left, R: right; TS: thoracic spine; CF: compression fracture; MVA: motor vehicle accident.
a
Pathologic fractures are represented.
underwent a mean of 19.6 injections (range, 2 – 45),
whereas the nonfracture group underwent a mean of
20.8 injections (range, 1 – 96) (P Å 0.65). The fracture
group had a mean age of 73.9 years (range, 52 – 88
years), and the nonfracture group had a mean age of
73.1 years (range, 45 – 96 years).
Characteristics of patients who experienced bone
fractures are summarized in Table 2. Of the 20 patients
who experienced fractures, 19 (95%) had an injection
administered within 1 month of their fracture date.
One patient who had received a total of 6 injections
had not received an injection for 32 months prior to
his fracture date. One patient experienced more than
one fracture; he had a left femoral intertrochanteric
fracture, a left maxillary sinus fracture, and a midthoracic vertebral compression fracture. The first two fractures occurred on separate dates. The vertebral compression fracture presumably occurred over an extended period of time; the patient did not recall a
specific event associated with localized spine pain.
Two patients had single fracture events involving more
than one bone. One patient fell while walking and
fractured three bones in the left ankle (medial and
posterior malleoli and the ipsilateral distal fibula) and
a second patient fractured his left lateral malleolus
and left fifth metatarsal, sustaining blunt trauma to
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the foot. Occult vertebral compression fractures were
identified by radiology reports in 3 patients. None of
these patients were aware of this pathology. Thirteen
patients were Stage D2 at the time of fracture, although
only two fractures were pathologic: a right midshaft
humerus fracture was sustained after a simple fall by
a patient with diffuse bone metastasis on bone scan
(‘‘superscan’’), and a left femoral intertrochanteric
fracture was sustained after a simple fall by a patient
with focal metastasis to the femur and thoracolumbar
junction on bone scan.
Ten fractures (45%) were evaluated and treated at
hospitals other than the three primary hospitals where
the LHRH-a was being administered. None of these
patients had follow-up fracture films made at their
primary hospital. No urology clinic chart notation regarding history of bone fracture during administration
of LHRH-a was made for any patient. Of 22 total fractures in 20 patients, 19 fractures (86%) were identified
in patient interviews. Radiologic evaluation was obtained, with reports available, for 12 fractures (55%)
at the primary hospitals and for 10 fractures (45%) at
outside hospitals.
Of 22 patients with Stage A or B disease, 4 (18%)
suffered fractures. By comparison, 15 of 139 patients
(11%) with Stage D disease suffered fractures (P Å
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CANCER February 1, 1997 / Volume 79 / Number 3
TABLE 3
Mean No. of Injections by Stage of Disease
Stage
Mean no. of injections
D (average of all)
D2
A–B
D0–D1
21.5
22.5
19.3
20.3
0.15). Only 2 of 61 patients (3%) with Stage D0 or
D1 disease suffered fractures, whereas 13 of 78 (17%)
patients with Stage D2 disease had fractures (P Å
0.008). The mean number of injections among these
groups was similar and was therefore unlikely to have
contributed to the different rates of fracture (Table 3).
DISCUSSION
LHRH-a therapy is palliative for patients with varying
stages of prostate carcinoma. The depot preparations
of leuprolide acetate and goserelin acetate work by
continuous stimulation of gonadotrophs, thereby
down-regulating LHRH receptors.25 This effect ultimately reduces serum testosterone to castration levels.
Serum androgens influence bone metabolism. A
positive correlation has been noted between testosterone levels and skeletal mass.11,12 Osteoblasts have androgen receptors,1 – 3 and androgens influence osteoblasts in a number of ways, including growth, proliferation, cytokine production, and bone matrix protein
production.4 – 7
Hypogonadism from LHRH-a, as well as castration, congenital diseases, and normal aging, will reduce bone mineral density and potentially cause osteoporosis. Goldray et al. demonstrated a reduction in
individual vertebral bone mineral density in 10 of 17
men during their first year of treatment with the longacting LHRH agonist, Decapeptyl (a preparation of
triptorelin), for benign prostatic hypertrophy.26 That
study also reported biochemical evidence of bone remodeling (increased serum osteocalcin levels and urinary hydroxyproline excretion). Women are sometimes treated for endometriosis or leiomyoma with a
LHRH-a, which shuts down the production of estrogen
by the ovaries. In a review by Fogelman,20 a decrease
in bone mineral density is well documented in females
receiving LHRH-a. Within 3 months of eliminating the
protective effect of estrogen on the skeleton, there is
a rise in serum parameters, reflecting an increase in
bone resorption (seen in urinary ratios of calcium to
creatinine and hydroxyproline to creatinine) and bone
formation (seen in serum alkaline phosphatase and
osteocalcin).
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There is an approximately 2 – 7% trabecular bone
loss in the spine after 6 months of treatment with a
LHRH-a, depending on the skeletal site studied and
the method of measurement. These changes are partially or completely reversible once the administration
of LHRH-a is stopped. Bone loss following castration
was studied by Stepan et al.,16 who reviewed 12 men
age 20 – 42 years in the years immediately following
castration. They found that, as with estrogen deficiency in women,27 there is an increase in bone resorption associated with testosterone deficiency. They
noted a progressive decrease in lumbar bone density
over time at a rate of 7% per year for the first 2 years;
this rate decreased to 1.5% per year at 6 – 11 years after
surgery. Serum biochemical indices of bone resorption
and bone formation were elevated as compared with
healthy, age-matched controls. Congenital diseases,
such as testicular feminization, Klinefelter’s syndrome,
and Kallman’s syndrome, which cause prepubertal hypogonadism, result in reduced bone mass.8,13 – 15 As
men age, changes in the hypothalamic-pituitary gonadal axis, a decrease in Leydig cell mass and function,
and a decrease in testicular perfusion result in lowered
total and free testosterone levels.28 – 29 Lowered testosterone levels are thought to contribute to the reduction
in bone mineral density associated with aging10 – 12 and
to the development of senile osteoporosis.21 Senile osteoporosis, the most common form of osteoporosis
noted in the elderly population, has a number of contributing causes in addition to hypogonadism, including metabolic causes, nutritional deficiencies, and inactivity.21 Reduced bone mass and fractures have also
been associated with hypogonadism secondary to hyperprolactinemia, anorexia, and hemochromatosis.16–19
Of men evaluated for vertebral fractures and osteoporosis, 5 – 33% have hypogonadism,30 – 32 and there is an
increased likelihood of hip fractures in hypogonadal
elderly men.33
There is a clear relationship between a decreased
bone mineral density and an increased fracture incidence. As men age, their skeletons become more fragile, and there is an increased incidence of proximal
femur and spine fractures among them.21 A reduction
in femur and spine bone mineral density has been
demonstrated in men with hip and vertebral fractures
as compared with controls.34 – 36 These fractures are examples of osteoporotic fractures that occur as a result
of minimal to moderate trauma in the absence of underlying bone pathology. The associated morbidity
and mortality of osteoporotic fractures (e.g., hip and
vertebral fractures) is significant, with a 30% mortality
rate reported for men age 75 years or older after hip
fractures.37 Thus, with our expanding elderly popula-
W: Cancer
Bone Fractures and LHRH Agonists/Townsend et al.
tion, osteoporosis in men has become a major public
health and medical cost issue.22 – 24
The fracture incidence among patients receiving
LHRH-a for the treatment of prostate carcinoma has
not been documented. Horan examined the radiology
reports of 21 of 116 patients receiving LHRH-a for
prostate carcinoma and found nonpathologic fractures in 5 patients (24%): 3 vertebral compression fractures, 1 femoral intertrochanteric fracture, and 1 rib
fracture.38 Neither the length of LHRH-a administration nor whether the vertebral compression fractures
were radiographically detectable prior to LHRH-a
therapy was noted. Collinson et al.39 described two
patients who developed osteoporosis and vertebral
compression fractures after medical castration with
monthly goserelin injections. The first patient was a
man age 64 years with a tumor classified as T3NXM0
who had received LHRH-a for 6 years and had a new
onset of back pain. Spine films demonstrated generalized osteopenia and compression fractures at T7 – 8
and T12. Magnetic resonance imaging of the spine
ruled out metastasis to bone. No mention was made
of precastration comparison radiographs. The patient
had symptomatic improvement after receiving calcium supplements and intermittent disodium etidronate. The second patient was a man age 70 years with
Stage A adenocarcinoma of the prostate who had received 2.5 years of monthly goserelin intramuscular
injections. Spine films were obtained to evaluate a new
onset of back pain, which revealed wedging of the T8
vertebral body. Two and one-half years later, these
films were repeated, revealing additional wedging of
T7 – 8, T12, and L2 vertebral bodies with worsened osteopenia. The patient had symptomatic relief when
treated with calcitonin, intermittent disodium etidronate, and calcium. Reports of at least three other similar patients have described osteoporosis and vertebral
compression fractures associated with LHRH-a.40 – 42
This study was designed to examine the incidence
of bone fractures in our population of patients receiving LHRH-a. Among men older than 65 years, the incidence of hip fractures is 4 – 5 in 1000, with an incidence
of 2.2 in 1000 among men age 65 – 74 years and 6.4 in
1000 among men age 75 – 84 years.43 – 44 In our study
population, there were 6 proximal femur fractures (4
intertrochanteric and 2 femoral neck). All fractures occurred after minimal to moderate trauma (e.g., a simple fall from standing, transferring from a chair, or
‘‘tripping’’). One fracture was pathologic, with radiographic evidence of osteoblastic metastases at the fracture site. The 5 nonpathologic fractures were consistent with osteoporotic fractures. The average age of
these patients at the time of fracture was 77.4 years
(range, 72 – 80 years). The incidence of osteoporotic
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549
fractures in this study was 5%, which was over three
times the incidence of hip fractures in men belonging
to the same age group. On the other hand, there was
no significant difference in the average number of
LHRH-a injections between patients with fractures
and those without fractures.
Only 50% of the patients who experienced bone
fractures were evaluated and treated at the hospital at
which they received their LHRH-a injections, and none
of the patients had their fractures documented in their
urology clinic notes. This implies that urologists are
unlikely to be aware of fractures experienced by their
patients receiving LHRH-a unless the patients are specifically questioned about them.
Knowing the incidence of osteoporosis and bone
fractures among men receiving LHRH-a for the treatment of prostate carcinoma is important in the evaluation of bone pain and bone fractures because it can
help physicians avoid making incorrect diagnoses of
metastasis to bone. It is a factor to consider when
deciding whether hormonal therapy or watchful waiting is more appropriate for the asymptomatic elderly
patient with prostate carcinoma.
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