An emerging pattern of subtrochanteric stress fractures:

A long-term complication of alendronate therapy?*

Author links open overlay panelErnest Beng KeeKwekaSeo KiatGohaJoyce Suang BeeKohaMeng AiPngbTet SenHowea
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https://doi.org/10.1016/j.injury.2007.08.036Get rights and content

Summary
Background

Subtrochanteric insufficiency fractures in post-menopausal patients have not been

commonly reported in the literature. A recent increase in the incidence of such
fractures occurring in patients while on alendronate therapy led us to conduct a
retrospective review of these patients in our institution.

Methods

Seventeen patients, with a mean age of 66 years, sustained low energy

subtrochanteric fractures within a 20-month period. These patients were
incidentally found to be on alendronate therapy for an average of 4.8 years. Clinical
data and history were reviewed and roentgenograms were evaluated by a single
investigator. All additional imaging and bone mineral density measurements
available were analysed.

Results

A characteristic fracture configuration suggestive of an insufficiency stress fracture

was identified on plain radiographs. This consisted of (a) cortical thickening in the
lateral side of the subtrochanteric region, (b) a transverse fracture, and (c) a medial
cortical spike. In addition, 9 (53%) patients had bilateral findings of stress reactions
or fractures, and 13 (76%) had symptoms of prodromal pain.

Conclusions

These insufficiency fractures could possibly have developed from the over
suppression of bone turnover from prolonged alendronate therapy, in keeping with
recently published evidence. This study further highlights the need for heightened
awareness of alendronate's potential adverse effects.
We analyzed cases of 320 athletes with bone scan- positive stress fractures (M = 145, F =
175) seen over 3.5 years and assessed the results of conservative management. The
most common bone injured was the tibia (49.1 %), followed by the tarsals (25.3%), metatar
sals (8.8%), femur (7.2%), fibula (6.6%), pelvis (1.6%), sesamoids (0.9%), and spine
(0.6%). Stress fractures were bilateral in 16.6% of cases. A significant age difference
among the sites was found, with femoral and tarsal stress fractures occurring in the oldest,
and fibular and tibial stress fractures in the youngest. Run ning was the most common
sport at the time of injury but there was no significant difference in weekly running mileage
and affected sites. A history of trauma was significantly more common in the tarsal bones.
The average time to diagnosis was 13.4 weeks (range, 1 to 78) and the average time to
recovery was 12.8 weeks (range, 2 to 96). Tarsal stress fractures took the longest time to
diagnose and recover. Varus alignment was found frequently, but there was no significant
difference among the fracture sites, and varus alignment did not affect time to diagnosis or
recovery. Radiographs were taken in 43.4% of cases at the time of presentation but were
abnormal in only 9.8%. A group of bone scan- positive stress fractures of the tibia, fibula,
and meta tarsals (N = 206) was compared to a group of clinically diagnosed stress
fractures of the same bone groups (N = 180), and no significant differences were found.
Patterns of stress fractures in athletes are different from those found in military recruits.
Using bone scan for diagnosis indicates that tarsal stress fractures are much more
common than previously realized. Time to diagnosis and recovery is site-dependent.
Technetium99 bone scan is the single most useful diagnostic aid. Conservative treatment of
stress fractures in athletes is satisfactory in the majority of cases.

Low Bone Density Is an Etiologic Factor for

Stress Fractures in Athletes
Kathryn H. Myburgh, PhD; Janice Hutchins, BSc Med; Abdul B. Fataar, MMed; Stephen F. Hough, MMed;
Timothy D. Noakes, MMed

Objective: To determine whether low bone density and other risk factors for osteoporosis are
associated with stress fractures in athletes.
Design: Case-control study.
Setting: Institutional sports injury clinic with primary and secondary care.
Participants: Twenty-five athletes (nineteen women) with scintigraphically confirmed stress
fractures matched for sex, age, weight, height, and exercise history with 25 control athletes
with no history of bone injury.
Measurements and Main Results: Bone mineral density measured by dual-energy x-ray
absorptiometry was significantly lower in athletes with fractures than in control athletes: In the
spine, bone mineral density was 1.01 ± 0.14 g/cm2 in athletes with fractures and 1.11 ± 0.13
g/cm2 in control athletes (P = 0.02). In the femoral neck, it was 0.84 ± 0.09 g/cm2 in athletes
with fractures and 0.90 ± 0.11 g/cm2 in control athletes (P = 0.005). It was also significantly
lower in the Ward triangle (P = 0.01) and the greater trochanter (P = 0.01). Eight athletes with
fractures and no control athletes had less than 90% of predicted age-related spine density (P =
0.01), and three athletes with fractures had bone mineral densities that were 2 SDs or more
below this predicted level. More athletes with fractures than control athletes had current
menstrual irregularity (amenorrhea or oligomenorrhea) (P < 0.005). Fewer athletes with
fractures were using oral contraceptives (P < 0.05). Seven-day diet records indicated similar
energy and nutrient intakes, except athletes with fractures had lower calcium intakes (697 ± 242
mg/d compared with 832 ± 309 mg/d; P = 0.02). Dairy product intake was lower in athletes
with fractures since leaving high school (P < 0.05). The incidence of a family history of
osteoporosis was similar in both groups.
Conclusions: In athletes with similar training habits, those with stress fractures are more likely
to have lower bone density, lower dietary calcium intake, current menstrual irregularity, and
lower oral contraceptive use.

Risk Factors for Recurrent Stress Fractures in Athletes

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Raija Korpelainen, MSc, Sakari Orava, MD, PhD, Jarmo Karpakka, MD, PhD, ...

First Published May 1, 2001 Research Article

https://doi.org/10.1177/03635465010290030901

Article information 

Abstract

Our aim was to identify factors predisposing athletes to multiple stress fractures,
with the emphasis on biomechanical factors. Our hypothesis was that certain
anatomic factors of the ankle are associated with risk of multiple stress fractures
of the lower extremities in athletes. Thirty-one athletes (19 men and 12 women)
with at least three separate stress fractures each, and a control group of 15
athletes without fractures completed a questionnaire focusing on putative risk
factors for stress fractures, such as nutrition, training history, and hormonal
history in women. Bone mineral density was measured by dual-energy x-ray
absorptiometry in the lumbar spine and proximal femur. Biomechanical features
such as foot structure, pronation and supination of the ankle, dorsiflexion of the
 ankle, forefoot varus and valgus, leg-length inequality, range of hip rotation,
simple and choice reaction times, and balance in standing were measured.
There was an average of 3.7 (range, 3 to 6) fractures in each athlete, totaling
114 fractures. The fracture site was the tibia or fibula in 70% of the fractures in
men and the foot and ankle in 50% of the fractures in women. Most of the
patients were runners (61%); the mean weekly running mileage was 117 km.
Biomechanical factors associated with multiple stress fractures were high
longitudinal arch of the foot, leg-length inequality, and excessive forefoot varus.
Nearly half of the female patients (40%) reported menstrual irregularities.
Runners with high weekly training mileage were found to be at risk of recurrent
stress fractures of the lower extremities

RANK/RANKL/OPG pathway: Genetic associations

with stress fracture period prevalence in elite athletes
Ian Varley Email the author Ian Varley
, 
David C. Hughes Email the author David C. Hughes
, 
Julie P. Greeves Email the author Julie P. Greeves
, 
Trent Stellingwerff Email the author Trent Stellingwerff
, 
Craig Ranson Email the author Craig Ranson
, 
William D. Fraser Email the author William D. Fraser
, 
Craig Sale Correspondence information about the author Craig Sale Email the author Craig
Sale
Edited by: Bente Langdahl

PlumX Metrics
DOI: https://doi.org/10.1016/j.bone.2014.10.004

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Article Info
 Abstract
 Full Text
 References
Highlights
 •Genetic associations with stress fracture injury were shown in elite athletes.

 •SNPs located near the RANK/RANKL/OPG signalling pathway are associated with stress fracture injury.

 •These data suggest a potential role for these SNPs in the regulation of bone strength and adaptation to

mechanical loading.

Abstract
Context
The RANK/RANKL/OPG signalling pathway is important in the regulation of bone turnover, with single nucleotide

polymorphisms (SNPs) in genes within this pathway associated with bone phenotypic adaptations.

Objective
To determine whether four SNPs associated with genes in the RANK/RANKL/OPG signalling pathway were associated

with stress fracture injury in elite athletes.

Design, participants, and methods

Radiologically confirmed stress fracture history was reported in 518 elite athletes, forming the Stress Fracture Elite

Athlete (SFEA) cohort. Data were analysed for the whole group and were sub-stratified into male and cases of multiple

stress fracture groups. Genotypes were determined using proprietary fluorescence-based competitive allele-specific PCR

assays.

Results
SNPs rs3018362 (RANK) and rs1021188 (RANKL) were associated with stress fracture injury (P < 0.05). 8.1% of the

stress fracture group and 2.8% of the non-stress fracture group were homozygote for the rare allele of rs1021188. Allele

frequency, heterozygotes and homozygotes for the rare allele of rs3018362 were associated with stress fracture period

prevalence (P < 0.05). Analysis of the male only group showed 8.2% of rs1021188 rare allele homozygotes had suffered a

stress fracture whilst 2.5% of the non-stress fracture group were homozygous. In cases of multiple stress fractures,

homozygotes for the rare allele of rs1021188 and individuals possessing at least one copy of the rare allele of rs4355801

(OPG) were shown to be associated with stress fracture injury (P < 0.05).

Conclusions
The data support an association between SNPs in the RANK/RANKL/OPG signalling pathway and the development of

stress fracture injury. The association of rs3018362 (RANK) and rs1021188 (RANKL) with stress fracture injury

susceptibility supports their role in the maintenance of bone health and offers potential targets for therapeutic

interventions.