Minocycline-Induced Bone Discoloration: A Case Report

Abstract

Minocycline is a semisynthetic second-generation tetracycline derivative that is widely used as a broad-spectrum antibiotic and anti-inflammatory agent1. Long-term treatment with tetracycline and its related derivatives causes discoloration and hyperpigmentation of the skin, bone, teeth, sclerae, thyroid, and oral mucosa2-11. Minocycline shares the same basic ringed structure found in other tetracyclines, with the exception of a dimethylamino group substitution at C7 and a functional group absence at C6. These differences in chemical structure result in more lipophilic properties than in other members of the tetracycline family12. Whereas tetracycline is known to cause discoloration in bone by oxidation-induced color change after binding irreversibly to hydroxyapatite, which is later deposited at the mineralization front on unmineralized mature osteoid, minocycline poorly chelates calcium and is thought to cause bone discoloration by a less well-understood mechanism13. Findings, including minocycline’s ability to discolor fully formed mature teeth as well as the presence of iron with trace amounts of calcium in minocycline-induced dark pigment, give credence to this idea14-16.

Because of its lipophilic nature, minocycline is believed to achieve extensive tissue penetration, and in vitro protein-binding studies have also shown minocycline to bind collagen6,17. Once deposited, it is believed that minocycline is either degraded or lysosomally oxidized from its naturally yellow crystalline appearance to a black deposit3,18. Gross examination often reveals a bluish-gray or black discoloration of the bone and surrounding soft tissue, although these findings can be mutually exclusive1.

The incidence of minocycline-induced discoloration of bone is unknown since it is more commonly found as an incidental finding during routine surgical procedures. However, staining of adult dentition has been reported to occur in 3% to 6% of patients on long-term minocycline …

Full text

Minocycline-Induced Bone Discoloration
ACaseReport
Charles M. Chan, MD, David G. Hicks, MD, and Brian D. Giordano, MD
Investigation performed at the University of Rochester Medical Center, Rochester, New York
Minocycline is a semisynthetic second-generation tet-
racycline derivative that is widely used as a broad-
spectrum antibiotic and anti-inflammatory agent
1
.
Long-term treatment with tetracycline and its related deriva-
tives causes discoloration and hyperpigmentation of the skin,
bone, teeth, sclerae, thyroid, and oral mucosa
2-11
. Minocycline
shares the same basic ringed structure found in other tetracy-
clines, with the exception of a dimethylamino group substitution
at C7 and a functional group absence at C6. These differences in
chemical structure result in more lipophilic properties than in
other members of the tetracycline family
12
.Whereastetracycline
is known to cause discoloration in bone by oxidation-induced
color change after binding irreversibly to hydroxyapatite, which
is later deposited at the mineralization front on unmineralized
mature osteoid, minocycline poorly chelates calcium and is
thought to cause bone discoloration by a less well-understood
mechanism
13
. Findings, including minocycline’s ability to dis-
color fully formed mature teeth as well as the presence of iron
with trace amounts of calcium in minocycline-induced dark
pigment, give credence to this idea
14-16
.
Because of its lipophilic nature, minocycline is believed
to achieve extensive tissue penetration, and in vitro protein-
binding studies have also shown minocycline to bind colla-
gen
6,17
. Once deposited, it is believed that minocycline is either
degraded or lysosomally oxidized from its naturally yellow
crystalline appearance to a black deposit
3,18
. Gross examination
often reveals a bluish-gray or black discoloration of the bone
and surrounding soft tissue, although these findings can be
mutually exclusive
1
.
The incidence of minocycline-induced discoloration of
bone is unknown since it is more commonly found as an in-
cidental finding during routine surgical procedures. However,
staining of adult dentition has been reported to occur in 3% to
6% of patients on long-term minocycline therapy at dosages
greater than 100 mg daily
19
. The majority of reported cases
involving bone are confined to the craniofacial skeleton, al-
though cases in the shoulder, pelvic girdle, spine, hand, foot,
and femur have been reported
14,20-25
. In this study, we describe a
case of minocycline-induced discoloration of the acetabular
rim and adjacent femoral neck found on hip arthroscopy for
symptomatic femoroacetabular impingement (FAI). To our
knowledge, there have been no previous reports of minocycline-
induced bone discoloration identified by hip arthroscopy. The
patient was informed that data concerning the case would be
submitted for publication, and he provided consent.
Case Report
Aseventeen-year-old male athlete was referred to the sports
medicine service for evaluation of bilateral hip pain. The
symptoms had been present for two years and gradually had
become more pronounced, particularly on the right hip. The
patient could not recall a specific event resulting in injury to
either hip. Running and strenuous activities exacerbated the
pain. Medical, surgical, and family histories were otherwise un-
remarkable. The patient did not have any constitutional symp-
toms or dermatologic manifestations. There was no history of
Fig. 1
Arthroscopic view of the femoral neck after osteochondroplasty demon-
strated brownish-black discoloration of cancellous bone.
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his institution), from a third party in support of any
aspect of this work. One or more of the authors, or his institution, has had a financial relationship, in the thirty-six months prior to submission of this work,
with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had
any other relationships, or has engaged in any other activities, that could be perceived to influence or have the pote ntial to influence what is written in this
work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
1
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JBJS Case Connect 2012;2:e47 dhttp://dx.doi.org/10.2106/JBJS.CC.K.00153

other musculoskeletal, connective tissue, or metabolic disorders
with either the patient or the family.
Physical examination indicated tenderness with hip flex-
ion, adduction, and internal rotation, as well as asymmetric hip
flexion, abduction, and external rotation, suggesting both FAI
and internal impingement of the iliopsoas tendon. Reproducible
snapping of the iliopsoas tendon with provocative maneuver-
ing could also be self-elicited. Magnetic resonance imaging of
the right hip demonstrated mild signal changes at the transi-
tional zone of the chondral-labral junction and a concentrically
reduced hip joint. An ultrasound-guided iliopsoas bursal in-
jection provided partial symptomatic relief, while a subsequent
intra-articular anesthetic injection resulted in full relief for
twenty-four hours.
Additional treatment options were discussed, and the
patient elected to undergo arthroscopy of the right hip. Intra-
operatively, an acetabular labral tear with full-thickness articular
cartilage delamination, anterior acetabular rim prominence, and
asphericity of the femoral head-neck junction was found. In
addition, a brownish-black discoloration to all osseous sur-
faces, including the acetabulum and femoral head-neck junc-
tion, was noted. The discoloration extended to both cortical
and cancellous bone, which was evident by the discoloration
that was observed after acetabuloplasty and femoral head-neck
osteochondroplasty (Fig. 1). The surrounding soft-tissue struc-
tures remained unaffected. A Jamshidi needle (CareFusion, San
Diego, California) was introduced percutaneously into the joint
to perform a biopsy of the bone. Several cores were obtained
from the supra-acetabular region adjacent to the anteroinferior
iliac spine. The specimen was sent in formalin for histopatho-
logic analysis. Following biopsy, the acetabular labral tear was
repaired with two suture anchors, and a partial iliopsoas ten-
don release was performed. Postoperatively, the patient was
restricted to partial weight-bearing (20 lb), and he reported
improvement in symptoms at the outpatient office one week
following surgery.
Histopathological examination was performed without
decalcification and revealed normal bone tissue without evi-
dence of additional pathology. The specimens were viewed
under ultraviolet light, and they demonstrated multiple linear
bands of fluorescence, suggestive of minocycline staining (Fig. 2).
Additional questioning on postoperative office visits revealed
that the patient had been prescribed minocycline therapy for
acne over a six-month period leading up to surgery.
Discussion
It is rare to encounter discolored bone during surgical pro-
cedures, and it can be a concerning finding to the orthopaedic
surgeon because such discoloration is often considered to be
indicative of an underlying pathologic process. Minocycline-
induced bone discoloration should be considered as the pri-
mary differential diagnosis, particularly in patients who have
a recent history of minocycline use. Confirmatory testing can
be performed, with detection of fluorescence on exposure to
ultraviolet light. This property is highlighted in tetracycline
labeling of bone, which is a technique commonly used for
histomorphometric analyses of bone.
Tetracycline and its derivatives fluoresce on exposure to
ultraviolet light and can be used as supravital in vivo markers of
mineralization. When tetracycline is given to a patient and a
subsequent bone biopsy is processed in an undecalcified fashion,
bone surfaces will show distinct linear uptake in approximately
20% of bone surfaces when unstained sections are viewed
by standard fluorescence microscopy. If two doses, separated by
time, are given, a bone apposition rate can be calculated by di-
viding the distance between the two linear fluorescent labels by
the time between the dosage administrations
26
.Innormalbi-
opsies, both single and double distinct labels are observed; in
pathologic states, the labels have specific morphologic features
that reflect the condition of the mineralizing bone at the osteoid
surfaces
27
. Our patient was exposed to a single continuous dos-
age of minocycline, and therefore, fluorescence was detected
throughout the entire biopsied sample.
Whereas previous authors have noted a time-dependent
nature to the pigmentation effect, we report that such discol-
oration can occur with just twenty-four weeks of minocycline
usage. The potential long-term adverse effects of minocycline-
induced discoloration on human bone are unknown. Animal
models have shown a dose-related inhibition of osseous re-
sorption with minocycline treatment
28
. In ovariectomized rat
models simulating osteoporosis, minocycline treatment for eight
weeks produced moderate increases in bone mineral density,
with notable changes in the microanatomic structure of tra-
becular bone
29
. No effect was seen in cortical bone on histo-
logical examination.
To the best of our knowledge, there have been no re-
ports attributing structural compromise in adult human bone
to long-term minocycline exposure. Middleton et al. reported
a case of minocycline-induced bone discoloration in a fifty-
seven-year-old woman with symptomatic bilateral hallux valgus
Fig. 2
Histopathological examination of biopsied bone examined under ultravi-
olet light demonstrated multiple linear bands of autofluorescence (10·
magnification).
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VOLUME 2dNUMBER 3dSEPTEMBER 12, 2012
MINOCYCLINE-INDUCED BONE DISCOLORATION

who underwent correction surgery
22
. The patient had previ-
ously been exposed to minocycline for a four-year period. At
six weeks postsurgery, the patient was weight-bearing com-
fortably, and she subsequently developed radiographic union
of the osteotomy sites. McCleskey and Littleton reported a
case of an eighty-one-year-old man who underwent total knee
arthroplasty for osteoarthritis
23
. Intraoperatively, it was observed
that the patient had minocycline-induced discoloration of both
the femur and the tibia. One year after surgery, the patient had
radiographic evidence of secure fixation and no change in
alignment of the arthroplasty components. Similar findings have
been reported in minocycline-induced discolored bone in the
acromion,clavicle, metacarpal, proximal part of the femur, distal
part of the femur, iliac crest, and vertebrae
14,20,21,24,25
. Our report
also indicates that surgery can be safely performed at sites where
minocycline-induced bone discoloration is found.
Historically, minocycline has been a commonly used
wide-spectrum antibiotic for a variety of infections. With a
greater number of people undergoing orthopaedic proce-
dures, incidental findings of minocycline-induced bone dis-
coloration will likely occur. We encourage surgeons to become
familiar with this benign process because such knowledge can
facilitate appropriate timely diagnosis, limit unnecessary lab-
oratory testing, and prevent undue stress for the patient and the
treating physician. n
Charles M. Chan, MD
David G. Hicks, MD
Brian D. Giordano, MD
Department of Orthopaedics and Rehabilitation (C.M.C. and B.D.G.),
Department of Pathology and Laboratory Medicine (D.G.H.),
University of Rochester Medical Center, 601 Elmwood Avenue,
Box 665, Rochester, NY 14642.
E-mail address for C.M. Chan: Charles_Chan@URMC.Rochester.edu.
E-mail address for D.G. Hicks: David_Hicks@URMC.Rochester.edu.
E-mail address for B.D. Giordano:
Brian_Giordano@URMC.Rochester.edu
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