Case Connector | Minocycline-Induced Bone Discoloration: A Case Report

Case Reports | September 12, 2012

Minocycline-Induced Bone Discoloration: A Case Report

Charles M. Chan, MD¹; David G. Hicks, MD¹; Brian D. Giordano, MD¹

¹ 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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Investigation performed at the University of Rochester Medical Center, Rochester, New York

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 potential 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.

JBJS Case Connector, 2012 Sep 12;2(3):e47 1-3. doi: 10.2106/JBJS.CC.K.00153

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Extract

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 mucosa^2-11. 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 idea^14-16.

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Introduction

Introduction | Case Report | Discussion

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 collagen^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 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 therapy at dosages greater than 100 mg daily¹⁹. The majority of reported cases involving bone are confined to the craniofacial skeleton, although 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

Introduction | Case Report | Discussion

A seventeen-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 unremarkable. The patient did not have any constitutional symptoms or dermatologic manifestations. There was no history of other musculoskeletal, connective tissue, or metabolic disorders with either the patient or the family.

Physical examination indicated tenderness with hip flexion, 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 maneuvering could also be self-elicited. Magnetic resonance imaging of the right hip demonstrated mild signal changes at the transitional zone of the chondral-labral junction and a concentrically reduced hip joint. An ultrasound-guided iliopsoas bursal injection 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. Intraoperatively, 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 surfaces, including the acetabulum and femoral head-neck junction, 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 structures 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 histopathologic analysis. Following biopsy, the acetabular labral tear was repaired with two suture anchors, and a partial iliopsoas tendon 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.

Fig. 1

Arthroscopic view of the femoral neck after osteochondroplasty demonstrated brownish-black discoloration of cancellous bone.

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Histopathological examination was performed without decalcification and revealed normal bone tissue without evidence 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.

Fig. 2

Histopathological examination of biopsied bone examined under ultraviolet light demonstrated multiple linear bands of autofluorescence (10× magnification).

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Discussion

Introduction | Case Report | Discussion

It is rare to encounter discolored bone during surgical procedures, 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 primary 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 dividing the distance between the two linear fluorescent labels by the time between the dosage administrations²⁶. In normal biopsies, 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 surfaces²⁷. Our patient was exposed to a single continuous dosage 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 discoloration 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 resorption with minocycline treatment²⁸. 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 trabecular bone²⁹. No effect was seen in cortical bone on histological examination.

To the best of our knowledge, there have been no reports 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 who underwent correction surgery²². The patient had previously been exposed to minocycline for a four-year period. At six weeks postsurgery, the patient was weight-bearing comfortably, 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 osteoarthritis²³. 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 procedures, incidental findings of minocycline-induced bone discoloration will likely occur. We encourage surgeons to become familiar with this benign process because such knowledge can facilitate appropriate timely diagnosis, limit unnecessary laboratory testing, and prevent undue stress for the patient and the treating physician.

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Topics

acetabulum ; acne vulgaris ; minocycline ; hip pain ; biopsy of bone ; hip arthroscopy ; abnormal color ; acetabular labrum tear ; femoral acetabular impingement ; osteochondroplasty

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Charles M. Chan, David G. Hicks, Brian D. Giordano; Minocycline-Induced Bone DiscolorationA Case Report. JBJS Case Connector. 2012 Sep;2(3):e47 1-3.

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