Minocycline-induced black bone disease with synovial pigmentation in a patient undergoing revision anterior cruciate ligament surgery: A case report

IntroductionLong-term use of minocycline at high doses is associated with hyperpigmentation with multiple sites of involvement. While the cutaneous organs and the oral cavity are most commonly affected, bone discoloration is a rare entity.Case presentationA 19-year-old male patient with a history of acne vulgaris and intermittent treatment with high dose minocycline for three years presented with recurrent anterior cruciate ligament (ACL) tear. During arthroscopic surgery, however, hyperpigmentation of the femur and synovium was observed. Abnormal tissue was biopsied and confirmed through histopathological examination to contain melanin-related minocycline pigmentation. Revision surgery was re-scheduled with no intraoperative complications and excellent long-term clinical outcomes.Clinical discussionThere are several possible causes of hyperpigmentation, including hemosiderin deposition, infection, aseptic necrosis, demineralization, and metastatic disease. Black bone disease, caused by minocycline-induced hyperpigmentation, is rare. While the appearance is grossly abnormal in black bone disease, there has been no evidence suggesting that tissue integrity is compromised.ConclusionThis case confirms that hyperpigmentation does not affect bone integrity and that surgical procedures can be performed safely. Knowing the adverse effects of minocycline administration could reduce inappropriate postponement of surgical procedures, thereby saving time and resources.     

Minocycline-induced Periarticular Black Bones in Inflamed Joints Which Underwent Arthroplastic Reconstruction

Background

Minocycline-induced pigmentation of bone (black bone) is well described in tooth-bearing intra-oral bone, but is less known in periarticular bone in patients who have undergone total joint arthroplasty. On a retrospective basis, we investigated the short-term clinico-radiological results of total joint arthroplasties in which the patient developed minocycline-induced periarticular black bone.

Methods

We found 5 cases (0.08%), in 4 patients, of periarticular bone pigmentation revealed during total joint arthroplasties (2 hips, 2 knees, and 1 ankle) in our series of total joint surgeries (6,548 cases) over a 10-year time period in our 3 institutes. Their mean age was 56 years at surgery. All patients had received long-term minocycline treatment. Mean dosage and duration of minocycline was 160 mg/day and 2.2 years, respectively. Minocycline had been prescribed for reactive arthritis (one), rheumatoid arthritis (two) and late infection after total joint arthroplasty (two patients). Mean follow-up period was 3.4 years after the surgeries.

Results

All cases had black or brown pigmentation in the periarticular bones during the surgery. There was no pigmentation in the cartilage or soft tissues of the joints. The mean Japanese Orthopaedic Association (JOA) score or Japanese Society for Surgery of the Foot (JSSF) scale for rheumatoid arthritis foot and ankle joints at latest follow-up (case 1, 66; case 2, 87; case 3, 77; case 4, 77; case 5, 80) improved compared to those of pre-surgery (case 1, 47; case 2, 45; case 3, 55; case 4, 34; case 5, 55). No implant loosening was noted on radiographic examination during the follow-up period. No abnormal bone formation, bone necrosis, hemosiderin deposition, malignancy or metallic debris was found on histological examination.

Conclusions

No clinico-radiological symptoms of total joint arthroplasties showed in the patients with minocycline-induced periariticular black bone in the short-term. Systemic minocycline treatment has the potential to induce significant black pigmentation of many tissues. In particular, minocycline-induced pigmentation of periarticular bone may be accelerated by inflammation due to rheumatic or pyogenic arthritis. Surgeons should recognize the risk of bone pigmentation in inflamed joints due to the systemic treatment of minocycline and explore its influence on periarticular bone and total joint arthroplasty in the long-term.     

Black thyroid resulting from short-term doxycycline use: case report, review of the literature, and discussion of implications

BACKGROUND: Black thyroid pigmentation has been considered pathognomonic for chronic minocycline ingestion for more than 30 years. Although never conclusively linked to overt disease, evidence clearly exists that minocycline is a competitive inhibitor of thyroid peroxidase in metabolically active thyroid tissue. This offers a potential mechanism of pigment accumulation, which can account for the occasional finding of hypopigmentation in thyroid carcinomas. To our knowledge, an association with tetracycline derivatives other than minocycline has not been documented. METHODS: Herein is a case report of a patient with gross black thyroid tissue containing a hypopigmented papillary thyroid carcinoma. Twelve days before surgery, the patient was placed on doxycycline, a tetracycline derivative, to optimize an in vitro fertilization regimen. RESULTS: The gross specimen was diffusely black in color with a 1.5-cm hypopigmented focus of papillary thyroid cancer. Hematoxylin-eosin staining, as well as electron micrographs, was consistent with findings associated with minocycline ingestion. CONCLUSIONS: Black thyroid is rare and only previously associated with chronic minocycline ingestion. This report documents a black thyroid in a patient after short-term exposure to doxycycline. Pigment accumulation in normal tissue is thought to occur by inhibition of thyroid peroxidase. Minocycline is a competitive inhibitor of this enzyme in its native configuration. Thyroid carcinomas are known to have abnormal thyroid peroxidase, which could account for reports of hypopigmented tumors within grossly darkened thyroid tissue. Hypopigmented foci within such "black thyroid" deserve through pathologic examination.     

Black Bone Disease of the Foot: A Two-Year Follow-Up Case Study

“Black bone disease” is a term commonly used to describe a condition characterized by a blue/green/brown discoloration to the bone that often resembles infracted or necrotic bone. The chronic use of minocycline or tetracycline has been reported in previous data as a cause of this discoloration to the skin, bone, and teeth. However, the occurrence in bone is rare, with few studies reported regarding the discoloration. We previously presented a case of this condition encountered during cheilectomy of the first metatarsophalangeal joint in a patient who had had long-term usage of minocycline for adult acne. Two years after the initial case, the patient returned for correction of a hammertoe deformity on the second left proximal phalanx of the same foot. We present the findings and photographs from the second surgery. In addition, we have provided the relevant case data and figures from the first case for ease of comparison.     

Black Bone Disease of the Foot: A Case Study and Review of Literature Demonstrating a Correlation of Long-term Minocycline Therapy and Bone Hyperpigmentation

The chronic use of minocycline and tetracycline has been widely reported in published studies to cause discoloration of skin and teeth. There are very few case reports with regard to discoloration of bone. Those cases reported have been termed black bone disease or blue bone disease because the resulting change to the bone is a blue, green, or brown discoloration that resembles necrotic bone. Documentation of the occurrence in bone, however, is rare, with very few studies noted and only 1 other case that reported changes to the bones of the foot. The mechanism responsible for bone discoloration is not clearly understood. We present a case of this condition encountered during cheilectomy of the first metatarsophalangeal joint in a patient who had required long-term usage of minocycline for adult acne.     

Minocycline prevents the decrease in bone mineral density and trabecular bone in ovariectomized aged rats

In the current study, we examined the effects of minocycline, on the osteopenia of ovariectomized aged rats. Old female rats were randomly divided into five groups: sham, ovariectomized control and ovariectomized treated with minocycline, 17β-estradiol, or both agents. Bone samples were collected 8 wk after the treatment. Ovariectomy reduced bone mineral density of the whole femur and at the condylar, distal metaphyseal and head-neck-trochanter regions 10%–19% and the loss of bone density was prevented by treatment with minocycline or 17β-estradiol. Histomorphometric analysis of distal femur showed ovariectomy reduced the trabecular bone area, the trabecular bone number, trabecular bone thickness and increased the trabecular bone separation. The microanatomic structure of trabecular bone also showed that the number of nodes, node to node, cortical to node, node to free end was reduced by ovariectomy. Treatment with minocycline attenuated the effect of ovariectomy on trabecular bone in aged animals. In contrast, cortical bone was not affected by ovariectomy or minocycline treatment. The effect of minocycline on bone turnover was also examined. Minocycline increased osteoid surface, mineralizing surface, mineral apposition rate, bone formation rate and reduced eroded surface. We have therefore concluded that the modest increase in bone mineral density and the improvement in the trabecular bone status noted in minocycline treated ovariectomized aged rats is likely due to an increase in bone formation coupled with a decrease in bone resorption.     

Nodular hyperplasia, black thyroid, and chronic minocycline ingestion in a teenager.

An 18-year-old man with left-lobe thyroid hemiagenesis underwent isthmectomy for management of a nodule that failed to take up radioactive iodine during a nuclear scan. The resected tissue, which demonstrated nodular hyperplasia, and the remaining right lobe, were black. The association between deep staining and chronic minocycline ingestion was subsequently recognized. Twelve years later, the patient remained asymptomatic, suggesting that complete resection of tetracycline-stained thyroid tissue is unnecessary.     

Minocycline-induced black bone disease encountered during total knee arthroplasty

Finding discolored bone intraoperatively can be confusing and concerning to orthopedic surgeons. Multiple causes of pigmented bone exist, including ochronosis, metabolic bone diseases, metal deposits, sequestrum, metastatic disease, and minocycline use. Bone quality is an important consideration in intraoperative decision making with respect to components and fixation options in total joint arthroplasty. Abnormal bone encountered in routine arthroplasty can raise concerns over the integrity and healing potential of the bone when the etiology is uncertain.Minocycline is a drug routinely used for the treatment of acne, rosacea, and rheumatoid arthritis. Pigmentation is a commonly recognized adverse reaction associated with most of the drugs in the tetracycline family, affecting the skin, nails, teeth, oral mucosa, bones in the oral cavity, ocular structures, cartilage, thyroid, and other visceral structures.This article describes a case of pigmented bone secondary to minocycline use in a 55-year-old woman undergoing total knee arthroplasty. This entity has rarely been documented in the orthopedic literature; however, orthopedic surgeons should be aware of this side effect secondary to the widespread use of minocycline. Questions concerning the effect of minocycline on bone metabolism and structural integrity have yet to be fully answered, but an understanding and recognition of the entity will help guide surgeons with intraoperative decision making.     

Desmoplastic fibroma. A case report

A desmoplastic fibroma occurring in the distal forearm of a 14-year-old black boy is described and the historical background of the tumour together with an outline of the disease emphasizes the differential diagnosis between this condition and other fibrous lesions of soft tissue and bone. The clinical and radiological features as well as the treatment of desmoplastic fibroma are discussed. It is believed that this is the first such patient reported in Africa.     

米诺环素对骨癌痛-吗啡耐受大鼠脊髓CX3C趋化因子受体1mRNA表达的影响

目的 探讨米诺环素对骨癌痛-吗啡耐受大鼠脊髓CX3C趋化因子受体1(CX3CR1)mRNA表达的影响.方法 清洁级雌性SD大鼠,体重180～200 g,月龄3月,经L3,4间隙行鞘内置管,取鞘内置管成功的大鼠60只,采用随机数字表法,将大鼠随机分为4组:正常对照组(C组,n=10)、米诺环素对照组(M组,n=10)、骨癌痛-吗啡耐受组(BM组,n=20)和米诺环素治疗组(BM+M组,n=20).C组不作任何处理;BM组和BM+M组右侧胫骨上段骨髓腔注入Walker256细胞10 μl(400个/μl)制备骨癌痛模型,术后第10天开始鞘内注射吗啡20 μg/kg(100 μl),2次/d,连续7 d,制备骨癌痛-吗啡耐受模型,注射吗啡第8天分别经鞘内注射20μl生理盐水或米诺环素0.25 mg/kg(20 μl),1次/d,连续3 d;M组不行手术,于BM组注射吗啡第8天时鞘内注射米诺环素0.25 mg/kg,1次/d,连续3 d.于术前、术后3、6、9 d、鞘内注射吗啡4、7、10、12 d(T0～7)时测定机械缩足阈值(MWT)和机械缩足持续时间(MWD).C组和M组于T7时,BM组和BM+M组于T6,7时取L4～6脊髓节段,采用免疫组化法检测小胶质细胞标记物——OX-42表达,采用实时PCR法检测CX3CR1 mRNA表达水平.结果 与C组和M组比较,BM组T2,3.5～7时、BM+M组T2,3,5,时MWT降低,MWD延长,CX3CR1 mRNA和OX-42表达上调(P＜0.01).与BM组比较,BM+M组L6,7时MWT升高,MWD缩短,CX3CR1 mRNA和OX-42表达下调(P＜0.01).C组和M组上述指标差异无统计学意义(P＞0.05).结论 米诺环素可抑制骨癌痛-吗啡耐受大鼠脊髓CX3CR1 mRNA的表达,可能是其拮抗吗啡耐受的机制之一.

Abstract：

Objective To investigate the effect of minocycline on spinal CX3 C chemokine receptor 1(CX3 CR1)mRNA expression in morphine-tolerant rats with bone cancer pain.Methods Sixty female SD rats weighing 180-200 g in which intrathecal(IT)catheter was successfully placed at L3,4 interspace without complications were randomly divided into 4 groups:control group(group C,n=10);minocycline group(group M,n=10);bone cancer pain + morphine tolerance group(group BM,n=20)and bone cancer pain+morphine tolerance+ minocycline group(group BM+M,n=20).Bone cancer pain was induced by injection of breast cancer cells(Walker256)10μl(400/μl)into upper segment of bone marrow of right tibia.Morphine tolerance was induced by IT injection of morphine 20 μg/kg twice a day for 7 consecutive days starting from the 10th day after intratibia injection in BM and BM + M groups. Minocycline 0.25 mg/kg was injected IT once a day for 3 consecutive days in group M and after the model of bone cancer pain and morphine tolerance was established in group BM + M. Mechanical withdrawal threshold (MWT) and mechanical withdrawal duration (MWD) were determined before (T0, baseline) and at3, 6 and 9 days after operation (T1-3) and at 4, 7, 10 and 12 days after IT morphine injection was started (T4-7).The animals were sacrificed at T6 and T7 respectively in BM and BM + M groups and at T7 in C and M groups.The lumbar segment of the spinal cord (L4-6) was removed for determination of CX3 CR1 mRNA (by RT-PCR) and OX-42 expression (by immuno-histochemistry) .Results There was no significant difference in MWT and MWD at all time points between group C and group M. MWT was significantly decreased while MWD prolonged in morphine tolerant rats with cancer pain in group BM as compared with C and M groups. The hyperalgesia was significantly attenuated by IT minocycline in group BM + M. Spinal CX3 CR1 mRNA and OX-42 expression was significantly increased in group BM than in C and M groups. IT minocycline attenuated the increase in spinal CX3 CR, mRNA and OX-42 expression induced by bone cancer. Conclusion IT minocycline can inhibit spinal CX3CR1 mRNA expression, thereby antagonizing morphine tolerance in morphine-tolerant rats with bone cancer pain.     

Minocycline-induced lupus in adolescents: clinical implications for physical therapists

STUDY DESIGN: Resident's case problem. BACKGROUND: In the United States, minocycline is a frequently prescribed medication for the treatment of moderate to severe acne, a common condition in adolescents. The use of minocycline has been associated with severe adverse effects that frequently comprise a musculoskeletal component, including drug-induced lupus. Physical therapists have the responsibility to identify drug reactions that mimic musculoskeletal symptoms. The patient described herein was a 15-year-old adolescent boy who had taken minocycline for 14 days. He was initially treated by his primary physician on the 15th day of minocycline therapy for symptoms of fever, joint swelling, and a rash. The patient presented to a physical therapist on the 22nd day with complaints of severe myalgia, arthralgia, and severely limited mobility secondary to pain. The patient was referred to a pediatric rheumatologist because of the systemic nature and severity of the symptoms. DIAGNOSIS: The patient was subsequently diagnosed as having drug-induced lupus by a pediatric rheumatologist. The patient's myalgia and arthralgia subsided within 6 weeks, but his strength, coordination, and endurance did not reach their prior levels for 3 to 4 months. DISCUSSION: Physical therapists who include a comprehensive pharmacovigilance component in their patient examination may recognize musculoskeletal symptoms that arise from a nonmusculoskeletal origin. Minocycline is commonly prescribed in the United States as an antibiotic and for treatment of acne and rheumatoid arthritis. Therefore, physical therapists should screen for minocycline use when an adolescent patient or a patient with rheumatoid arthritis presents with diffuse musculoskeletal symptoms. An automated medication monitoring system would provide physical therapists with a means of accessing current information on medication use.     

Glucocorticoids are not always deleterious for bone

A 23‐year‐old man with the rare sclerosing bone disorder van Buchem disease presented with progressively worsening headaches that eventually became persistent and associated with papilledema. Increased intracranial pressure was diagnosed, and the patient had a ventriculoperitoneal drain inserted as well as simultaneously receiving treatment with prednisone. Before starting treatment, there was biochemical evidence for increased bone turnover and for steady increases in bone mineral density (BMD) at the spine and total hip despite the patient having reached his peak height of 197 cm at the age of 19 years. Treatment with prednisone for 2 years resulted in biochemical and histologic suppression of bone formation as well as of bone resorption and arrest of further bone accumulation. Our data suggest that glucocorticoids (GCs) may represent an attractive alternative to the high‐risk surgical approaches used in the management of patients with progressive sclerosing bone disorders. Our findings also suggest that whereas sclerostin may not be required for the action of GCs on bone formation, it may well be important for the action of GCs on bone resorption. The exact mechanism by which sclerostin may be involved in the regulation of bone resorption is as yet to be explored. © 2010 American Society for Bone and Mineral Research.     

Arthroplasty for ochronotic arthritis: no failure of 11 replacements in 3 patients followed 6-12 years

BACKGROUND: Alkaptonuria is a rare single-gene disorder characterized by black pigmentation of cartilage and other connective tissues. Premature degenerative arthritis affects the large joints in many of these of patients. Medical treatment is limited to a protein-restricted diet (phenylalanine and tyrosine) with surgery reserved for end-stage joint disease. As in other metabolic bone diseases, there are concerns about the quality and strength of affected bones and therefore the suitability and longevity of replacement arthroplasty. The histopathology and outcome of joint replacement for alkaptonuric arthritis is unknown and limited to sporadic case reports. PATIENTS AND RESULTS: We describe 11 joint replacements in 3 patients with alkaptonuric polyarthropathy, including shoulder and elbow replacements not previously reported. No prosthetic failures occurred in up to 12 years of follow-up. INTERPRETATION: Total joint replacement is an acceptable treatment for degenerative joint disease in alkaptonuric patients, with implant survival comparable to that found in patients with osteoarthritis.     

Petrous bone Langerhans cell histiocytosis treated with radiosurgery

Langerhans cell histiocytosis (LCH) is a rare disease that may show as a solitary or multifocal lesion of bone, soft tissue or viscera. Involvement of the temporal bone has been described in 15-61% of patients with LCH, usually in association with multisystemic involvement. We report the case of a 30-year-old man presenting with vertigo and fluctuating hearing loss caused by monosystemic LCH of the left petrous bone. The patient was treated with radiosurgery (covering dose 10 Gy at 85% isodose, maximum dose 11.76 Gy). Two years after treatment, no evidence of recurrent disease was found in the CT scan or MRI. We discuss the treatment of temporal bone LCH, traditionally based on surgery, low-dose radiation therapy and intralesional steroids. To our knowledge, this is the first reported case of LCH of the petrous bone successfully treated with radiosurgery. This approach may be interesting in cases of LCH located on nonaccessible areas of the temporal bone.     

Surgery for clavicular and humeral fractures in an osteopetrotic patient: a case report

Osteopetrosis is a rare disease characterised by generalised sclerosis of the bone. Surgical treatment for fractures in osteopetrotic bones is difficult due to their hardness. We report successful surgical treatment of humeral and clavicular fractures in a 30-year-old osteopetrotic patient with severe multiple trauma. Two years after surgery, the patient had a full range of movement at the shoulder and elbow, with good bone union and alignment.     

RANK Ligand: A Key Role in Cancer-Induced Bone Destruction?

ContextProstate cancer (PCa) is associated with a high risk of bone metastases; androgen-deprivation therapy is associated with significant bone loss. Bone metastases and bone loss are both linked to an increased risk of skeletal-related events, which in turn can reduce quality of life and life expectancy. Understanding of the pathophysiology underlying bone disease in patients with cancer is therefore important for the development of new treatments that can prevent or reverse it as well as for the improvement of patient outcomes.ObjectiveTo provide an overview of bone metabolism in the normal state and to describe recent developments in our understanding of the pathophysiology underlying bone disease induced by cancer as well as cancer treatment–induced bone loss (CTIBL).Evidence acquisitionThis article is based on a presentation at an Amgen-sponsored satellite symposium held at the European Association of Urology Congress in Stockholm, Sweden, in March 2009.Evidence synthesisSkeletal integrity is maintained by a balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. The proteins osteoprotegerin and RANK Ligand play key roles in preserving this balance by preventing and promoting osteoclast activity, respectively. In bone disease associated with cancer, however, the balance shifts in favour of RANK Ligand, resulting in a vicious cycle of osteoclast activation and tumour growth; the same may be true in CTIBL. Denosumab, a fully human monoclonal antibody that binds to and inhibits RANK Ligand, has been shown to block osteoclast-mediated bone resorption and is currently under development as a potential treatment for bone abnormalities associated with cancer and its treatment.ConclusionsInhibition of the RANK Ligand pathway by the human monoclonal antibody denosumab may provide a novel treatment option for bone disease in PCa. Further studies are underway.     

Mycobacterium haemophilum and mycobacterium xenopi associated infection in a renal transplant patient

The case is presented of a renal-transplant patient in Europe with a Mycobacterium haemophilum infection in association with M. xenopi infection. Clinical signs suggested the diagnosis of mycobacteriosis, which was confirmed by a skin biopsy. Despite antitubercular treatment which rapidly eliminated M. xenopi, the patient's condition did not improve until M. haemophilum was identified. Minimal inhibitory concentrations of various antimicrobial compounds showed a lack of efficacy of isoniazid, and rifampin had no clinical effect. The patient recovered only after careful surgical drainage of the lesions and the administration of minocycline. The pathogenesis of such mycobacterioses is discussed, with focus on the immunodepressive status which in our patient may have been partially induced by a cytomegalovirus reinfection.     

Long-term follow-up observations on treatment in Paget's disease of bone

The development of specific inhibitors of bone resorption has revolutionized the treatment of Paget's disease. The diphosphonates, the calcitonins, and mithramycin are capable of inducing marked suppression of disease activity for prolonged periods as judged by biochemical, kinetic, and histologic techniques. Whereas the effects of the calcitonins and mithramycin persist only for the duration of treatment, diphosphonate treatment consistently results in a reduction of disease activity for many months or even years after stopping treatment. The question arises whether the long-term control of the disease activity confers significant clinical advantages to the patient. Relief of bone pain, spinal neurologic syndromes, immobilization hypercalcemia, and high-output cardiac failure are related to the degree of biochemical control attained by treatment. New bone formed during treatment is lamellar and radiologic progression of disease is favorably modified. It is not yet known whether long-term treatment will decrease bone enlargement and deformity or reduce the risk of fracture.     

Paget's disease of the bone after treatment with Denosumab: a case report

Bone affection in Paget's disease is characterized by increased bone turnover localised at one or more sites of the skeleton. Bisphosphonates are the drugs of choice when treating the increased bone turnover in Paget's disease. However, in cases of decreased kidney function only less effective treatments that are available as bisphosphonates are contraindicated in these patients. We present a case of a male patient aged 86 years with GFR of 11 mL/min and Paget's disease successfully treated by Denosumab. The bone turnover and pain decreased upon treatment.     

Interstitial nephritis,hepatic failure,and systemic eosinophilia after minocycline treatment

This report describes a 15-year-old white boy who presented with fever, back pain, a disseminated exanthematous rash, renal failure, and hepatopathy 3 weeks after the initiation of oral minocycline therapy for facial acne. Marked peripheral and urine eosinophilia were noted. A bone marrow aspiration showed more than 50% eosinophils without any evidence of malignancy, and a simultaneous kidney biopsy showed acute interstitial nephritis (AIN). The patient's symptoms and laboratory findings improved after high-dose steroid therapy was initiated, worsened when it was withheld, and improved again after it was reinitiated in view of the biopsy findings. The patient recovered completely, and steroids were tapered to discontinuation over 3 months. Over a year later, the patient's peripheral blood mononuclear cells (PBMCs) were cultured for 2 weeks in the presence or absence of minocycline ex vivo, and minocycline was found to induce the emergence of CD4⁺ cells after 1 week in culture. In conclusion, this article shows for the first time several new aspects of minocycline-induced morbidity: renal and hepatic failure can occur together, and AIN and elevated blood eosinophil counts can be accompanied by marked bone marrow eosinophilia, suggesting a systemic allergic response as the underlying pathomechanism. Furthermore, the initial phase of such a response appears to involve CD4⁺ T cells detectable ex vivo. Lastly, high-dose treatment with corticosteroids appears to be beneficial in this setting. © 2001 by the National Kidney Foundation, Inc.