Two cases demonstrating thalidomide's efficacy in refractory lupus nephritis.

Renal involvement in systemic lupus erythematosus (SLE) is common and has been associated with an increased risk of mortality [1]. Early diagnosis is imperative to control proteinuria and prevent the progression to end-stage renal disease. Standard induction therapies include cyclophosphamide (CYC) and mycophenolate mofetil (MMF); however, it has been estimated that approximately 30% of patients are refractory to these standard treatments after 1 year [2]. We present two cases of patients diagnosed with lupus nephritis (LN) who demonstrated persistent proteinuria while on standard treatments that markedly improved after addition of thalidomide (THD). A literature review was performed indicating that THD use with prednisolone (PL) was more efficacious than MMF with PL in resolving lupus nephritis in a mouse model. Thalidomide, which was well tolerated, was associated with a reduction in the protein-to-creatinine ratio with sustained results in both of our patient cases. These cases suggest more clinical data is needed to explore the potential utility of thalidomide in the treatment of LN.

Recent advances and future directions in understanding and treating Chlamydia-induced reactive arthritis.

INTRODUCTION: Reactive arthritis (ReA) is an inflammatory disease that can follow gastrointestinal or genitourinary infections. The primary etiologic agent for post-venereal ReA is the bacterium Chlamydia trachomatis; its relative, C pneumoniae, has also been implicated in disease induction although to a lesser degree. Studies have indicated that the arthritis is elicited by chlamydiae infecting synovial tissue in an unusual biologic state designated persistence. We review clinical aspects, host-pathogen interactions, and treatments for the disease. Areas covered: We briefly discuss both the historic and,more extensively, the current medical literature describing ReA, and we provide a discussion of the biology of the chlamydiae as it relates to elicitation of the disease. A summary of clinical aspects of Chlamydia-induced ReA is included to give context for approaches to treatment of the arthritis. Expert commentary: Basic research into the biology and host-pathogen interactions characteristic of C trachomatis has provided a wealth of information that underlies our current understanding of the pathogenic processes occurring in the ReA synovium. Importantly, a promising approach to cure of the disease is at hand. However, both basic and clinical research into Chlamydia-induced ReA has lagged over the last 5 years, including required studies relating to cure of the disease.

Inactivation of DAP12 in PMN inhibits TREM1-mediated activation in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulated and chronic systemic inflammatory responses that affect the synovium, bone, and cartilage causing damage to extra-articular tissue. Innate immunity is the first line of defense against invading pathogens and assists in the initiation of adaptive immune responses. Polymorphonuclear cells (PMNs), which include neutrophils, are the largest population of white blood cells in peripheral blood and functionally produce their inflammatory effect through phagocytosis, cytokine production and natural killer-like cytotoxic activity. TREM1 (triggering receptor expressed by myeloid cells) is an inflammatory receptor in PMNs that signals through the use of the intracellular activating adaptor DAP12 to induce downstream signaling. After TREM crosslinking, DAP12's tyrosines in its ITAM motif get phosphorylated inducing the recruitment of Syk tyrosine kinases and eventual activation of PI3 kinases and ERK signaling pathways. While both TREM1 and DAP12 have been shown to be important activators of RA pathogenesis, their activity in PMNs or the importance of DAP12 as a possible therapeutic target have not been shown. Here we corroborate, using primary RA specimens, that isolated PMNs have an increased proportion of both TREM1 and DAP12 compared to normal healthy control isolated PMNs both at the protein and gene expression levels. This increased expression is highly functional with increased activation of ERK and MAPKs, secretion of IL-8 and RANTES and cytotoxicity of target cells. Importantly, based on our hypothesis of an imbalance of activating and inhibitory signaling in the pathogenesis of RA we demonstrate that inhibition of the DAP12 signaling pathway inactivates these important inflammatory cells.

An MRI assessment of chronic synovial-based inflammation in gout and its correlation with serum urate levels.

It is unclear when the synovial-based inflammatory process of gout begins. The aim of this study was to determine the percentage of patients with inter-critical gout who have chronic synovial-based inflammation as evidenced by synovial pannus on a contrast-enhanced magnetic resonance imaging (MRI) of their most involved joint and determine if the presence and/or severity correlates with their serum urate levels. All patients received a 3 T MRI of their index joint, serum urate level, CRP, and creatinine. The primary endpoint was to determine the prevalence of synovial pannus and the correlation of serum urate levels with the presence and/or severity of the synovial pannus on that same joint. MRI erosions, tophi, swelling, effusion, and osteitis were also documented. Seventy-two of 74 subjects (90% men) completed the protocol. Fifty-three of 72 (74%) index joints were the first metatarsophalangeal joint. Thirty-nine (54.2%) of the patients were on urate-lowering therapy; 15 (20.8%) and 7 (9.7%) were taking colchicine or a NSAID daily, respectively. Of the 72 subjects, 63 (87.5%) had synovial pannus on their MRI with good inter-reader agreement between the two radiologists. The mean serum urate level was 7.93 mg/dL. There was no correlation with the presence (p = 0.33) or severity (p = 0.34) of synovial pannus and serum urate levels. There was also no correlation with the presence or severity of synovial pannus and the secondary endpoints. The majority of patients with inter-critical gout have evidence of chronic synovial-based inflammation. However, the presence and severity of this inflammation do not appear to correlate with serum urate levels.

Attack rate of Chlamydia-induced reactive arthritis and effect of the CCR5-Delta-32 mutation: a prospective analysis.

OBJECTIVE: Factors that predispose patients to Chlamydia-induced reactive arthritis (CiReA) are poorly defined. Data indirectly suggest chemokine receptor-5 (CCR5)-delta-32 mutation might play a role in CiReA. We investigated the attack rate of CiReA and we hypothesized that the CCR5-delta-32 allele may modulate disease susceptibility. METHODS: Patients who tested positive for Chlamydia trachomatis after either (1) symptoms of an acute venereal disease or (2) sexual contact with an individual known to be positive for the same organism were followed in a prospective fashion. All patients were contacted at Week 6 after their acute infection and queried for symptoms of CiReA. Patients who had new-onset symptoms suggestive of CiReA were followed at Weeks 12, 26, and 52. All subjects were tested for CCR5-delta-32 mutation. RESULTS: A total of 365 study participants were enrolled, with average age 24.4 years, 201 men (55%) and 164 women (45%). We followed up with 149 patients (41%) at Week 6. Twelve of 149 participants (8.1%) had symptoms suggestive of CiReA at Week 6. None of these 12 patients was positive for the CCR5-delta-32 mutation. Of the 12 patients that had symptoms at Week 6, we were able to follow up with 7 through Week 52. All 7 had complete resolution of their symptoms by Week 26. Overall, 25/365 (6.8%) subjects were positive for the CCR5-delta-32 mutation. CONCLUSION: The attack rate of CiReA in our study was higher than previously reported, but the CCR5-delta-32 mutation does not seem to play a role in CiReA disease susceptibility.

Chlamydia trachomatis is present and metabolically active during the remitting phase in synovial tissues from patients with chronic Chlamydia-induced reactive arthritis.

BACKGROUND: Patients with chronic Chlamydia-induced reactive arthritis (ReA) often show a remitting-relapsing disease phenotype. Some information regarding bacterial and host responses to one another during active disease is available but no information for quiescence. This article presents the first molecular genetic insight into the behavior of bacterium and host during remitting ReA. METHODS: Synovial biopsies were procured from the knees of 4 patients with quiescent ReA by the Parker-Pearson technique. Nucleic acids prepared from them were analyzed by real-time polymerase chain reaction (PCR) and reverse transcription-PCR, and results were compared with data averaged from the knee synovial tissue samples of 10 patients with active ReA. RESULTS: Real-time PCR indicated that bacterial load in remitting samples was approximately 20% of that in active disease samples. Transcripts from the p60-encoding gene were equal to or higher than those seen in active disease. Messenger RNAs (mRNAs) from the paralog p60-encoding genes were equal to or lower than those of active disease. Host mRNAs encoding interleukin-10, tumor necrosis factor-α and interferon-γ were 4-fold lower than those in active disease samples, whereas monocyte chemotactic protein 1 and regulated upon activation, normal t-cell expressed, and secreted mRNA levels were equal to or higher. CONCLUSIONS: Bacterial load in synovial tissue of patients with remitting disease is lower than that of active disease, but mRNAs encoding proinflammatory proteins are equal to or higher than those of active disease. Transcription in the host is attenuated for cytokines and chemokines. These initial results demonstrate that organism is present and metabolically active in synovium during the remitting phase of chronic Chlamydia-induced ReA and that the genetic events characterizing quiescence are complex.

Rilonacept in the treatment of acute gouty arthritis: a randomized, controlled clinical trial using indomethacin as the active comparator.

INTRODUCTION: In phase-3 clinical trials, the interleukin (IL-1) blocker, rilonacept (IL-1 Trap), demonstrated efficacy for gout flare prevention during initiation of urate-lowering therapy. This trial evaluated rilonacept added to a standard-of-care, indomethacin, for treatment of acute gout flares. METHODS: Adults, aged 18-70 years, with gout presenting within 48 hours of flare onset and having at least moderate pain as well as swelling and tenderness in the index joint were randomized to subcutaneous (SC) rilonacept 320 mg at baseline plus oral indomethacin 50 mg TID for 3 days followed by 25 mg TID for up to 9 days (n = 74); SC placebo at baseline plus oral indomethacin as above (n=76); or SC rilonacept 320 mg at baseline plus oral placebo (n=75). The primary efficacy endpoint was change in pain in the index joint (patient-reported using a Likert scale (0=none; 4=extreme)) from baseline to the average of values at 24, 48 and 72 hours (composite time point) for rilonacept plus indomethacin versus indomethacin alone. Comparison of rilonacept monotherapy with indomethacin monotherapy was dependent on demonstration of significance for the primary endpoint. Safety evaluation included clinical laboratory and adverse event (AE) assessments. RESULTS: Patient characteristics were comparable among the groups; the population was predominantly male (94.1%), white (75.7%), with mean±SD age of 50.3±10.6 years. All treatment groups reported within-group pain reductions from baseline (P<0.0001). Although primary endpoint pain reduction was greater with rilonacept plus indomethacin (-1.55±0.92) relative to indomethacin alone (-1.40±0.96), the difference was not statistically significant (P=0.33), so formal comparison between monotherapy groups was not performed. Pain reduction over the 72-hour period with rilonacept alone (-0.69±0.97) was less than that in the other groups, but pain reduction was similar among groups at 72 hours. Treatment with rilonacept was well-tolerated with no reported serious AEs related to rilonacept. Across all groups, the most frequent AEs were headache and dizziness. CONCLUSIONS: Although generally well-tolerated, rilonacept in combination with indomethacin and rilonacept alone did not provide additional pain relief over 72 hours relative to indomethacin alone in patients with acute gout flare. TRIAL REGISTRATION: ClinicalTrials.gov registration number NCT00855920.

Chlamydia and chronic arthritis.

Certain bacterial infections have been demonstrated to be causative of reactive arthritis. The most common bacterial trigger of reactive arthritis is Chlamydia trachomatis. Chlamydia pneumoniae is another known cause, albeit far less frequently. Although Chlamydia-induced reactive arthritis will often spontaneously remit, approximately 30% of patients will develop a chronic course. Modern medicine has provided rather remarkable advances in our understanding of the chlamydiae, as these organisms relate to chronic arthritis and the delicate balance between host and pathogen. C. trachomatis and C. pneumoniae both have a remarkable ability to disseminate from the initial site of infection and establish persistently viable organisms in distant organ sites, namely the synovial tissue. How these persistent chlamydiae contribute to disease maintenance remains to be fully established, but recent data demonstrating that long-term combination antimicrobial treatment can not only ameliorate the symptoms but eradicate the persistent infection suggest that these chronically infecting chlamydiae are indeed a driving force behind the chronic inflammation. We are beginning to learn that this all appears possible even after an asymptomatic initial chlamydial infection. Both C. trachomatis and C. pneumoniae are a clear cause of chronic arthritis in the setting of reactive arthritis; the possibility remains that these same organisms are culpable in other forms of chronic arthritis as well.

The molecular basis for disease phenotype in chronic Chlamydia-induced arthritis.

Genital Chlamydia trachomatis infections can elicit an inflammatory arthritis in some individuals, and recent surprising studies have demonstrated that only ocular (trachoma) strains, not genital strains, of the organism are present in the synovial tissues of patients with the disease. This observation suggests an explanation for the small proportion of genitally-infected patients who develop Chlamydia-induced arthritis. Other recent studies have begun to identify the specific chlamydial gene products that elicit the synovial inflammatory response during both active and quiescent disease, although much more study will be required to complete the understanding of that complex process of host-pathogen interaction. Several newly developed experimental methods and approaches for study of the process will enable identification of new therapeutic targets, and possibly strategies for prevention of the disease altogether.

Chlamydia-induced reactive arthritis: hidden in plain sight?

Reactive arthritis belongs to the group of arthritidies known as the spondyloarthritides. There are two main types of reactive arthritis: post-venereal and post-enteric. Chlamydia trachomatis is felt to be the most common cause of reactive arthritis, in general. Until recently, even the terminology for the condition itself was unclear as multiple eponyms and names have been associated with reactive arthritis. In recent years, a great deal has been learnt about the epidemiology, pathophysiology and treatment of reactive arthritis and Chlamydia-induced reactive arthritis, specifically. Prospective epidemiologic data suggest that Chlamydia-induced reactive arthritis is underdiagnosed. Other truths being actively revealed include data suggesting that the pathogen itself (i.e., Chlamydia) might play an equally important role, or perhaps even more important, than the host with disease susceptibility; asymptomatic chlamydial infections might be a common cause of ReA and the two variants of reactive arthritis might respond differently to treatment in spite of the congruent clinical presentation. However, much about this syndrome remains shrouded in mystery. Data covered in this review suggest that Chlamydia-induced reactive arthritis might be a common condition that clinicians fail to recognise. An emphasis is placed on disease awareness since viable treatment options are emerging.

Combination antibiotics for the treatment of Chlamydia-induced reactive arthritis: is a cure in sight?

The inflammatory arthritis that develops in some patients subsequent to urogenital infection by the obligate intracellular bacterial pathogen Chlamydia trachomatis, and that induced subsequent to pulmonary infection with C. pneumoniae, both have proved difficult to treat in either their acute or chronic forms. Over the last two decades, molecular genetic and other studies of these pathogens have provided a good deal of information regarding their metabolic and genetic structures, as well as the detailed means by which they interact with their host cells. In turn, these insights have provided for the first time a window into the bases for treatment failures for the inflammatory arthritis. In this article we discuss the biological bases for those treatment failures, provide suggestions as to research directions that should allow improvement in treatment modalities, and speculate on how treatment regimens that currently show promise might be significantly improved over the near future using nanotechological means.

Virtual rheumatology: using simulators and a formal workshop to teach medical students, internal medicine residents, and rheumatology subspecialty residents arthrocentesis.

BACKGROUND: Arthrocentesis is an important skill for medical practitioners at all levels of training. Previous studies have indicated a low comfort level and performance of arthrocentesis among primary care physicians that could be improved with hands-on training. OBJECTIVES: The objective of this study was to improve comfort with knee and shoulder arthrocentesis at all levels of medical training, including medical students, internal medicine residents, and rheumatology subspecialty residents, and in arthrocentesis of the elbow, wrist, and ankle for advanced subspecialty residents in rheumatology through the use of a formal workshop using simulators. METHODS: Fourth-year medical students and internal medicine residents were recruited from the University of South Florida. The rheumatology advanced subspecialty residents were participants from University of South Florida and from the American College of Rheumatology national meetings in 2008 and 2009. A 1-hour PowerPoint lecture followed by a hands-on practice session using Sawbones models (shoulder and knee for all groups, and elbow, wrist, and ankle additionally for the advanced subspecialty residents). A preworkshop self-assessment survey allowed the participant to rate his/her comfort level with arthrocentesis on a scale of 1 to 5. A survey with identical questions was completed immediately after the workshop. A follow-up survey was distributed by e-mail 3 to 6 months after the workshop. RESULTS: One hundred forty-one medical students, 75 internal medicine residents, and 39 rheumatology subspecialty residents participated from January 2008 until January 2010. Mean comfort level in knee and shoulder arthrocentesis improved from preworkshop comfort level for all joints and among all participants. In addition, rheumatology subspecialty resident mean comfort level improved for ankle from 2.37 to 3.65, elbow from 2.56 to 3.80, and wrist from 2.31 to 3.77 (P < 0.0001). CONCLUSIONS: Our study involved a very large number of participants encompassing different levels of training and is the largest number of advanced subspecialty rheumatology residents studied with regard to joint injection training. We have confirmed that a formal joint injection workshop using simulators is an effective method of improving comfort level in arthrocentesis among participants from all levels of medical training. Future studies should evaluate the effect of such training on actual clinical use and competence.

Sarcoidosis mimicking lymphoma on FDG-PET imaging.

Sarcoidosis is an inflammatory, systemic disease characterized by noncaseating granulomas. We describe a case of a 52-year-old female who presented with fevers, chills, night sweats, and weight loss of four months' duration. Lymphoma was suspected, and results of advanced imaging procedures were also consistent with lymphoma. However, mediastinal lymph-node biopsy, bone-marrow aspiration, and biopsy revealed noncaseating granulomas. She was diagnosed with sarcoidosis and had a positive therapeutic response to drug therapy. This case study illustrates that sarcoidosis can be a pitfall in 18-F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging, which may lead to false-positive diagnosis of malignancy. PET-positive lesions do not always indicate malignancy, and histological confirmation of the lesions with biopsy should always be performed.

Bacterial agents in spondyloarthritis: a destiny from diversity?

The spondyloarthritides (SpAs) are a group of diseases that share clinical, radiographic and laboratory features; these arthritides also display a tendency for family aggregation. Given the intimate relationship that these types of arthritis share, it suggests that the SpAs might share a common aetiology. Of all the SpAs, the role of bacteria is most clearly defined in reactive arthritis. Tremendous recent insights into the pathophysiology of reactive arthritis have been made, demonstrating that the causative bacteria play a much more complex role than previously thought. The bacteria that are proven to cause reactive arthritis, one of the five types of SpA, will be reviewed and their role in the pathophysiology of reactive arthritis will be examined. The speculative data suggesting links between various other bacteria and the other types of SpAs will be critically analysed. Although these data are not definitive, when viewed using the paradigm that the SpAs might actually represent a common end point from several diverse starting points, they are provocative, suggesting that bacteria might, indeed, be aetiological for the entire group of SpAs.

Functional CCR5 receptor protects patients with arthritis from high synovial burden of infecting Chlamydia trachomatis.

INTRODUCTION: The CCR5 chemokine receptor occurs in a wild-type (wt) and a nonfunctional deleted form (Δ32). Reports suggested that Chlamydia-induced reproductive tract pathology is attenuated in women bearing Δ32. The authors asked whether the mutation affects synovial prevalence and burden of Chlamydia trachomatis. METHODS: Polymerase chain reaction (PCR) defined CCR5 genotype in synovial tissue DNA from 218 individuals: 21 controls, 110 with reactive arthritis (ReA), 83 with undifferentiated oligoarthritis (UO), 4 with osteoarthritis (OA). Disease durations were 0.5 to 21 years. Additional PCR assays defined the presence of C trachomatis DNA. Bacterial load was assessed by real-time PCR in selected samples. RESULTS: Five controls were wt/Δ32, 16 were wt/wt; 2 of 21 controls (both wt/wt) were PCR positive for C trachomatis. Eighty-five (44%) patients with arthritis were PCR positive for C trachomatis (69 ReA and 16 UO). For patients with ReA, 14 (13%) had wt/Δ32, 10 (71%) of whom were PCR positive. Nineteen patients with UO (23%) were wt/Δ32, with 1 (1%) PCR positive. No differences existed for gender or other factors. One patient with OA had wt/Δ32. In ReA and UO samples, wt/Δ32 heterozygotes had a 5- to 10-fold higher bacterial burden than did wt/wt patients (P = 0.03), regardless of diagnosis. CONCLUSION: These results indicate that the wt/wt genotype is associated with attenuated synovial bacterial load compared with loads in wt/Δ32 patients. Although no alleles other than Δ32 were assessed, our data suggest that this allele provides little/no protection from ReA in patients infected with Chlamydia- but it may provide some protection in patients with UO. The basis of this possible differential effect of CCR5 genotype is under study.

The evolving story of Chlamydia-induced reactive arthritis.

PURPOSE OF REVIEW: There have been tremendous recent insights into our understanding of the epidemiology, pathophysiology, and treatment of Chlamydia-induced reactive arthritis (CiReA). Some of these advances embellish our previous understanding of CiReA, whereas others suggest that a change in the paradigm is required. RECENT FINDINGS: Epidemiological data suggest that we are underdiagnosing CiReA and emerging data suggest that asymptomatic chlamydial infections might be a common cause. Although the clinical manifestations of CiReA are indistinct from the postenteric variety, there appear to be important differences in the pathophysiology of these clinically congruent entities. The hallmark difference pertains to synovial-based viable chlamydial organisms, although in an aberrant state, known as chlamydial persistence. Specific chlamydial serovars appear to be causative of CiReA. Emerging potential therapies include antitumor necrosis factor treatment and combination antibiotics. However, the data with the former are particularly scant and there are theoretical concerns with their use in this setting. Recent data regarding prolonged combination antibiotics are particularly encouraging. SUMMARY: A history of a chlamydial infection may prove to be a poor guide for the diagnosis of CiReA and prolonged combined antimicrobial therapy could be an effective treatment strategy.

The pathogenic role of Chlamydia in spondyloarthritis.

PURPOSE OF REVIEW: Topics relating to the spondyloarthropathies have been reviewed recently, but the detailed roles of Chlamydia trachomatis and C. pneumoniae in induction of spondyloarthritis have not been discussed. This review focuses on new information regarding how these pathogens elicit joint disease, with emphasis on C. trachomatis in its role in Chlamydia-induced reactive arthritis. RECENT FINDINGS: Molecular methods continue to provide insights into the molecular genetic and cell biologic basis for chlamydial pathogenesis. For chlamydiae, residence in the synovium in patients with acute or chronic Chlamydia-induced arthritis involves organisms in an unusual infection state designated persistence. The profiles of overall metabolism and gene expression characteristic of chlamydial persistence have been assessed and unusual aspects noted, including transcriptional attenuation of one hsp60 paralog and upregulation of expression for another. Strain determinations have demonstrated that genital serotypes of C. trachomatis are not present in the joint; rather, inflammation at that site is elicited by ocular serotypes of the organism. This indicates that much remains to be learned concerning the biology of chlamydial dissemination from the urogenital tract. Analyses of undifferentiated spondyloarthritis continue to suggest that chlamydiae, and perhaps other pathogens function in the etiology of the disease. Progress has been made in developing effective treatment for patients with Chlamydia-induced arthritis. SUMMARY: Molecular genetic analyses regarding the role of chlamydiae in induction of inflammatory arthritis have increased our detailed understanding of the pathogenic mechanisms utilized by these organisms in the joint. Importantly, progress has been made in developing effective therapies for treatment of Chlamydia-induced arthritis.

A safety assessment of tumor necrosis factor antagonists during pregnancy.

IMPORTANCE OF THE FIELD: Disease modifying antirheumatic drugs are being increasingly utilized in the treatment of many autoimmune disorders. TNF-alpha antagonists have become the standard of care in treating many of these autoimmune diseases. Because these autoimmune disorders often affect women in their childbearing years, the safety of anti-TNF therapy in pregnancy becomes important. AREAS COVERED IN THIS REVIEW: We critically review the current literature on anti-TNF therapy safety in pregnancy. The available data regarding the anti-TNFs in the setting of pregnancy from 1999 to the present are reviewed. WHAT THE READER WILL GAIN: Case reports and small case series have produced conflicting results, yet their results should only be viewed with cautious interest. Two database reviews suggest little to no risk of congenital anomalies, whereas a much larger independent review of the FDA database reveals congenital anomalies born to mothers who were exposed to anti-TNFs during pregnancy. An ongoing prospective registry (Organization of Teratology Information Services) suggests that about 7 - 10% of children born to mothers taking a TNF antagonist during pregnancy are born with congenital anomalies. TAKE HOME MESSAGE: Whether or not these data represent a significant increase, or if a definitive pattern of birth defects exists, remains in question. All these sources have limitations, which are discussed. Further studies are needed to definitively determine the safety and role of anti-TNFs in pregnancy.

Atypical insufficiency fracture of the tibia associated with long-term bisphosphonate therapy.

Osteoporosis is a major public health threat affecting millions of individuals in the United States. Bisphosphonate therapy is currently recognized as a first-line treatment of osteoporosis through the inhibition of osteoclast activity. Concerns have been raised about potential oversuppression of bone turnover and the development of atypical skeletal fragility associated with long-term use of bisphosphonates. A number of case reports in the literature have documented atypical insufficiency fractures in patients on long-term bisphosphonate therapy. This case outlines what we believe is the second documented atypical tibial insufficiency fracture in a patient on long-term bisphosphonate therapy, and highlights the need for increased awareness of atypical insufficiency fractures as well as the need for more data concerning the long-term effects of bisphosphonate therapy.