Gianluigi Fabbriciani

Adefovir induced hypophosphatemic osteomalacia.

To the Editor,It is known that there is a high rate of nephrotoxicity with a dosage of 60–120 mg/day of adefovir-dipivoxil (Hepsera®). However, a dosage of 10 mg/day has been found to be safe [1,2]...

Gamma-delta T lymphocytes and 25-hydroxy vitamin D levels as key factors in autoimmunity and inflammation: The case of zoledronic acid-induced acute phase reaction

Zoledronic acid (ZA) infusion for osteoporosis is frequently associated with the onset of an acute phase reaction (APR) secondary to the activation of γδ T cell receptor (TCR) lymphocytes (γδ T cells) and to low vitamin D levels, similar to what is observed in chronic inflammation and autoimmunity. In this study we investigated whether the phenotype of γδ T cells is associated with APR and 25-OH vitamin D (25-OHvD) levels. For flow-cytometry analysis, peripheral blood samples were obtained from 52 osteoporotic women prior to 5 mg ZA intravenous infusion and from nine women (five with APR) one week later. Twenty-six/52 (50%) patients reported APR and APR+ cases had a higher percentage of central memory Th1-like γδ T cells. One week after ZA infusion, APR was associated with a decreased percentage of central memory Th1-like γδ T cells, an increase in the percentage and activation of effector memory Th1-like γδ T cells, and an increase in Th17-like γδ T cells. Lower 25-OHvD levels were significantly associated with APR, but no correlation was found between 25-OHvD level and γδ T cell percentage or subsets. In conclusion, patients experiencing APR related to ZA infusion have lower 25-OHvD levels and we suggest that the higher percentage of central memory Th1-like γδ T cells and the expansion of effector memory Th1-like and Th17-like γδ T cells are associated with the occurrence of APR.

Antiretroviral Therapy and Adverse Skeletal Effects

To the Editor: We read with interest the article by Davidge Pitts and Kearns1 entitled “Update on Medications With Adverse Skeletal Effects.” In our opinion, antiretroviral compounds should also be added to the list of “bad-to-the-bone” drugs. During the past 10 years, the average life expectancy of adults with human immunodeficiency virus (HIV) infection has increased because of effective antiretroviral therapy (ART), and the care of HIV-infected individuals has shifted from management of opportunistic infections to prevention and treatment of the metabolic complications of ART, including osteoporosis. In particular, the synergy between HIV and/or ART-related bone damage with age-associated bone loss could lead to a serious health threat. Several clinical studies have shown that during ART, bone loss is an early event and occurs rapidly, especially within 6 months of initiation. The Strategies for Management of Antiretroviral Therapy (SMART) study has shown that institution of an ART may be followed by a 6% decrease in bone mineral density (BMD) during the first 2 years regardless of the drug combination. Furthermore, continuous ART is associated with reduced BMD and increased fracture risk compared with intermittent, CD4 cell count–guided ART.2 Therefore, osteopenia/osteoporosis, occasionally osteomalacia, and an increased risk of fracture are reported as major adverse effects of ART, especially in a regimen including the nucleotide reverse-transcriptase inhibitor tenofovir3 and protease inhibitors. The mechanism by which antiretroviral drugs act on the bone is multifactorial and not completely clear but is mediated in part by a direct effect on osteoblasts and osteoclasts, increased catabolism of vitamin D, and mitochondrial damage. Interestingly, the mitochondrial damage can also cause proximal renal tubulopathy. Indeed, 1.6% to 22% of tenofovir-treated patients experience phosphate wasting and 1-hydroxylation defects of vitamin D due to proximal renal tubulopathy, leading to osteomalacia with multiple fractures, bone pain, and proximal muscle weakness. According to the European AIDS Clinical Society guidelines, in HIV-positive patients, especially those treated with ART, dual energy x-ray absorptiometry should be performed; if BMD is abnormal, secondary causes of osteoporosis should be ruled out (eg, hypovitaminosis D, hyperparathyroidism, hyperthyroidism, malabsorption, hypogonadism/amenorrhea, autoimmune diseases, diabetes mellitus, chronic liver diseases), and lateral lumbar and thoracic spine radiography should be performed. If hypophosphatemia is present, a diagnosis of renal Fanconi syndrome should be considered. Currently, ART-induced bone loss can be managed with a reduction of risk factors for osteoporosis, including ensuring vitamin D supplementation (800-2000 IU of vitamin D3 daily4 or up to 2000 IU in patients treated with efavirenz5) to maintain a plasma 25-hydroxyvitamin D concentration greater than 30 ng/mL (75 nmol/L). Other interventions include supplemental dietary calcium (1-1.2 g/d), weight-bearing exercise, and (sometimes) bisphosphonates (oral alendronate, 70 mg once weekly, or zoledronate, 5 mg intravenously once yearly). Furthermore, substituting another drug for tenofovir should be considered for patients presenting with hypophosphatemia, renal Fanconi syndrome, progressive decline of glomerular filtration rate, or fragility fractures.4

Polyostotic Paget disease involving bones of the upper extremity.

Paget disease of bone (PD) is a common skeletal disease. It is usually polyostotic and most frequently involves the pelvis, femur, spine, skull, and tibia. The bones of the upper extremity in poly- or monostotic PD are rarely affected. A patient with PD involving the third left metacarpal bone and carpal bones of the right hand is described.

Osteoanabolic therapy: a valid option to reduce refracture risk after vertebral augmentation procedures?

Dear Editor, We read with interest the article by Beall et al [1] entitled BPatients with prior vertebral or hip fractures treated with teriparatide in the Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) observational study .̂ In their post hoc analysis aimed to assess the effect of teriparatide (TPTD) in osteoporotic (OP) patients with prior vertebral (VFX) or hip fractures, the authors included 179 subjects treated with vertebral augmentation procedures (VAP)—kyphoplasty/vertebroplasty (KP/VP)—for previous VFX before starting TPTD, reporting a significant decline over time of new VFX in this group and suggesting a time element to the effect of TPTDwith increased efficacy after the first 6 months of treatment.. However, the paper doesnot clarify whether part of the decrease in new VFX is due to TPTD’s ability to prevent the occurrence of new VFX shortly after VP/KP, considered one of the main side effects of VAP, as it does not take into account the interval between VAP and TPTD starting. We evaluated a single-centre experience of treating with TPTD patients at high risk of new VFX following VAP and report 18-month outcomes as the effect of TPTD in preventing new VFX after VAP. Between September 2005 and January 2012, 145 patients with postmenopausal OP and VFX were started on TPTD. We identified a sample of 20 patients who started TPTD therapy (plus calcium and vitamin D, as needed) within 1 month after KP and report on 18 subjects that completed at least 18 months of treatment (one patient discontinued TPTD after a few days because of side effects and one after a few months due to personal reasons). Baseline characteristics of the patients were age 75 ± 10 years (mean ± SD), 25-OH vitamin D levels 11.9 ± 9.97 ng/mL, and femoral neck T-score was −2.8 ± 0.87; 11 patients underwent multiplelevel KP (3 patients: 3 KP; 8 patients: 2 KP) due to multiple VFX diagnosed concurrently (5 patients) or to a subsequent VFX after a first KP (6 patients). None of the patients experienced a new VFX during the whole TPTD treatment period. Moreover, back pain significantly decreased through the follow-up (VAS baseline vs VAS 18 months: 58.8 ± 23.2 vs 26.3 ± 16.3, p < 0.05 using Mann-Whitney U). A previous study demonstrated TPTD as a useful treatment for new-onset VFX after VP [2] but our study is the first to suggest a role for osteoanabolic therapy in preventing refracture after VAP in OP patients. Results are pharmacologically plausible as TPTD induces increase in bone formation markers after 1 month of therapy and may quickly restore bone architecture and integrity [3]. Limitations of our study include its observational nature and small sample size but it is encouraging that no VFX occurred in a 18-month follow-up period in a cohort of patients with a very high baseline FX risk, as the refracture rate after VAP is reported to be between 12 % and 52 % [4]. This provides further evidence of efficacy of TPTD treatment in this group of patients. A response to these comments is available at DOI 10.1007/s00198-0163657-9.

ACUTE PHASE REACTIONS AFTER ZOLEDRONIC ACID INFUSION: PROTECTIVE ROLE OF 25-HYDROXYVITAMIN D AND PREVIOUS ORAL BISPHOSPHONATE THERAPY

OBJECTIVE The most common adverse reaction to zoledronic acid (ZOL) infusion is the acute phase reaction (APR), characterized by transient, usually mild, flu-like symptoms. Previous treatment with oral amino-bisphosphonates (BPs) was reported as an independent protective factor for APR, and an association between APR and 25-hydroxyvitamin D (25(OH)D) levels in BP-naïve patients treated with ZOL was identified. The aims of our study were to confirm this association and to see if it was different in patients previously treated with oral BPs compared with BP-naïve patients and to investigate the role of 25(OH)D for the time of APR onset. METHODS We included 153 consecutive patients with postmenopausal osteoporosis undergoing their first ZOL infusion. Sixty-eight had been previously treated with oral BPs. Clinical, demographic, and serologic data were recorded. RESULTS 25(OH)D levels were significantly lower in patients experiencing APR compared to patients without APR (26.3 ± 12.7 vs. 37.0 ± 13.5 ng/mL, respectively; P<.0001). Patients with 25(OH)D <30 ng/mL had a significantly higher risk of APR (odds ratio [OR] 4.2 [95% confidence interval [CI] 2.1-8.2]) occurring in 65%. APR was significantly less frequent in patients previously treated with oral BPs than in BP-naïve subjects (33.8% [23/68] vs 52.9% [45/85], P = .018), but only a weak association remained after correction for 25(OH)D (OR 0.5, 95% CI 0.3-1.1, P = .08). CONCLUSION Higher baseline 25(OH)D levels appear to be protective for APR post-ZOL infusion. The role of previous treatment with oral BPs as an independent protective factor for APR should be evaluated in a larger cohort. ABBREVIATIONS APR = acute phase reaction; BPs = amino-bisphosphonates; CI = confidence interval; 25(OH)D = 25-hydroxyvitamin D; OP = osteoporosis; OR = odds ratio; PTH = parathyroid hormone; ROC = receiver operating characteristic; ZOL = zoledronic acid.

THU0132 Prevalence and Predictive Value of Serum Autoantibodies in the General Population: Results of a Longitudinal Study on 2690 Subjects with a 13-Year Observation

Background The prevalence of serum autoantibodies in the general population is generally obtained from large datasets including blood donors or employees and are thus poorly representative. Similarly, it is challenging to determine the risk of developing an autoimmune disease in subjects found to be positive for serum autoantibodies in the absence of clinical suspicion. Objectives To determine the prevalence and predictive value of ANA, ENA, and ACPA antibodies in the general population participating in a 13-year longitudinal study. Methods The general population of a Northern Italian area was enrolled in 1998/1999 in a study to determine the prevalence of viral hepatitis infections. Resident subjects aged 18-75 were randomized 1:4 and 71% of subjects took part in the study (mean age 42, range 18-75, female/male 1.15). In 2011 serum samples (n=2690) were blindly tested for ANA, ENA, anti-CCP using commercially available indirect immunofluorescence and ELISA (Aesku.Diagnostics). For all subjects we sought for exemptions (i.e. the fiscal mechanism that allows subjects with a chronic condition to waive copayments for visits, medications, and blood tests) specific for autoimmune diseases (including connective tissue disease, CTD, and rheumatoid arthritis, RA) over the following 13 years. We should note that this approach does not account for 11% of the population which, for economic limits or advanced age, have a waiver overcoming the disease-specific exemptions. Administrative data were ultimately analyzed to determine the long-term predictive value of serum autoantibodies in terms of odd ratios (OR). Results Serum ANA were detected in 18.1% (for titers ≥1:80) and 5.7% (for titers ≥1:160) of tested samples and the observed pattern was speckled in 71% of cases. The prevalence of specific anti-ENA autoantibodies ranged between 0.1% (Jo-1) and 1.9% (anti-nucleosome) while ACPA were positive in 4.7% of subjects (0.9% considering only medium-to-high titers). In all cases, prevalence rates were higher in female individuals but the predominance was lower than classically reported for CTD and RA. The OR for developing any autoimmune disease for ANA positive individuals over 13 years was 2.77 (95% confidence interval -CI- 1.73-4.44). The OR of developing a CTD for individuals with high-titer ANA was 12.20 (95% CI 2.41-61.59) while the OR of developing RA with positive ACPA was 10.86 (95% CI 1.96-59.98). Conclusions We report that the prevalence of serum ANA, ENA, and ACPA may be higher than previously reported when a general unselected population is studied. Further, the serum positivity confers a significant risk of developing an autoimmune disease when subjects are observed for a sufficient period of time. Disclosure of Interest None Declared