Denosumab for the treatment of primary pediatric osteoporosis.

Primary osteoporosis is rare in children and adolescents and its optimal pharmacological management is uncertain. Bisphosphonates are commonly used while denosumab has only been administered to a few children with osteogenesis imperfecta. We studied a treatment-naïve 13.5-year-old boy with severe osteoporosis and multiple vertebral deformities who presented with back pain and difficulty in walking. Causes of secondary osteoporosis were excluded and there were no abnormalities in genes known to cause bone fragility. He was treated with denosumab 60 mg subcutaneously every 3 months for 30 months, and he was pain-free within 6 weeks after the first injection. Lumbar spine BMD and femoral neck BMD increased with treatment by 65.6% and 25.3%, respectively, and deformed vertebrae regained their normal shape; linear growth was not impaired. During the second year of treatment, transient hypercalcemia (maximum 3.09 mmol/l) before the denosumab injection was observed. In conclusion, denosumab was highly effective in this case of primary pediatric osteoporosis, with remarkable clinical and radiological response. Transient hypercalcemia was probably due to amplification of the effect of growth spurt and puberty on bone remodeling by the transient, short-term discontinuation of the drug. Furthermore, our data suggest that mobilization of calcium from treatment-induced sclerotic transverse lines in bone metaphyses may contribute to the development of hypercalcemia.

Factors associated with high 24-month persistence with denosumab: results of a real-world, non-interventional study of women with postmenopausal osteoporosis in Germany, Austria, Greece, and Belgium.

Persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium found that persistence with denosumab remains consistently high after 24 months in patients at high risk of fracture. PURPOSE: Continued persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of clinical practice evaluated medication-taking behavior of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium and factors influencing persistence. METHODS: Subcutaneous denosumab (60 mg every 6 months) was assigned according to prescribing information and local guidelines before and independently of enrollment; outcomes were recorded during routine practice for up to 24 months. Persistence was defined as receiving the subsequent injection within 6 months + 8 weeks of the previous injection and adherence as administration of subsequent injections within 6 months ± 4 weeks of the previous injection. Medication coverage ratio (MCR) was calculated as the proportion of time a patient was covered by denosumab. Associations between pre-specified baseline covariates and 24-month persistence were assessed using multivariable logistic regression. RESULTS: The 24-month analyses included 1479 women (mean age 66.3-72.5 years) from 140 sites; persistence with denosumab was 75.1-86.0%, adherence 62.9-70.1%, and mean MCR 87.4-92.4%. No covariate had a significant effect on persistence across all four countries. For three countries, a recent fall decreased persistence; patients were generally older with chronic medical conditions. In some countries, other covariates (e.g., older age, comorbidity, immobility, and prescribing reasons) decreased persistence. Adverse drug reactions were reported in 2.3-6.9% patients. CONCLUSIONS: Twenty-four-month persistence with denosumab is consistently high among postmenopausal women in Europe and may be influenced by patient characteristics. Further studies are needed to identify determinants of low persistence.

Serum leptin, adiponectin and ghrelin concentrations in post-menopausal women: Is there an association with bone mineral density?

OBJECTIVE: Adipokines and ghrelin exert well-documented effects on energy expenditure and glucose metabolism. Experimental data also support a role in bone metabolism, although data from clinical studies are conflicting. The purpose of this cross-sectional study was to investigate the association of serum concentrations of leptin, adiponectin and ghrelin with bone mineral density (BMD) in post-menopausal women. METHODS: BMD in lumbar spine and femoral neck, and circulating leptin, adiponectin and ghrelin concentrations were measured in 110 healthy post-menopausal women. Patients with secondary causes of osteoporosis were excluded. RESULTS: Osteoporosis was diagnosed in 30 (27%) women and osteopenia in 54 (49%). Serum leptin concentrations were positively correlated with both lumbar spine (r=0.343, p<0.01) and femoral neck BMD (r=0.370, p<0.01). Adiponectin concentrations were negatively associated with BMD at both sites (r=-0.321, p<0.01 and r=-0.448, p<0.01 respectively). No significant correlation between ghrelin concentrations and BMD was found. Osteoporotic women had lower body weight, body mass index (BMI) and leptin concentrations, but higher adiponectin concentrations compared with non-osteoporotic women. In multivariate stepwise regression analysis, the association of adiponectin concentrations with BMD remained significant only for femoral neck, after adjustment for body weight or BMI. CONCLUSIONS: An inverse association between adiponectin and femoral neck BMD was found in post-menopausal women, independently of body weight. The positive association between leptin and BMD was dependent on body weight, whereas no effect of ghrelin on BMD was evident.

Denosumab versus zoledronic acid in patients previously treated with zoledronic acid.

UNLABELLED: Denosumab and zoledronic acid are potent antiresorptives. In this study in patients pre-treated with zoledronic acid, denosumab achieved similar increases with zoledronic acid in lumbar spine BMD despite the more prominent reduction of bone turnover markers. Denosumab reversibly reduced endogenous RANKL. INTRODUCTION: We aimed to compare yearly changes in lumbar spine (LS) bone mineral density (BMD), bone turnover markers, free soluble receptor activator of nuclear factor kappaB ligand (sRANKL) and sclerostin levels between denosumab and zoledronic acid. METHODS: Postmenopausal women with low bone mass previously treated with zoledronic acid for 1 year were assigned to denosumab injection (n = 32) or zoledronic acid infusion (n = 26). Procollagen type 1 N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (CTx), sRANKL, and sclerostin levels were measured in serum samples obtained at baseline and 3, 6, and 12 months after denosumab injection or zoledronic acid infusion. LS BMD was measured at baseline and 12 months. RESULTS: The mean LS increase was 4.5 and 4.4% with denosumab and zoledronic acid, respectively (p = 0.560). Denosumab caused a larger decrease in CTx at 3 months (p < 0.001) and P1NP at 3 (p < 0.001), 6 (p = 0.021), and 12 months (p = 0.042). Denosumab significantly decreased sRANKL by 87.4% at 3 months (p < 0.001). Sclerostin levels were not changed with either intervention (p = 0.162 and p = 0.214, respectively). CONCLUSIONS: In patients previously treated with zoledronic acid, denosumab reduces bone turnover more than zoledronic acid, but the increases in LS BMD are comparable. Furthermore, denosumab administration results in reversible inhibition of the metabolically significant endogenous free soluble RANKL levels. Serum sclerostin is not affected by either agent.

Cost-effective osteoporosis treatment thresholds in Greece.

UNLABELLED: A Greek-specific cost-effectiveness analysis determined the FRAX-based intervention thresholds. Assuming a willingness to pay of 30,000 , osteoporosis treatment is cost-effective in subjects under the age of 75 with 10-year probabilities for hip and major osteoporotic fractures of 2.5 and 10 %, respectively, while for older patients, the same thresholds are raised to 5 and 15 %. INTRODUCTION: The purpose of this study was to determine the FRAX calculated fracture probabilities at which therapeutic intervention can be considered as cost-effective in the Greek setting. METHODS: A Markov cohort model was populated with Greek data, and quality-adjusted life years (QALYs) were used to calculate the cost-effective thresholds for an annual medication cost of 733.7 by gender and age. Average FRAX-based 10-year probabilities for both major osteoporotic and hip fractures were multiplied by the model-derived relative risk at which a cost of 30,000 for each QALY gained was observed for treatment versus to no intervention. RESULTS: A biphasic intervention threshold model is supported by our findings. Osteoporosis treatment becomes cost-effective when absolute 10-year probabilities for hip and major osteoporotic fractures reach 2.5 and 10 %, respectively, among both men and women under the age of 75. For older subjects, the proposed intervention thresholds are raised to 5 and 15 % 10-year probability for hip and major osteoporotic fractures, respectively. CONCLUSIONS: Cost-effective osteoporosis treatment may be facilitated in Greece if FRAX algorithm is used to identify subjects with 10-year probabilities for hip and major osteoporotic fractures of 2.5 and 10 %, under the age of 75, while for older patients, the relevant thresholds are 5 and 15 %, respectively.

Circulating irisin is associated with osteoporotic fractures in postmenopausal women with low bone mass but is not affected by either teriparatide or denosumab treatment for 3 months.

UNLABELLED: In vitro data suggest that myokine irisin may affect bone metabolism by promoting osteoblast differentiation while inhibiting osteoclast differentiation. In this study, circulating irisin levels were associated with previous osteoporotic fractures but not with bone mass and were not affected by denosumab or teriparatide treatment for 3 months. INTRODUCTION: This study aimed to evaluate predictors of circulating irisin in postmenopausal women with low bone mass and to assess a potential effect of denosumab or teriparatide treatment for 3 months. METHODS: Serum samples for irisin measurement were obtained from (a) postmenopausal women with low bone mass (lumbar spinal [LS] or femoral neck [FN] bone mineral density [BMD] T-score ≤-2.0) and their age-matched controls at baseline and 3 months after denosumab (Dmab) injection (Dmab group, n = 50; Dmab control group, n = 25) and (b) women with more severe disease (LS or FN BMD T-score ≤-2.8) and their age-matched controls at the above-mentioned time points after teriparatide (TPTD) initiation (TPTD group, n = 25; TPTD control group, n = 25). RESULTS: At baseline, irisin levels were inversely correlated with age (partial coefficient (r p ) = -0.24; p = 0.009), parathyroid hormone (PTH) (r p = -0.30; p = 0.001), and creatinine (r p = -0.23; p = 0.016) in univariate analysis, and were lower in women with (n = 26; 41.6 ± 2.7 ng/dL) than without previous osteoporotic fracture(s) (n = 99; 51.0 ± 1.6 ng/dL; p = 0.007). In multiple linear regression, previous osteoporotic fracture(s) and PTH were independently negatively associated with irisin [p = 0.04, CI -16.1 to -0.4 and p = 0.002, CI -0.3 to -0.07, respectively], but only the association with PTH remained after controlling for creatinine levels. Serum irisin levels were not different between women with or without low bone mass and were not affected by either Dmab or TPTD treatment for 3 months. CONCLUSIONS: Circulating irisin levels were associated with previous osteoporotic fracture(s); whether this association is independent or is due to confounding by lower muscle mass, potentially reflected by lower creatinine levels, remains to be fully clarified.

Circulating periostin levels do not differ between postmenopausal women with normal and low bone mass and are not affected by zoledronic acid treatment.

Periostin is a secreted extracellular matrix protein preferentially expressed in bone by osteocytes and periosteal osteoblasts. Reduced periostin expression may affect osteoblast differentiation and collagen type I synthesis and predispose to osteoporosis and increased fracture risk. We aimed to evaluate circulating periostin levels in postmenopausal women with low bone mass, their possible correlations with clinical and laboratory parameters, as well as the 3-month effect of zoledronic acid. Serum samples for periostin, 25-hydroxyvitamin D, parathyroid hormone (PTH), C-terminal telopeptide of type I collagen (CTx), and total alkaline phosphatase (tALP) were obtained from 46 postmenopausal women with low bone mass at baseline and 3 months after zoledronic acid infusion and from 30 age-matched, postmenopausal controls with normal bone mass at baseline. There was no difference in periostin levels between women with normal and low bone mass (250±15 vs. 272±14 ng/ml, respectively; p=0.279). Periostin remained essentially unchanged after zoledronic acid infusion (262±18 ng/ml; p=0.130). Serum periostin levels at baseline were not affected by previous bisphosphonate treatment, and were correlated only to tALP (rs=0.351; p=0.018). In multiple linear regression analysis, tALP (B=3.17; 95% CI=0.59-5.79; p=0.018) was associated with serum periostin levels at baseline, independently from previous anti-osteoporotic treatment, age, body mass index, and 25-hydroxyvitamin D. In conclusion, serum periostin levels do not differ between postmenopausal women with normal and low bone mass and are not affected by zoledronic acid treatment. Women with higher tALP have independently higher periostin levels.

Disease-modifying anti-rheumatic drugs for refractory severe knee synovitis in patients with peripheral spondyloarthritis: efficacy and predictors of response.

OBJECTIVES: In this study we aimed to evaluate the efficacy of disease-modifying anti-rheumatic drugs (DMARDs) for severe knee synovitis, refractory to low-dose oral corticosteroids and/or non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular (IA) corticosteroid injections, in patients with peripheral spondyloarthritis (SpA). We also examined the association between the clinical response of knee synovitis and demographic and clinical parameters of the studied patients. METHOD: Patients with SpA-related arthritis including resistant and severe knee synovitis, defined as the presence of swelling, tenderness, and a decreased range of movement on clinical examination, treated with DMARDs between January 2005 and January 2012 were studied retrospectively. No evidence of knee synovitis was considered a clinical response to DMARDs. RESULTS: Forty-five patients [mean age 41.0 ± 1.9 years; 33 (73.3%) males] were studied. In 14 (31.1%) of the patients there was a clinical response of knee synovitis, while the remaining 31 (68.9%) patients were non-responders. Response to DMARD therapy was associated with disease subtype (p = 0.011) and HLA-B27 (p = 0.023) but not with a history of psoriasis (p = 0.067) or age at disease onset (p = 0.054). However, only a history of psoriasis could independently predict the response to DMARDs [adjusted odds ratio (OR) 0.232, p = 0.049]. CONCLUSIONS: One-third of the patients with peripheral SpA and severe resistant knee synovitis had a clinical response to DMARD therapy. Disease subtype and HLA-B27 were associated with the response of knee synovitis to DMARDs, but only psoriasis could independently predict this response.

Circulating activin-A is elevated in postmenopausal women with low bone mass: the three-month effect of zoledronic acid treatment.

UNLABELLED: Activin-A is expressed in bone and seems to regulate osteoclastogenesis. In this study, serum activin-A was increased in postmenopausal women with low bone mass and was positively correlated to age and negatively to lumbar spinal bone mineral density (BMD). Serum activin-A levels did not change 3 months after zoledronic acid infusion. INTRODUCTION: The aims of the study were to evaluate prospectively the circulating activin-A levels in postmenopausal women with low bone mass and explore possible correlations with clinical and laboratory data, as well as the 3-month effect of zoledronic acid infusion. METHODS: Postmenopausal women with low bone mass assigned to receive zoledronic acid infusion (Patients, n = 47) and age-matched, postmenopausal women with normal bone mass (Controls, n = 27) were recruited on an outpatient basis. Main outcome measurement was serum activin-A levels. RESULTS: Serum activin-A was higher in patients at baseline compared to controls (p < 0.001) and activin-A in the serum of patients and controls was positively correlated with age (Spearman's coefficient of correlation [rs] = 0.325; p = 0.005) and negatively with lumbar spinal (LS) BMD (rs = -0.425; p < 0.001). In multiple linear regression analysis, only age (B = 8.93; 95 % CI = 4.39-13.46; p < 0.001) was associated with serum activin-A levels at baseline, independent from group (patients or controls), previous anti-osteoporotic treatment, LS BMD and follicle-stimulating hormone. Circulating activin-A levels were not affected 3 months after zoledronic acid infusion. CONCLUSIONS: Serum activin-A is increased in postmenopausal women with low bone mass compared with postmenopausal women with normal bone mass and is positively correlated to age and negatively to LS BMD.

High circulating sclerostin is present in patients with thalassemia-associated osteoporosis and correlates with bone mineral density.

Osteoporosis is a severe complication of thalassemia. Sclerostin is a Wnt signaling inhibitor, which is produced by osteocytes and inhibits osteoblast function. Sclerostin is implicated in the pathogenesis of osteoporosis of different etiology. The aim of the study was to evaluate circulating sclerostin in 66 patients (median age 42 years) with thalassemia and osteoporosis who participated in a phase 2, randomized study (zoledronic acid vs. placebo) and the results were compared with those of 30 healthy controls (median age 44 years) without osteopenia/osteoporosis and 62 women with postmenopausal osteoporosis (median age 63 years). At baseline, thalassemic patients with osteoporosis had elevated circulating levels of sclerostin (median: 605 pg/ml, range: 22-1,227 pg/ml) compared to healthy controls without osteopenia/osteoporosis (250 pg/ml, 0-720 pg/ml, p<0.001) and reduced levels of sclerostin compared with postmenopausal women with osteoporosis (840 pg/ml, 181-1,704 pg/ml, p<0.001). Thalassemia patients had also increased serum dickkopf-1 (Dkk-1) and high bone turnover. Circulating sclerostin levels correlated with bone mineral density in lumbar spine (r=0.619, p<0.001), distal radius (r=0.401, p=0.001) and femoral neck (r=0.301, p=0.021). Zoledronic acid did not alter sclerostin levels after 12 months of therapy, although it reduced circulating Dkk-1. We conclude that circulating sclerostin is elevated in thalassemia patients with osteoporosis and correlated with their BMD, but it was not reduced post zoledronic acid administration. These findings suggest that high sclerostin may serve as a marker of increased osteocyte activity in thalassemia patients. Drugs targeting sclerostin may also be used in this difficult to treat disorder associated with bone loss.

Long-term effects of thyroid fine-needle biopsy on the thyroid-related biochemical parameters.

AIMS: Thyroid fine-needle biopsy (FNB) is a simple, reliable, inexpensive and generally safe diagnostic procedure in the management of thyroid nodules. FNB may trigger biochemical alterations through destruction of thyroid follicles. We aimed to investigate long-term post-FNB alterations in serum thyroid-related parameters. METHODS: One hundred and ten consecutive patients with thyroid nodular disease were subjected to FNB. Thyroid stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3), thyroglobulin (Tg), thyroglobulin autoantibodies (anti-Tg), thyroid-peroxidase autoantibodies (anti-TPO) were measured in all subjects at baseline, 10 days, 2 and 6 months. Subsequently, patients were divided into subgroups according to the technique of FNB, the presence of disease characteristics as thyroid autoimmunity (Hashimoto's thyroiditis), goitre, singularity-maximum diameter-blood pattern of the nodule(-s), the number of passes and the administration of L-thyroxine (LT4). RESULTS: A significant increase in Tg, anti-Tg and FT3 levels was observed. These alterations were more prominent within patients with dominant nodule's maximum diameter ≥ 2 cm or without Hashimoto's thyroiditis. Tg and anti-Tg levels were significantly increased only in patients not being on LT4. On the other hand, FNB technique did not affect any of the measured parameters. CONCLUSION: Our data suggest that FNB results in statistically significant but clinically insignificant increases in Tg, anti-Tg and FT3 levels, implying a thyroid trauma of some level, more likely to happen in patients with larger nodules. The FNB technique used has no effect on the thyroid-related biochemical parameters.

Selenomethionine treatment in patients with autoimmune thyroiditis: a prospective, quasi-randomised trial.

AIMS: To test whether selenium administration affects autoantibodies to thyroid peroxidase (anti-TPO) and thyroglobulin (anti-TG) titres in chronic autoimmune (Hashimoto's - HT) thyroiditis. METHODS: A prospective, open-label, quasi-randomised study in 86 HT patients (n = 86) assigned to either selenomethionine (Seme) 200µg daily for 3 months (Se3, n = 15) or 6 months (Se6, n = 46) or placebo (Control, n = 25). Serum Se, anti-TPO, anti-TG and thyroid hormones were measured in all patients at baseline, 3 and 6 months. A subgroup of 18 patients (twelve on Se6 and six controls) were subjected in thyroid fine-needle biopsy at baseline and 6 months to detect changes in lymphocyte infiltration. RESULTS: No significant difference in anti-TPO levels was recorded after 3 (p = 0.88) or 6 months (p = 0.62) on Seme. Anti-TG levels decreased both at 3 months (p = 0.001) and 6 months (p = 0.001). No significant changes in thyroid stimulating hormone, free thyroxine and free triiodothyronine levels or in the lymphocytes' number in thyroid cytology specimens were detected. Age, gender, duration of disease, baseline anti-TPO levels and per cent change in Se levels could not predict the response of anti-TPO levels to Seme administration. CONCLUSION: Our data suggest that Seme administration in pharmacological doses for a period of 6 months seems to have no significant effect on serum thyroid auto-antibodies' levels or lymphocyte infiltration of the thyroid gland.

Serum sclerostin levels positively correlate with lumbar spinal bone mineral density in postmenopausal women--the six-month effect of risedronate and teriparatide.

UNLABELLED: Sclerostin is expressed by osteocytes and inhibits bone formation by osteoblasts. In this study, serum sclerostin was positively correlated with either lumbar spinal bone mineral density or T-score. Furthermore, serum sclerostin was increased after 6 months treatment with risedronate, whereas remained unchanged after 6 months teriparatide treatment. INTRODUCTION: The primary aim of this study was the evaluation of serum sclerostin levels in postmenopausal women and their association with bone mineral density (BMD) and bone turnover markers. The secondary aim was the evaluation of treatment with either teriparatide (TPTD) or risedronate (RIS) on serum sclerostin levels in women with postmenopausal osteoporosis. METHODS: Women with postmenopausal osteoporosis, assigned to receive either TPTD (TPTD group, n = 13) or RIS (RIS group, n = 36) for 6 months, and non-osteoporotic early postmenopausal women (NOEP group, n = 13) were recruited. Main outcome measure was serum sclerostin levels. RESULTS: Serum sclerostin was higher in the NOEP group at baseline compared with either TPTD group (p = 0.007) or RIS group (p = 0.049). Sclerostin was positively correlated with both lumbar spinal (LS) BMD (r = 0.353; p = 0.005) and T-score (r = 0.501; p < 0.001) and negatively correlated with intact parathyroid hormone (r = -0.343; p = 0.024) at baseline. Multiple regression analysis showed that either LS BMD (Beta = 0.653; p = 0.018) or T-score (Beta = 0.711; p = 0.005) were independent predictors of serum sclerostin levels. No significant correlation was observed between serum sclerostin and bone turnover markers or estradiol at baseline. Sclerostin was significantly increased 6 months post-treatment in RIS group (p = 0.002), whereas remained statistically unaffected in the TPTD group. CONCLUSIONS: Serum sclerostin is decreased in women with postmenopausal osteoporosis compared with non-osteoporotic early postmenopausal women and is positively correlated to either LS BMD or LS T-score. Furthermore, serum sclerostin was increased after 6 months treatment with RIS, whereas remained essentially unchanged after 6 months TPTD treatment.

Rare potential complications of thyroid fine needle biopsy.

UNLABELLED: Thyroid fine needle biopsy (FNB) is the procedure of choice for the management of thyroid nodules. Serious complications after FNB are rare, but there is also an underestimation of complication risk because of record, selection and publication biases. HYPOTHESIS: Apart from the well-documented post-FNB complications, we hypothesized that there are potential complications following FNB, albeit supported by limited evidence in the literature. According to our hypothesis, there may be five distinct expected rare complications: 1) cyst fluid leakage; 2) anaphylactic reaction; 3) pneumothorax; 4) thromboembolism and 5) needle tract seeding of medullary thyroid carcinoma (MTC) or thyroid lymphoma. CONCLUSIONS: Cyst fluid leakage and pneumothorax may be of minimal clinical significance. Needle tract seeding of MTC or thyroid lymphoma may not have significant clinical consequences, if someone considers the easiness and effectiveness of surgical removal of needle tract seeding in cases of differentiated thyroid carcinoma. On the contrary, anaphylactic reaction or thromboembolism may be life-threatening. The performers of thyroid FNB are hereby encouraged to publish these complications, if they ever occur, because awareness of them could render FNB even safer.

Paget's disease of bone and calcium homeostasis: focus on bisphosphonate treatment.

Paget's disease of bone (PDB) is the second most common metabolic bone disease. Bisphosphonates (BPs) are currently the drugs of choice for PDB. PDB and osteomalacia are both common in the elderly. The concept of relative vitamin D deficiency in patients with PDB was suggested long ago, but it has not yet elucidated. Both diseases predispose to fractures, but their combined action to fragility has not been studied yet. The older BPs, mainly etidronate, further inhibit bone mineralization. Mineralization defects have also been described in patients with PDB treated with pamidronate. Moreover, hypocalcemia and secondary hyperparathyroidism after treatment with BPs have been described in PDB. Hypocalcemia seems to be more severe after treatment with the more potent, intravenous zoledronic acid, which is currently the treatment of choice for PDB. The counteracting hyperparathyroidism pathophysiologically intends to increase renal reabsorption of calcium and 1.25-dihydroxy vitamin D production and to stimulate osteoclasts in order to prevent long-term hypocalcemia. However, the effect of PTH on osteoclasts is, at least partly, restricted in patients taking BPs. Secondary hyperparathyroidism is a potentially detrimental condition, especially in patients already suffering from another bone disease. Serum calcium and vitamin D deficiency should be restored before BP treatment and calcium and vitamin D administration should be possibly continued for longer after achieving normocalcemia, which may shorten the duration of secondary hyperparathyroidism. QUICK SUMMARY: Mineralization defects and hypocalcemia with secondary hyperparathyroidism have been described in patients with Paget's disease of bone treated with bisphosphonates. Secondary hyperparathyroidism may be a potentially detrimental condition for patients with Paget's disease of bone.

Zoledronic acid-induced transient hepatotoxicity in a patient effectively treated for Paget's disease of bone.

Bisphosphonate (BP)-induced hepatotoxicity is very rare. There are only a few reports of liver injury after BP treatment, including aledronate and risedronate in postmenopausal osteoporosis patients. We describe hereby the case of a patient with Paget's disease of bone accompanied by nonalcoholic fatty liver disease (NAFLD) who developed transient hepatotoxicity after zoledronic acid (ZOL) treatment. NAFLD had been diagnosed 1 year before presentation, based on liver ultrasonography (US). One day after infusion, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) were increased by 8.1, 6.7, and 6.7 times, respectively, compared with pretreatment values. Serum bilirubin remained normal. US revealed hepatic mild homogenous brightness without focal lesion of the liver or biliary ducts. Subsequent biochemical and serologic investigation did not reveal a specific liver or systematic disease. The patient remained asymptomatic, and ALT, AST, and GGT were normalized 7 days post-treatment. Although the mechanism by which ZOL may cause liver damage is elusive, physicians should be aware of this possible adverse effect and ZOL cautiously administered in NAFLD patients.