Managing bone health with zoledronic acid: a review of randomized clinical study results.

AIM: To systematically review randomized, controlled clinical trials for managing osteoporosis, cancer treatment-induced bone loss, and bone metastases from breast cancer using zoledronic acid (ZOL). METHOD: A systematic review of published literature and meeting abstracts was conducted to examine the efficacy of ZOL dosing strategies in clinical trials of osteoporosis, adjuvant therapy for breast cancer, and bone metastases from breast cancer. Bone resorption rates, tumor burden, skeletal health goals, and clinical data were considered when assessing ZOL in each setting. RESULTS: Dosing schedules vary between approved indications for osteoporosis and bone metastases and the investigational use in women receiving endocrine therapy for BC, taking into consideration the different levels of bone loss and tumor burden in each setting. Gradual bone loss in healthy postmenopausal women with osteopenia or osteoporosis can be prevented or treated with the approved biennial or annual ZOL (5 mg), respectively. Rapid bone loss in patients receiving adjuvant chemotherapy and/or endocrine therapy for early-stage BC and low tumor burden is managed in the clinical setting with ZOL 4 mg every 6 months. In patients with bone metastases, very high tumor burden, high bone resorption levels, and decreases in bone integrity are managed by the approved ZOL schedule (4 mg every 3-4 weeks) to prevent skeleton-related events. CONCLUSIONS: Dosing schedules are based on clinical evidence and vary depending on goals of therapy, rate of bone loss, and tumor burden. ZOL 5 mg every 12 months and every 24 months are approved for osteoporosis and osteopenia, respectively, whereas ZOL 4 mg every 6 months has been used during adjuvant endocrine therapy and ZOL 4 mg every 3-4 weeks is approved for managing bone metastases.

Bone demineralization in the lumbar spine of dogs submitted to prednisone therapy.

Glucocorticoids are drugs widely used in veterinary medicine; however, besides their clinical benefits, their use can trigger undesirable effects. A clinical trial was performed on eight healthy dogs with the intent of evaluating possible alterations in the bone mineral density after therapy with prednisone using a helical computed tomography. All animals received prednisone orally at a dose of 2 mg/kg of weight for 30 days. The bone mineral density was determined by obtaining the vertebral body radiodensity of the second lumbar vertebra values immediately before and after the administration of the medication. The experimental protocol allowed for the characterization of a significant (P < 0.01) reduction of the vertebral body radiodensity of the second lumbar vertebra. At the end of the experiment, it was characterized by a loss of bone mass of approximately 14%. None of the animals presented pathologic fracture at the end of the administration of the medication. This study verified that the alterations in the bone metabolism of the dogs submitted to the therapy with prednisone in a dosage of 2 mg/kg occur rapidly, which recommends a monitoring of the patients for the prevention of pathologic fractures.

Value of routine screening for bone demineralization in an urban population of patients with epilepsy.

BACKGROUND: Reduced bone mineral density (BMD) is increasingly recognized in patients receiving antiepileptic drug therapy. The precise prevalence is not known due to variability across populations studied. We set out to characterize the prevalence of abnormal BMD in an urban population of patients with epilepsy with the intent to determine the value of routine BMD screening. METHODS: We performed a cross-sectional study of 130 consecutive patients seen thorough our Comprehensive Epilepsy Center. BMD was measured using dual X-ray absorptiometry and was reported as T-score and Z-score. Additional information collected for each patient included age, race, gender, current and prior AEDs, ambulatory state, menopausal state, concomitant medications potentially associated with reduced bone mineralization, and comorbid illness potentially associated with reduced bone mineralization. Associations between reduced bone mineralization and variables were tested for significance using Fisher's exact test, Student's t-test, and Wilcoxon rank sum test. RESULTS: The average age of the entire study population was 43.5 (+/-12.5) years. Fifty-five percent of patients had T-score less than or equal to -1, the WHO criterion for osteopenia in postmenopausal women. The prevalence of Z-scores less than -2.0 was 15%, which is more than sixfold greater than expected. The markers for decreased BMD included older age or menopause in women, longer duration of therapy, and a history of use of phenytoin or phenobarbital. Assisted ambulation was also associated with low BMD. CONCLUSION: Our results indicate that reduced bone mineralization is prevalent and a significant health concern in an urban population of patients with epilepsy. Because of the high prevalence of reduced bone mineralization reported in numerous studies including this study, routinely screening for reduced bone mineralization is warranted in patients receiving anticonvulsant therapy.

Skeletal demineralization and fractures caused by fetal magnesium toxicity.

Two surviving female infants, born from a triplet pregnancy at 30 weeks gestation, were noted to have severe osteopenia and multiple fractures diagnosed at 20 days of age. Their mother had been treated for preterm labor with intravenous magnesium sulfate from week 22 until their birth at 30 weeks gestation. At birth, the triplets exhibited craniotabes with enlarged fontanelles and sutures. All developed Respiratory Distress Syndrome (RDS) and the two surviving infants required prolonged respiratory support. Serum calcium and phosphate levels were normal and alkaline phosphatase levels were increased. The infants were treated with supplements of calcium and phosphorous, with resultant healing of the multiple fractures without deformity. Fetal magnesium toxicity impairs bone mineralization and can lead to serious bone demineralization that may cause fractures in the newborn period that complicate recovery from respiratory disease. Early recognition and treatment may minimize complications related to osteopenia caused by fetal magnesium toxicity.

In vitro evaluation of adhesion/proliferation of human gingival fibroblasts on demineralized root surfaces by toluidine blue O in antimicrobial photodynamic therapy.

BACKGROUND: Antimicrobial photodynamic therapy (aPDT) in Dentistry has important effects as bacterial destruction in areas with periodontal disease. Some dyes applied in aPDT could present low pH and, consequently, result in tooth demineralization. This study evaluated demineralization produced by aPDT with toluidine blue O (TBO) at low pH and analyzed adhesion/proliferation of human gingival fibroblasts (HGF). METHODS: In the 1st phase, bovine enamel and root dentin fragments received 2 treatments: PDT4 group (TBO-100 µg/ml-pH 4-60s) plus laser (660 nm, 45 J/cm(2), 1.08 J, 30 mW, 30 s, spot 0.024 cm(2), 1.25 W/cm(2), sweeping, non-contact) and CA group (citric acid plus tetracycline-pH 1-180 s). Surface hardness loss and tooth wear were statistically analyzed (Student's t test, ANOVA/Tukey, p<0.05). In the 2nd phase, human dentin fragments were divided in C (control group-scaling and root planing), PDT4 and CA. HGF (10(4), 5th passage) were cultured on these fragments for 24, 48 and 72 h and counted in scanning electron microscopy photographs. Number of HGF was analyzed using repeated-measures ANOVA and Tukey (p<0.05). RESULTS: Percentage of surface hardness loss was similar in dentin for PDT4 (71.5%) and CA (76.1%) (p>0.05) and higher in enamel for CA (68.0%) compared to PDT4 (34.1%) (p<0.05). In respect to wear, no difference was found between PDT4 (dentin: 12.58 µm, enamel: 12.19 µm respectively) and CA (dentin: 11.74 µm and enamel: 11.03 µm) (p>0.05). Number of HGF was higher after 72 h in CA group (2.66, p<0.05) compared to PDT4 (2.2) and C (1.33). CONCLUSION: PDT4 is not as aggressive as CA for enamel. However, dentin demineralized promoted by PDT4 does not stimulate HGF adhesion and proliferation as CA.

Prevention of bone demineralization by calcium supplementation in precocious puberty during gonadotropin-releasing hormone agonist treatment.

We have previously demonstrated a negative impact on peak bone mass in girls with precocious puberty treated with GnRH agonist (GnRHa). Several studies have shown that a high calcium intake positively influences bone mass in prepubertal girls and leads to a higher peak bone mass. The aim of this study was to evaluate the effect of calcium supplementation in girls with precocious puberty during GnRHa treatment. Forty girls affected by true central precocious puberty and treated with the GnRHa triptorelin were studied for 2 yr. After diagnosis, the patients were randomly assigned to three groups: group A, treated only with GnRHa; group B, treated for 12 months solely with GnRHa and then supplemented with calcium gluconolactate/carbonate (1 g calcium/day in two doses) for 12 months; and group C, treated from the beginning with combined GnRHa and calcium. Bone mineral density (BMD) at the lumbar spine was measured by dual energy x-ray absorptiometry at the beginning of the study and after 12 and 24 months and was expressed as the calculated true volumetric density (BMDv) in milligrams per cm3. Group A showed a decrease in absolute BMDv levels, in SD score for chronological age (CA), and even more in SD score for bone age (BA). Group B showed the same behavior during the first year, but this trend was reversed in the second year, when calcium supplementation was added to GnRHa treatment. Group C showed an increase in absolute BMDv levels and in SD score for CA and BA. BMDv variations (expressed as absolute values, SD score for CA, and SD score for BA) became statistically significant at 24 months between groups C and A (P = 0.036, P = 0.032, and P = 0.025, respectively). The behavior of the lumbar spine BMDv in the three groups is consistent with a positive effect of calcium supplementation during GnRHa treatment. In calcium-supplemented patients, the normal process of bone mass accretion at puberty is preserved despite GnRHa treatment. Therefore, the reduction in BMD during GnRHa treatment in girls with precocious puberty is at least completely reversible and preventable if calcium supplementation is associated from the beginning.

Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment.

We present the 5-year results of the effect of adjuvant chemotherapy on bone mineral density (BMD) and the efficacy of clodronate in the prevention of bone loss in 73 premenopausal women with primary breast cancer. All patients were treated with cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. The patients were randomised to oral clodronate 1600 mg daily for 3 years or to a control group. At 5 years, patients were divided into those with preserved menstruation and those with amenorrhoea. Changes in BMD correlated significantly with the menstrual function after chemotherapy. The change in the lumbar spine BMD at 3 and 5 years were +0.6 and -1.3% in the menstruating group and -7.5 and -10.4% in the amenorrhoeic group (P=0.0001 and 0.0001, respectively), and in femoral neck +1.7 and -0.3%, and -3.5 and -5.8% (P=0.002 and P=0.001, respectively). Three-year clodronate treatment significantly reduced the bone loss in the lumbar spine -3.0% compared with controls -7.4% at three years (P=0.003), but no significant difference was found in the femoral neck: -1.7% versus -2.8%, respectively (P=0.86). These differences between the study groups were still seen at 5 years: in the lumbar spine -5.8% versus -9.7% (P=0.008) and femoral neck -3.5% versus -5.1% (P=0.91). In conclusion, chemotherapy-induced ovarian failure in premenopausal women caused a temporary accelerated bone loss of the lumbar spine. Adjuvant clodronate treatment significantly reduced this bone loss. Two years after the termination of treatment, the bone loss was still significantly less in the clodronate group compared with the control group.

Rapid hip bone loss in active Crohn's disease patients receiving short-term corticosteroid therapy.

BACKGROUND: Uncertainty over whether corticosteroids cause bone loss in patients with Crohn's disease may reflect their short, intermittent use. AIM: We investigated whether a 2-month course of prednisolone is associated with detectable bone loss. METHODS: Fifteen patients with active Crohn's disease and 19 controls with inactive Crohn's disease were recruited. Bone mineral density of the lumbar spine and hip was measured at baseline and 2 and 8 months. RESULTS: At 2 months, significant bone loss was found in patients with active disease (femoral neck -2.7%, P < 0.002; Ward's triangle -3.9%, P < 0.01). Although bone mineral density was still lower at 8 months, these differences were no longer significant (-1.3% and -3.4%, femoral neck and Ward's triangle, respectively). No significant change in hip bone mineral density was observed in controls. Previous corticosteroid use was not significantly associated with baseline bone mineral density, although significant independent associations were observed between weight, site of disease and lumbar spine bone mineral density, and between dietary calcium deficiency and femoral neck and Ward's triangle bone mineral density. CONCLUSION: Significant bone loss at the hip can be detected in patients receiving corticosteroid treatment for 2 months for active Crohn's disease ; however, it remains unclear whether this is because of disease activity or its treatment. This rapid bone loss may represent a risk factor for fracture and justify bone protective therapy.

Possible limited bone loss with suppressive thyroxine therapy is unlikely to have clinical relevance.

To determine the effect of suppressive doses of thyroxine (T4) on bone mass, we studied 50 women on suppressive doses of T4 for 3-27 years (mean of 11 years). Twenty-five had nontoxic goiter and 25 had well-differentiated thyroid carcinoma. Fifty controls were matched for age, menopausal status, and body mass index. Bone mineral density (BMD) was measured in the lumbar spine (LS), femoral neck (FN), trunk (TK), and extremities (EXT) by dual-energy X-ray absorptiometry (DXA). In addition, the trunk area was measured by neutron activation analysis and recorded as a calcium bone index (CaBI). Twenty-one patients were restudied with DXA measurements at a mean of 1.5 +/- 0.5 (1 SD) years. The total population of 50 patients showed no difference in bone mass from controls. In patients with nontoxic goiter, there was no evidence of any loss in bone mass. Cancer patients showed insignificant reductions of 2-5% in BMD of LS, FN, and TK and a significant 5% reduction in BMD of EXT, compared to controls, and a 12% reduction in CaBI compared to goiter patients. Cancer patients had a slightly higher (p < 0.001) mean daily dose of T4 than goiter patients (0.23 vs 0.15 mg/day) but had a similar degree of TSH suppression. BMD and CaBI values did not correlate with free T4 index) with the daily T4 dose, accumulative dose, or with duration of T4 therapy. There were no significant changes in bone mass in either goiter or cancer patients restudied after a mean of 1.5 years.(ABSTRACT TRUNCATED AT 250 WORDS)

An unexpected outcome during testing of commercially available demineralized bone graft materials: how safe are the nonallograft components?

STUDY DESIGN: Radiographic and histologic analyses of commercially available bone graft materials were performed. OBJECTIVE: To compare the osteoinductive efficacy of commercially available demineralized bone matrix material. SUMMARY OF BACKGROUND DATA: The relative in vivo bone formation and toxicology of the nonallograft components the make up various commercially available demineralized bone matrix products are not known. METHODS: An in vivo bone formation model was used in 30 athymic rats. Six different bone grafting materials were tested in subcutaneous and intermuscular locations. After 4 weeks, radiographic and histologic testing of bone formation was performed. RESULTS: Eight of nine rats implanted with Grafton demineralized bone matrix products died 1 to 4 days after implantation of the bone graft material. None of the remaining 10 animals implanted with the four other grafting materials died. The experiment was modified and completed with a lower dose of bone graft material. Pathologic analysis indicated that the cause of death was hemorrhagic necrosis of the kidneys, most likely caused by a toxic effect on the glomeruli and tubules. A possible causative factor may have been the glycerol in the graft material. CONCLUSIONS: Although the volume of Grafton product per kilogram of body weight used in this study was approximately eight times the maximum volume used in humans, the authors believe that this data must be reported because this product is used substantially in clinical settings. In addition, the osteoinductive performance and relative safety of the nonallograft components in all commercially available demineralized bone grafts are not known.

Spontaneous external auditory canal cholesteatoma complicated by rheumatoid arthritis--case report and review of the literature.

A 63-year-old woman with rheumatoid arthritis sought medical assistance for dull and chronic pain in her left ear two and half years after her initial diagnostic examination. Otoscopic examination revealed that the posteroinferior wall of the bony external ear canal was eroded and that the small cavity was filled with squamous debris. The condition was diagnosed as external auditory canal cholesteatoma (EACC). The existence of EACC might suggest complications of bone disease, aging cerumen gland, or a low migratory rate of the epithelium.

[A densitometric assessment of skeletal mineral levels in prostate cancer patients treated with hormones]. / Densitometricheskaia otsenka mineral'noi plotnosti kostei u bol'nykh rakom predstatel'noi zhelezy na fone gormonoterapii.

An assessment of the densitometry data on 76 patients established a progressively falling level of minerals in the skeleton as a result of treatment with hormones for prostate cancer. The basal mineral levels had been identified by means of dual-energy X-ray absorptiometry. While said changes were immediately caused by maximum androgen deprivation, tumor influence and medication contributed too.

A SNP in steroid receptor coactivator-1 disrupts a GSK3ß phosphorylation site and is associated with altered tamoxifen response in bone.

The coregulator steroid receptor coactivator (SRC)-1 increases transcriptional activity of the estrogen receptor (ER) in a number of tissues including bone. Mice deficient in SRC-1 are osteopenic and display skeletal resistance to estrogen treatment. SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen. We hypothesized that single nucleotide polymorphisms (SNP) in SRC-1 may impact estrogen and/or tamoxifen action. Because the only nonsynonymous SNP in SRC-1 (rs1804645; P1272S) is located in an activation domain, it was examined for effects on estrogen and tamoxifen action. SRC-1 P1272S showed a decreased ability to coactivate ER compared with wild-type SRC-1 in multiple cell lines. Paradoxically, SRC-1 P1272S had an increased protein half-life. The Pro to Ser change disrupts a putative glycogen synthase 3 (GSK3)ß phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3ß increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3ß-mediated phospho-ubiquitin clock previously described for the related coregulator SRC-3. To assess the potential clinical significance of this SNP, we examined whether there was an association between SRC-1 P1272S and selective ER modulators response in bone. SRC-1 P1272S was associated with a decrease in hip and lumbar bone mineral density in women receiving tamoxifen treatment, supporting our in vitro findings for decreased ER coactivation. In summary, we have identified a functional genetic variant of SRC-1 with decreased activity, resulting, at least in part, from the loss of a GSK3ß phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.

Adherence to treatment with selective serotonin reuptake inhibitors and the risk for fractures and bone loss: a population-based cohort study.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are suspected of increasing the risk of bone loss and osteoporotic fractures. OBJECTIVE: The aim of this study was to investigate the association between adherence to SSRI treatment and the risk of bone loss-related events. METHODS: The data used in this retrospective cohort study are part of the ongoing medical documentation routinely collected in a large health maintenance organization in Israel. Specifically, we used the information collected between January 2004 and April 2010. The study cohort included 10 621 women who were new users of SSRIs. Bone loss-related events were defined as fractures or initiation of bisphosphonate treatment. Adherence level was assessed by calculating the proportion of days covered (PDC) with an SSRI from the date of first dispensed SSRI (index date) to the end of follow-up and was categorized as low (PDC ≤20%), intermediate (PDC 21-79%) and high (PDC ≥80%). To validate the study model, we conducted a similar analysis on patients using antiepileptic drugs, which are known to be positively associated with an increased risk of osteoporotic fractures. RESULTS: Higher adherence to SSRI treatment was significantly associated with an increased risk of bone loss-related events in a dose-response manner. The adjusted hazard ratio for bone loss-related events adjusted for age, physician visits and body mass index in patients who were covered with an SSRI for 21-79% of the time and 80% or more of the time was 1.15 (95% CI 0.97, 1.37) and 1.40 (95% CI 1.14, 1.73) compared with patients who were covered for less than 21% of the follow-up period. CONCLUSION: Exposure to SSRI treatment is associated with an increased risk of bone loss-related events. Further studies are required to determine the causality of the association and its relevance to the clinical use of SSRIs.

Cadmium is more toxic on volume bone mineral density than tissue bone mineral density.

It has been showed that Cd induces low areal bone mineral density, but we do not know the effect of Cd on cubic bone density. This study was aimed to investigate the effects of Cd on volumetric bone mineral density (VBMD) and tissue bone mineral density (TBMD) in male rats. Twenty-four Sprague-Dawley male rats were randomly divided into four groups that were given cadmium chloride by subcutaneous injection at doses of 0, 0.1, 0.5, and 1.5 mg/kg body weight for 8 weeks, respectively. Then, microcomputed tomography scanning was performed on the proximal tibia, and region of interest was reconstructed using microview software. The VBMD, bone volume fraction of rats treated with 1.5 mg Cd/kg, were significantly decreased compared to control (p < 0.01). The trabecular numbers of rats exposed to Cd were all significantly decreased relative to control (p < 0.05). The trabecular separation of rats treated with 1.5 mg Cd/kg was obviously increased compared to control (p < 0.01). However, Cd had no obvious influence on TBMD. Cd induced low VBMD but not TBMD; Cd effect on bone may be related with trabecular bone loss but not with trabecular bone demineralization.

Prolonged maternal magnesium administration and bone metabolism in neonates.

BACKGROUND: Magnesium sulfate (MgSO(4)) has been used as a tocolytic agent in cases of refractory preterm labor. Prolonged maternal administration of MgSO(4) may induce bone demineralization in the neonate. However, the effects of MgSO(4) on serum biochemistry related to bone metabolism in neonates remain unclear. AIM: To assess the effects of prolonged maternal administration of MgSO(4) on fetuses and neonates. STUDY DESIGN: This retrospective case-control study examined 167 neonates. Cases comprised 58 neonates whose mothers had received intravenous MgSO(4) administration for >5 days. Neonatal serum levels of magnesium (Mg), calcium (Ca), phosphorus (P) and alkaline phosphatase (ALP) were reviewed. We also investigated whether subject neonates showed appearance of osteopenia at the metaphyseal lines on radiography at birth. RESULTS: Mean serum Mg and P levels were significantly higher, and Ca levels were significantly lower, in cases than in controls at birth. Mean serum ALP level was 1188.5IU/l in cases, significantly higher than that in controls at birth. Bone abnormalities were noted on radiography in 2 subjects. By 3 weeks old, serum ALP levels did not differ significantly between cases and controls. Logistic regression analysis revealed maternal administration of MgSO(4) and multiple pregnancies were significantly related to serum ALP level in neonates at birth. CONCLUSION: Prolonged maternal administration of MgSO(4) significantly affects neonatal serum biochemistry related to bone metabolism. Potential long-term adverse effects on neonates and how Mg affects fetal bone metabolism in utero need to be investigated in future studies.