The relation between bisphosphonate use and non-union of fractures of the humerus in older adults

Summary  While nitrogen-containing bisphosphonates have been shown to reduce fracture risk in postmenopausal women and men, their safety in the period after a fracture is unclear. In fully adjusted multivariable regression models, bisphosphonate use in the post-fracture period was associated with an increased probability of non-union [odds ratio (OR) 2.37, 95% confidence interval (CI) 1.13–4.96]. Clinicians might consider waiting for several months before introduction of a bisphosphonate after a fracture. Introduction  While nitrogen-containing bisphosphonates have been shown to reduce fracture risk in postmenopausal women and men, their safety in the period after a fracture is unclear. We examined the risk of non-union associated with post-fracture bisphosphonate use among a group of older adults who had experienced a humerus fracture. Methods  We conducted a nested case–control study among subjects who had experienced a humerus fracture. From this cohort, cases of non-union were defined as those with an orthopedic procedure related to non-union 91–365 days after the initial humerus fracture. Bisphosphonate exposure was assessed during the 365 days prior to the non-union among cases or the matched date for controls. Multivariable logistic regression models were examined to calculate the OR and 95% CI for the association of post-fracture bisphosphonate use with non-union. Results  From the cohort of 19,731 patients with humerus fractures, 81 (0.4%) experienced a non-union. Among the 81 cases, 13 (16.0%) were exposed to bisphosphonates post-fracture, while 69 of the 810 controls (8.5%) were exposed in the post-fracture interval. In fully adjusted multivariable regression models, bisphosphonate use in the post-fracture period was associated with an increased odds of non-union (OR 2.37, 95% CI 1.13–4.96). Albeit limited by small sample sizes, the increased risk associated with bisphosphonate use persisted in the subgroup of patients without a history of osteoporosis or prior fractures (OR 1.91, 95% CI 0.75–4.83). Conclusions  In this study of older adults, non-union after a humerus fracture was rare. Bisphosphonate use after the fracture was associated with an approximate doubling of the risk of non-union.     

Zoledronate reverses mandibular bone loss in osteoprotegerin-deficient mice

Summary  To characterize the changes in osteoprotegerin-deficient (OPG−/−) mice mandibles and the possible mandibular bone loss prevention by zoledronate. This preventive effect in the mandible differed from that in the proximal tibia and was independent of the OPG pathway. Introduction  The study aimed to characterize both the changes in the mandible in osteoprotegerin-deficient (OPG^−/−) mice and possible mandibular bone loss prevention by zoledronate. Methods  Twenty-eight 6-week-old female mice (C57BL/6J), including OPG^−/− (n = 21) and wild-type (WT) (n = 7) mice, were assigned to four groups after 2 weeks of acclimatization to local vivarium conditions: wild mice with vehicle (WT group); OPG^−/− mice with vehicle (OPG^−/− group); and OPG^−/− mice that were subcutaneously injected with either 50 or 150 μg/kg zoledronate (Zol-50 and Zol-150 groups, respectively). Mice were sacrificed at 4 weeks after these treatments and after fasting for 12 h. Sera were harvested for biochemical analyses. The right mandible and tibia of each mouse were selected for microCT analysis. Student’s t-test was performed for comparisons of bone parameters at different sites in the WT group. Analysis of variance (ANOVA) was used to compare the biomarkers and bone parameters in the different treatment groups. Results  Serum bone-specific alkaline phosphatase (B-ALP) and tartrate-resistant acid phosphatase 5b (TRACP-5b) were significantly decreased in WT mice as compared to the levels in the OPG^−/− mice (P < 0.05). Zoledronate treatment decreased the high serum B-ALP activity observed in OPG^−/− mice to the levels seen in WT mice, while serum TRACP-5b concentrations were decreased to levels even lower than those in WT mice. There were substantial variations in BMD and microstructure of the mandibular and proximal tibial trabeculae. Mandibular bone loss was less affected by OPG gene deprivation than the proximal tibia was. Both zoledronate groups showed greater BMD, trabecular BV/TV, Tb.Th, Tb.N, and Conn.D and a significant decrease in Tb.Sp and SMI as compared to the findings in OPG^−/− mice (P < 0.05). However, higher apparent BMD and more compact plate-like trabeculae were observed in the mandible after treatment with zoledronate as compared to the findings in the proximal tibia. No significant differences were found in any parameter in both zoledronate groups. Conclusions  The present study showed that zoledronate could reverse the significant bone loss in mice mandibles that was induced by OPG gene deficiency. This preventive effect, which was accompanied with considerable inhibition of bone turnover, differed in the mandible and in the proximal tibia and was independent of the OPG pathway. Drs. Sheng and Xu contributed equally to this work.     

Ten-year fracture probability identifies women who will benefit from clodronate therapy—additional results from a double-blind, placebo-controlled randomised study

Summary

Fracture risk prediction can be enhanced by the concurrent assessment of other clinical risk factors. This study demonstrates that the estimation of an individual’s 10-year probability of fracture by the FRAX® algorithm identifies patients at high risk of fracture who will respond to bisphosphonate therapy.

Introduction

Treatments for osteoporosis are targeted largely to patients with low bone density (BMD) or a prior fragility fracture. Fracture risk prediction can be enhanced by the concurrent assessment of other clinical risk factors, but it is important to determine whether the risk so identified can be reduced by intervention. We determined the effect of a bisphosphonate on fracture rates when risk was calculated using a new risk algorithm (FRAX®).

Methods

Women aged 75 years or more were recruited to a randomised, double-blind controlled trial of 800 mg oral clodronate (Bonefos®) daily over 3 years. Baseline clinical risk factors were entered in the FRAX® model to compute the 10-year probability of major osteoporotic fractures with or without input of femoral neck BMD. The interaction between fracture probability and treatment efficacy was examined by Poisson regression.

Results

In 3,974 women, the interaction between fracture probability and treatment efficacy was significant when probability was assessed without BMD (p?=?0.043), but not when BMD was included (p?=?0.10). Efficacy was more evident in those deemed at highest risk. For example women lying at the 75th percentile of fracture probability in the absence of BMD (10-year probability 24%) treatment reduced fracture risk by 27% (HR 0.73, 95%CI 0.58–0.92). In those with a fracture probability of 30% (90th percentile), the fracture risk reduction was 38% (HR 0.62, 0.46–0.84).

Conclusions

The estimation of an individual’s 10-year probability of fracture by the FRAX® algorithm identifies patients at high risk of fracture who will respond to bisphosphonate therapy.     

RisedronatE and ALendronate Intervention over Three Years (REALITY): minimal differences in fracture risk reduction

Summary  The comparative effectiveness of alendronate and risedronate has received limited evaluation. Among 19,063 new users of bisphosphonates, risedronate users had a higher relative rate of hip fracture compared to alendronate users, but the difference in absolute fracture rate was small. We conclude that the agents have comparable efficacy. Introduction  Bisphosphonates differ in their in vitro potency, avidity for bone, and rapidity of onset in clinical trials. To address potential differences between bisphosphonates in comparative effectiveness, we compared new users of alendronate and risedronate to determine if there were differences in the risk of clinical fractures at 1 year and beyond. Methods  Using claims data from a U.S. health care organization, we identified new, adherent users of weekly alendronate or risedronate and assessed subsequent fractures. We calculated fracture incidence rate differences and ratios between the two agents. Results  There were no significant differences in fracture rates between alendronate users (n = 12,956) and risedronate users (n = 6,107) at 1 year. Using all available data, the rate of hip fracture was higher among risedronate users compared to alendronate users (absolute rate difference approximately five per 1,000 person-years). Risedronate users had a higher relative rate (RR) of hip fracture (RR = 1.77, 95% CI 1.15–2.74) and similar rates of clinical vertebral and nonvertebral fractures compared to alendronate users. Conclusions  The absolute rate of clinical fractures among alendronate and risedronate users was similar both at 1 year and beyond, suggesting comparable effectiveness between agents. Some of the investigators (JRC and KGS) receive salary support from the National Institutes of Health (AR053351, AR052361) and the Arthritis Foundation (JRC).     

Bone Turnover in Bone Biopsies of Patients with Low-Energy Cortical Fractures Receiving Bisphosphonates: A Case Series

Recent reports of long-term bisphosphonate-treated patients developing cortical fractures have raised concerns that such fractures may relate to excessive suppression of bone turnover after prolonged use of these drugs. To evaluate the bone histology of patients presenting with cortical fractures after bisphosphonate therapy, we conducted a retrospective analysis of patients treated at Washington University Bone Health Program presenting with a history of low-energy cortical fractures (femoral shaft, pelvis, rib, metatarsal, and ankle), who had received bisphosphonates for at least two consecutive years and had undergone bone biopsy. Fifteen of 54 patients who underwent bone biopsy between November 2004 and March 2007 met the criteria. Of these, 10 patients had findings of suppressed trabecular bone remodeling, as demonstrated by lack of double tetracycline labels. There were no significant differences in bone density, clinical features, and biochemical features between those with suppressed turnover and the other five subjects with normal remodeling. However, the low-turnover group had received bisphosphonates (primarily alendronate) for a significantly longer duration (6.5 ± 0.6 vs. 3.9 ± 0.8 years, P = 0.02). Thus, about two-thirds of patients presenting with cortical fractures while on long-term treatment with bisphosphonates had suppressed turnover. Since the prevalence of such histological findings in nonfracture patients remains unknown, the impact of suppressed bone turnover on the development of cortical fractures cannot be determined. Considering the widespread use of bisphosphonates, it appears that the overall risk of cortical fractures is low. However, there may be a subset of as yet unidentified patients who could be predisposed to this complication.     

二磷酸盐对破骨细胞的影响

二磷酸盐自30多年前被发现对破骨细胞有抑制作用以来,已成为临床上重要抗骨吸收药物。二磷酸盐分为含氮二磷酸盐和不含氮二磷酸盐两类。含氮二磷酸盐对抑制破骨细胞骨吸收机制是通过抑制甲羟戊酸途径实现的,而不含氮二磷酸盐则通过竞争性抑制ADT/ATP移位酶而发挥作用。同时二磷酸盐对成骨细胞与破骨细胞间信号的调节也有重要作用,但其对破骨细胞的具体调节机制尚存在较大争议,仍有待进一步研究。     

Comparative effects of risedronate,atorvastatin, estrogen and SERMs on bone mass and strength in ovariectomized rats

Objective

The aim of this study was to investigate bone protective effects of risedronate, atorvastatin, raloxifene and clomiphene citrate in ovariectomized rats.

Methods

Our study was conducted on 63 rats at Experimental Research Center of Celal Bayar University. Six-month-old rats were divided into seven groups. There were five drug administered ovariectomized groups, one ovariectomized control group without drug administration and one non-ovariectomized control group without drug administration. Eight weeks postovariectomy, rats were treated with the bisphosphonate risedronate sodium, the statin atorvastatin, the estrogen 17β-estradiol and the selective estrogen receptor modulators (SERMs) raloxifene hydrochloride and clomiphene citrate by gavage daily for 8 weeks. At the end of the study, rats were killed under anesthesia. For densitometric evaluation, left femurs and tibiae were removed. Left femurs were also used to measure bone volume. Right femurs were used for three-point bending test.

Results

Compared to ovariectomized group, femur cortex volume increased significantly in non-ovariectomized group (p = 0.016). Compared to non-ovariectomized group, distal femoral metaphyseal and femur midshaft bone mineral density values were significantly lower in ovariectomized group (p = 0.047). In ovariectomy + atorvastatin group, whole femur and femur midshaft bone mineral density and three-point bending test maximal load values were significantly higher than ovariectomized group (p = 0.049, 0.05, and 0.018). When compared to the ovariectomized group, no significant difference was found with respect to femoral maximum load values in groups treated with risedronate, estrogen, raloxifene and clomiphene (p = 0.602, 0.602, 0.75, and 0.927). In ovariectomy + risedronate group, femur midshaft bone mineral density values were significantly higher than the values in ovariectomized group (p = 0.023). When compared to ovariectomized group, no significant difference was found with respect to femur midshaft bone mineral density values in groups treated with estrogen, raloxifene and clomiphene (p = 0.306, 0.808, and 0.095).

Conclusions

While risedronate sodium prevented the decrease in bone mineral density in ovariectomized rats, atorvastatin maintained mechanical characteristics of bone and also prevented the decrease in bone mineral density as risedronate sodium.     

Aminobisphosphonates Cause Osteoblast Apoptosis and Inhibit Bone Nodule Formation In Vitro

Bisphosphonates are widely used for the treatment of bone diseases associated with increased osteoclastic bone resorption. Bisphosphonates are known to inhibit biochemical markers of bone formation in vivo, but it is unclear to what extent this is a consequence of osteoclast inhibition or a direct inhibitory effect on cells of the osteoblast lineage. In order to investigate this issue, we studied the effects of various bisphosphonates on osteoblast growth and differentiation in vitro. The aminobisphosphonates pamidronate and alendronate inhibited osteoblast growth, caused osteoblast apoptosis, and inhibited protein prenylation in osteoblasts in a dose-dependent manner over the concentration range 20-100 microM. Further studies showed that alendronate in a dose of 0.1 mg/kg inhibited protein prenylation in calvarial osteoblasts in vivo, indicating that alendronate can be taken up by osteoblasts in sufficient amounts to inhibit protein prenylation at clinically relevant doses. Pamidronate and alendronate inhibited bone nodule formation at concentrations 10-fold lower than those required to inhibit osteoblast growth. These effects were not observed with non-nitrogen-containing bisphosphonates or with other inhibitors of protein prenylation and were only partially reversed by cotreatment with a fourfold molar excess of ss-glycerol phosphate. We conclude that aminobisphosphonates cause osteoblast apoptosis in vitro at micromolar concentrations and inhibit osteoblast differentiation at nanomolar concentrations by mechanisms that are independent of effects on protein prenylation and may be due in part to inhibition of mineralization. While these results need to be interpreted with caution because of uncertainty about the concentrations of bisphosphonates that osteoblasts are exposed to in vivo, our studies clearly demonstrate that bisphosphonates exert strong inhibitory effects on cells of the osteoblast lineage at similar concentrations to those that cause osteoclast inhibition. This raises the possibility that inhibition of bone formation by bisphosphonates may be due in part to a direct inhibitory effect on cells of the osteoblast lineage.     

Intramuscular Neridronate in Postmenopausal Women with Low Bone Mineral Density

Compliance to osteoporosis treatment with oral bisphosphonates is very poor. Intermittent intravenous bisphosphonate is a useful alternative, but this route is not readily available. Neridronate, a nitrogen-containing bisphosphonate that can be given intramuscularly (IM), was tested in a phase 2 clinical trial in 188 postmenopausal osteoporotic women randomized to IM treatment with 25 mg neridronate every 2 weeks, neridronate 12.5 or 25 mg every 4 weeks, or placebo. All patients received calcium and vitamin D supplements. The patients were treated over 12 months with 2-year posttreatment follow-up. After 12-month treatment, all three doses were associated with significant bone mineral density (BMD) increases at both the total hip and spine. A significant dose–response relationship over the three doses was observed for the BMD changes at the total hip but not at the spine. Bone alkaline phosphatase decreased significantly by 40–55% in neridronate-treated patients, with an insignificant dose–response relationship. Serum type I collagen C-telopeptide decreased by 58–79%, with a significant dose–response relationship (P < 0.05). Two years after treatment discontinuation, BMD declined by 1–2% in each dose group, with values still significantly higher than baseline at both the spine and the total hip. Bone turnover markers progressively increased after treatment discontinuation, and on the second year of follow-up the values were significantly higher than pretreatment baseline. The results of this study indicate that IM neridronate might be of value for patients intolerant to oral bisphosphonates and unwilling or unable to undergo intravenous infusion of bisphosphonates.     

Bisphosphonate Treatment Increases the Size of the Mandibular Condyle and Normalizes Growth of the Mandibular Ramus in Osteoprotegerin-Deficient Mice

Osteoprotegerin (OPG) is a novel secreted member of the tumor necrosis factor receptor family which plays a crucial role in negative regulation of osteoclastic bone resorption. OPG-deficient (OPG–/–) mice develop severe osteoporosis caused by significant enhancement of bone resorption by osteoclasts. We investigated the effect of administering bisphosphonate on mandibular growth and development in OPG–/– mice. Eight-week-old male OPG–/– mice and wild-type (WT) mice were administered bisphosphonate (1.25 mg/kg body weight) intraperitoneally once every 3 days for 30 days. All bone formation-related parameters and bone resorption-related parameters were significantly lower in OPG–/– mice with bisphosphonate than in those without bisphosphonate. The volume of the whole condyle and the mandibular length in OPG–/– mice without bisphosphonate were significantly smaller than in WT mice without bisphosphonate. Bisphosphonate treatment of the OPG–/– mice resulted in an increase in the volume of the mandibular condyle and mandibular ramus length. In fact, the mandibular ramus length in OPG–/– mice with bisphosphonate was similar to the length in WT mice without bisphosphonate. Histologically, the surface irregularity of the mandibular condyle that was observed in the OPG–/– mice without bisphosphonate tended to be less marked in the OPG–/– mice with bisphosphonate, and the proportion of the area of the cartilage layer relative to the whole condyle was significantly larger in OPG–/– mice with bisphosphonate than in those without bisphosphonate. In conclusion, bisphosphonate treatment results in an increase in mandibular condylar dimensions and normalization of mandibular ramus growth.