Risk Of Morphometric Vertebral Fractures Research Articles

OR32-6 Pre-Surgical GH Levels Predict the Risk of Morphometric Vertebral Fracture, Which Is an Early and Frequent Event in the Natural History of Acromegaly

Introduction. Acromegalic osteopathy is an emerging complication of the disease, characterized by increased bone turnover, deterioration in bone microarchitecture and high risk of vertebral fractures (VFs). However, the prediction of VFs in this clinical setting is still a matter of uncertainty, since the pathogenesis of acromegalic osteopathy is multifactorial and fractures may occur even in presence of normal bone mineral density. Purpose of the study. We aimed at evaluating the prevalence and determinants of VFs in a cohort of patients (pts) with acromegaly at hospital admission for transsphenoidal (TNS) surgery. Patients & Methods. We retrospectively enrolled 65 pts (34M/31F; age 50.4±11.7yrs) attending the Neurosurgery Unit before TNS surgery. All pts had a confirmed diagnosis of acromegaly (nadir GH during OGTT 75gr > 0.4 ng/mL and IGF-I above age-standardized upper normal limit), in whom all parameters of other pituitary axes (TSH, fT3, fT4, ACTH, cortisol, PRL, LH, FSH, E2/Testosterone) and a thoracic X-ray carried out for anesthesiological reasons were available. We performed a vertebral morphometric evaluation of the thoracic spine on X-ray images (MTRx), according to Genant grading. Data are presented as mean±SD; normally distributed continuous variables were analyzed with Student-t test; categorical data were analyzed with Fisher’s exact test. Results. Medical pre-treatment with SRLs was prescribed in 37 pts (56.9%, 19M/18F). At morphometric evaluation, 21 pts (32.3%, 11M/10F) presented with VFs (14 pts with mild VFs, 7 pts with moderate VFs). The fractured pts showed significantly higher GH levels when compared to non-fractured (20.1±28.0 ng/mL vs. 7.5±7.0 ng/mL; p<0.01). Conversely, no significant differences in thyroid, adrenal and gonadal parameters, as well as IGF-I and PRL levels between the two groups were observed. In multiple logistic regression analysis, GH was independently associated with the risk of any fracture (OR 1.09, 95%CI 1.01-1.17; p=0.03) and severity of VFs (1.04, 95%CI 1.01-1.07; p=0.03). Conclusions. For the first time, we observed that VFs are a very frequent, early and sometimes severe complication of acromegaly. Our findings also showed that pre-surgical GH levels were able to predict the risk and the severity of VFs at MTRx in patients with acromegaly.

A systematic review and meta-analysis of the effect of bisphosphonate drug holidays on bone mineral density and osteoporotic fracture risk.

We performed a systematic review and meta-analysis on the effect of drug holidays (discontinuation) on BMD and fracture risk. We searched PubMed, Embase, and Cochrane Library databases to locate controlled clinical trials and cohort studies evaluating the effect of drug holidays/discontinuation versus osteoporosis treatment continuation. We performed random-effects meta-analyses of hazard ratios of hip and any clinical osteoporotic fracture for individuals who discontinued bisphosphonates compared to persistent users. Thirteen records reporting results from eight different studies met inclusion criteria. The FLEX study found a reduced clinical vertebral fracture risk with 10years of alendronate therapy compared to 5 (RR 0.45, 95% CI 0.24-0.85), and the HORIZON extension studies found a reduced risk of morphometric vertebral fracture with 6years of zoledronic acid therapy compared to 3 (OR = 0.51, 95% CI 0.26-0.95); subgroup analyses showed that women with low hip BMD T-scores after the initial treatment period benefitted from continued treatment in terms of reduced vertebral fracture risk. Meta-analysis of adjusted hazard ratios of hip and any clinical osteoporotic fracture for women who discontinued bisphosphonates revealed no significant differences in the risk of hip fracture (summary estimate of HR 1.09, 95% CI 0.87-1.37) or any clinical fracture (summary estimate of HR 1.13, 95% CI 0.75-1.70) compared to persistent users. Bisphosphonate discontinuation may be considered for women who do not have low hip BMD after 3 to 5years of initial treatment, while women who have low hip BMD may benefit from treatment continuation.

FRAX and the effect of teriparatide on vertebral and non-vertebral fracture.

Daily teriparatide injections have been shown to reduce vertebral and non-vertebral fractures. Here, we demonstrate that the magnitude of fracture risk reduction is independent of baseline fracture probability assessed by FRAX. Daily administration of 20 or 40 μg teriparatide has been shown to significantly decrease the risk of vertebral and non-vertebral fracture compared with placebo. The aim of the present study was to evaluate fracture risk assessed at baseline using the FRAX® tool and to determine the efficacy of teriparatide as a function of baseline fracture risk. One thousand six hundred thirty-seven postmenopausal women in the pivotal phase three trial, randomly assigned to receive placebo (n = 544), teriparatide 20 μg per day (n = 541) or teriparatide 40 μg per day (n = 552), were studied. Baseline clinical risk factors were entered into country-specific FRAX models to compute the 10-year probability of major osteoporotic fractures with or without input of femoral neck BMD. Because there was no difference in effect of 20 and 40 μg teriparatide daily on fracture occurrence, the two active groups were merged. The interaction between probability of a major fracture and treatment efficacy was examined by Poisson regression. The 10-year probability of major osteoporotic fractures (with BMD) ranged from 2.2-67.2 %. Treatment with teriparatide was associated with a 37 % decrease in all non-vertebral fractures (95 % CI 10-56 %) and a 56 % decrease in low-energy non-vertebral fractures (95 % CI 24-75 %) compared with placebo. The risk of morphometric vertebral fractures decreased significantly by 66 % (95 % CI 50-77 %). Hazard ratios for the effect of teriparatide on the fracture outcome did not change significantly with increasing fracture probability (p > 0.30). Similar findings were noted for the interaction when BMD was excluded from the FRAX model, or when probability of hip fracture was used as the marker of baseline risk. We conclude that teriparatide significantly decreases the risk of non-vertebral and morphometric vertebral fractures in women by a similar extent, irrespective of baseline fracture probability.

Reassessment of Fracture Risk in Women After 3 Years of Treatment With Zoledronic Acid: When is it Reasonable to Discontinue Treatment?

Data are needed to guide therapeutic decisions about stopping bisphosphonates after an initial treatment period. To define significant predictors of fracture and quantify fracture incidence in risk factor-defined subgroups of women who discontinue zoledronic acid (ZOL) after 3 years of treatment. To determine if continuing ZOL reduces fracture risk in subgroups. This study is based on data from the 3 year extension of HORIZON. Subjects were in the ZOL arm of the Multicenter HORIZON trial. One thousand two hundred thirty three women who previously received 3 ZOL treatments during the Core trial. Randomization to three additional annual ZOL (Z6, n = 616) or placebo infusions (Z3P3, n = 617). The risk of morphometric vertebral fractures (MorphVertFx) and clinical nonvertebral fractures (NVF). The incidence of MorphVertFx in Z3P3 was predicted by femoral neck (FN) t-score ≤-2.5 [OR 3.3 (1.4, 8.0), p = .008], total hip (TH) t-score ≤-2.5 [OR 4.0 (1.8, 9.0), p = .0007], and incident MorphVertFx during Core [OR 4.75 (1.4, 16.8), p < .015]. Incidence of NVF was predicted by TH t-score [for 1 decline, HR 1.7 (1.2, 2.6), p = .008], incident NVF during Core [HR 2.5 (1.2, 5.3), p = .014], and prevalent vertebral fracture [HR 3.0 (1.4, 6.3), p = .005]. For MorphVertFx, there were no significant treatment subgroup interactions; absolute fracture reductions with continued ZOL were greatest in high-risk subgroups. For NVF, there were no significant treatment reductions overall or in subgroups and no significant interactions. After 3 years of ZOL, in women who have a TH t-score above -2.5, no recent incident fracture and no more than one risk factor (almost 55% of the population), risk for subsequent fracture (over three additional years) is low if treatment is discontinued (for MorphVertFx, average risk 3.2% and for NVF, average risk 5.8%). In these patients, discontinuation for up to 3 years is reasonable.

Acromegaly and bone disease.

To provide an update on current understanding of osteoporosis associated with acromegaly. Patients with acromegaly have an increased risk of morphometric vertebral fractures. This seems to correlate with acromegaly activity and its duration, but it persists after biochemical control is achieved. Coexistent hypogonadism, diabetes mellitus and over-replacement with glucocorticoids have additional detrimental effects. Bone mineral density can be normal, increased or decreased, and is usually discordant with occurrence of fractures. However, a decrease in the hip bone mineral density during follow-up has been associated with development of new vertebral fractures. Bone turnover markers are increased and tend to normalize after biochemical control of acromegaly. Hypercalcemia rarely occurs in acromegaly and may be parathyroid hormone-dependent or 1,25 dihydroxy-vitamin D dependent. The latter improves with biochemical control of acromegaly. Screening with thoracic and lumbar vertebral radiographs is indicated in patients with acromegaly. We recommend biochemical control of acromegaly, treatment of hypogonadism and other risk factors of osteoporosis and avoiding supraphysiologic doses of glucocorticoids. Further studies are needed to understand mechanisms of skeletal fragility in acromegaly and clinical impact of vertebral fractures. Further studies of tailored therapy for patients with acromegaly and osteoporosis are also needed.

Vertebral fracture risk factors in postmenopausal women over 50 in Valencia, Spain. A population-based cross-sectional study

PurposeThis study aims to estimate the prevalence of risk factors for osteoporotic vertebral fracture and analyze the possible associations between these factors and the presence of densitometric osteoporosis and prevalent morphometric vertebral fracture. MethodsData from a population-based cross-sectional sample of 804 postmenopausal women over the age of 50years old living in the city of Valencia (Spain) were used. The women were interviewed to identify the prevalence of osteoporotic fracture risk factors and underwent a densitometry and a dorsolumbar spine X-ray. ResultsThe most prevalent risk factors were densitometric osteoporosis (31.7%), history of parental hip fracture (19.4%), hypoestrogenism (19%), and body mass index (BMI) ≥30kg/m2 (35.2%). After adjusting for all covariables, densitometric osteoporosis was associated with increased age [odds ratio (OR)65–69years: 2.84, 95% confidence interval (CI): 1.75–4.61; OR70–74years: 4.01, 95% CI: 2.47–6.52; OR75+years: 5.96, 95% CI: 3.27–10.87] and inversely associated with high BMI (OR25.0–29.9: 0.51, 95% CI: 0.34–0.76; OR≥30: 0.30, 95% CI: 0.19–0.46). Morphometric vertebral fracture was associated with age (OR65–69years: 2.04, 95% CI: 1.03–4.05; OR70–74years: 4.05, 95% CI: 2.11–7.77; OR75+years: 8.43, 95% CI: 3.97–17.93), poor educational level (OR: 1.70, 95% CI: 1.06–2.72) and with densitometric osteoporosis and BMI ≥30kg/m2 (OR: 3.35, 95% CI: 1.85–6.07). ConclusionsThe most prevalent osteoporotic fracture risk factors were having a high BMI and the presence of densitometric osteoporosis. A higher risk of morphometric vertebral fracture in women with both low bone mineral density and high BMI was found. This association, if confirmed, has important implications for clinical practice and fracture risk tools. We also found a higher risk in women with a poor educational level. More attention should be addressed to these populations in order to control modifiable risk factors.

The effects of intravenous zoledronic acid in Chinese women with postmenopausal osteoporosis

The aim of this study was to assess the efficacy and safety of a once-yearly zoledronic acid treatment for Chinese women with postmenopausal osteoporosis in Taiwan and Hong Kong. This post hoc subpopulation analysis, from the Health Outcome and Reduced Incidence with Zoledronic Acid One Yearly Pivotal Fracture Trial, enrolled 323 Chinese women with osteoporosis who were randomly given either annual infusions of zoledronic acid or placebo for 3 consecutive years. The incidence of fractures and changes in bone mineral density (BMD) were measured; adverse events (AEs) and tolerability were recorded and assessed. The results of this study at 36months demonstrate that there was a significantly reduced risk of morphometric vertebral fracture and clinical vertebral fracture in subjects treated with zoledronic acid (P<0.05). In addition, there were significant increases of BMD by 4.9%, 4.3%, and 7.0% in the total hip, femoral neck, and trochanter, respectively, in the zoledronic acid group compared with the placebo group (P<0.001 for all comparisons). The incidences of AEs were comparable between the two groups. Thus, once-yearly zoledronic acid treatment showed bone protection effects by reducing the risk of vertebral fracture and increasing BMD in Chinese women with postmenopausal osteoporosis.

A meta-analysis of the efficacy of raloxifene on all clinical and vertebral fractures and its dependency on FRAX®

Introduction Multiple Outcomes of Raloxifene Evaluation (MORE), a placebo controlled phase III study of raloxifene in postmenopausal osteoporosis, showed that both doses tested (60 mg and 120 mg daily) reduced the risk of vertebral fracture. There was no significant effect on non-vertebral fracture. Aims The aim of the present study was to evaluate the distribution of fracture risk assessed at baseline using the FRAX® tool in MORE and to determine the efficacy of raloxifene as a function of baseline fracture risk. The effects of raloxifene (60 and 120 mg daily combined) with placebo on the risk of all clinical fractures as well as the risk of morphometric vertebral fracture were examined as a function of baseline fracture risk. Methods Baseline clinical risk factors and BMD were entered in the FRAX® model to compute the 10-year probability of major osteoporotic fractures. The interaction between fracture probability and treatment efficacy was examined by Poisson regression. Results The 10-year probability of major osteoporotic fractures (with BMD) ranged from 0.9% to 77.2%. The incidence of clinical fractures and morphometric vertebral fractures increased with increasing baseline fracture probabilities. Treatment with raloxifene was associated with an 18% decrease in all clinical fractures compared to placebo treatment (hazard ratio HR = 0.82; 95% CI = 0.71–0.95; p = 0.0063) and a 42% decrease in incident morphometric vertebral fractures (HR = 0.58; 95% CI = 0.48–0.69; p < 0.001). Efficacy was shown over the whole range of fracture probability and the interaction between fracture probability and treatment was not significant. The efficacy or raloxifene on vertebral fracture risk was significantly greater at lower ages. At the 90th percentile of age (75 years) vertebral fracture risk was reduced by 31% irrespective of FRAX® probabilities. In contrast at younger ages, efficacy was higher and increased further still with decreasing fracture probability. Conclusion We conclude that raloxifene (60 and 120 mg doses combined) significantly decreased the risk of all clinical fractures and morphometric fractures in women. Overall, there was no significant interaction between efficacy and fracture probability. In the case of morphometric vertebral fractures efficacy decreased significantly with increasing age.

The role of zoledronic acid in the management of osteoporosis

Bisphosphonates are the current standard of care for treatment of osteoporosis. However, oral bisphosphonates are associated with complicated dosing regimens because of poor absorption and have the potential for upper gastrointestinal (GI) tract irritation, resulting in poor adherence and persistence. Zoledronic acid (ZOL) 5 mg, a once-yearly intravenous bisphosphonate, is approved for treatment and prevention of postmenopausal osteoporosis, increasing bone mass in men with osteoporosis, and treatment and prevention of glucocorticoid-induced osteoporosis. Because it is administered as an infusion, ZOL ensures adherence and persistence over the entire 12-month dosing interval and bypasses the GI absorption/irritation problems associated with oral bisphosphonates. The objective of this study was to review the safety and efficacy of 5 mg ZOL and its potential for improving patient compliance. Published reports dating back to 2001 were reviewed, with emphasis on osteoporosis treatment. In the HORIZON-Pivotal Fracture Trial, annual infusions of 5 mg ZOL produced significant reductions in risk of morphometric vertebral fractures (70%) and hip fractures (41%) vs placebo over 3 years in postmenopausal women with osteoporosis. In the HORIZON-Recurrent Fracture Trial, an annual infusion of 5 mg ZOL after repair of a recent low-trauma hip fracture was associated with significant reductions in risk for new clinical fractures (35%) vs placebo. In men with osteoporosis, an annual treatment of ZOL over 2 years increased lumbar spine bone mineral density (BMD) by 6% compared with baseline. In patients starting or continuing treatment with chronic glucocorticoids, ZOL resulted in significantly greater increases in lumbar spine BMD over 1 year than an oral bisphosphonate. In postmenopausal women with osteopenia, a single infusion of ZOL over a 2-year period produced significantly greater gains in lumbar spine and hip BMD than placebo. ZOL is generally safe and well tolerated. Five milligrams of ZOL has the potential to improve compliance with osteoporosis therapy and, consequently, to reduce fracture risk in clinical practice.

Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX ®

Introduction Bazedoxifene has been shown to significantly decrease the risk of vertebral fractures in postmenopausal women. No significant effect was noted on the risk of clinical fractures, but fracture risk reduction was reported in a post hoc subgroup analysis in a high risk group categorised on the basis of BMD and prior fracture. Aims The aim of this study was to re-evaluate the efficacy of bazedoxifene on fracture outcomes avoiding subgroup analysis by examining the efficacy of intervention as a function of fracture risk. Methods The phase III study was a double-blind, randomised, placebo- and raloxifene-controlled randomised 3-year multinational study that enrolled 7492 osteoporotic women aged 55 years or more (mean age = 66 years). For the present analysis, women taking raloxifene were excluded ( n = 1849), and we compared the effects of two doses of bazedoxifene (20 and 40 mg daily combined) with placebo on the risk of all clinical fractures as well as the risk of morphometric vertebral fracture. The risk of a major osteoporotic fracture was assessed using region specific FRAX ® algorithms, and the relationship between pre hoc 10-year fracture probabilities and efficacy examined by Poisson regression. Results Overall, bazedoxifene was associated with a significant 39% decrease in incident morphometric vertebral fractures (hazard ratio HR = 0.61; 95% CI = 0.43–0.86; p = 0.005) and a non-statistically significant 16% decrease in all clinical fractures (hazard ratio HR = 0.84; 95% CI = 0.67–1.06; p = 0.14) compared to placebo. Hazard ratios for the effect of bazedoxifene on all clinical fractures decreased with increasing fracture probability. In patients with 10-year fracture probabilities at or above 16%, bazedoxifene was associated with a significant decrease in the risk of all clinical fractures. The 16% probability threshold corresponded to the 80th percentile of the study population. Hazard ratios for the effect of bazedoxifene on morphometric vertebral fractures also decreased with increasing fracture probability. In patients with 10-year fracture probabilities above 6.9% (corresponding to the 41st percentile), bazedoxifene was associated with a significant decrease in the risk of morphometric vertebral fractures. At equivalent fracture probability percentiles, the treatment effect of bazedoxifene was greater on vertebral fracture risk than on the risk of all clinical fractures. For example, at the 90th percentile of FRAX ® probability, bazedoxifene was associated with a relative risk reduction of 33% (95% CI = 7–51%) for all clinical fractures and 51% reduction (95% CI = 21–69%) for morphometric vertebral fractures. The findings were robust to several sensitivity analyses. Conclusion Bazedoxifene (20 and 40 mg doses combined) significantly decreased the risk of all clinical fractures and morphometric vertebral fractures in women at or above a FRAX ® based fracture probability threshold. These results, consistent with the previous subgroup analysis, suggest that bazedoxifene should be targeted preferentially to women at high fracture risk.

Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis

A single infusion of intravenous zoledronic acid decreases bone turnover and improves bone density at 12 months in postmenopausal women with osteoporosis. We assessed the effects of annual infusions of zoledronic acid on fracture risk during a 3-year period. In this double-blind, placebo-controlled trial, 3889 patients (mean age, 73 years) were randomly assigned to receive a single 15-minute infusion of zoledronic acid (5 mg) and 3876 were assigned to receive placebo at baseline, at 12 months, and at 24 months; the patients were followed until 36 months. Primary end points were new vertebral fracture (in patients not taking concomitant osteoporosis medications) and hip fracture (in all patients). Secondary end points included bone mineral density, bone turnover markers, and safety outcomes. Treatment with zoledronic acid reduced the risk of morphometric vertebral fracture by 70% during a 3-year period, as compared with placebo (3.3% in the zoledronic-acid group vs. 10.9% in the placebo group; relative risk, 0.30; 95% confidence interval [CI], 0.24 to 0.38) and reduced the risk of hip fracture by 41% (1.4% in the zoledronic-acid group vs. 2.5% in the placebo group; hazard ratio, 0.59; 95% CI, 0.42 to 0.83). Nonvertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and 77%, respectively (P<0.001 for all comparisons). Zoledronic acid was also associated with a significant improvement in bone mineral density and bone metabolism markers. Adverse events, including change in renal function, were similar in the two study groups. However, serious atrial fibrillation occurred more frequently in the zoledronic acid group (in 50 vs. 20 patients, P<0.001). A once-yearly infusion of zoledronic acid during a 3-year period significantly reduced the risk of vertebral, hip, and other fractures. (ClinicalTrials.gov number, NCT00049829.)