Vertebral Incidence Research Articles

Impact of changes in physical activity and incident fracture after acute ischemic stroke

Stroke survivors are at an increased risk of falls and fractures. Physical activity is inversely associated with the fracture risk in the general population. However, the association between incident fracture risk and changes in habitual physical activity before and after an index stroke remains unclear. This study attempted to explore the association between incident fracture risk and changes in physical activity after stroke. Using the claims database of the National Health Insurance Program in Korea, participants with their first ischemic stroke between 2010 and 2016 were enrolled in the study. The participants were divided into four groups according to changes in physical activity habits evaluated using two consecutive self-reported questionnaires before and after stroke, if available: persistent non-exercisers, exercise dropouts, new exercisers, and persistent exercisers. The primary outcome was a composite of vertebral, hip, and other fractures. We performed multivariable Cox proportional hazard regression analysis and provided adjusted hazard ratios and 95% confidence intervals for each outcome. Among 202,234 participants included from 1,005,879 datasets, 16,621 (8.22%) experienced any type of fracture as the primary outcome. After multivariable adjustment, exercise dropouts (n = 37,106), new exercisers (n = 36,821), and persistent exercisers (n = 74,647) had a significantly reduced risk of any type of fracture (aHR 0.932, 95% CI 0.893–0.973; aHR 0.938, 95% CI 0.900–0.978; aHR 0.815, 95% CI 0.780–0.852, respectively) compared to the persistent non-exercisers (n = 53,660). Furthermore, regardless of pre-stroke exercise status, those who exercised ≥ 1000 metabolic equivalents of tasks post-stroke had a significantly reduced risk of fractures. Initiating or continuing moderate-to-vigorous regular physical activity after acute ischemic stroke was associated with a significantly lower risk of incident fractures, including hip, vertebral, and other types.

Self-reported sleep characteristics and risk for incident vertebral and hip fracture in women

ObjectiveTo examine the relationships between self-reported sleep characteristics and risk of incident vertebral fracture and hip fracture in women. DesignLongitudinal cohort study. SettingNurses’ Health Studies (NHS: 2002-2014, NHSII: 2001-2015). ParticipantsTotal 122,254 female registered nurses (46,129 NHS, 76,125 NHSII) without prior history of fracture. ExposureSleep was characterized by 4 sleep-related domains—sleep duration, sleep difficulty, snoring, and excessive daytime sleepiness—assessed by self-reported questionnaires. OutcomesSelf-reports of vertebral fracture were confirmed by medical record review and hip fracture was assessed by biennial questionnaires. ResultsOver 12-14 years of follow-up, 569 incident vertebral fracture cases (408 in NHS, 161 in NHSII) and 1,881 hip fracture cases (1,490 in NHS, 391 in NHSII) were documented. In the pooled analysis, the multivariable-adjusted HR (95% CI) for vertebral fracture was 1.20 (0.86, 1.66) for sleep duration ≤5 hours vs. 7 hours and 0.82 (0.60, 1.12) for ≥9 vs. 7 hours; 1.63 (0.93, 2.87) for sleep difficulties all-the-time vs. none/little-of-the-time (p-trend = 0.005); 1.47 (1.05, 2.05) for snoring every night/week vs. never/occasionally (p-trend = 0.03), and 2.20 (1.49, 3.25) for excessive daytime sleepiness daily vs. never (p-trend < 0.001). In contrast, associations were not observed with hip fracture risk. ConclusionPoorer sleep characteristics were associated with risk of vertebral fracture. Our study highlights the importance of multiple dimensions of sleep in the development of vertebral fractures. Further research is warranted to understand the role of sleep in bone health that may differ by fracture site, as well as sleep interventions that may reduce the risk of fracture.

Impact of teriparatide therapy in Indian postmenopausal women with osteoporosis with regard to DXA-derived parameters.

Background:There is paucity of literature on the impact of teriparatide on hip geometry and bone microarchitecture globally and none from the Indian subcontinent. This study examined the outcome of teriparatide therapy on vertebral fractures, bone mineral density (BMD), hip structural analysis (HSA), and trabecular bone score (TBS) in Indian postmenopausal women with severe osteoporosis.Methodology:Ambulatory postmenopausal women above the age of 50 years with either severe osteoporosis or vertebral fractures, or both, were recruited. All patients received cholecalciferol (2000 IU/day), calcium carbonate (elemental calcium 1 g/day), and teriparatide (20 mcg subcutaneously/day) for 24 months. Baseline bone biochemistry, BMD, TBS, and HSA were assessed and repeated after 24 months of therapy. Incident vertebral and nonvertebral fractures were also studied.Results:A total of 51 postmenopausal women with mean (SD) age of 65.7(8.6) years, and mean (SD) body mass index of 22.7 (3.5) kg/m2 were recruited in this study. Vertebral fractures were present in 74.5% (38/51) at baseline. Following teriparatide therapy, significant improvement was observed in the BMD (g/cm2) at both the lumbar spine (0.706–0.758: p < 0.001) and femoral neck (0.551–0.579: p = 0.047) as well as the TBS (1.160–1.271: p < 0.001). Most indices of proximal hip geometry also showed significant improvement following teriparatide therapy at 24 months. Incident vertebral fractures were noted in only 7.8% (4/51) of participants, while 92% (47/51) of participants did not develop any new vertebral fractures on follow-up.Conclusion:In South Indian postmenopausal women with either severe osteoporosis or vertebral fractures, or both, teriparatide was effective in improving the bone mineral parameters and bone quality.

Part 2: When Should Bisphosphonates Be Used in Children with Chronic Illness Osteoporosis?

Part 1 of this review on secondary osteoporosis of childhood was devoted to understanding which children should undergo bone health monitoring, when to label a child with osteoporosis in this setting, and how best to monitor in order to identify early, rather than late, signs of bone fragility. In Part 2 of this review, we discuss the next critical step in deciding which children require bisphosphonate therapy. This involves distinguishing which children have the potential to undergo "medication-unassisted" recovery from secondary osteoporosis, obviating the need for bisphosphonate administration, from those who require anti-resorptive therapy in order to recover from osteoporosis. Unlike children with primary osteoporosis such as osteogenesis imperfecta, where the potential for recovery from osteoporosis without medical therapy is limited, many children with secondary osteoporosis can undergo complete recovery in the absence of bisphosphonate intervention. Over the last decade, natural history studies have unveiled the spectrum of this recovery, which spans overt deterioration (i.e., incident vertebral and non-vertebral fractures and declines in bone mineral density (BMD)), to spectacular reclamation of BMD, and complete restoration of normal vertebral dimensions after spine fractures. The fact that reshaping of vertebral bodies following fractures is growth-dependent underscores the need to identify and treat those at risk for permanent vertebral deformity in a timely fashion. The decision to treat a child with a bisphosphonate hinges on distinguishing bone fragility from typical childhood fractures, and determining the potential for medication-unassisted recovery following an osteoporotic fragility fracture. While improvements in BMD are a well-known sign of recovery, restitution of bone structure is also a key indicator of recuperation, one that is unique to childhood, and that plays a pivotal role in the decision to intervene or not.

Local Bone Mineral Density, Subcutaneous and Visceral Adipose Tissue Measurements in Routine Multi Detector Computed Tomography-Which Parameter Predicts Incident Vertebral Fractures Best?

In this case-control study the value of bone mineral density (BMD) at different vertebral levels, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) to identify patients with incident osteoporotic vertebral fractures in routine multi-detector computed tomography (MDCT) exams was assessed. Material and methods: Seventeen patients who underwent baseline and follow-up routine contrast-enhanced MDCT and had an incident osteoporotic vertebral fracture at follow-up were included. Seventeen age-, sex- and follow-up duration-matched controls were identified. Trabecular BMD (from Th5 to L5) as well as cross-sectional area of SAT and VAT were extracted. Results: BMD performed best to differentiate patients with an incident fracture from controls at the levels of Th5 (area under the curve [AUC] = 0.781, p = 0.014), Th7 (AUC = 0.877, p = 0.001), and Th9 (AUC = 0.818, p = 0.005). Applying multivariate logistic regression BMD at Th7 level remained the only significant predictor of incident vertebral fractures (Th5-L5) with an odds ratio of 1.07 per BMD SD decrease. VAT and SAT did not show significant differences between the fracture and control group (p > 0.05). Conclusion: The local BMD measurement appears to be more suitable than standard mean BMD from L1–L3 for fracture risk assessment.

Relationship between diffuse idiopathic skeletal hyperostosis and fragility vertebral fracture: a prospective study in older men.

To analyse the risk of incident vertebral and non-vertebral fracture in men with DISH. In 782 men ages 50-85 years, DISH was diagnosed using Resnick's criteria. In men followed prospectively for 7.5 years, a radiographic incident vertebral fracture was defined by a decrease of ≥20% or ≥4mm in any vertebral height vs baseline. Self-reported incident non-vertebral fractures were confirmed by medical records. Men with DISH had higher BMD at the lumbar spine (P < 0.05), but not at other skeletal sites. After adjustment for confounders including disc space narrowing (DSN) and endplate irregularity, the risk of vertebral fracture was higher in men with DISH vs men without DISH [10/164 (6.1%) vs 16/597 (2.7%), P < 0.05; odds ratio (OR) 2.89 (95% CI 1.15, 7.28), P < 0.05]. DISH and low spine BMD were each associated with a higher vertebral fracture risk. The vertebral fracture risk was higher in men who had both DISH and severe DSN. DISH and endplate irregularities (EIs) were each associated with higher vertebral fracture risk. DISH, DSN and EIs define the intervertebral space dysfunction, which was associated with higher vertebral fracture risk [OR 3.99 (95% CI 1.45, 10.98), P < 0.01]. Intervertebral space dysfunction improved the vertebral fracture prediction (ΔAUC = +0.111, P < 0.05), mainly in men with higher spine BMD (>0.9 g/cm2; ΔAUC = +0.189, P < 0.001). DISH was not associated with the risk of non-vertebral fracture. DISH is associated with higher vertebral fracture risk, independently of other risk factors. Assessment of the intervertebral space dysfunction components may improve the vertebral fracture prediction in older men.

Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Antiresorptive Drugs: Proportion of Treatment Effect Explained.

Few analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction seeking to estimate the proportion of treatment effect explained (PTE) by BTMs. Pooling such information would be useful to assess new ARs or novel dosing regimens. In the Foundation for the National Institutes of Health (FNIH) Bone Quality project, we analyzed individual-level data from up to 62,000 participants enrolled in 12 bisphosphonate (BP) and four selective estrogen receptor modulator (SERM) placebo-controlled fracture endpoint trials. Using BTM results for two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and pro-collagen I N-propeptide [PINP]) and one bone resorption marker (C-terminal telopeptide of type I collagen [CTX]) and incident fracture outcome data, we estimated the PTE using two different models. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 5 years of follow-up. For vertebral fracture, the results showed that changes in all three BTMs at 6 months explained a large proportion of the treatment effect of ARs (57 to >100%), but not for and non-vertebral or hip fracture. We conclude that short-term AR treatment-related changes in bone ALP, PINP, and CTX account for a large proportion of the treatment effect for vertebral fracture. Change in BTMs is a useful surrogate marker to study the anti-fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Two adipocytokines, leptin and adiponectin, independently predict osteoporotic fracture risk at different bone sites in postmenopausal women

Although associations among obesity, adipocytokines, and bone mineral density have been reported, the influence of adipocytokines on osteoporotic fractures remains unclear. This study aimed to assess the impact of the adipocytokines leptin and adiponectin on the risk of incident vertebral and long-bone fractures in postmenopausal women. Clinical data were obtained from the retrospective Nagano Cohort Study of outpatients followed at a single primary care institute in Nagano Prefecture, Japan, between 1993 and 2018. The primary outcome was the occurrence of incident vertebral or long-bone fractures. In total, 1167 Japanese postmenopausal women (mean age: 65.9years) completed the follow-up and the average observation period was 7.2years. The subjects were divided into 4 groups (quartile 1 to 4) based respective leptin and adiponectin values. Kaplan-Meier analysis demonstrated a significantly lower incident long-bone fracture rate in the higher quartiles of serum leptin levels (p=0.002). A significantly higher and more rapid occurrence of incident vertebral fractures, but not long-bone fractures, was found in the highest adiponectin quartile (p<0.001). A Cox proportional hazards model adjusted for confounders including age, body weight, and either leptin or adiponectin revealed lower leptin levels and higher adiponectin levels as significant independent risk factors for incident long-bone fractures (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.50-0.96; p=0.03) and vertebral fractures (HR 1.18, 95% CI 1.02-1.37; p=0.02), respectively. Therefore, serum leptin and adiponectin may be independent risk factors for osteoporotic fractures affecting different bone types and sites. Determining patient adipocytokine levels may help predict the occurrence of specific osteoporotic fractures, thereby enabling optimal treatment for osteoporosis and improving quality of life.

Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Anti-Resorptive Drugs: A Meta-Regression.

Few pooled analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction. Such information would be useful to assess new ARs or novel dosing regimens. In the Foundation for the National Institutes of Health (FNIH) Bone Quality project, we analyzed individual-level data from 28,000 participants enrolled in 11 bisphosphonate (BP) and three selective estrogen receptor modulator (SERM) placebo-controlled fracture endpoint trials. Using BTM results for two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and pro-collagen I N-propeptide [PINP]) and two bone resorption markers (N-terminal and C-terminal telopeptide of type I collagen) and incident fracture outcome data, we performed a meta-regression relating the mean net effect of treatment on change in bone turnover (active minus placebo % difference after 3 to 12 months) to the log of study-wide fracture risk reduction, and used linear regression to plot the best fitting line. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 4 years of follow-up. Change in bone ALP and PINP were available for over 16,000 and 10,000 participants, respectively. For vertebral fracture, the results showed a strong relationship between treatment-related bone ALP or PINP changes and vertebral fracture risk reduction (r2 = 0.82 [p < 0.001] and r2 = 0.75 [p = 0.011], respectively) Relationships were weaker and no longer statistically significant for nonvertebral (r2 = 0.33 [p = 0.053] and r2 = 0.53 [p = 0.065], respectively) and hip fracture (r2 = 0.17 [p = 0.24] and r2 = 0.43 [p = 0.11], respectively) outcomes. Analyses limited to BP trials gave similar results. For all fracture types, relationships were weaker and nonsignificant for bone resorption markers. We conclude that short-term AR treatment-related changes in bone ALP and PINP strongly predict vertebral fracture treatment efficacy, but not nonvertebral or hip fracture treatment efficacy. Change in bone formation markers might be useful to predict the anti-vertebral fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs. © 2017 American Society for Bone and Mineral Research.

Effectiveness of Oral Bisphosphonates in Reducing Fracture Risk Among Oral Glucocorticoid Users: Three Matched Cohort Analyses.

The benefit of oral bisphosphonates in reducing fracture risk in glucocorticoid-induced osteoporosis is controversial. We aimed to estimate the effectiveness of oral bisphosphonates in reducing fracture risk in a cohort of new chronic oral glucocorticoid users. We created three matched cohorts using health care administrative data from Ontario, Canada. We included residents aged 66 years and older initiating chronic oral glucocorticoids (≥450 mg prednisone equivalent and ≥2 glucocorticoid prescriptions within a 6-month window) between January 1998 and September 2014. Exposed patients were those who initiated an oral bisphosphonate (alendronate, etidronate, or risedronate) within the first 6 months of starting chronic oral glucocorticoid therapy. Exposed cohorts (3945 alendronate, 5825 risedronate, and 8464 etidronate) were each matched 1:1 to unexposed patients on glucocorticoid exposure, fracture risk factors, and propensity score. We examined incident hip (primary outcome), vertebral, forearm, and humerus fractures using Cox proportional hazard models. Alendronate (hazard ratio [HR] = 0.46, 95% confidence interval [CI] 0.25-0.80) and risedronate (HR = 0.58, 95% CI 0.36-0.90) were associated with reduced hip fracture risk. Alendronate (HR = 0.52, 95% CI 0.39-0.68), etidronate (HR = 0.59, 95% CI 0.48-0.73) and risedronate (HR = 0.47 95% CI 0.36-0.60) were associated with reduced vertebral fracture risk. No risk reduction in forearm or humerus fractures was apparent for any bisphosphonate. Among older chronic glucocorticoid initiators, all oral bisphosphonates reduced vertebral fracture risk, yet only alendronate and risedronate reduced hip fracture risk. Results were similar between men and women. We provided compelling evidence that early initiation of oral bisphosphonates during chronic oral glucocorticoid therapy is beneficial to prevent osteoporotic fractures. © 2017 American Society for Bone and Mineral Research.

Older men with severe disc degeneration have more incident vertebral fractures-the prospective MINOS cohort study.

Data on the relationship between disc degeneration (DD) and fragility fractures in men are limited. The aim of this study was to prospectively analyse the risk of vertebral and non-vertebral fractures in men with thoracolumbar DD according to the severity of its radiological signs: disc space narrowing (DSN), osteophytes and endplate sclerosis. Men >50 years of age (n = 765) had lateral spine radiographs and DXA and were monitored prospectively. We analysed the risk of incident vertebral (7.5 years) and non-vertebral fractures (10 years) in men according to the severity of DD. After adjustment for age and weight, BMD increased with increasing total DSN score, endplate sclerosis and osteophytosis. Over 7.5 years, 28 incident vertebral fractures occurred in 27 men. After adjustment for age, BMI, spine BMD, prior fractures and abdominal aortic calcifications, the vertebral fracture risk was 3-fold higher in the upper DSN quartile vs men without DSN. After adjustment for the same confounders, vertebral fracture risk was also nearly 3-fold higher in the upper DSN quartile vs the three lower quartiles combined. Over 10 years, 61 men sustained non-vertebral fragility fractures. After adjustment for age, BMI, hip BMD, abdominal aortic calcifications and prior falls and fractures, the non-vertebral fracture risk decreased with increasing DSN score. The risk of non-vertebral fracture was half as high in men above the median total DSN score vs men below the median. In older men, severe DD is associated with higher BMD. Multilevel severe DSN is associated with higher vertebral fracture risk and lower non-vertebral fracture risk.

Serum Periostin Is Associated With Fracture Risk in Postmenopausal Women: A 7-Year Prospective Analysis of the OFELY Study

Periostin (POSTN) is a secreted γ-carboxyglutamic acid-containing protein expressed mainly in the periosteum in adult individuals. POSNT deficient mice develop periodontis and osteoporosis with decreased bone strength. The relationship between serum POSTN and bone metabolism and fracture risk in postmenopausal women is unknown. Serum POSTN was measured in 607 postmenopausal women (mean age 66.6 ± 8.4 y) from the Os des Femmes de Lyon cohort at the ninth annual follow-up visit (baseline visit of the current analysis). Nonvertebral and clinical vertebral incident fragility fractures were reported annually during 7 years. Areal bone mineral density (BMD; measured by dual energy X-ray absorptiometry) of the hip and bone markers (intact N-terminal propeptide of type I collagen, osteocalcin, and serum type I collagen C-telopeptide) were also measured. At baseline, serum POSTN did not correlate with age, bone markers, and BMD. After a median of 7 years of follow-up, 75 women sustained an incident clinical vertebral or nonvertebral fragility fracture. The proportion of women who had an incident fracture was significantly higher in women with levels of POSTN in the highest quartile than that of women in the three other quartiles (19.5% vs 10.1%, P = .018) after adjustment for age and prevalent fracture. The highest quartile of POSTN was associated with an increased risk of incident fracture with a relative risk (95% confidence interval) of 1.88 (1.1-3.2) after adjustment for age, prevalent fracture, and hip BMD T-score. Patients with both low hip BMD (T-score < -2.5) and high levels of POSTN (fourth quartile) had a relative risk of fracture of 7.1 (95% confidence interval 2.4-21.8) after adjustment for age. High serum POSTN levels are independently associated with increased fracture risk in postmenopausal women. These data suggest that serum POSTN could be useful to improve fracture risk assessment.

Fracture incidence after 3 years of aromatase inhibitor therapy.

The purpose of this study was to describe the fracture incidence and bone mineral density (BMD) evolution in a large cohort of post-menopausal women with breast cancer after 3 years of aromatase inhibitor (AI) therapy. A prospective, longitudinal study in real-life setting. Each woman had an extensive medical assessment, a biological evaluation, a BMD measurement, and systematic spinal X-rays at baseline and after 3 years of AI therapy. Women with osteoporosis at baseline (T-score < -2.5 and/or non-traumatic fracture history) were treated by oral weekly bisphosphonates. Among 497 women (mean age 63.8 ± 9.6 years) included in this study, 389 had a bone evaluation both at baseline and after 3 years of AI therapy: 267 women (mean age 61.2 ± 8.6) with no osteoporosis at baseline and 122 women (mean age 67.2 ± 9.1) with osteoporosis at baseline justifying a weekly oral bisphosphonate treatment. Women without bisphosphonates had a significant decrease in spine BMD (-3.5%, P < 0.01), neck BMD (-2.0%, P < 0.01), and total hip BMD (-2.1%, P < 0.01) over the 3 years but only 15 of them (5.6%) presented an incident vertebral or non-vertebral fracture. In osteoporotic women treated with bisphosphonates, spine and hip BMD were maintained at 3 years but 12 of them (9.8%) had an incident fracture. These fractured women were significantly older (74.1 ± 9.8 versus 66.5 ± 8.8) but also presented BMD loss during treatment suggesting poor adherence to bisphosphonate treatment. This real-life study confirmed that AIs induced moderate bone loss and low fracture incidence in post-menopausal women without initial osteoporosis. In women with baseline osteoporosis and AI therapy, oral bisphosphonates maintain BMD but were associated with a persistent fracture risk, particularly in older women.

Impact of androgen suppression and zoledronic acid on bone mineral density and fractures in the Trans‐Tasman Radiation Oncology Group (TROG) 03.04 Randomised Androgen Deprivation and Radiotherapy (RADAR) randomized controlled trial for locally advanced prostate cancer

To study the influence of adjuvant androgen suppression and bisphosphonates on incident vertebral and non-spinal fracture rates and bone mineral density (BMD) in men with locally advanced prostate cancer. Between 2003 and 2007, 1071 men with locally advanced prostate cancer were randomly allocated, using a 2 × 2 trial design, to 6 months i.m. leuprorelin (androgen suppression [AS]) before radiotherapy alone ± 12 months additional leuprorelin ± 18 months zoledronic acid (ZdA), commencing at randomization. The main endpoint was incident thoraco-lumbar vertebral fractures, which were assessed radiographically at randomization and at 3 years, then reassessed by centralized review. Subsidiary endpoints included incident non-spinal fractures, which were documented throughout follow-up, and BMD, which was measured in 222 subjects at baseline, 2 years and 4 years. Incident vertebral fractures at 3 years were observed in 132 subjects. Their occurrence was not increased by 18 months' AS, nor reduced by ZdA. Incident non-spinal fractures occurred in 72 subjects and were significantly related to AS duration but not to ZdA. Osteopenia and osteoporosis prevalence rates at baseline were 23.4 and 1.4%, respectively, at the hip. Treatment for 6 and 18 months with AS caused significant reductions in hip BMD at 2 and 4 years (P < 0.01) and ZdA prevented these losses at both time points. In an AS-naïve population, 18 months of ZdA treatment prevented the sustained BMD losses caused by 18 months of AS treatment; however, the study power was insufficient to show that AS duration or ZdA influenced vertebral fracture rates.

Advances in Target-Specific Therapy for Osteoporosis

Bone is constantly being remodeled, with resorption preceding formation. In the individual who is not losing bone mass, bone remodeling is balanced, with the osteoblast forming the same amount of bone that has been resorbed by the osteoclast. Remodeling in the aging skeleton, aided and abetted by estrogen deficiency after the menopause, is not balanced, with bone resorption exceeding bone formation; as a result, bone loss ensues. The earliest therapeutic attempts to correct this imbalance were focused on inhibiting bone resorption, thus bringing the bone remodeling unit into better balance. When alendronate, an amino-containing bisphosphonate, was approved by the US Food and Drug Administration in 1995 (1–3), it was known that it reduced bone resorption, but the molecular mechanism of action (inhibition of a key enzyme in the mevalonate pathway, farnesyl pyrophosphate synthase) was not understood until later (4, 5). Subsequently, other bisphosphonates (risedronate, ibandronate, and zoledronic acid) joined the family of approved bisphosphonates for the treatment of osteoporosis. Along with estrogen, raloxifene (an estrogen analog), and calcitonin, these agents together are called “antiresorptive” drugs. Although it is true that their initial mechanistic effect is to reduce bone resorption, these drugs also reduce bone formation. Their therapeutic effect depends on the inhibition of resorption being greater than inhibition of formation. Although the classification of these drugs as antiresorptives is not correct because they are general antiremodeling agents, it is unlikely that other more accurate terms such as “anticatabolic” or “antiremodeling” will replace the common classification that is universally used. These antiresorptive agents appear to be generally safe and well tolerated and, with specific reference to alendronate, risedronate, and zoledronic acid, are associated with significant increases in bone mineral density (BMD) and reductions in the incidence of vertebral, hip, and nonvertebral fractures. Despite their safety and efficacy, these drugs maintain skeletal microstructure but do not rebuild it. In 2002, the therapeutic landscape for osteoporosis changed with the approval of teriparatide as a therapy for osteoporosis (6). Teriparatide is the amino-terminal sequence of human PTH [rhPTH (1–34)]. Although chronically elevated levels of PTH cause bone loss by increasing bone resorption, intermittent use of teriparatide or the full-length molecule, PTH (1–84), is associated with a distinct osteoanabolic effect. The pharmacokinetics of this effect are described by an early increase in bone formation, rather exclusively, followed soon thereafter by an increase in bone resorption. Thus, an “anabolic window” is created, helping to explain the osteoanabolic properties of this drug. As with the bisphosphonates, the use of teriparatide for the treatment of osteoporosis was based on empiric observations, with the molecular mechanisms of action worked out only later. As noted for the antiresorptive agents, the terminology for teriparatide is a bit garbled because teriparatide’s actions are not exclusively osteoanabolic. Its effects are also associated in time with an increase in bone resorption. The osteoanabolic effect due to the anabolic window is relatively short-lived. The true osteoanabolic effect, namely when teriparatide is exclusively stimulating bone formation, is likely to be an increase in bone modeling, that is bone formation on quiescent bone surfaces. Similar in principle, however, to the antiresorptives (inhibition of bone resorption is chronically greater than inhibition of bone formation), the efficacy of teriparatide is prolonged beyond the modeling period because bone formation exceeds bone resorption

Updates on mechanism of action and clinical efficacy of risedronate in osteoporosis

Risedronate is a heterocyclic orally active aminobisphosphonate and it belongs to the bisphosphonate category: these drugs are powerful bone resorption inhibitors, thanks to their affinity for hydroxyapatite crystals at bone mineral matrix level and to their inhibiting effects on osteoclast activity, using the ability of inhibiting enzyme FPPS. Recent observations have reported that risedronate can decrease resorption entity, not only of the trabecular bone, but also of the cortical bone, modifying therefore the (bone compact) thickness and the cortical porosity entity, which is largely responsible of femoral fracture especially among elderly patients. Various controlled studies have proved the efficacy of risedronate in reducing fragility fracture risk significantly. In particular, it is able to lower in a very significant way the incidence of vertebral, non-vertebral and femoral fractures, with precocity of effects after only six months of therapy. The extension of protocols, moreover, has marked its efficacy even after seven years of treatment. Under the metabolic profile, these studies have also shown that risedronate activity can reduce bone resorption markers and increase bone density values at lumbar and femoral level. Results emerged from a group of women aged over 80 are relevant: risedronate has proved capable of decreasing femoral fracture risk. Also in male and steroidal osteoporosis, clinical controlled studies have shown that risedronate is effective in decreasing vertebral fracture incidence. Lastly, tolerability: the main side effects concern the gastrointestinal tract and they are usually rare, of minor entity and can be solved by sospending the treatment. Acute phase reaction is rare, due to risedronate oral administration; it is also valid for osteonecrosis of the jaw and atypical fractures.

Prevention of incident fractures in patients with prevalent fragility fractures: Current and future approaches.

Fragility fractures are a significant, independent risk factor for new fractures, but treatment uptake in subjects with prevalent fractures is disappointing. We addressed the question of the efficacy of pharmacological interventions in reducing the risk of incident fractures in patients with prevalent fragility fractures. For this, we reviewed randomised controlled trials (RCTs), pre-planned and post-hoc analyses of RCTs of approved agents for the treatment of osteoporosis. Results showed that a number of agents decrease the risk of incident vertebral and nonvertebral fractures in subjects with prevalent vertebral fractures, justifying the recommendation of treating such patients independently of the level of bone mineral density (BMD). By contrast, the evidence of antifracture efficacy of these agents in patients with prevalent nonvertebral fractures is limited. Advances in our understanding of the regulation of bone metabolism at the molecular level have identified targets for the development of new therapeutics for osteoporosis, some of which are currently in phase 3 clinical development.

Serum 25-hydroxyvitamin D below 25 ng/mL is a risk factor for long bone fracture comparable to bone mineral density in Japanese postmenopausal women

There is emergent evidence for divergent associations between 25(OH)D levels and fractures by race and ethnicity, but data on Asian populations are sparse. We investigated this association in a primary care cohort of 1470 postmenopausal Japanese women followed for a mean period of 7.2 years and explored a potential threshold of 25(OH)D. Endpoints were incident vertebral, proximal femur, and long bone fractures. Rate ratios were estimated using multivariate Poisson regression adjusted for lumbar or femur bone mineral density (BMD) less than -2.5 SD of the young adult mean (YAM), age, weight, presence of diabetes mellitus, parathyroid hormone, estimated glomerular filtration rate, prior fracture, back pain, present medications and past medical history. Mean age was 63.7 ± 10.7 years and osteoporosis patients were 41.3 %. The background data of the present participants were almost identical to the subjects participating in the National Health and Nutrition Survey of 2003. Overall, 49.6 % of the subjects had a 25(OH)D value <20 ng/mL and 27.8 % had a 25(OH)D value from 20 to 24 ng/mL. The propensity score for exposure to 25(OH)D < 25 ng/mL in the present and independent community dwelling populations, namely the Miyama and Taiji cohorts, were not significantly different, suggesting no evidence for selection bias. The generalized additive models showed clear decreasing trends in incidence rates of proximal femur and long bone fractures at higher levels of 25(OH)D, and the annual incidence rate of proximal femur fracture was around 0.0005 in women with 25(OH)D > 25 ng/mL, probably leading to the decreasing trend in long bone fracture. Multivariate-adjusted rate ratios of 25(OH)D < 25 ng/mL were 1.01 (95 % confidence interval [CI], 0.84-1.22, p = 0.88) for vertebral fracture, 2.71 (95 % CI 0.94-7.83, p = 0.07) for proximal femur fracture, and 2.20 (95 % CI 1.37-3.53, p < 0.01) for long bone fracture. The respective rate ratios of a BMD level lower than -2.5 SD of the YAM were 1.61 (95 % CI 1.33-1.94, p < 0.01), 1.52 (95 % CI 0.67-3.45, p = 0.32), and 1.54 (95 % CI 1.02-2.33, p = 0.04). In conclusion, 25(OH)D is a leading risk factor for long bone fracture comparable to BMD in Japanese postmenopausal women. The contribution of 25(OH)D to fracture risks is substantial even below 25 ng/mL and is possibly site-specific. We recommend measuring the serum 25(OH)D level in primary care settings.

SAT0347 Risk factors associated with incident hip fractures in 9,720 japanese patients with rheumatoid arthritis: A prospective observational cohort study

BackgroundPatients with rheumatoid arthritis (RA) have a high risk of hip fracture. Limited data exist in the literature concerning risk factors for incident hip fractures in patients with RA. Previously,we...

THU0405 Prevalence of and Factors Associated with Vitamin D Deficiency in 4,793 Japanese Patients with Rheumatoid Arthritis

BackgroundVitamin D (25[OH]D) deficiency is reported to be common in patients with rheumatoid arthritis (RA). Low vitamin D (25[OH]D) levels are also reported to be associated with disease activity, physical...