Accelerated Bone Mineral Density Research Articles

Off-treatment bone mineral density changes in postmenopausal women receiving anastrozole for 5 years: 7-year results from the IBIS-II prevention trial

BackgroundAnastrozole has been associated with substantial accelerated bone mineral density (BMD) loss during active treatment.MethodsOne thousand four hundred and ten women were included in a BMD substudy and stratified into three strata according to their baseline T-score at spine or femoral neck. The primary objective of this analysis was to investigate whether DXA BMD at the spine and hip changed two years after treatment cessation (between years 5 and 7) in those who did not receive risedronate.ResultsFive- and seven-year BMD data were available for a total of 528 women who did not receive risedronate. In women with normal BMD at baseline, an increase in BMD at the lumbar spine after anastrozole withdrawal was observed 1.25% (95% CI 0.73 to 1.77) (P = 0.0004), which was larger than in those on placebo (0.14% (−0.29 to 0.56))). At the hip, BMD remained unchanged between years 5 and 7 for those previously on anastrozole but continued to a decrease in those who had been randomised to placebo (−1.35% (−1.70 to −0.98)).ConclusionsThese are the first results reporting BMD changes after stopping anastrozole in a breast cancer prevention setting. Our results show that the negative effects of anastrozole on BMD in the preventive setting are partially reversible.

Radiographic Emphysema, Circulating Bone Biomarkers, and Progressive Bone Mineral Density Loss in Smokers.

Osteoporosis is common in individuals with chronic obstructive pulmonary disease. Lung-specific factors, including radiographic emphysema, independently associate with low bone mineral density in cross-sectional smoking cohorts. However, factors associated with progressive bone loss in smokers are understudied and largely unknown. To determine the relationship between radiographic emphysema, circulating bone metabolism markers, and pulmonary function and accelerated bone mineral density loss in smokers. Two hundred and forty male and female current and former smokers, 40 years of age or older, underwent baseline and 2-year assessments of pulmonary function, computed tomography-assessed emphysema, dual X-ray absorptiometry-measured bone mineral density, and circulating bone metabolism biomarker levels (type I collagen C-telopeptide [CTX], amino-terminal propeptide of type I procollagen [P1NP]). The association of radiographic emphysema, bone metabolism biomarker levels, and pulmonary function with accelerated hip bone mineral density loss, defined by the 75th percentile of annual hip bone mineral density decline, was determined by logistic regression modeling with adjustment for age, sex, inhaled and intermittent steroid use, active smoking, body mass index, and the presence of baseline low hip bone mineral density. Of those participants with accelerated hip bone mineral density loss, 22% had moderate or severe visually assessed emphysema compared with 7.2% of smokers without accelerated bone mineral density decline. Moderate to severe visually assessed emphysema (odds ratio, 2.84; 95% confidence interval, 1.01-7.98 compared with trace/mild or no visually assessed emphysema) and the 75th percentile of CTX levels (odds ratio, 2.38; 95% confidence interval, 1.20-4.72 compared with CTX levels below the 75th percentile), a marker of bone resorption, were associated with accelerated hip bone mineral density decline after adjustment for covariates and the presence of baseline low hip bone mineral density. FEV1% predicted was not associated with accelerated bone mineral density decline after adjustment for covariates. Multivariate modeling showed moderate to severe visually assessed emphysema, and the 75th percentiles of CTX were independently associated with accelerated hip bone mineral density decline after adjustment for covariates. Emphysema and elevated markers of bone resorption are independently associated with progressive bone mineral density loss in smokers. These clinical markers may guide targeted bone mineral density screening and monitoring in smokers at highest risk.

Evidence-based prevention and treatment of osteoporosis after spinal cord injury: a systematic review.

Spinal cord injury (SCI) results in accelerated bone mineral density (BMD) loss and disorganization of trabecular bone architecture. The mechanisms underlying post-SCI osteoporosis are complex and different from other types of osteoporosis. Findings of studies investigating efficacy of pharmacological or rehabilitative interventions in SCI-related osteoporosis are controversial. The aim of this study was to review the literature pertaining to prevention and evidence-based treatments of SCI-related osteoporosis. In this systematic review, MEDLINE, EMBASE, PubMed, and the Cochrane Library were used to identify papers from 1946 to December 31, 2015. The search strategy involved the following keywords: spinal cord injury, osteoporosis, and bone loss. Finally, 56 studies were included according to the inclusion criteria. Only 16 randomized controlled trials (involving 368 patients) were found. We found following evidences for effectiveness of bisphosphonates in prevention of BMD loss in acute SCI: very low-quality evidence for clodronate and etidronate, low-quality evidence for alendronate, and moderate-quality evidence for zoledronic acid. Low-quality evidence showed no effectiveness for tiludronate. In chronic SCI cases, we found low-quality evidence for effectiveness of vitamin D3 analogs combined with 1-alpha vitamin D2. However, low-quality inconsistent evidence exists for alendronate. For non-pharmacologic interventions, very low-quality evidence exists for effectiveness of standing with or without treadmill walking in acute SCI. Other low-quality evidences indicated that electrical stimulation, tilt-table standing, and ultrasound provide no significant effects. Very low-quality evidence did not show any benefit for low-intensity (3days per week) cycling with functional electrical stimulator in chronic SCI. No recommendations can be made from this review, regarding overall low quality of evidence as a result of high risk of bias, low sample size in most of the studies, and notable heterogeneity in type of intervention, outcome measurement, and duration of treatment. Therefore, future high-quality RCT studies with higher sample sizes and more homogeneity are strongly recommended to provide high-quality evidence and make applicable recommendations for prevention and treatment of SCI-related bone loss.

Factors influencing the late phase of recovery after bone mineral density loss in allogeneic stem cell transplantation survivors.

Accelerated bone mineral density loss (BMDL) occurs early after allogeneic stem cell transplantation (SCT) and is related to factors such as steroids and chronic GvHD. In order to understand the natural history of BMDL of SCT in the longer term, we evaluated a longitudinal cohort of 148 survivors with a median follow-up of 12 years (range 3-22 years). All women received hormone replacement therapy, and routine calcium/vitamin D supplementation was recommended but ∼50% of patients still had suboptimal vitamin D levels and bisphosphonates were rarely utilized. BMD significantly improved from 5 to 20+ years but the femoral neck and forearm remained vulnerable sites. Younger age, higher pretransplant body mass index (BMI) and increment in BMI post transplant were significantly associated with increased BMD and protected against osteopenia/osteoporosis. These findings support consideration of BMD loss in SCT survivors in two phases, an early phase of BMD loss (3-5 years) followed by a later phase of BMD recovery, with different protective and aggravating factors. Treatment- and transplant-related factors (such as steroids, immunosuppressives, chronic GvHD, vitamin D) are known to impact the early phase of BMD loss but age and BMI are more influential in the late phase of BMD recovery.

Switching from tenofovir to abacavir in HIV-1-infected patients with low bone mineral density: changes in bone turnover markers and circulating sclerostin levels.

Tenofovir is involved in accelerated bone mineral density (BMD) loss. We recently published a hip BMD improvement at week 48 [+2.1% (95% CI: -0.6, 4.7) (P = 0.043)] in HIV-infected patients with osteopenia/osteoporosis randomized to switch from tenofovir to abacavir (n = 26), although without reaching statistical significance compared with those who maintained tenofovir (n = 28). Here, we present changes at week 48 in bone markers [C-terminal telopeptide of collagen type 1 (CTX), osteocalcin and procollagen type 1 N propeptide (P1NP)] as well as in circulating levels of three proteins involved in bone regulation [osteoprotegerin, receptor activator for NF-κB ligand (RANKL) and sclerostin, a selective regulator of bone formation through the Wnt pathway] in 44 of these patients. χ(2) or Fisher and Student t-tests were performed according to the distribution of the variables. Bone markers decreased only in the abacavir group [mean (SD) CTX changed from 0.543 (0.495) to 0.301 (0.306) ng/mL; mean (SD) osteocalcin changed from 23.72 (22.20) to 13.95 (12.40) ng/mL; and mean (SD) P1NP changed from 54.68 (54.52) to 28.65 (27.48) ng/mL (P < 0.001 in all cases)], reaching statistical significance between the groups at week 48. Osteoprotegerin did not vary, but sclerostin significantly increased in the abacavir group [from 29.53 (27.91) to 35.56 (34.59) pmol/L, P = 0.002]. No significant differences in osteoprotegerin and sclerostin were detected between the groups at week 48. RANKL values were below the limit of detection in all samples. The switch from tenofovir to abacavir seems to induce a positive effect on bone tissue, since bone turnover markers decreased. In addition, circulating sclerostin levels increased, a change associated with improved bone properties.

Disease Activity and Bone Mineral Density of MCP Joints in Patients with Rheumatoid and Psoriatic Arthritis: Is There a Correlation?—A Study in Patients Treated with Methotrexate and an Anti-TNFα Agent

Background. Bone damage in rheumatoid arthritis (RA) and in psoriatic arthritis (PsA) includes an accelerated bone mineral density (BMD) reduction. The objective was to evaluate BMD variations of the metacarpophalangeal joints (MCPs) in patients starting treatment with methotrexate (MTX) or etanercept. Methods. Patients affected by RA or PsA with hand joints involvement and with moderate or high disease activity, were enrolled in this study. All patients underwent clinical examination, laboratory exams, and a DXA scan of the most affected hand, as assessed with an ultrasound examination at the baseline, at the time of enrolment and after 1, 3, 6, and 12 months. Patients non-responders to MTX received combination therapy, while patients with no previous treatment initiated MTX. Results. 22 patients were enrolled. In both RA and PsA groups, BMD increased independently of the treatment. However, in the patients affected by RA, a slight BMD decrease was observed at the last checkup. Globally, the BMD variations of the MCPs were strongly correlated with the disease activity. At the reduction of DAS28, the scores corresponded an increase of BMD. Conclusions. MCPs BMD is inversely correlated to disease activity. BMD increase seems to be correlated with the response to treatment and not with the drug itself.

Protection of bone in premenopausal women with breast cancer: focus on zoledronic acid

Maintaining bone health is important for patients with breast cancer (BC), the most commonly diagnosed cancer in American women. Indeed, bone loss is common throughout the BC disease continuum. In the metastatic BC setting, patients are likely to develop bone metastases, a painful complication that can lead to potentially debilitating skeletal-related events. Bone health is equally important for patients with early BC. During adjuvant therapy for early BC, the largest challenge to bone health is from accelerated bone mineral density (BMD) loss. Although decreased BMD is well recognized in older, postmenopausal women, it may be underestimated in younger, premenopausal women undergoing endocrine therapy for BC. The rate and extent of cancer therapy-induced bone loss (from chemotherapy or endocrine therapy) are substantially greater than normal decreases in BMD during menopause. Bisphosphonates such as zoledronic acid (ZOL) are antiresorptive agents indicated for the treatment of bone metastases from BC. Clinical trials over the past few years suggest that, although not yet approved for this indication, ZOL can prevent cancer therapy-induced bone loss and improve BMD in premenopausal women receiving adjuvant (endocrine or chemo-) therapy for BC. Furthermore, the benefits of ZOL therapy may go beyond maintaining bone health and include potential anticancer benefits together with favorable tolerability and cost/benefit profiles. This review will focus specifically on the role of ZOL in preserving the bone health of premenopausal women with BC.

The Relationship Between Proton Pump Inhibitor Use and Longitudinal Change in Bone Mineral Density: A Population-Based From the Canadian Multicentre Osteoporosis Study (CaMos)

Proton pump inhibitor (PPI) use has been identified as a risk factor for hip and vertebral fractures. Evidence supporting a relationship between PPI use and osteoporosis remains scant. Demonstrating that PPIs are associated with accelerated bone mineral density (BMD) loss would provide supportive evidence for a mechanism through which PPIs could increase fracture risk. We used the Canadian Multicentre Osteoporosis Study data set, which enrolled a population-based sample of Canadians who underwent BMD testing of the femoral neck, total hip, and lumbar spine (L1-L4) at baseline, and then again at 5 and 10 years. Participants also reported drug use and exposure to risk factors for osteoporosis and fracture. Multivariate linear regression was used to determine the independent association of PPI exposure and baseline BMD, and on change in BMD at 5 and 10 years. In all, 8,340 subjects were included in the baseline analysis, with 4,512 (55%) undergoing year 10 BMD testing. After adjusting for potential confounders, PPI use was associated with significantly lower baseline BMD at the femoral neck and total hip. PPI use was not associated with a significant acceleration in covariate-adjusted BMD loss at any measurement site after 5 and 10 years of follow-up. PPI users had lower BMD at baseline than PPI non-users, but PPI use over 10 years did not appear to be associated with accelerated BMD loss. The reasons for discordant findings between PPI use at baseline and during follow-up require further study.

Common Genetic Variants Are Associated with Accelerated Bone Mineral Density Loss after Hematopoietic Cell Transplantation

BackgroundBone mineral density (BMD) loss commonly occurs after hematopoietic cell transplantation (HCT). Hypothesizing that genetic variants may influence post-HCT BMD loss, we conducted a prospective study to examine the associations of single nucleotide polymorphisms (SNP) in bone metabolism pathways and acute BMD loss after HCT.Methods and FindingsWe genotyped 122 SNPs in 45 genes in bone metabolism pathways among 121 autologous and allogeneic HCT patients. BMD changes from pre-HCT to day +100 post-HCT were analyzed in relation to these SNPs in linear regression models. After controlling for clinical risk factors, we identified 16 SNPs associated with spinal or femoral BMD loss following HCT, three of which have been previously implicated in genome-wide association studies of bone phenotypes, including rs2075555 in COL1A1, rs9594738 in RANKL, and rs4870044 in ESR1. When multiple SNPs were considered simultaneously, they explained 5–35% of the variance in post-HCT BMD loss. There was a significant trend between the number of risk alleles and the magnitude of BMD loss, with patients carrying the most risk alleles having the greatest loss.ConclusionOur data provide the first evidence that common genetic variants play an important role in BMD loss among HCT patients similar to age-related BMD loss in the general population. This infers that the mechanism for post-HCT bone loss is a normal aging process that is accelerated during HCT. A limitation of our study comes from its small patient population; hence future larger studies are warranted to validate our findings.

Accelerated Bone Mineral Density Loss Occurs with Similar Incidence and Severity, But with Different Risk Factors, after Autologous versus Allogeneic Hematopoietic Cell Transplantation

Bone mineral density (BMD) loss occurs commonly in patients after allogeneic hematopoietic cell transplantation (HCT), primarily because of steroid use, but little is known about BMD change post-autologous HCT. In a prospective study of 206 consecutive first HCT patients, we measured acute BMD change at the lumbar spine and dual femur between baseline and day +100, and evaluated risk factors for bone loss. Accelerated BMD loss in this 4-month period occurred after both autologous and allogeneic HCT with similar severity (median, 0.03 g/cm(2) versus 0.03 g/cm(2) at the spine; 0.03 g/cm(2) versus 0.05 g/cm(2) at the femur, respectively). This is equivalent to 7 to 17 years' worth of bone loss by aging. Risk factors for BMD loss were different between autologous and allogeneic HCT patients: lymphoma was associated with greater bone loss after autologous HCT than myeloma, whereas higher steroid dose was the most significant risk factor after allogeneic HCT. Multivariable risk models explained 11% to 30% of the variation in HCT-related BMD change. Surprisingly, BMD loss post-autologous HCT occurred with similar incidence and severity to allogeneic HCT, even in the absence of steroid use. Evaluation of clinical strategies to prevent and reverse HCT-related BMD loss is necessary in both autologous and allogeneic HCT patients.

This Month in Gastroenterology

This Month in Gastroenterology

Proton-Pump Inhibitor Use Is Not Associated With Osteoporosis or Accelerated Bone Mineral Density Loss

Proton-Pump Inhibitor Use Is Not Associated With Osteoporosis or Accelerated Bone Mineral Density Loss

Proton-Pump Inhibitor Use Is Not Associated With Osteoporosis or Accelerated Bone Mineral Density Loss

Proton-Pump Inhibitor Use Is Not Associated With Osteoporosis or Accelerated Bone Mineral Density Loss

Proton-Pump Inhibitor Use Is Not Associated With Osteoporosis or Accelerated Bone Mineral Density Loss

Recent studies have shown an association between proton-pump inhibitor use (PPI) and hip fracture. The mechanism by which PPI use promotes the development of hip fracture is uncharacterized. Therefore, we sought to determine whether PPI use is associated with osteoporosis or accelerated bone mineral density (BMD) loss. We used the Manitoba Bone Mineral Density Database to determine the relationship between chronic PPI use and osteoporosis on an initial assessment of BMD and on BMD loss between successive assessments of BMD. In the cross-sectional study, cases with osteoporosis at the hip or lumbar vertebrae (T-score < or =-2.5) were matched to 3 controls with normal BMD (T-score > or =-1.0). In the longitudinal analysis, the change in BMD among PPI users and nonusers between successive BMD assessments was assessed. Conditional logistic regression and multivariate linear regression were used to obtain estimates of the association between PPI use and osteoporosis and of the annualized change in BMD associated with PPI use. PPI use was not associated with having osteoporosis at either the hip (OR, 0.84; 95% CI, 0.55-1.34) or the lumbar spine (OR, 0.79; 95% CI, 0.59-1.06) for PPI use >1500 doses over the previous 5 years. In the longitudinal study no significant decrease was observed in BMD at either site attributable to PPI use. PPI use does not appear to be associated with either the presence of osteoporosis or accelerated BMD loss. The association between PPI use and hip fracture is probably related to factors independent of osteoporosis.

Clinical and Genetic Factors Underlying Acute Bone Mineral Density Loss by 100 Days after Blood and Marrow Transplantation: A Potential Early Regimen-Related Complication

Accelerated bone mineral density (BMD) loss after blood and marrow transplantation (BMT) has been described, with corticosteroid dose as the most important risk factor. Loss of BMD exponentially increases fracture risk, where a 10–15% decrease in BMD approximately doubles the risk. Our preliminary study [BMT 41:393–398, 2008] demonstrated that BMD loss frequently occurs even among patients with little to no steroid exposure. In the general population, common genetic variations are estimated to contribute as much as 50–80% of the phenotypic variation in bone-related traits, however genetic factors have not been examined in relation to BMD loss post-BMT. In the current study, we prospectively measured BMD by dual energy X-ray absorptiometry (DXA) scans at the lumbar spine and dual femur on all adult (≥18 yrs) first autologous or allogeneic BMT patients at our center. Pre- and post-BMT serum levels of 25(OH)D, parathyroid hormone (PTH) and Ca++ were collected within 2 weeks of each DXA scan. From 1/2006 and 4/2008, 151/157 (96%) BMT patients had a DXA scan a median 22 days pre-BMT, and 106/151 had a second DXA scan a median 100 days post-BMT. Reasons for not having a second DXA were early mortality (n=32) or medically unfit (n=13). Median age was 51 yrs, 61% were male, and 92% were White. The diseases included ALL (5%), AML (23%), lymphoma (39%), MDS/aplastic anemia (9%), and myeloma/amyloidosis (25%). BMT type was 57% autologous and 43% allogeneic, with 86% receiving blood stem cells. Conditioning and treatment regimens were myeloablative (74%) or reduced intensity (26%). While BMD for the majority remained in the normal range, there was a significantly accelerated BMD loss in most patients. After standardizing the time between pre- and post-BMT DXAs to 100 days, the median BMD change was −0.031 g/cm2 at the spine and −0.043 g/cm2 at the femur, which equates to a median annual loss rate of 9.2% and 14.4%, respectively. In men and premenopausal women, the average annual BMD loss rate is 0.2–0.4% per year, and increases after menopause to 1–2% per year. When compared to the expected BMD loss rates among healthy adults and adjusted for gender and age, the loss seen in BMT patients measured in a 4 month period was equivalent to aging their bones by approximately 12 yrs at the spine and 9 yrs at the femur. Serum levels of 25(OH) D, PTH, or Ca++ were not associated with BMD measured pre- or post-BMT nor with BMD loss. Multivariate analysis demonstrated the following significant risk factors for BMD loss at the spine: steroid dose, baseline BMD, and conditioning regimen; and at the femur: steroid dose, baseline BMD, age, gender, BMI and stem cell type. The multivariate models did not demonstrate a difference between autologous and allogeneic BMT. To estimate the performance of these clinical factors in explaining the variance in BMD loss, we calculated R2 of the best multivariate models. Although statistically significant (P<0.0001), our best model explained only 17% of the variance in BMD loss at the spine and 44% at the femur. We are currently analyzing 170 genetic polymorphisms selected from 46 candidate genes from 6 pathways: vitamin D-related genes, cytokines and their receptors, bone matrix genes, estrogen-related genes, PTH and steroid-related genes, and other genes. Gene-based and pathway-based approaches will be used to identify genetic factors that play an important role in BMD loss related to BMT. Finally, a complete model integrating clinical and genetic factors will be built to predict risk of bone loss, and early interventions can therefore be tailored to patients at high risk. It is clear that accelerated BMD loss occurs early after BMT which increases the risk of osteopenia, osteoporosis and fractures at an earlier age in the BMT population than in the general population. Thus, BMD loss could be considered a regimen-related toxicity due to its close proximity to and association with BMT.

Predictors of bone loss after hip fracture.

Although accelerated bone mineral density (BMD) loss follows hip fracture, little is known about factors associated with this loss. We examined potential predictors of BMD loss in a cohort of community-dwelling women who had sustained hip fracture and who were followed for 1 year after fracture. BMD was measured at the femoral neck, intertrochanteric region, and total body, during hospitalization and 2, 6, and 12 months later. Demographic, health, lifestyle, clinical, surgical, and functional characteristics at baseline, and postfracture activity were evaluated for associations with baseline BMD and BMD 1 year later. To examine possible BMD-dependent effects, high and low baseline BMD groups were defined. None of the studied factors consistently predicted either baseline BMD or BMD at 1 year after fracture, among women with either high or low baseline BMD. Baseline BMD was the only factor that substantially and consistently predicted change, explaining 70% to 90% of variation. These results suggest that BMD will not be preserved by general rehabilitative measures and that prompt, specific intervention to minimize bone loss after hip fracture is an essential element of clinical management of the hip fracture patient.