The effect of alendronate on bone mass after distal forearm fracture.

Fracture and immobilization of an extremity lead to bone loss at the fracture and at adjacent sites. We conducted a 1-year, single-center, prospective, randomized, double-blind study to determine whether bone loss would occur in the distal radius after a Colles' fracture and whether this loss could be prevented using an antiresorptive drug (alendronate). Thirty-seven women with a recent fracture of the distal forearm and low bone mineral density (BMD) of the lumbar spine were randomized to receive either 10 mg alendronate daily or placebo. BMD of both forearms was measured at baseline and after 3, 6, and 12 months. The results of four women who developed reflex sympathetic dystrophy were not included in the analysis. In the placebo group, there was a significant reduction at 3 months and 6 months in BMD of total radius (p < 0.01), one-third distal radius (p < 0.01), middistal radius (p < 0.05), and ultradistal radius (p < 0.01) on the fractured side. The loss in BMD at one-third distal radius remained significant at month 12 (p < or = 0.001). In the alendronate group BMD of total distal radius, one-third distal radius, and middistal radius at the fractured side remained unchanged. BMD of ultradistal radius increased significantly at months 3, 6, and 12, compared with baseline (p < 0.05). The difference between the two treatment groups was significant at 3 months and 6 months and borderline significant (p = 0.054) after 1 year in total distal radius. In ultradistal radius the differences were significant at all time points. We conclude that BMD of the distal radius of a recently fractured forearm decreases significantly in the 6 months after fracture and the resulting deficit remains evident at least 1 year after fracture. This bone loss can be prevented by alendronate.     

Bone Turnover and the Response to Alendronate Treatment in Postmenopausal Osteoporosis

This study investigated whether bone turnover influences the response to alendronate in women with postmenopausal osteoporosis. One hundred postmenopausal osteoporotic women were randomized to receive either alendronate (10 mg/day) plus calcium (1000 mg/day) (n = 50) or calcium alone (n = 50). Vertebral and radial bone density, measured by DXA, and markers of bone turnover were assessed at baseline and after 1 and 2 years. At the end of treatment, alendronate users showed an increase of 5.0% and 2.3%, respectively, at the lumbar spine and ultradistal radius; in the group treated only with calcium, bone mineral density (BMD) decreased by 1.6% at the lumbar spine and 1.3% at the ultradistal radius. The difference between the two groups was significant (P < 0.001). The patients were divided into high (HT) or low (LT) bone turnover groups, as assessed by 24-hour whole body retention (WBR%) of ^99mTc-methylene-diphosphonate. The response to alendronate treatment was greater in HT patients compared with LT patients. In fact, at the end of the study period, BMD at the lumbar spine had increased by 7.9% in HT patients and by 3.0% in LT patients; the difference between the two groups was significant (P < 0.001). No significant difference between the two groups was found for BMD at the ultradistal radius. In conclusion, the present study demonstrates that 2-year treatment with alendronate has highly positive effects on bone mass at both the lumbar spine and ultradistal radius. The increase in bone mass, especially at the axial level, is influenced by bone turnover. Therefore, the evaluation of bone turnover may be useful in predicting the response to alendronate treatment. Received: 23 April 1998 / Accepted: 10 June 1999     

The volumetric bone density and cortical thickness in adult patients affected by osteogenesis imperfecta.

In patients with osteogenesis imperfecta (OI), a disease characterized by abnormal bone fragility, bone mineral density (BMD) was found to be relatively preserved. Quantitative computed tomography (QCT) is the only available method for directly measuring in vivo both volumetric density and the cross-sectional area. Here we report the data from dual-energy X-ray absorptiometry DXA (spine and hip) and peripheral (pQCT) (ultradistal and proximal radius) measurement of 27 adult patients affected by OI, mostly of type I, compared with a group of healthy persons. In the patients with OI, areal BMD values at both femoral neck and lumbar spine were considerably lower than in control subjects (-32 and -36%, respectively; p<0.001 for body weight and height adjusted values). pQCT volumetric density at the ultradistal radius was 19% lower than in control subjects and this difference rose to 32% for purely cancellous bone tissue. The whole bone cross-sectional area of ultradistal radius, as measured by pQCT, was superimposable to normal. At the proximal radius, both cross-sectional area and cortical area, together with Bending Breaking Resistance Index (BBRI), were significantly lower in OI (-23; -22; -32% respectively; p<0.001 for body weight and height adjusted values), but cortical volumetric density was even slightly higher in the OI group than in control subjects. In conclusion, it appears that the most obvious defect in adults with OI is the inability to acquire an adequate thickness of the cortices of long bone and to achieve or maintain normal trabecular density.     

Which bone densitometry and which skeletal site are clinically useful for monitoring bone mass?

Long-term precision, as well as reproducibility, is important for monitoring bone mineral density (BMD) alteration in response to aging or therapy. In order to investigate which bone densitometry and which skeletal site are clinically useful for monitoring bone mass, we examined the standardized long-term precision of several bone density measurements in 83 healthy Japanese women. Annual BMD measurements were performed for 5 or 6 years using dual X-ray absorptiometry (DXA) on the lumbar spine, radius (EXP5000) and calcaneus (HeelScan); peripheral quantitative computed tomography (pQCT) on the radius (Densiscan1000); and quantitative ultrasound (QUS) on the calcaneus (Achilles+). The long-term precision error for the individual subject was given by the standard error of estimate (SEE), and the standardized long-term precision was defined as the percentage coefficient of variation (CV%) divided by the percentage ratio of the annual bone-loss rate. Based on the CV% of spinal DXA, speed of sound (SOS) and diaphyseal pQCT showed significantly higher precision than others, while radial ultradistal (UD) DXA and heel DXA showed significantly lower precision. The long-term precision errors of other measurements were statistically the same as that of the spinal DXA. The spinal DXA, the radial DXA, and pQCT at both the distal metaphysis and diaphysis showed high rates of annual bone loss. The radial trabecular BMD (pQCT) was significantly higher than that of spinal DXA. The annual rates of bone loss of QUS and of heel DXA were significantly lower than that of spinal DXA. Taken together, standardized long-term precision was obtained in the spinal DXA and radial pQCT. In conclusion, spinal DXA and radial pQCT were considered the most useful monitoring method for osteoporosis, while QUS was considered less useful.     

Peripheral quantitative computed tomography is useful to monitor response to alendronate therapy in postmenopausal women

A forearm fracture (Colles’ fracture) is often the first sign of osteoporosis and may suggest underlying skeletal fragility. Therefore, establishment of a more accurate and reliable method for the measurement of bone mineral density (BMD) at the distal radius would be beneficial for patients who suffer from osteoporosis. The objective of this study was to evaluate the usefulness of peripheral quantitative computed tomography (pQCT) to monitor the response to alendronate therapy at the distal radius in early postmenopausal Japanese women. Thirty-two early postmenopausal women who were diagnosed with osteoporosis or osteopenia were randomized to either alendronate or control treatment. We analyzed the BMD of the distal radius by pQCT, lumbar spine by dual-energy X-ray absorptiometry (DXA) and the biochemical markers of bone turnover (deoxypyridinoline) at baseline, 3, 6 and 12 months. The control group showed a significant decrease from baseline in the trabecular BMD of the radius at 12 months (3.5 ± 3.7%; p < 0.01), whereas the alendronate group showed a significant increase (4.3 ± 8.1%). The changes in the trabecular BMD of the radius between the alendronate and control groups were statistically different at 6 and 12 months (p < 0.01). However, in the total BMD at the diaphysis of the radius, no significant differences were seen in the changes in bone densities between the alendronate and control groups after 1 year of treatment. pQCT detected significant differences in BMD of the radius in early postmenopausal women after 1 year of treatment with alendronate. Collectively, our preliminary clinical trial showed that pQCT might be useful to monitor response to alendronate therapy, especially at the radius, and it might explain why alendronate prevents Colles’ fracture.     

Preferential reductions of paraarticular trabecular bone component in ultradistal radius and of calcaneus ultrasonography in early-stage rheumatoid arthritis

Rheumatoid arthritis (RA) is a major cause of secondary osteoporosis and is frequently associated with both paraarticular and generalized osteoporosis. The present study was designed to investigate the preferential sites of reduction of bone mineral density (BMD), in the early stage of RA, with special emphasis on the differential effect of RA on BMD in trabecular and cortical components. The participants (30 RA patients and 26 healthy participants) were all female with disease duration of less than 1 year. BMD in the radius was measured at 4% (ultradistal site) and 20% (midshaft) to the ulnar length proximal to the end of radius by peripheral quantitative computed tomography. BMD in lumbar spine was measured by dual X-ray absorptiometry and the osteo-sono assessment index (OSI) of the calcaneus by ultrasound. RA patients showed lower BMD preferentially in the trabecular component, but not in cortical bone component of the ultradistal radius than age-matched normal controls. Calcaneus OSI was also significantly reduced. The radial midshaft and lumbar spine did not differ significantly between RA patients and normal controls. Trabecular BMD in the ultradistal radius exhibited negative correlations with serum CRP, ESR, and RF, and calcaneus OSI with M-HAQ score. In conclusion, it was suggested that disease activity of RA and impairment of daily physical activity might be a significant determinant of deterioration of bone structure in paraartciular distal radius and calcaneus, respectively, in early-stage RA patients.     

Impact of bone mineral density in reducing fracture risk in patients receiving alendronate plus alfacalcidol therapy

BackgroudChanges in bone mineral density (BMD) are a potential surrogate marker for fracture endpoints in clinical trials. However little is known whether the increase in BMD in response to combination treatment with alendronate plus alfacalcidol is associated with fracture risk reduction. We aimed to evaluate the impact of BMD on fracture risk in osteoporosis patients, using the data from the randomized clinical trial comparing alendronate plus alfacalcidol with alendronate alone.MethodsWe selected 412 patients with two or more prevalent vertebral fractures and who had BMD measurements at baseline and after 6, 12, and/or 24 months out of 2022 patients from the database of the Japanese Osteoporosis Intervention Trial. Patients in this subset who received combination treatment with alendronate plus alfacalcidol had shown a lower risk of fracture than patients treated with alendronate alone. We used Poisson regression model analysis to calculate the proportion of treatment effect (PTE) that was attributable to BMD increases in patients receiving combination treatment.ResultsThe highest PTE attributable to changes in BMD was 1.2% in patients with a BMD increase of 3% or more in the lumbar spine. For BMD measurements of the radius, the highest PTE was 2.8% with a BMD increase of 0% or more. For BMD measurements of the metacarpal bone, the highest PTE was 1.2% with a BMD increase of 3% or more. In patients with a BMD greater than or equal to 70% of the young adult mean in the lumbar spine, the PTE attributable to BMD was 0.2%. In patients with a BMD greater than or equal to 70% of the young adult mean in the radius, the PTE attributable to BMD was 0.3%.ConclusionsThe additional effects of alfacalcidol in reducing fracture risk do not likely result from increased BMD; other mechanisms remain a possibility.     

Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension.

To determine the effects of continuation versus discontinuation of alendronate on BMD and markers of bone turnover, we conducted an extension trial in which 1099 older women who received alendronate in the FIT were re-randomized to alendronate or placebo. Compared with women who stopped alendronate, those continuing alendronate for 3 years maintained a higher BMD and greater reduction of bone turnover, showing benefit of continued treatment. However, among women who discontinued alendronate and took placebo in the extension, BMD remained higher, and reduction in bone turnover was greater than values at FIT baseline, showing persistence of alendronate's effects on bone. INTRODUCTION: Prior trials including the Fracture Intervention Trial (FIT) have found that therapy with alendronate increases BMD and decreases fracture risk for up to 4 years in postmenopausal women with low BMD. However, it is uncertain whether further therapy with alendronate results in preservation or further gains in BMD and if skeletal effects of alendronate continue after treatment is stopped. MATERIALS AND METHODS: We conducted a follow-up placebo-controlled extension trial to FIT (FIT long-term extension [FLEX]) in which 1099 women 60-86 years of age who were assigned to alendronate in FIT with an average duration of use of 5 years were re-randomized for an additional 5 years to alendronate or placebo. The results of a preplanned interim analysis at 3 years are reported herein. Participants were re-randomized to alendronate 10 mg/day (30%), alendronate 5 mg/day (30%), or placebo (40%). All participants were encouraged to take a calcium (500 mg/day) and vitamin D (250 IU/day) supplement. The primary outcome was change in total hip BMD. Secondary endpoints included change in lumbar spine BMD and change in markers of bone turnover (bone-specific alkaline phosphatase and urinary type I collagen cross-linked N-telopeptide). RESULTS: Among the women who had prior alendronate therapy in FIT, further therapy with alendronate (5 and 10 mg groups combined) for 3 years compared with placebo maintained BMD at the hip (2.0% difference; 95% CI, 1.6-2.5%) and further increased BMD at the spine (2.5% difference; 95% CI, 1.9-3. 1%). Markers of bone turnover increased among women discontinuing alendronate, whereas they remained stable in women continuing alendronate. Cumulative increases in BMD at the hip and spine and reductions in bone turnover from 8.6 years earlier at FIT baseline were greater for women continuing alendronate compared with those discontinuing alendronate. However, among women discontinuing alendronate and taking placebo in the extension, BMD remained higher and reduction in bone turnover was greater than values at FIT baseline. CONCLUSIONS: Compared with women who stopped alendronate after an average of 5 years, those continuing alendronate maintained a higher BMD and greater reduction of bone turnover, showing benefit of continued alendronate treatment on BMD and bone turnover. On discontinuation of alendronate therapy, rates of change in BMD at the hip and spine resumed at the background rate, but discontinuation did not result in either accelerated bone loss or a marked increase in bone turnover, showing persistence of alendronate's effects on bone. Data on the effect of continuation versus discontinuation on fracture risk are needed before making definitive recommendations regarding the optimal length of alendronate treatment.     

Response rate of bone mineral density to teriparatide in postmenopausal women with osteoporosis

PURPOSE: It is desirable for clinicians to know what bone mineral density (BMD) response they can expect in women treated with osteoporosis therapies. The focus of this analysis was to determine what percentage of women attained a lumbar spine BMD response to teriparatide that equaled or exceeded the least significant change (LSC) value of 3%. METHODS: Data from three clinical trials involving postmenopausal women with osteoporosis were examined. The Fracture Prevention Trial was a double-blinded, placebo-controlled clinical trial examining the safety and efficacy of teriparatide 20 and 40 microg/day. The other two trials were double-blinded, head-to-head comparisons of alendronate 10 mg/day and teriparatide 20 or 40 microg/day, respectively. Only treatment-compliant women who had lumbar spine BMD measurements at all specified time points in these trials were included. For reference, we also examined the percentage of women with lumbar spine BMD responses to alendronate. Hip BMD responses that equaled or exceeded 3% were also examined. RESULTS: According to the LSC criteria, 91% of the teriparatide 20 microg/day group and 94% of the teriparatide 40 microg/day group were lumbar spine BMD responders at 18 months in the Fracture Prevention Trial. In the teriparatide 20 microg/alendronate head-to-head trial, 94% of women receiving teriparatide had a lumbar spine BMD response that equaled or exceeded the 3% criterion at 18 months compared to 75% of those receiving alendronate 10 mg/day (p < 0.01). In the teriparatide 40 microg/day group of the other head-to-head trial, 92% of women achieved the 3% criterion for the lumbar spine at 12 months compared to 69% of those receiving alendronate 10 mg/day (p < 0.01). The median 3-month change in amino-terminal extension peptide of procollagen type 1 [PINP] in women who had a lumbar spine BMD response to teriparatide at 18 months was larger than in women who did not have a lumbar spine BMD response. However, the median 3-month PINP change in lumbar spine BMD nonresponders still exceeded the LSC value of 10 microg/L. Although the percentage of teriparatide-treated women with a hip BMD response that met the 3% criterion was significantly greater than for placebo, there was no significant difference between the percentage of teriparatide 20 microg/day and alendronate 10 mg/day responders in the comparison trial. The baseline characteristics of teriparatide lumbar spine responders and nonresponders were similar. CONCLUSION: This analysis demonstrates that the vast majority of treatment-compliant postmenopausal women with osteoporosis and minimal prior bisphosphonate exposure have a lumbar spine BMD response to teriparatide that meets or exceeds the LSC. The characteristics of teriparatide responders and nonresponders were not significantly different; thus, we were unable to discern any characteristics that could be used to identify potential nonresponders.     

Effects of short-term alendronate on bone mineral density in haemodialysis patients

BACKGROUND: Low bone mineral density (BMD) is common in dialysis patients. Low BMD predicts the fracture risk in the general population. Bisphosphonate therapy improves BMD and lowers the fracture risk in many populations, but has not been tested in dialysis patients because of concerns about toxicity. In this investigation, the effect of a short course of alendronate on BMD in haemodialysis (HD) patients is evaluated. METHODS: Thirty-one healthy HD patients were randomized to placebo versus 40 mg alendronate, taken once a week for 6 weeks. Hip and lumbar spine BMD were measured by dual energy X-ray absorptiometry at baseline and at 6 months. Osteocalcin, parathyroid hormone, calcium, phosphorous and alkaline phosphatase levels were assayed at baseline and at 1, 3 and 6 months. RESULTS: The BMD and T-scores in specific regions of the hip were stable in the treatment group and decreased in the placebo group (P=0.05). The lumbar spine density increased minimally in both groups. In the treatment group, osteocalcin levels declined significantly at 1 month (P<0.05) and remained low. The main side-effect in the alendronate group was occurrence of gastroesophageal reflux symptoms in three subjects. CONCLUSIONS: Low-dose alendronate, administered for a limited duration, appears to be well tolerated in dialysis patients. The BMD and T-scores declined at certain hip regions in the placebo group over 6 months, while remaining stable in the treatment group, suggesting a bone-preserving effect of alendronate. Further studies of longer duration, and including examination of bone histology, are needed to assess whether bisphosphonates can be used to preserve BMD in dialysis patients.     

A systematic review of the effect of alendronate on bone mineral density in men.

Alendronate is known to increase bone mineral density (BMD) at the lumbar spine and hip in women, but less information is available in men. We conducted a systematic review of randomized controlled trials to determine whether oral alendronate improves BMD at the lumbar spine and hip in men with low bone mass or prevalent fractures, compared with men treated with placebo, calcium, or vitamin D. In three trials in men, BMD (measured by dual-energy X-ray absorptiometry) increased at 2-3 yr (compared to baseline) at the lumbar spine and femoral neck in alendronate-treated patients compared to controls. The pooled estimates of changes in BMD with 10 mg of alendronate daily compared to controls were as follows: 7.8% over 2-3 yr (95% confidence interval [CI] = 4.8- 10.8) at the lumbar spine and 3.8% (95% CI = 2.3-5.3) at the femoral neck (p < 0.001 for treatment effect in each analysis). Statistically significant heterogeneity of treatment effect was noted between trials. We conclude that 10 mg of oral daily alendronate is significantly associated with increase in BMD at the lumbar spine and hip in men over 2-3 yr and that these changes are similar to those previously observed in postmenopausal women.     

Risk of fracture among women who lose bone density during treatment with alendronate. The Fracture Intervention Trial

It is commonly believed that the response to treatment in patients on alendronate is proportional to the increase in bone mineral density (BMD), and that those who lose BMD during treatment might not respond to treatment. In the Fracture Intervention Trial 6,459 women were randomly assigned to treatment with alendronate or placebo; BMD was measured annually, and new spine fractures were assessed by lateral spine films, taken at baseline and end of follow-up. Among subjects who took at least 70% of the study drug (5,220 women), we compared reductions in risk of spine fractures at end of follow-up (3 or 4 years) within various levels of change in total hip and spine BMD after 1 and 2 years of treatment, after adjustment for differences in characteristics between the treatment and control groups. Women losing BMD at the lumbar spine (0% to 4%) while on alendronate had a reduction of 60% in vertebral fracture risk [OR=0.40 (0.16, 0.99)] compared to their counterparts in the placebo group. The few women that lost more than 4% did not have a significant benefit [OR=0.15 (0.02, 1.29)]. Those who gained BMD (0% to 4%) during treatment had a reduction in risk of 51% [OR=0.49 (0.30, 0.78)]. Similarly, women who lost total hip BMD (0% to 4%) during the first year on alendronate had a 53% decreased risk of vertebral fracture compared to their controls taking placebo [OR=0.47 (0.27, 0.81)], whereas those gaining BMD (0% to 4%) had a comparable risk reduction [OR=0.49 (0.34, 0.71)]. This was not observed for the few women who lost more than 4% [OR=0.61 (0.11, 3.45)]. Patients who lost BMD at both the hip and spine were not protected by alendronate. Among patients who adhere to treatment with alendronate, even those who lose BMD benefit from a substantial reduction in risk of vertebral fracture. So, the reduction in bone turnover induced by alendronate might be more important than BMD changes. The few women who lose the most BMD (more than 4% per year) might not benefit from the treatment.This paper was written for the Fracture Intervention Trial Research GroupPresented in part at the 22nd Annual Meeting of the American Society for Bone and Mineral Research, Toronto, Canada, 2000     

Effect of aging on trabecular and compact bone components of proximal and ultradistal radius

Bone densitometry has become a major tool for osteoporosis risk assessment. The traditional dual-energy X-ray absorptiometry (DXA) methods are able to evaluate the bone mineral content (BMC; mg/cm) and the areal density (BMD; mg/cm²), but only quantitative computed tomography (QCT) has the potential to measure the true volumetric bone density in the sense of mass per unit volume (mg/cm³). Peripheral QCT (pQCT) measurements were carried out at the non-dominant radius using a Stratec XCT 960 (Unitrem, Roma) in 241 postmenopausal and 29 premenopausal women. The sites of evaluation were both the ultradistal and the proximal radius. The technique used has a coefficient of variation of 2% and it allows separation of the bone section into trabecular and cortical bone on the basis of density threshold. Bone mass of radius, hip and spine was also evaluated by DXA procedures. The bone density data obtained by pQCT were significantly correlated with all DXA measurements. The correlation coefficients between their respective BMD values ranged from 0.48 to 0.75, but for the BMC values of the radius the correlation coefficients ranged from 0.82 to 0.93. The BMD values measured by DXA, but not by pQCT, were positively related with patient heights. All pQCT density measurements, including those obtained at the proximal radius and containing exclusively cortical bone, where negatively related with age and years since menopause. A partial volume effect, which is increasingly relevant the thinner are the bone cortices, might explain that. However, by applying increasing density thresholds, cortical bone density seems to decrease with age as a consequence of a gradual density diminution from the inner part of the bone cortex outwards. Trabecular bone density decreases with aging, but its overall mass does not change as a consequence of an age-related enlargement of trabecular area. Thus, the proportion of trabecular bone over total bone rises, and this might be relevant for our understanding of the age-related changes in bone turnover and rate of bone loss.     

Peripheral Quantitative Computed Tomography of the Femoral Neck in 60 Japanese Women

Peripheral quantitative computed tomography (pQCT) is able to evaluate trabecular and cortical bone separately, and to determine geometric properties from cross-sectional images for noninvasive assessments of mechanical strength. In order to assess the diagnostic value of pQCT of the femoral neck, 60 healthy women were examined with a new pQCT machine, XCT-3000 (Norland-Stratec, Germany), which is suitable for direct measurement of the hip. The region of interest chosen was the center of the femoral neck. pQCT of the distal radius and dual energy X-ray absorptiometry (DXA) of the lumbar spine and femoral neck were also performed. The study demonstrated that total bone mineral density (BMD) (femoral MD) and trabecular BMD (femoral-TBD) decreased with advancing age. Percent cortical area showed a small but significant decrease with advancing age and % trabecular area increased slightly. Both the endosteal perimeter and the periosteal perimeter were relatively constant with aging. Bone strength index (BSI) and stress-strain index (SSI), which reflect the mechanical strength of bone, declined with advancing age, especially after menopause. Femoral TBD correlated strongly with femoral neck BMD by DXA and L2-L4 BMD by DXA but femoral-CBD did not correlate with femoral neck BMD by DXA. Volumetric BMD of the femoral neck and distal radius were closely correlated. It is concluded that (1) cortical thinning occurs with aging by endocortical resorption and loss of femoral-TBD; (2) loss of femoral-CBD occurred at a slower rate than radial CBD, perhaps due to the weight-bearing effect; (3) biomechanical parameters such as the BSI and SSI may reflect increasing fragility of the femoral neck in pre- and postmenopausal women; (4) pQCT of the femoral neck had diagnostic value at least equivalent to that of DXA or pQCT of the distal radius. Received: 23 June 1998 / Accepted: 1 July 1999     

Comparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass: A Randomized,Blinded, Phase 3 Trial

Denosumab is a fully human monoclonal antibody that inhibits bone resorption by neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This phase 3, multicenter, double‐blind study compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone mass. One thousand one hundred eighty‐nine postmenopausal women with a T‐score ≤ ?2.0 at the lumbar spine or total hip were randomized 1:1 to receive subcutaneous denosumab injections (60 mg every 6 mo [Q6M]) plus oral placebo weekly (n = 594) or oral alendronate weekly (70 mg) plus subcutaneous placebo injections Q6M (n = 595). Changes in BMD were assessed at the total hip, femoral neck, trochanter, lumbar spine, and one‐third radius at 6 and 12 mo and in bone turnover markers at months 1, 3, 6, 9, and 12. Safety was evaluated by monitoring adverse events and laboratory values. At the total hip, denosumab significantly increased BMD compared with alendronate at month 12 (3.5% versus 2.6%; p < 0.0001). Furthermore, significantly greater increases in BMD were observed with denosumab treatment at all measured skeletal sites (12‐mo treatment difference: 0.6%, femoral neck; 1.0%, trochanter; 1.1%, lumbar spine; 0.6%, one‐third radius; p ≤ 0.0002 all sites). Denosumab treatment led to significantly greater reduction of bone turnover markers compared with alendronate therapy. Adverse events and laboratory values were similar for denosumab‐ and alendronate‐treated subjects. Denosumab showed significantly larger gains in BMD and greater reduction in bone turnover markers compared with alendronate. The overall safety profile was similar for both treatments.     

BMD changes and predictors of increased bone loss in postmenopausal women after a 5‐year course of alendronate

Management of women discontinuing bisphosphonates after 3 to 5 years of treatment is controversial. Little is known about how much bone mineral density (BMD) is lost after discontinuation or whether there are risk factors for greater rates of bone loss post‐discontinuation. We report patterns of change in BMD and prediction models for the changes in BMD in postmenopausal women during a 5‐year treatment‐free period after alendronate (ALN) therapy. We studied 406 women enrolled in the Fracture Intervention Trial (FIT) who had taken ALN for a mean of 5 years and were then enrolled in the placebo arm of the FIT Long‐Term Extension (FLEX) trial for an additional 5 years, describing 5‐year percent changes in total hip, femoral neck, and lumbar spine BMD over the treatment‐free period. Prediction models of 5‐year percent changes in BMD considered all linear combinations of candidate risk factors for bone loss such as BMD at the start of the treatment‐free period, the change in BMD on ALN, age, and fracture history. Serum for three markers of bone turnover was available in 76 women, and these bone turnover markers were included as candidate predictors for these 76 women. Mean 5‐year BMD changes were –3.6% at the total hip, –1.7% at the femoral neck, and 1.3% at the lumbar spine. Five‐year BMD losses of >5% were experienced by 29% of subjects at the total hip, 11% of subjects at the femoral neck, and 1% of subjects at the lumbar spine. Several risk factors such as age and BMI were associated with greater bone loss, but no models based on these risk factors predicted bone loss rates. Although about one‐third of women who discontinued ALN after 5 years experienced >5% bone loss at the total hip, predicting which women will lose at a higher rate was not possible.     

Effect of alendronate on bone mineral density and bone turnover markers in post-gastrectomy osteoporotic patients

Alendronate decreases the urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX; about 45% at 3 months) and serum levels of alkaline phosphatase (ALP; about 27% at 24 months), leading to an increase in lumbar spine bone mineral density (BMD; about 9% at 24 months) in postmenopausal Japanese women with osteoporosis. However, the effectiveness of oral bisphosphonates on osteoporosis remains to be established in patients who have undergone a gastrectomy. The objective of the present case series study was to examine the effect of alendronate on BMD and bone turnover markers in post-gastrectomy osteoporotic patients. Sixteen patients (3 men and 13 postmenopausal women) with osteoporosis, who had undergone a gastrectomy (mean age: 69.1 years), were recruited in our outpatient clinic. All the patients were treated with alendronate (5 mg daily or 35 mg weekly) for 24 months. The effects of alendronate on lumbar spine (women) or total hip (men) BMD and urinary NTX and serum ALP levels were examined. A total or partial gastrectomy had been performed for eight patients each. The mean duration after surgery was 16.0 years. With alendronate therapy, urinary NTX levels significantly decreased at 3 months (−27.0%). Serum ALP levels decreased (−12.1%) and lumbar spine BMD increased (+5.2%), but total hip BMD did not significantly change (+0.6%) at 24 months. No severe adverse events were observed, and alendronate therapy was well tolerated. These results suggest that alendronate mildly increases lumbar spine BMD by mildly reducing bone turnover in osteoporotic patients after a gastrectomy.     

Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the fracture intervention trial.

We used data from the Fracture Intervention Trial to assess the relationship change in bone turnover after 1 year of alendronate or placebo treatment and subsequent hip, non-spine, and spine fracture risk among 6186 postmenopausal women. In the alendronate group (n = 3105), greater reductions in one or more biochemical marker were associated with a lower risk of fracture. INTRODUCTION: There are few data on the relationship between short-term change in biochemical markers of bone turnover and non-spine fracture risk among bisphosphonate-treated women, and the clinical use of such measurements is unknown. MATERIALS AND METHODS: We measured biochemical markers of bone turnover (bone-specific alkaline phosphatase [bone ALP], intact N-terminal propeptide of type I collagen, and C-terminal crosslinked telopeptide of type 1 collagen) and BMD of the spine and hip at baseline and after 1 year of alendronate or placebo. During a mean follow-up of 3.6 years, 72 hip, 786 non-spine, and 336 vertebral fractures were documented. RESULTS AND CONCLUSIONS: Each 1 SD reduction in 1-year change in bone ALP was associated with fewer spine (odds ratio = 0.74; CI: 0.63, 0.87), non-spine (relative hazard [RH] = 0.89; CI: 0.78, 1.00; p < 0.050), and hip fractures (RH = 0.61; CI: 0.46, 0.78). Alendronate-treated women with at least a 30% reduction in bone ALP had a lower risk of non-spine (RH = 0.72; CI: 0.55, 0.92) and hip fractures (RH = 0.26; CI: 0.08, 0.83) relative to those with reductions <30%. We conclude that greater reductions in bone turnover with alendronate therapy are associated with fewer hip, non-spine, and vertebral fractures, and the effect is at least as strong as that observed with 1-year change in BMD.     

Corticosteroid effects on proximal femur bone loss

Prolonged high-dose corticosteroid therapy is known to result in an increased risk of osteoporotic fracture. Reductions in bone density have been demonstrated at the distal radius and lumbar spine in patients receiving corticosteroids; however there have been few studies of bone density in the hip (the most important site of osteoporotic fracture) in this context. To examine the effect of corticosteroids on the hip we measured bone mineral density (BMD) by dual-photon absorptiometry at three sites in the proximal femur as well as the lumbar spine in 32 patients aged 18-77 years who had been treated with corticosteroids (mean daily prednisone dose 12.7 mg) for up to 23 years. BMD was compared with the expected values using age regressions in normal subjects. BMD was significantly reduced in the femoral neck, Ward's triangle, and the trochanteric region (p less than 0.001 all sites). In the lumbar spine BMD was also significantly reduced (p less than 0.001). We also measured BMD serially in 29 patients receiving corticosteroids. BMD measurements were made in 12 patients who had already been treated with long-term corticosteroids at the time of first BMD measurement (chronic group) and from the commencement of corticosteroid therapy in 17 patients (acute group). The mean (+/- SEM) change in BMD (g/cm2 per year) in the lumbar spine and femoral neck were 0.006 +/- 0.006 and -0.021 +/- 0.007, respectively, for the chronic group and -0.02 +/- 0.005 and -0.039 +/- 0.006 for the acute group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of hormone replacement therapy on bone mineral density and axial transmission ultrasound measurements in cortical bone

The menopause has a large effect on bone density, and hormone replacement therapy (HRT) has been shown to be an effective treatment for preventing postmenopausal bone loss. The aim of this study was to compare the effects of HRT use on speed of sound (SOS) measurements at the radius, tibia, phalanx, and metatarsal with bone mineral density (BMD) measurements of the lumbar spine and proximal femur. The study population consisted of 278 healthy premenopausal women, 194 healthy postmenopausal women, and 126 healthy postmenopausal women currently receiving HRT for one or more years. SOS measurements were taken at the radius, tibia, phalanx, and metatarsal using the Sunlight Omnisense, and BMD measurements at the lumbar spine and proximal femur using Hologic QDR-4500 densitometers. Z-scores were calculated using the postmenopausal control group. Z-score differences between the postmenopausal controls and HRT group, for the entire group and with the HRT group subdivided into three groups based on duration of HRT usage, were calculated. Significant postmenopausal bone loss was found for all SOS and BMD measurements. A positive effect of HRT usage was found for all SOS measurement sites and lumbar spine BMD, although only the radius and tibia SOS and lumbar spine BMD reached statistical significance. The Z-score differences between the two groups were 0.44, 0.37, 0.15, and 0.26 for the radius, tibia, phalanx, and metatarsal SOS respectively, and 0.28, 0.00, and -0.03 for the lumbar spine, femoral neck, and total hip BMD respectively. A clear effect of the duration of HRT use was seen for the radius measurements, the differences being less marked elsewhere. In conclusion, these results demonstrate a positive effect of HRT on SOS measurements at the radius and tibia and BMD measurements of the lumbar spine.