Sydney Lou Bonnick

Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study.

Once‐weekly alendronate 70 mg and once‐weekly risedronate 35 mg are indicated for the treatment of postmenopausal osteoporosis. These two agents were compared in a 12‐month head‐to‐head trial. Greater gains in BMD and greater reductions in markers of bone turnover were seen with alendronate compared with risedronate with similar tolerability.

Importance of Precision in Bone Density Measurements

Bone densitometry, regardless of the specific technique, is not perfectly reproducible even when consistently performed in exact accordance with the manufacturers recommendations. Precision must be quantified at each densitometry facility in precision studies of the various skeletal sites used for monitoring. The precision, as the root-mean-square standard deviation or root-mean-square coefficient of variation, is then used to determine the change in bone density that constitutes the least significant change and the minimum interval between follow-up measurements. Until precision studies are performed, the least significant change cannot be determined for any level of statistical confidence, making the interpretation of serial studies impossible.

Consensus of an international panel on the clinical utility of bone mass measurements in the detection of low bone mass in the adult population

Low bone mass, in the asymptomatic patient, predicts future fracture risk as well as high cholesterol or high blood pressure predicts the risk of heart disease or stroke. In patients without fractures, osteoporosis can be diagnosed based on the extent of reduction in bone mass below mean peak bone mass of healthy young individuals. As bone mass decreases, fracture risk increases exponentially. Prevention of the first fracture is a clinical goal. Clinical situations in which an assessment of bone mass and fracture risk affects therapeutic decisions include estrogen deficiency, vertebral abnormalities, radiographic osteopenia, asymptomatic primary hyperparathyroidism, and longterm corticosteroid therapy. Serial measurements can also be used to monitor the effects of osteoporosis treatment in certain situations. The appropriate technique and skeletal site for bone mass measurements should be chosen based on the patients circumstances. A clinical interpretation can enhance the value of computer-generated bone mass measurement reports and enhance decision making.

The effects of gymnastics training on bone mineral density.

The purpose of this study was to examine the effect of 27 wk of gymnastics training on bone mineral density (BMD), body composition, insulin-like growth factor I (IGF-I), and osteocalcin. Subjects were 11 female intercollegiate gymnasts and 11 controls. Dual energy x-ray absorptiometry (Lunar DPX) was used to determine BMD (L2-L4 and femur) and to assess body composition. The gymnasts were significantly lower in weight (53.9 and 60.8 kg) and % body fat (22.6 and 30.6) compared with controls. After training, body weights of gymnasts remained the same but there was a significant increase in lean tissue mass of 2.9 kg (6.7%, P < 0.05). No changes in body composition were observed in the controls. The gymnasts had significantly higher mean lumbar (1.321 vs 1.225), and femoral neck (1.163 vs 1.079) BMD (g.cm-2) than the controls. Lumbar BMD increased significantly (1.3%) in gymnasts following training but femoral neck BMD did not increase. No BMD changes occurred in the control group. Regarding serum IGF-I, no differences were seen between the groups or across time. Serum osteocalcin values were significantly higher in the gymnasts than the controls, but no differences were found across time. In conclusion, gymnasts had significantly higher BMDs than controls, and a significant increase in lumbar BMD was seen in the gymnasts following 27 wk of training.

Clinical utility of bone mass measurements in adults: Consensus of an international panel

Low bone mass predicts future fracture risk as well as high cholesterol or high blood pressure can predict the risk of heart disease or stroke. Prevention of the first fracture should be a clinical goal. In patients without fractures, osteopenia and osteoporosis can be diagnosed based on the extent of reduction in bone mass below mean peak bone mass of young healthy individuals. As bone mass decreases, fracture risk increases exponentially. Clinical situations in which an assessment of bone mass and fracture risk affects therapeutic decisions include estrogen deficiency, vertebral abnormalities, radiographic osteopenia, asymptomatic primary hyperparathyroidism, and long-term corticosteroid therapy. Serial measurements can also be used to monitor the effects of osteoporosis treatments. The appropriate technique and skeletal site for bone mass measurements should be chosen based on the patients circumstances and the precision of measurement. A clinical interpretation can enhance the value of computer-generated bone mass measurement reports and improve decision making.

Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial.

OBJECTIVE: To compare the efficacy and safety of denosumab to ibandronate in postmenopausal women with low bone mineral density (BMD) previously treated with a bisphosphonate. METHODS: In a randomized, open-label study, postmenopausal women received 60 mg denosumab subcutaneously every 6 months (n=417) or 150 mg ibandronate orally every month (n=416) for 12 months. End points included percentage change from baseline in total hip, femoral neck, and lumbar spine BMD at month 12 and percentage change from baseline in serum C-telopeptide at months 1 and 6 in a substudy. RESULTS: At month 12, significantly greater BMD gains from baseline were observed with denosumab compared with ibandronate at the total hip (2.3% compared with 1.1%), femoral neck (1.7% compared with 0.7%), and lumbar spine (4.1% compared with 2.0%; treatment difference P<.001 at all sites). At month 1, median change in serum C-telopeptide from baseline was −81.1% with denosumab and –35.0% with ibandronate (P<.001); the treatment difference remained significant at month 6 (P<.001). Adverse events occurred in 245 (59.6%) denosumab-treated women and 230 (56.1%) ibandronate-treated women (P=.635). The incidence of serious adverse events was 9.5% for denosumab-treated women and 5.4% for ibandronate-treated women (P=.046). No clustering of events in any organ system accounted for the preponderance of these reports. The incidence rates of serious adverse events involving infection and malignancy were similar between treatment groups. CONCLUSION: In postmenopausal women previously treated with a bisphosphonate and low BMD, denosumab treatment resulted in greater BMD increases than ibandronate at all measured sites. No new safety risks with denosumab treatment were identified. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00936897. LEVEL OF EVIDENCE: I

Relationship of regional body composition to bone mineral density in college females.

The purpose of this study was to examine relationships between regional body composition and bone mineral density (BMD) in college females. Subjects were 12 nonathletic females (< 3 h.wk-1 of exercise) and 46 female varsity athletes: basketball (N = 14), volleyball (N = 13), gymnastics (N = 13), and tennis (N = 6). Dual energy x-ray absorptiometry was used to determine BMD and body composition. The mean (+/- SD) age, height, weight, and menarche for the subjects were 19.9 +/- 2.1 yr, 167.9 +/- 9.4 cm, 62.1 +/- 9.0 kg, and 13.6 +/- 1.7 yr, respectively. Mean lumbar (1.327 g.cm-2), femoral neck (1.172 g.cm-2), and total body (1.200 g.cm-2) BMD of the athletes were significantly greater than nonathletes (P < 0.05) but did not differ among the teams. Significant correlations were found between regional leg BMD and leg lean tissue mass (LTM) (r = 0.59, P < 0.001) and between arm LTM and arm and lumbar BMD (r = 0.47 and 0.56, respectively). Significant correlations were also found between leg fat mass and leg BMD (r = 0.40). However, only regional LTM was a significant predictor of BMD using stepwise multiple regression. In summary, regional LTM appears to be a better predictor of BMD than regional fat mass.

Treatment with alendronate plus calcium, alendronate alone, or calcium alone for postmenopausal low bone mineral density

ABSTRACT Objective: Bisphosphonates such as alendronate are widely used for postmenopausal osteoporosis. Supplemental calcium is also generally recommended. This trial directly compares alendronate to supplemental calcium and examines the effect of calcium supplementation on alendronate treatment. Methods: This 2-year, randomized, double-blind, multicenter trial enrolled healthy, postmenopausal women with low bone mineral density (BMD). Patients with a dietary calcium intake ≥ 800 mg/day received daily vitamin D 400 IU and alendronate 10 mg/calcium-placebo, alendronate 10 mg/elemental calcium 1000 mg, or alendronate-placebo/calcium 1000 mg (2:2:1). Endpoints included BMD, bone turnover markers (BTMs), and adverse events. Results: Randomized patients (N = 701) were an average of 20.4 years postmenopausal. After 24 months, increases in lumbar spine BMD differed significantly between patients receiving calcium alone (0.8%) and either alendronate alone (5.6%) or alendronate + calcium (6.0%) ( p < 0.001). Significant differences were also seen at the trochanter and femoral neck ( p < 0.001). BTMs were significantly lower with alendronate-containing treatments than calcium alone ( p < 0.001). Addition of calcium supplementation to alendronate did not significantly increase BMD compared to alendronate alone ( p = 0.29 to 0.97), but did result in a statistically significant, though small, additional reduction in urinary NTx. Adverse events were similar among treatment groups. Limitations include no assessment of vitamin D levels and a discontinuation rate of approximately 30%, although discontinuation rates were similar among treatment groups. Conclusions: In postmenopausal women with a daily intake of ≥ 800 mg calcium and 400 IU vitamin D, 24-month treatment with alendronate 10 mg daily with or without calcium 1000 mg resulted in significantly greater increases in BMD and reduction of bone turnover than supplemental calcium alone. Addition of supplemental calcium to alendronate treatment had no effect on BMD and resulted in a small, though statistically significant, additional reduction in NTx.

Clinical Value of Monitoring BMD in Patients Treated With Bisphosphonates for Osteoporosis

Osteoporosis is a common disease with serious medical and economic consequences. Despite great efforts to educate healthcare professionals and the public, it remains underdiagnosed and undertreated. BMD testing by DXA is an extraordinarily useful clinical tool for assessment of fracture risk and to diagnose osteoporosis before the first fracture occurs. DXA is the only technology for measuring BMD that can be used with FRAX, the World Health Organization fracture risk assessment algorithm that is becoming widely used throughout the world. Several organizations recommend serial DXA testing for monitoring pharmacologic therapy of osteoporosis. The utility of BMD testing to monitor therapy was questioned almost a decade ago when the concept of ‘‘regression to the mean’’ was raised. Although this concept has relevance at a population level, it was subsequently refuted as misleading and irrelevant to the clinical management of individual patients. A study published recently in BMJ by Bell et al. raises the question anew. Despite the title, ‘‘Value of Routine Monitoring of Bone Mineral Density after Starting Bisphosphonate Treatment: Secondary Analysis of Trial Data,’’ the authors conclude that monitoring BMD ‘‘in postmenopausal women in the first three years after starting treatment with a potent bisphosphonate is unnecessary and may be misleading.’’ The authors go on to state that ‘‘routine monitoring should be avoided in this early period.’’ These conclusions are based on a secondary analysis of pooled data from the two arms of the Fracture Intervention Trial (FIT) in which postmenopausal women with low BMD were randomized to alendronate or placebo. They conclude that using BMD to monitor response to treatment with alendronate was of no value because (1) >97% of the patients on treatment ultimately showed an increase in BMD and (2) the withinsubject variability was considerable. Several of the same authors used a similar approach in a post hoc analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) to conclude that monitoring the initial blood pressure response after perindopril (an angiotensinconverting enzyme inhibitor) therapy was unnecessary. The purpose of this commentary is to address issues raised by Bell et al. and to place the need for BMD monitoring into an appropriate clinical context. Whereas we applaud all efforts to apply the best available medical evidence to clinical decision-making, the validity and applicability of evidence should be closely scrutinized before making recommendations. The conclusion of the recent BMJ article, that monitoring therapy with BMD testing is unnecessary, rests on four assumptions: (1) the goal of monitoring is to document effectiveness by showing an increase in BMD, (2) the increase in BMD in virtually all treated subjects in FIT can be expected to occur in patients in clinical practice, (3) the response to one bisphosphonate in a clinical trial is indicative of the response to all bisphosphonates in clinical practice, and (4) within-person

Response to therapy with once-weekly alendronate 70 mg compared to once-weekly risedronate 35 mg in the treatment of postmenopausal osteoporosis.

SUMMARY Objective: The FACT study (Fosamax Actonel Comparison Trial) was a 1-year head-to-head trial comparing the efficacy and tolerability of once weekly (OW) alendronate 70 mg and OW risedronate 35 mg for the treatment of postmenopausal osteoporosis. The present analysis was performed to determine the percentage of patients who had changes during the study in BMD and biochemical markers (BCMs) of bone turnover above or below specific cut-off points. A subgroup analysis of upper gastrointestinal (UGI) tolerability was also performed. Research design and methods: 1053 postmenopausal women with low BMD were randomized to alendronate 70 mg OW (N = 520) or risedronate 35 mg OW (N = 533). The percentage of patients who had measured BMD gains ≥ 0%, ≥ 3%, and ≥ 5% after 12 months at the hip trochanter, total hip, femoral neck, and lumbar spine (LS) was analyzed. The percentage of patients who experienced any bone loss, and those with measured losses of 3% or more at these sites after 12 months, was determined. The percentage of patients achieving reductions in urinary N-telopeptide of type I human collagen (NTX) ≥ 40%, and serum C-telopeptide of type I collagen (CTx) ≥ 60%, bone-specific alkaline phosphatase (BSAP) ≥ 30%, and N terminal propeptide of type I procollagen (P1NP) ≥ 50% at 3 months and 12 months was also determined. Tolerability, based on adverse experience reporting, was evaluated in a subgroup of patients with a history of UGI disorders at baseline. Results: A greater percentage of alendronate- than risedronate-treated patients had measured BMD gains (≥ 0%) ( p < 0.05) at all sites at 12 months. Significantly more ( p < 0.01) alendronate- than risedronate-treated patients had measured gains in BMD ≥ 3% and ≥ 5% at the hip trochanter, total hip, and LS spine. Significantly more ( p < 0.05) risedronate- than alendronate-treated patients had an apparent loss of BMD (> 0% and ≥ 3% loss) at these same sites. After 3 months, significantly ( p < 0.001) more alendronate- than risedronate-treated patients achieved predefined reductions in all BCMs. Similar tolerability was demonstrated in both treatment groups, regardless of whether or not patients had a history of UGI disorders at baseline. Conclusions: Significantly more alendronate- than risedronate-treated patients achieved predefined increases in BMD at 12 months and reductions in BCMs at 3 months. Significantly more risedronate- than alendronate-treated patients were classified as apparent ‘non-responders’ (i.e. experienced any bone loss) after 12 months of therapy. The tolerability profiles of the two medications were similar.