Jose Zanchetta

Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women with Osteoporosis

BACKGROUND Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown. METHODS We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry. RESULTS New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache). CONCLUSIONS Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.

Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis

BACKGROUND Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis. METHODS We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. RESULTS As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. CONCLUSIONS Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)

Romosozumab in Postmenopausal Women with Low Bone Mineral Density

BACKGROUND Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation. METHODS In a phase 2, multicenter, international, randomized, placebo-controlled, parallel-group, eight-group study, we evaluated the efficacy and safety of romosozumab over a 12-month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density (a T score of -2.0 or less at the lumbar spine, total hip, or femoral neck and -3.5 or more at each of the three sites). Participants were randomly assigned to receive subcutaneous romosozumab monthly (at a dose of 70 mg, 140 mg, or 210 mg) or every 3 months (140 mg or 210 mg), subcutaneous placebo, or an open-label active comparator--oral alendronate (70 mg weekly) or subcutaneous teriparatide (20 μg daily). The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Secondary end points included percentage changes in bone mineral density at other sites and in markers of bone turnover. RESULTS All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in bone mineral density at the total hip and femoral neck, as well as transitory increases in bone-formation markers and sustained decreases in a bone-resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups. CONCLUSIONS In postmenopausal women with low bone mass, romosozumab was associated with increased bone mineral density and bone formation and with decreased bone resorption. (Funded by Amgen and UCB Pharma; ClinicalTrials.gov number, NCT00896532.).

Effect of Recombinant Human Parathyroid Hormone (1-84) on Vertebral Fracture and Bone Mineral Density in Postmenopausal Women with Osteoporosis: A Randomized Trial

Context Researchers have not previously reported the efficacy and safety of parathyroid hormone (1-84) (PTH) for the primary prevention of osteoporotic fractures. Contributions Among 2532 postmenopausal women with osteoporosis randomly assigned to receive PTH or placebo, PTH decreased new vertebral fractures. The magnitude of the effect depended on assumptions about fractures in the one third of patients who withdrew from the trial prematurely. Adverse effects included hypercalciuria, hypercalcemia, and nausea. Caution Endogenous PTH and vitamin D levels could affect patients response to the drug but were not assessed in the study. Implications Parathyroid hormone (1-84) effectively prevented new vertebral fractures but also increased hypercalciuria, hypercalcemia, and nausea. The Editors Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing patients to an increased risk for fracture (1). Optimal treatment for osteoporosis should improve the amount, density, and quality of bone, thereby reducing skeletal fragility and fractures. Antiresorptive agents, such as bisphosphonates, are commonly used for treating postmenopausal osteoporosis. Although these agents preserve bone architecture, they do not stimulate new bone formation or improve bone architecture. Anabolic or bone-forming agents are an alternative approach to the treatment of osteoporosis. Researchers have shown that parathyroid hormone (PTH) and certain peptide fragments of PTH increase bone mass and improve bone quality (2, 3). Teriparatide, a fragment of human PTH composed of its N-terminal 34 amino acids, has been approved for the treatment of postmenopausal women with osteoporosis who are at high risk for bone fracture. However, researchers have studied this agent only in women with prevalent vertebral fractures (4), and data demonstrating prevention of the first vertebral fracture are lacking. We conducted the Treatment of Osteoporosis with Parathyroid Hormone (TOP) Study to examine the efficacy and safety of PTH (1-84) versus placebo for treating postmenopausal women with osteoporosis. We designed the study to examine the change in incidence of all vertebral fractures between the treatment groups. We also designed the study to examine the efficacy of this new bone-forming agent in preventing a first vertebral fracture in women without a vertebral fracture. Methods Study Participants We included postmenopausal women 45 to 54 years of age if bone mineral density (BMD) was 3.0 SDs or more (T-score 3.0) below the mean peak bone mass of young adult women at the lumbar spine, femoral neck, or total hip with no prevalent vertebral fracture or if BMD T-score was2.5 and they had 1 to 4 vertebral fractures before enrollment. We included postmenopausal women 55 years of age or older if BMD T-score was2.5 and they had no vertebral fractures or if BMD T-score was2.0 and they had 1 to 4 vertebral fractures. We excluded women if baseline serum calcium level was greater than 2.66 mmol/L (>10.7 mg/dL) or if urinary calciumcreatinine ratio was 1.0 or more. We included women with mild hypercalcemia (serum calcium, 2.55 to 2.66 mmol/L [10.2 to 10.7 mg/dL]) and mild hypercalciuria (24-hour urine calcium7.6 mmol [302 mg]) at baseline. We did not measure baseline levels of serum PTH and vitamin D. We excluded women if they had taken bisphosphonates for a total of more than 12 months or for more than 90 days in the 12 months before enrollment. We allowed previous estrogen therapy if it had been discontinued for at least 4 weeks before the screening visit. We excluded women who had received PTH (or a peptide fragment or analogue), PTH-related protein, fluoride, or strontium and those who had a history of metabolic bone disease (other than osteoporosis), nephrolithiasis, or clinically significant hepatic or renal disorders. We also excluded women who were taking medications known to affect bone mineral metabolism. The ethics review committee for each center approved the study. All women provided written informed consent. An independent data and safety monitoring board reviewed the progress and safety of the study. Study Design We conducted a randomized, double-blind, placebo-controlled, parallel-group study in 168 centers in 9 countries. We randomly assigned the study drug to blocks of 4 patients by using a computer-generated algorithm and shipped it in blocks of 4 to each study site. Women at each site were sequentially assigned the uniquely numbered, randomly assigned study drug treatment kits by telephone. Women were stabilized for at least 2 weeks with supplemental calcium, 700 mg/d citrate salt, and vitamin D3, 400 U/d, and then received 100 g of recombinant human PTH or placebo daily by subcutaneous injection for 18 months with continued calcium and vitamin D3 supplementation. Patients were instructed to administer the injection in the morning in the thigh or abdomen by using an injector pen. Study Conduct and Outcome Measures The primary end point was the occurrence of new or worsened vertebral fractures (in all women and in women with and without a prevalent fracture) identified by radiography at baseline, month 18, or the final study visit. Radiologists assessed vertebral fractures in a blinded manner at a central reading organization by using a semiquantitative 4-point grading scale (5). An incident vertebral fracture (new or worsened) was identified by a change in grade of 1 or more from baseline. Secondary outcomes included changes in BMD at lumbar spine, hip, whole body, and forearm (distal one-third radius) that we measured by using dual-energy x-ray absorptiometry with Hologic (Hologic Inc., Bedford, Massachusetts) or Lunar (GE Medical Systems, Madison, Wisconsin) densitometers (reported as percentage change from baseline to standardize instrumental differences in determining absolute BMD) and stadiometric measurements of height. We measured whole body and forearm BMD only in a subset of approximately 300 women from selected sites with appropriate software. We reported nonvertebral clinical fractures and bone loss (>7% at lumbar spine or >9% at total hip or femoral neck) as adverse events. We did not distinguish between traumatic and fragility nonvertebral fractures. We used quantitative computed tomography (6, 7) to evaluate the effects of PTH treatment at month 18 on volumetric cortical and trabecular BMD at lumbar vertebra (L3) and the hip in 122 consenting women from a single center at which the technique was available. We assessed bone turnover markers (serum bone-specific alkaline phosphatase and urinary N-telopeptides of type I collagen) in the first 600 randomly assigned women in the study. We measured bone-specific alkaline phosphatase by using the Tandem R-Ostase immunoradiometric assay (interassay coefficient of variation, 8%) (Hybritech, San Diego, California). We measured N-telopeptides of type I collagen by using Osteomark enzyme-linked immunoabsorbent assay kits (interassay coefficient of variation, 4.0%) (Wampole Laboratories, Princeton, New Jersey) normalized to urine creatinine concentrations. We made safety assessments at months 1, 3, 6, 9, 12, 15, and 18 that included physical examinations, vital signs, electrocardiography (months 1, 12, and 18), adverse-event monitoring and central clinical laboratory assessments consisting of chemistry (including serum total calcium and creatinine), hematology, and urinalysis (including 24-hour urine collections and fasting, morning urinary calciumcreatinine ratios). Adverse events were reported spontaneously by patients, captured in a patients diary, or reported by a patient in response to an open-ended question from clinical study personnel. We used a central laboratory normal range for serum total calcium level of 2.15 to 2.55 mmol/L (8.6 to 10.2 mg/dL). We performed an analysis for antibodies to PTH with a validated electrochemiluminescent immunoassay by using biotinylated recombinant human PTH (range, 26.3 to 2632.5 pmol/L; intra-assay coefficient of variation, 8% to 16%) (Igen International, Inc., Gaithersburg, Maryland). We obtained iliac crest bone biopsy specimens at month 12 or 18 from a subset of 40 consenting women after tetracycline double-labeling (8) that we examined for abnormal bone structure. We anticipated that women might need to discontinue calcium supplementation and reduce the dosing frequency of the study drug to prevent excessive increases in serum calcium level, urinary calcium level, or both. We conservatively predefined hypercalcemia as a single, unconfirmed, predose serum total calcium value greater than 2.66 mmol/L (>10.7 mg/dL) and hypercalciuria as a 24-hour urinary calcium value of 7.6 mmol or more (302 mg) (increased to >9.0 mmol [>360 mg] during the study) or a fasting urinary calciumcreatinine ratio of 1.0 or more. If a woman developed hypercalcemia or hypercalciuria, we discontinued the daily calcium supplementation; if either condition continued, we reduced the dosing frequency of the study drug. Statistical Analysis We estimated the sample size for our study by assuming that 67% of the patients would not have a prevalent fracture; that the 18-month vertebral fracture incidence for patients with and without a prevalent fracture who received placebo would be 10% and 2.5%, respectively; and that 20% of the patients in each group would discontinue the study early without a new or worsened fracture. We expected a sample of 2600 patients (1300 per treatment group) to provide at least 90% power to detect a significant 60% or greater reduction in vertebral fracture incidence in the PTH treatment group compared with the placebo group (2-sided level of 0.05). We analyzed data by using SAS software, version 8.0 (SAS Institute, Inc., Cary, North Carolina). We used descriptive statistics to summarize demographic and other baseline variables. We assessed comparability of the treatment groups at baseline by using t-tests for continuous varia

Efficacy of Bazedoxifene in Reducing New Vertebral Fracture Risk in Postmenopausal Women With Osteoporosis: Results From a 3-Year, Randomized, Placebo-, and Active-Controlled Clinical Trial†

In this 3‐yr, randomized, double‐blind, placebo‐ and active‐controlled study, healthy postmenopausal women with osteoporosis (55–85 yr of age) were treated with bazedoxifene 20 or 40 mg/d, raloxifene 60 mg/d, or placebo. The primary endpoint was incidence of new vertebral fractures after 36 mo; secondary endpoints included nonvertebral fractures, BMD, and bone turnover markers. Among 6847 subjects in the intent‐to‐treat population, the incidence of new vertebral fractures was significantly lower (p < 0.05) with bazedoxifene 20 mg (2.3%), bazedoxifene 40 mg (2.5%), and raloxifene 60 mg (2.3%) compared with placebo (4.1%), with relative risk reductions of 42%, 37%, and 42%, respectively. The treatment effect was similar among subjects with or without prevalent vertebral fracture (p = 0.89 for treatment by baseline fracture status interaction). The incidence of nonvertebral fractures with bazedoxifene or raloxifene was not significantly different from placebo. In a posthoc analysis of a subgroup of women at higher fracture risk (femoral neck T‐score ≤ –3.0 and/or ≥1 moderate or severe vertebral fracture or multiple mild vertebral fractures; n = 1772), bazedoxifene 20 mg showed a 50% and 44% reduction in nonvertebral fracture risk relative to placebo (p = 0.02) and raloxifene 60 mg (p = 0.05), respectively. Bazedoxifene significantly improved BMD and reduced bone marker levels (p < 0.001 versus placebo). The incidence of vasodilatation, leg cramps, and venous thromboembolic events was higher with bazedoxifene and raloxifene compared with placebo. In conclusion, bazedoxifene significantly reduced the risk of new vertebral fracture in postmenopausal women with osteoporosis and decreased the risk of nonvertebral fracture in subjects at higher fracture risk.

The Effects of Tibolone in Older Postmenopausal Women

BACKGROUND Tibolone has estrogenic, progestogenic, and androgenic effects. Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain. METHODS In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of -2.5 or less at the hip or spine or a T score of -2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels. RESULTS During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P=0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups. CONCLUSIONS Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis. (ClinicalTrials.gov number, NCT00519857.)

Lasofoxifene in Postmenopausal Women with Osteoporosis

BACKGROUND The effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain. METHODS In this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of -2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke. RESULTS Lasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group. CONCLUSIONS In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials.gov number, NCT00141323.)

Effects of Teriparatide Versus Alendronate for Treating Glucocorticoid-Induced Osteoporosis Thirty-Six-Month Results of a Randomized, Double-Blind, Controlled Trial

OBJECTIVE To compare the bone anabolic drug teriparatide (20 microg/day) with the antiresorptive drug alendronate (10 mg/day) for treating glucocorticoid-induced osteoporosis (OP). METHODS This was a 36-month, randomized, double-blind, controlled trial in 428 subjects with OP (ages 22-89 years) who had received > or =5 mg/day of prednisone equivalent for > or =3 months preceding screening. Measures included changes in lumbar spine and hip bone mineral density (BMD), changes in bone biomarkers, fracture incidence, and safety. RESULTS Increases in BMD from baseline were significantly greater in the teriparatide group than in the alendronate group, and at 36 months were 11.0% versus 5.3% for lumbar spine, 5.2% versus 2.7% for total hip, and 6.3% versus 3.4% for femoral neck (P < 0.001 for all). In the teriparatide group, median percent increases from baseline in N-terminal type I procollagen propeptide (PINP) and osteocalcin (OC) levels were significant from 1 to 36 months (P < 0.01), and increases in levels of C-terminal telopeptide of type I collagen (CTX) were significant from 1 to 6 months (P < 0.01). In the alendronate group, median percent decreases in PINP, OC, and CTX were significant by 6 months and remained below baseline through 36 months (P < 0.001). Fewer subjects had vertebral fractures in the teriparatide group than in the alendronate group (3 [1.7%] of 173 versus 13 [7.7%] of 169; P = 0.007), with most occurring during the first 18 months. There was no significant difference between groups in the incidence of nonvertebral fractures (16 [7.5%] of 214 subjects taking teriparatide versus 15 [7.0%] of 214 subjects taking alendronate; P = 0.843). More subjects in the teriparatide group (21%) versus the alendronate group (7%) had elevated predose serum calcium concentrations (P < 0.001). CONCLUSION Our findings indicate that subjects with glucocorticoid-induced OP treated with teriparatide for 36 months had greater increases in BMD and fewer new vertebral fractures than subjects treated with alendronate.

Skeletal Effects of Raloxifene After 8 Years: Results from the Continuing Outcomes Relevant to Evista (CORE) Study

In the CORE breast cancer trial of 4011 women continuing from MORE, the incidence of nonvertebral fractures at 8 years was similar between placebo and raloxifene 60 mg/day. CORE had limitations for assessing fracture risk. In a subset of 386 women, 7 years of raloxifene treatment significantly increased lumbar spine and femoral neck BMD compared from the baseline of MORE.

Microarchitectural deterioration of cortical and trabecular bone: Differing effects of denosumab and alendronate

The intensity of bone remodeling is a critical determinant of the decay of cortical and trabecular microstructure after menopause. Denosumab suppresses remodeling more than alendronate, leading to greater gains in areal bone mineral density (aBMD). These greater gains may reflect differing effects of each drug on bone microarchitecture and strength. In a phase 2 double‐blind pilot study, 247 postmenopausal women were randomized to denosumab (60 mg subcutaneous 6 monthly), alendronate (70 mg oral weekly), or placebo for 12 months. All received daily calcium and vitamin D. Morphologic changes were assessed using high‐resolution peripheral quantitative computed tomography (HR‐pQCT) at the distal radius and distal tibia and QCT at the distal radius. Denosumab decreased serum C‐telopeptide more rapidly and markedly than alendronate. In the placebo arm, total, cortical, and trabecular BMD and cortical thickness decreased (−2.1% to −0.8%) at the distal radius after 12 months. Alendronate prevented the decline (−0.6% to 2.4%, p = .051 to <.001 versus placebo), whereas denosumab prevented the decline or improved these variables (0.3% to 3.4%, p < .001 versus placebo). Changes in total and cortical BMD were greater with denosumab than with alendronate (p ≤ .024). Similar changes in these parameters were observed at the tibia. The polar moment of inertia also increased more in the denosumab than alendronate or placebo groups (p < .001). Adverse events did not differ by group. These data suggest that structural decay owing to bone remodeling and progression of bone fragility may be prevented more effectively with denosumab.