A Possible New Drug for Postmenopausal Osteoporosis

Tibin K. Titus, Mercer University College of Pharmacy

Postmenopausal osteoporosis occurs due to estrogen deficiency resulting in an increase of mature osteoclasts, which will increase bone resorption into the blood. [1] Simultaneously, there is a decrease in calcium absorption and increase in calcium excretion through the gut. [1] Romosozumab is a new monoclonal antibody that is in development for treatment of osteoporosis in postmenopausal women at increased risk of fractures. [2] In a previous trial, romosozumab reduced the risk of fracture compared to placebo; however, it has not been compared with an active comparator. [2] This study was conducted with an active comparator, alendronate, to compare the two drugs for fracture prevention in postmenopausal women with osteoporosis. [3]

Romosozumab or alendronate for fracture prevention in women with osteoporosis (ARCH trial)
Design Phase 3, multicenter, international, randomized, double-blind trial; N= 4,093
Objective To compare the effectiveness of a treatment regimen with romosozumab and alendronate with alendronate treatment alone in reducing the risk of fracture among postmenopausal women with osteoporosis and a previous fracture
Study Groups Romosozumab (n= 2,046); Alendronate (n= 2,047)
Methods The women were randomized 1:1 for treatment with either 210 mg romosozumab subcutaneous injections given monthly or 70 mg of the oral alendronate weekly for 12 months, followed by open-label treatment with alendronate 70 mg weekly until month 36 in both groups. Radiographs and nonvertebral fractures were assessed at a center imaging facility.

All patients were given 500-100 mg of daily calcium and 600-800 IU of vit. D3 or D2 for the trial period

Inclusion criteria: ambulatory postmenopausal women, 55-90 years of age, t score < -2.5 at hip or femoral neck

Exclusion criteria: inability to take alendronate, history of metabolic bone metabolism, osteonecrosis of the jaw, a 25-hydroxyvitamin D level or less than 20 ng/ml, or current hyper or hypocalcemia

Duration June 2014 – June 2017
Primary Outcome Measure Cumulative incidences of new vertebral fracture and clinical fractures
Baseline Characteristics
Alendronate Romosozumab
Age 74.2±7.5 74.4±7.5
Age > 75 yr— no. (%) 1071 (52.3) 1073 (52.4)
Ethnic group— no. (%)
Hispanic 662 (32.3) 631 (30.8)
Non-Hispanic 1385 (67.7) 1415 (69.2)
Geographic region
Central or Eastern Europe or Middle East 798 (39.0) 835 (40.8)
Latin America 727 (35.5) 674 (32.9)
Western Europe, Australia, or New Zealand 264 (12.9) 269 (13.1)
Asia-Pacific or South Africa 216 (10.6) 213 (10.4)
North America 42 (2.1) 55 (2.7)
Body-mass index 25.36 ±4.42 25.46±4.41
Bone mineral density T score
Lumbar spine -2.99±1.24 -2.94±1.25
Total hip -2.81±0.67 -2.78±0.68
Femoral neck -2.90±0.50 -2.89±0.49
Previous osteoporotic fracture at > 45yr of age— no. (%) 2029 (99.1) 2022 (98.8)
Prevalent vertebral fracture- no.(%) 1964 (95.9) 1969 (96.2)
Grade of most severe vertebral fracture
Mild 73 (3.6) 68 (3.3)
Moderate 570 (27.8) 532 (26.0)
Severe 1321 (64.5) 1369 (66.9)
Previous nonvertebral fracture at > 45yr of age— no. (%) 770 (37.6) 767 (37.5)
Previous hip fracture 179 (8.7) 175 (8.6)
FRAX score 20.0±10.1 20.2±10.2
Results
Table 1. Fracture endpoints at pre-specified timepoints
Alendronate to Alendronate (N=2047), % Romosozumab to Alendronate (N=2046), % Risk ratio (95% CI) p value
12 month double-blind period
New vertebral fracture by multiple imputation 6.3 4.0 0.63 (0.47,0.85) 0.003
New vertebral fracture by LOCF 5.0 3.2 0.64 (0.46, 0.89) 0.008
New or worsening vertebral fracture 5.9 4.0 0.66 (0.49, 0.89) 0.006
Clinical vertebral fracture 0.9 0.5 0.56 (0.26, 1.22) 0.14
Clinical fracture 5.4 3.9 0.72 (0.54, 0.96) 0.027
Nonvertebral fracture 4.6 3.4 0.74 (0.54, 0.96) 0.027
Major nonvertebral fracture 4.3 2.9 0.67 (0.48, 0.94) 0.019
Hip fracture 1.1 0.7 0.64 (0.33, 1.26) 0.19
Osteoporotic fracture 9.2 6.5 0.71 (0.57, 0.88) 0.002
Major Osteoporotic fracture 4.2 3.0 0.72 (0.52, 1.01) 0.053
Month 24
New vertebral fracture by multiple imputation 11.9 6.2 0.52 (0.40, 0.66) <0.001
New or worsening vertebral fracture 8.0 4.1 0.50 (0.38, 0.66) <0.001
Clinical vertebral fracture 2.1 0.9 0.41 (0.24, 0.71) <0.001
Adverse Events Common Adverse Events: back pain (11.3% alendronate vs. 9.1% romosozumab)
Serious Adverse Events: cardiac ischemic event (0.3% alendronate vs. 0.8% romosozumab), heart failure (0.4% alendronate vs. 0.2% romosozumab), death (1.0% alendronate vs. 1.5% romosozumab)
Percentage that Discontinued due to Adverse Events: alendronate (7.2%), romosozumab (6.5%)
Study Author Conclusions This trial indicates that romosozumab for 12 months before alendronate significantly reduced fracture risk than with alendronate alone over alendronate alone for use in female patients with respect to risks of new vertebral fracture and clinical fractures.

 

 

The study had a high internal validity because of its double-blind, randomized design. This helps with limiting investigator bias in the study. The external validity of the study was also strengthened with the large sample size and by including appropriate subjects that these results may be applicable to the general patient population in clinical practice. However, <5% of the population was from North America. This may be a limitation as diet, lifestyle, and cultural differences may play a role in the outcomes. There were cardiovascular risks observed with the study drug; however, the study was not designed as a cardiovascular (CV) outcomes trial. Therefore, the U.S. Food and Drug Administration (FDA) is requiring the drug manufacturer to conduct a CV safety study before approving the drug. The risks of other fracture end points were significantly lower in the romosozumab group than in the alendronate group showing a 27% decrease of clinical fracture, 25% decrease of nonvertebral fracture, and 38% decrease of hip fracture. Hence, romosozumab followed by alendronate appears to be more efficacious than alendronate alone for the treatment of osteoporosis, suggesting it maybe a promising new therapy for the treatment of postmenopausal osteoporosis. However, use may not be recommended in patients at high risk of cardiovascular events until the CV safety study is completed.

 

 References

  1. Camacho PM, Petak SM, Binkley N, et al. American association of clinical endocrinologists and american college of endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract. 2016 Sep;22(9):1111-8.
  2. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis.N Engl J Med. 2016;375(16):1532–43.
  3. Saag KG, Peterson J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 2017;377(18):1417-1427.
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