Essay: Fracture Prevention in Women with Osteoporosis

General Study Overview

Title/Citation

Saag KG, Petersen J, Brandi ML, et. al. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis, N Engl of Med 2017; 377 (15): 1417-1427.

Funding

Amgen and UCB Pharma designed the trial, while only Amgen was involved with trial oversight and data analysis plan. Both companies were involved with the medical writing. Two of the authors were Amgen employees.

Objective

The objective of this study was to compare the effectiveness of a treatment starting with romosozumab which is then switched to alendronate vs. alendronate treatment alone in reducing the risk of fracture among postmenopausal women with osteoporosis and a previous fracture.

Background

Background

Osteoporosis is characterized by low bone density, decreased bone strength and increased risk of fracture.2 Bone loss process starts at menopause and accelerates after that point. There are two types of osteoporosis: primary and secondary. Primary is due to age and secondary is due t drug therapy. 13-18% of white women aged 50 or older have osteoporosis of the hip.  Essay: Fracture Prevention in Women with Osteoporosis.The prevalence in this group increased by 4% by age 50-59 and then increased to 52% by age 80. Management can be done through lifestyle changes including exercise, vitamin supplements, smoking cessation and nutrition. Pharmacological agents may also be used which include bisphosphonate, SERMs, parathyroid hormone, estrogen and calcitonin.3 Usual drug therapy indicated for osteoporosis intents to increase bone density and prevent progression of the disease. The current first line of therapy is alendronate.2

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Alendronate is indicated as first line therapy in the treatment and prevention of osteoporosis in postmenopausal females. Alendronate is a bisphosphonate that inhibits the bone resorption. This is done through inhibiting the osteoclasts. It is taken as a 10 mg tablet once daily or as 70 mg once a week. Common adverse events that are associated with the use of alendronate are headaches, abdominal pain, nausea and others also related to the gastrointestinal tract. 4 It is also associated with atypical femoral fracture and osteonecrosis. 5 Possible drug interactions that would cause a therapy modification are with antacids, calcium salts, iron salts, and multivitamins. Alendronate is contraindicated with use of parathyroid hormone since it alendronate diminishes the therapeutic effect of the parathyroid hormone and interfere with the normal blood calcium concentrations. 4

Romosozumab is a new bine forming monoclonal antibody. It binds to and inhibits sclerostin which helps to increase bone formation along with decreasing bone resorption.Essay: Fracture Prevention in Women with Osteoporosis. 1 The most prevalent adverse event that is associated with this drug therapy are cardiovascular events. 5

Previous Trials

Previous research on romosozumab were mostly previous clinical trials that tested the efficacy of the drug against the placebo and one trial against a biphosphonate. In each of the previous studies, romosozumab showed to increase the bone formation and decrease bone reabsorption. 6,7,8,9

Study Rationale

They chose to do this because there are not many studies on osteoporosis therapy with fracture endpoints.

Methods

Trial Design

– Phase 3, multicenter, international, parallel, randomized double blind trial

– Women were randomly assigned in a 1:1 ratio to receive either treatment

– Randomization stratified based on age (> 75 vs ≥ 75 years)

– After completion of the double blind treatment, all patient received open label weekly alendronate until end of trial

Study Population/ Inclusion Criteria

– Postmenopausal women aged 55 – 90 years old

– Osteoporosis patient at high risk for fracture defined as:

o A hip BMD T score of -2.5 or less and ≥ 1 moderate/severe vertebral fractures or ≥ 2 mild vertebral fractures

o A hip BMD T score of -2.0 or less and ≥ 2 moderate/severe vertebral fractures or a fracture of the proximal femur sustained 3 to 24 months before randomization

Exclusion Criteria

– Women excluded for an inability to take alendronate oral tablets

– Women who were contraindicated for alendronate

– Contraindicated for alendronate, including GFR >30 ml/min per 1.73 m2 of body-surface area

Treatment Regimens

– 70 mg of oral alendronate every week for 12 months

– 210 mg of romosozumab by subcutaneous injection once monthly for 12 months

– Both were followed by open-label 70 mg of alendronate after the first 12 months until the time of the primary analysis. Essay: Fracture Prevention in Women with Osteoporosis.

– Patients from both groups also received daily Vitamin D and calcium

– Treatment duration: 24 months

Outcome Measures

Primary end point:

– Cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture

Secondary end point:

– Bone mineral density at the lumbar spine, total hip and femoral neck at 12 and 24 months

– Total incidence of nonvertrebral fracture at the time of the primary analysis

– Other fracture categories, including hip fractures

– Bone turnover markers at baseline and months 1, 3, 6, 9, 12, 15, 18

Time Frame:

– 24 month period

Safety

– incidence of adverse events

Statistical Analysis

Primary:

α: 0.05 (two sided)

β: 0.04 (94% power) in clinical fracture

0.05 (95% power) in vertebral fracture

δ: 30% lower risk of clinical fracture

50% lower risk of vertebral fracture

N: 2047 patients were assigned to alendronate and 2046 patients were assigned to romosozumab

– Analysis is based on intention to treat

– The difference between the primary endpoint was analyzed by using a post hoc analysis of the ventricular fractures

– The secondary analyses were done using Cox proportional hazards model with adjustment of age, the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T score.Essay: Fracture Prevention in Women with Osteoporosis.

– Risk ratios were determined using Mantel Haenszel model was used for new incidence vertebral and new or worsening vertebral fractures.

– Treatment comparsion was done using a logistic regression model with adjustment for age, the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T score

Results

Enrollment

– A total of 4093 patients underwent randomization

– 2047 patients received 70 mg of oral alendronate every week for 12 months

– 2046 patients received 210 mg of romosozumab by subcutaneous injection once monthly for 12 months

– 3645 (89.3%) completed the 12 months of the trial

– 3150 (77.0%) completed the primary analysis period

Baseline Characteristics

Category

Mean (Alendonrate)

Mean (Romosozumab)

Age

74.2 (52.3)

74.4 (52.4)

Previous fracture at ≥ 45

2029 (99.1)

2022 (98.8)

Prevalent vertebral fracture

1964 (95.9)

1969 (96.2)

Prevalent nonvertebral fracture

770 (367.6)

767 (37.5)

Previous hip fracture

179 (8.7)

175 (8.6)

Bone Density T scores

Lumbar -2.99

Total hip -2.81

Femoral hip -2.9

Lumbar -2.94

Total hip -2.78

Femoral hip -2.89

There were no statistically significant between group differences in baseline characteristics.

Treatment Efficacy

Fracture (primary outcome)

– Over the 24 month period, treatment with romosozumab followed by alendronate resulted in 48% lower risk of new vertebral fractures alendronate alone (95% CI, .40 -.66, P<0.001)

– 27% lower risk of clinical fracture at primary anaylsis with romosozumab followed by alendronate than just alendronate (95% CI, 0.61-0.88, P<0.001)

– Romosozumab group has a cumulative incidence of 9.7% and alendronate group had an incidence of 13.0%

Nonvertebral fracture (secondary outcome)

– 19% lower risk with romosozumab (95% CI, 0.66-0.99, P=0.04)

Bone Mineral Density (secondary outcome)

– Greater gains in bone density from baseline in all measured sites with romosozumab

Bone Turnover Markers (secondary outcome)

– Increased levels of the bone formation marker P1NP and decreased level of bone resorption marker β-CTX with use of romosozumab

Adverse Effects

– Similar between two treatment groups during 12 month double blind period

– In the first 12 months, injection site reactions were reported in more patients receiving romosozumab; 4.4% vs 2.6%

– Higher chance of cardiovascular adverse events in romosozumab compared to alendronate; 2.5% vs 1.9%

– In the open label portion of the study, atypical femoral fracture and osteonecrosis of the jaw was observed with alendronate use

Author’s Conclusions

After 24 month of treatment, those treated with romosozumab followed by alendronate showed statistically significantly decrease in the risks of new vertebral, clinical, nonvertebral and hip fractures. Romosozumab treatment resulted in lower vertebral and clinical fractures which imply reduction in fracture risk.Essay: Fracture Prevention in Women with Osteoporosis.  Adverse events and serious adverse events were balanced between the two groups so neither would has an advantage over the other in that sense. Rapid gains in bone mineral density from bone forming therapy with romosozumab were associated with lower risk of fracture than with alendronate. In conclusion, these results suggest an important benefit of using romosozumab and a possible change in common treatment practice of first line use of alendronate on women who had osteoporosis and a previous fracture.

Discussion

Strengths

– The demographics and clinical characteristics of the patients at baseline were balanced between the two groups.

– The population was international so showed more relevance to a diverse group of ethnicities.

– The study was randomized and each group is equal in characteristics. Accurate measurements were made.

– Participants were given the therapeutic dosage of alendronate.

– The title was unbiased and demonstrate the purpose of the study

– There was a decrease in fractures that were caused due to osteoporosis with the use of romosozumab.

– There is a definite endpoint that was easily measured and can be replicated if necessary. The result was clinically and statistically significant.

Limitations

– It was only confined to a certain age group, meaning it is clinically relevant towards that group and not for any early onset osteoporosis in females.

– It can not be applied to secondary onset osteoporosis.

– Since romosozumab is used in clinical setting, the dosage that was administered may not be therapeutically ideal and cause more or less adverse reactions. There was no placebo comparison in the study.

– Cardiovascular outcomes was not an endpoint that was measured so no conclusion could be made towards the drugs effects on cardiovascular events. Essay: Fracture Prevention in Women with Osteoporosis.

– May not be clinically significant in other population groups that might use this drug

Conclusions

Overall, Romosozumab leads to decrease fractures that are associated to osteoporosis in women when compared to the current first line of therapy, alendronate. The findings from this study suggest that the first line of therapy for fractures associated with osteoporosis might change from alendronate to romosozumab. There is need for further research to ensure that there is more benefit than risk from using romosozumab over alendronate in osteoporosis patients. There also needs to be further research pertaining to the cardiovascular adverse events that occur with romosozumab. Based on the data provided by this study, I would recommend this therapy to patients, since there was a statistically and clinically significant improvement in the primary and secondary outcomes that were measured. However, I would make sure to monitor patient closely for adverse events that might occur since it is a newer therapy.

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References

1. Saag KG, Petersen J, Brandi ML, et. al. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis, N Engl of Med 2017; 377 (15): 1417-1427.

2. McClung MR, Grauer A, Boonen, S, et. al. Romosozumab in Postmenopausal Women with Low Bone Mineral Density, N Engl of Med 2014; 370: 412-420.

3. Ettinger B, Harris ST, Kendler D, et. al. Management of osteoporosis in postmenopausal women: 2006 position statement of The North American Menopause Society, The Journal of the North American Menopause Society 2006; 13(3): 340-367.

4. Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc.; November 20, 2017.

5. Rosen C. Romosozumab — Promising or Practice Changing?, N Engl of Med 2017;377:1479-1480.

6. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016;375:1532-43. Essay: Fracture Prevention in Women with Osteoporosis.

7. Keaveny TM, Crittenden DB, Bolognese MA, et al. Greater gains in spine and hip strength for romosozumab compared with teriparatide in postmenopausal women with low bone mass. J Bone Miner Res 2017;32:1956-62

8. Langdahl BL, Crittenden DB, Bolognese MA, et. al. Romosozumab (sclerostin monoclonal antibody) versus Teriparatide in Postmenopausal Women with Osteoporosid Transitioning from Oral Bisphosphonate Therapy: a randomized, open-label, phase 3 trial, Lancet 2017; 390(10102):1584-1594.

9. Ishibahsi H, Crittenden DB, Miyauchi A, et. al. Romosozumab increases bone mineral density in postmenopausal Japanese women with osteoporosis: A phase 2 study. Bone 2017; 103: 209-215. Essay: Fracture Prevention in Women with Osteoporosis.