How Effective Is Denosumab for Osteoporosis?

Denosumab (also known as AMC-162, trade name Prolia) is a bone resorption inhibitor with a unique mechanism of action, which specifically targets the receptor activator of NF- kB ligand, RANKL), inhibits osteoclast activation and development, reduces bone resorption, and increases bone density. On May 28, 2010, the European Commission approved this product for the treatment of osteoporosis and prostate cancer-related bone loss in postmenopausal women. It is also used in patients who are currently ineffective or intolerable by other treatment methods to reduce Patient's risk of fracture. This product was approved for the first time in 27 member states of the European Union and Norway, Iceland and Liechtenstein. In June of the same year, this product was approved by the FDA for marketing.

Denosumab traits

This product is a humanized IgG2 monoclonal antibody, produced by mammalian (Chinese hamster ovary) cells through genetic engineering. Its molecular formula is C ₆₄₀₄ H ₉₉₀₈ N ₁₇₂₄ O ₂₀₀₄ S ₅₀ with a relative molecular mass of about 147,000.

Pharmacological effects of denosumab

This product is the first approved monoclonal antibody that specifically targets RANK ligands. RANK ligand is a transmembrane or soluble protein necessary for osteoclasts to maintain their structure, function and survival. Human RANKL mRNA is mainly in bone, bone marrow and lymphoid tissues, and its main role in bone is to stimulate the differentiation and activity of osteoclasts, and to inhibit the apoptosis of osteoclasts. Osteoclasts are responsible for bone resorption, and osteoclast precursors must have low levels of macrophage colony-stimulating factor and RANKL during differentiation into mature osteoclasts. This product has a high affinity with RANKL, preventing RANK ligands from activating RANK on the surface of osteoclasts, inhibiting osteoclast activation and development, reducing bone resorption, increasing bone density and bone strength of both cortical bone and trabecular bone, Promote bone reconstruction and reduce the incidence of vertebra, non-vertebra and hip fractures in postmenopausal women with osteoporosis.

The effect of this product on bone reconstruction can be evaluated by measuring some bone turnover marks (BTMs), such as bone resorption markers N-telopeptide (NTX), bone formation markers bone specificity Bone-specific alkaline phosphatase (BSAP). A phase I clinical study in healthy postmenopausal women showed that a dose-dependent decrease in NTX levels in morning urine can be observed on day d 2 after administration, and this decline can last for 6 months, with the largest decrease compared to baseline The ratio can reach 84%. This effect is reversible. When serum denosumab levels disappear, NTX levels rise again, reflecting the reversibility of its effect on bone reconstruction. As treatment continues, these effects will continue for a new cycle.

Clinical evaluation of denosumab

The FDA approved this product for osteoporotic women at high risk of fractures after menopause, which helps reduce the incidence of vertebral, non-vertebral and hip fractures in postmenopausal osteoporosis women. This product is also used in patients who are currently ineffective or intolerable with other treatments to reduce the risk of fractures.

A randomized, placebo-controlled, phase II clinical trial evaluated the efficacy and safety of this product in treating osteoporosis in postmenopausal women. Patients were randomly divided into 7 groups of this product [41 to 54 subjects in each group, subcutaneous injection of this product 6, 14, 30 mg (both every 3 months), 14, 60, 100 or 210 mg (both every 6 months)], the positive control group (70 mg oral alendronate, once a week) and the placebo group. The main evaluation index was the change of bone mineral density (BMD) and baseline level in the spine of patients after treatment. Results showed that spinal BMD in the treatment group increased by 3.0% to 6.7% compared with baseline after 12 months, compared to the control group, which increased by 4.6%, and the placebo group, which decreased by 0.8%. (P <0.001). After 24 months, spinal BMD in the treatment group increased by 4.13% to 8.89%, while it decreased by 1.18% in the placebo group. Significant increases in BMD in the hip 1 and distal 1/3 segments of the treatment group compared with placebo were also observed. During this period, there were no significant differences in patient tolerance, BTM levels, and incidence of adverse reactions between the different groups. Among the 7 treatment groups, the 60 mg (once every 6 months) group has an ideal balance point in terms of safety and effectiveness, and will continue to perform phase III clinical trials at this dose.

A 3-year randomized, double-blind, placebo-controlled phase III clinical trial FREEDOM (Fragment Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) evaluated the effectiveness and safety of this product in treating osteoporosis in postmenopausal women. Patients were randomized into either the treatment group (60 mg subcutaneously, once every 6 months, n = 3 902) or placebo (n = 3 906). The main evaluation index was the incidence of new spinal fractures during 3 years, and the secondary indicators included the incidence of hip and non-vertebral fractures during the observation period and the time of the first fracture. The subjects were between 60 and 90 years of age, with an average age of 72.3 years. The basic value of the T-score of the spine or total hip was-4.0 to-2.5 (mean-2.8). About 23% of the subjects had a history of at least one fracture before entering the trial. All patients were supplemented with elemental calcium 1000 mg and vitamin D 400-800 IU daily. The results showed that compared with the placebo group, the incidence of new spinal fractures in the treatment group was reduced by 68% (2.3% in the treatment group and 7.2% in the placebo group, P <0.001). The incidence of internal fractures was reduced by 40% (0.7% in the treatment group, 1.2% in the placebo group, P = 0.036), and the incidence of non-vertebral fractures was relatively reduced by 20% (6 in the treatment group). 5%, compared with 8.0% in the placebo group, P = 0.011).

Another randomized, placebo-controlled phase III clinical trial, DEFEND (Denosumab Fortifies Bone Density), evaluates the effect of this product in preventing osteoporosis in postmenopausal women. The average age of the subjects was 59.4 years, and the T-scores of the spine were between -1.0 and -2.5 (mean: -1.61). They were randomly divided into treatment groups (60 mg subcutaneously, each Once every 6 months, n = 166) or placebo (n = 166), all patients were supplemented with elemental calcium 1 000 mg per day, and vitamin D supplementation was determined based on the subject's plasma 25-hydroxyvitamin D level . The main evaluation index was the change of the BMD of the spine from the baseline level measured by Dual Energy X-ray Absorptionmetry (DXA). The results showed that after 24 months, compared with the placebo, the product significantly increased the BMD value of the spine (the treatment group increased by 6.5%, while the placebo group decreased by 0.6%). In addition, the BMD values of all tested sites including hip and distal radius in the treatment group increased significantly. At the same time, markers for bone resorption and formation were significantly reduced. The overall incidence of adverse reactions during the observation period was similar to that of the placebo group.

A 1-year, double-blind, randomized controlled phase III clinical trial DECIDE (Determining Efficacy: Comparison of Initiating Denosumab versus alEndronate) compared the effectiveness and safety of this product and alendronate sodium. A total of 1 189 postmenopausal patients Women were enrolled. The mean baseline T-score of lumbar vertebrae was 2.6, and the average age was 64 years. Patients were randomly divided into two groups: the treatment group (60 mg subcutaneously, once every 6 months, n = 594), and the control group (alendronate sodium 70 mg, once every 6 months, n = 595). All subjects were supplemented with 500 mg of elemental calcium daily, and the dose of vitamin D was adjusted based on plasma 25-hydroxyvitamin D levels. After 12 months, BMD was increased at all sites (hip, spine, femoral neck, trochanter, and distal radius of the 1/3 segment) at all test sites. Both groups had increased BMD, but the treatment group had increased values compared to the control group. More significant (BMD of total hips increased by 3.5 and 2.6, respectively, P <0.001) at the primary end point. The incidence of adverse reactions was similar between the two groups. A questionnaire survey of patients showed that most patients (77%) were more willing to receive subcutaneous injections of this product twice a year.

Evaluation of Denosumab Safety

A three-year, multicenter, randomized, double-blind, placebo-controlled phase III clinical trial involving 7,808 patients evaluated the safety of this product. The all-cause mortality rate was 1.8% (n = 70) and 2.3% (n = 90) in the treatment and placebo groups, respectively.The incidence of nonfatal serious adverse events in the treatment and placebo groups was 25.0% and 24.2%; 2.4% and 2.1% of patients in the treatment and placebo groups withdrew from the trial due to adverse events, respectively. The most common adverse reactions reported in clinical trials were back pain (34.7%), limb pain (11.7%), musculoskeletal pain (7.6%), hypercholesterolemia (7.2%), and Cystitis (5.9%), the most common adverse reactions leading to withdrawal are breast cancer, back pain and constipation. Other common adverse reactions include: anemia (3.3%), angina pectoris (2.6%), atrial fibrillation (2.0%), dizziness (5.0%), abdominal pain (3.3%), flatulence (2 .2%), gastroesophageal reflux disease (2.1%), peripheral edema (4.9%), weakness (2.3%), upper respiratory infections (4.9%), pneumonia (3.9 %), Pharyngitis (2.3%), shingles (2.0%), spinal osteoarthritis (2.1%), sciatica (4.6%), insomnia (3.2%), rash (2 5%), itching (2.2%).

Another 4-year, randomized, placebo-controlled phase II clinical trial also evaluated the safety of this product. In this trial, the incidence of total adverse reactions and the incidence of severe adverse reactions in the treatment group were not significantly different from those in the placebo or alendronate groups. However, the trial reported that the rate of serious hospital-infected infections in the treatment group was 3.2%, while none in the placebo group and the alendronate group.

In the other two clinical trials, the incidence of mandibular necrosis was 1.1% to 2.0%, which may be related to the large amount of denosumab in these two trials (120 mg, once a month) .

Other adverse reactions requiring attention include hypocalcemia and imbalances in mineral metabolism. In addition, this product is a human-derived monoclonal antibody and may be immunogenic for long-term use.

Denosumab drug interactions

No drug-drug interactions have been reported for this product.

Denosumab precautions

Hypocalcemia must be corrected before starting treatment with this product. For patients who are prone to hypocalcemia and mineral metabolism imbalance (for example, history of hypoparathyroidism, history of thyroid surgery, history of parathyroid surgery, malnutrition, small bowel resection, severe renal insufficiency), clinical Monitor their creatinine and mineral levels (such as phosphorus and magnesium) closely, and instruct them to pay attention to the symptoms of hypocalcemia and to add sufficient calcium and vitamin D.

Patients who are also taking immunosuppressants or whose immune system is compromised may have an increased risk of serious infections. Physicians need to fully consider the benefit-risk ratio before prescribing denosumab to such patients. For severe infections with this product, the physician should assess the need to continue treatment with this product.

Mandibular necrosis (which can occur spontaneously) is usually accompanied by local infection with tooth extraction and delayed healing. Routine oral examination should be performed before starting the treatment of this product, and good oral hygiene should be maintained after the start of treatment. If patients with mandibular necrosis occur, treatment for mandibular necrosis may worsen the condition, and drug withdrawal should be considered at this time.