Benefits of denosumab for osteoporosis

Benefits of denosumab for osteoporosis

ABOUT. ERSHOVA

, Doctor of Medical Sciences, Professor, Yaroslavl State Medical Academy,
A.V.
NAZAROVA , Candidate of Medical Sciences,
GUZ YaO KB SMP im.
N.V. Solovyova (Review of literature data)

Today, in the arsenal of a practicing doctor there is a sufficient number of effective drugs used for pathogenetic therapy of osteoporosis. According to the latest recommendations of the Russian Osteoporosis Association, the first-choice drugs for the treatment of osteoporosis, along with nitrogen-containing bisphosphonates and strontium ranelate, also include denosumab, the clinical effectiveness of which in reducing the risk of non-vertebral and vertebral fractures has been proven in long-term multicenter clinical trials.

The following drugs are registered in the Russian Federation for the treatment of osteoporosis (Table 1) [1]:

1st line drugs – alendronate, risedronate, ibandronate, zoledronic acid, strontium ranelate, denosumab; The 2nd line drug, salmon calcitonin, is currently prohibited for use in AP.

All first-line drugs act primarily by suppressing pathologically active resorption and are antiresorptive drugs, while strontium ranelate is a bidirectional drug that simultaneously suppresses increased resorption and activates bone formation.

Undoubtedly, all drugs have their advantages and disadvantages. Thus, bisphosphonates irreversibly suppress resorption, therefore, when prescribing them for a long period, it is always necessary to remember the possibility of the formation of so-called “frozen bone” [2] with a certain probability of atypical fractures (1 case per 1000 patients per year), which limits the time period of their use [3, 4, 5].

Denosumab is a fully human monoclonal antibody against RANK ligand. Denosumab is the first antiresorptive drug whose action is based on the regulation of the RANK-L-RANK-OPG bone remodeling system. Due to its unique pharmacokinetics, denosumab has certain advantages over other drugs used in the treatment of osteoporosis.

It has been approved for use in postmenopausal osteoporosis since June 2010. In the process of developing denosumab, a new opportunity has emerged to clarify the mechanisms of bone tissue remodeling in the interaction between competitive molecules RANK ligand (RANK-L), osteoprotegerin (OPG) and osteoclast receptors produced by osteoblasts. RANK) [6].

It was found that the main mechanism of bone loss and the development of fractures is an increase in osteoclastogenesis and bone resorption, because under conditions of estrogen deficiency, the balance in the RANK-L-RANK-OPG system is disturbed, and the amount of RANK-L exceeds the amount of osteoprotegerin. When the concentration of RANK-L in the bone microenvironment significantly exceeds the concentration of OPG, then more RANK ligand can bind to its receptor on the osteoclast, RANK. This RANK-L–RANK interaction results in a marked increase in osteoclast differentiation and activation, and thus increases bone resorption. If the concentration of OPG produced by osteoblasts exceeds the concentration of RANK-L, then less RANK ligand binds to the osteoclast receptor (RANK), as a result of which osteoclast differentiation and activation do not occur, and the process of bone resorption slows down. Therefore, the balance between RANK-L and OPG produced by osteoblasts is the determining internal factor of the bone microenvironment that regulates resorption [7].

Denosumab, a fully human monoclonal antibody to RANK-L, was the first product developed to reduce bone resorption by blocking the anchoring of RANK-L to RANK. Its mechanism of action is shown in Figure 1. A four-year phase II study [8] showed that the effect of denosumab was completely reversible based on time course analysis of DXA and bone markers (CTX). However, the reasons for the return of CTX and bone mineral density (BMD) to baseline values ​​after denosumab discontinuation are unknown, which may be due to a bone mechanostatic mechanism.

It is known that bisphosphonates must be taken up by osteoclasts and are mainly located on the bone surface. Unlike bisphosphonates, denosumab does not bind to bone tissue. It circulates in the intercellular fluid, binding RANKL, inhibiting the formation, maturation, functioning and survival of osteoclasts. This fact explains why patients with osteoporosis who are already being treated with bisphosphonates may benefit from switching to denosumab therapy. A comparative study showed that switching to denosumab resulted in a greater increase in BMD and a greater reduction in bone resorption than with continued alendronate therapy [9, 17].

Similar results (a significantly greater increase in BMD during denosumab therapy) were demonstrated by comparative studies with ibadronate and risedronate among women in whom bisphosphonate therapy was not sufficiently effective [18, 19]. The FREEDOM study showed that denosumab compared with placebo reduced the risk of vertebral, non-vertebral and hip fractures by -68%, -20% and -40%, respectively [20].

Moreover, in patients over 75 years of age, the reduction in the risk of hip fractures reached 62% [21]. According to a review by Sutton EE and Riche DM [11], in a number of clinical trials, the effectiveness of denosumab in increasing bone mineral density is comparable to the effectiveness of alendronate, but is associated with a lower risk of osteonecrosis of the jaw and atypical fractures, but with a greater risk of infections and neoplasms.

However, another systematic review of four heterogeneous randomized controlled trials combining data from 1942 women found low-quality evidence for the hypothesis that denosumab reduces the risk of fractures more than alendronate, and the incidence of neoplasms and infections was similar in the denosumab and alendronate groups [12 ].

Denosumab may be recommended for use in patients after taking bisphosphonates if they are intolerant or ineffective, as well as for the period of the so-called. "medicinal holidays"

It should be noted that denosumab is an IgG 2 fully monoclonal antibody, so neutralizing antibodies are not formed to it. In addition, denosumab does not bind to TNF ligand - an inducer of apoptosis (TRAIL - a survival factor for tumor cells), and has no significant effect on the number of lymphocytes (CD3), T cells (CD 4, CD 8, CD 54) , or B-cells (CD 20) [13].

Most drugs have limitations for use in patients with low creatinine clearance values. For bisphosphonates, according to the instructions for use, with a creatinine clearance <35 ml/min, the risk of accumulation increases, and therefore there are restrictions on use, and the use of strontium ranelate with a creatinine clearance <30 ml/min is contraindicated. Denosumab, on the contrary, can be used even in patients with severe chronic renal failure. Meanwhile, according to the Public Health and Nutrition Examination Survey (NHANES) III, 85% of women with osteoporosis have mild or moderate renal dysfunction [14].

In order to determine the safety and effectiveness of the use of denosumab in patients with osteoporosis and impaired renal function, Jamal SA et al. [15] reanalyzed data in postmenopausal women with varying levels of renal impairment (FREEDOM RCT). The analysis included 7808 women aged 60 to 90 years with T-score BMD values ​​between -2.5 SD and -4.0 SD at the lumbar spine or total hip. Exclusion criteria included hyper- or hypoparathyroidism, current hypocalcemia (albumin-corrected serum calcium concentration less than 2.13 mmol/L) or vitamin D deficiency (25-hydroxyvitamin D level less than 30 nmol/L). At the same time, 3902 women received denosumab and 3906 received placebo for 36 months. Serum creatinine and albumin-corrected calcium were measured every 6 months.

Based on the classification of the National Society of Chronic Kidney Diseases (K/DOQI Guidelines 2002), stages of renal dysfunction were assessed: stage 1 (normal renal function or renal damage with normal or increased glomerular filtration) - eGFR 90 ml/minute or more; stage 2 (renal damage with moderate decrease in glomerular filtration) - eGFR 60 - 89 ml/minute, stage 3 (moderate decrease in glomerular filtration) - eGFR 30 - 59 ml/minute, stage 4 (severe decrease in glomerular filtration) - eGFR 15 - 29 ml/minute. When calculated using the Cockcroft-Gault formula, 73 women had stage 4 chronic renal failure, 2817 had stage 3, 4069 had stage 2, and the remaining 842 women had stage 1 renal impairment. When calculated using the MDRD formula, 17 women had stage 4, 1078 had stage 3, 5413 had stage 2, and another 1298 women had stage 1.

When calculating the risk of vertebral and non-vertebral fractures depending on the stage of chronic kidney disease (CKD), no statistically significant relationships were identified; the reduction in the risk of fracture did not depend on the level of kidney function. The incidence of vertebral fractures was lower in the denosumab group compared with placebo for all stages of CKD, but this reduction was not statistically significant in the stage 4 CKD group. Also, the incidence of nonvertebral fractures was lower in the denosumab group compared with placebo, but this was not statistically significant for CKD stages 3 and 4. Due to the small number of proximal femoral fractures (43 in the placebo group and 26 in the denosumab group), differences by CKD stage were not calculated. The increase in BMD was also independent of kidney function, and there were no statistically significant differences depending on the stage of CKD.

The investigators found no differences in the incidence of adverse events, serious adverse events, serious adverse events related to infection, or cardiovascular events between the denosumab and placebo groups, stratified by CKD stage of CKD. In addition, there were no changes in glomerular filtration rate calculated using both formulas over 36 months of follow-up.

In addition, a 16-week open-label clinical trial was conducted at 12 US centers to evaluate the pharmacokinetics, pharmacodynamics and safety of denosumab in patients with varying degrees of decreased renal function [16]. The study included 55 patients: 12 with normal renal function, 13 with mild CKD, 13 with moderate CKD, 9 with severe CKD, 8 with severe renal failure (dialysis group). The proportion of women (51%) to men (49%) was similar, and the majority of patients (69%) were white. The average age of the participants was 64+15 years. Subjects received a single subcutaneous injection of 60 mg denosumab. Renal function in the groups was calculated using the Cockcroft-Gault equation and a formula developed by the US Food and Drug Administration (FDA), where the study was designed. Our results indicate that renal function did not significantly influence the pharmacokinetics or pharmacodynamics of denosumab, suggesting that denosumab dose adjustment based on glomerular filtration rate is not necessary. A rapid decrease in serum concentrations of the bone resorption marker 1C-telopeptide (CTX) was recorded throughout the study in all groups. The most common adverse events were: hypocalcemia (15%), pain in the extremities (15%) and nausea (11%). Most adverse events were rated by investigators as mild to moderate in severity. Administration of calcium and vitamin D supplements was not an original requirement of the study protocol but was implemented during the trial. Hypocalcemia was not reported in any patient while taking calcium and vitamin D. In seven patients, serum calcium was 7.5 – 8.0 mg/dl (1.9 – 2.0 mmol/l), in 5 patients (four of them with progressive kidney disease) calcium was below 7.5 mg/l dl (<1.9 mmol/l). Two patients (1 with symptomatic, 1 with asymptomatic hypocalcemia) were hospitalized for intravenous treatment with calcium gluconate.

Thus, denosumab has an important advantage over bisphosphonates - no effect on renal function, the drug is not excreted by the kidneys, and there is no need for dose adjustment in patients with reduced renal function. Supplemental calcium and vitamin D should be recommended in patients initiating denosumab therapy, especially in patients with reduced renal function.

Denosumab is a 1 ml subcutaneous solution containing 60 mg of active substance, administered once every 6 months. Indications for treatment with Denosumab are: postmenopausal osteoporosis; treatment of bone loss in women receiving aromatase inhibitor therapy for breast cancer and in men with prostate cancer receiving hormone deprivation therapy; treatment of senile osteoporosis in men. There are few contraindications: hypersensitivity to any of the components of the drug; hypocalcemia. During the course of treatment, it is recommended to additionally take calcium supplements and vitamin D.

Bibliography

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Prolia

Denosumab is a fully human monoclonal antibody (IgG2) that has high affinity and specificity for the receptor activator of nuclear factor kappa B (RANKL) ligand and thereby prevents the activation of the only RANKL receptor, the activator of nuclear factor kB (RANK), located on the surface of osteoclasts and their predecessors. Thus, preventing the RANKL/RANK interaction inhibits osteoclast formation, activation, and survival. As a result, denosumab reduces bone resorption and increases the mass and strength of cortical and trabecular bone layers. Pharmacodynamic effects

Denosumab 60 mg resulted in a rapid decrease in serum concentrations of the bone resorption marker 1C-telopeptide (CTX) by approximately 70% within 6 hours of subcutaneous administration and by approximately 85% over the next 3 days. The reduction in CTX concentrations remained stable over the 6-month dosing interval. The rate of decline in serum CTX concentrations was partially attenuated by decreasing denosumab serum concentrations, reflecting the reversibility of the effects of denosumab on bone remodeling. These effects were observed throughout the course of treatment. Consistent with the physiological relationship between the processes of formation and resorption during bone tissue remodeling, a decrease in the content of bone formation markers (for example, bone-specific alkaline phosphatase and serum N-terminal propeptide of type 1 collagen) was observed from the first month after the first dose of denosumab. Markers of bone turnover (markers of bone formation and bone resorption) generally reached pre-treatment concentrations no later than 9 months after the last dose of the drug. After resumption of denosumab treatment, the degree of reduction in CTX concentrations was similar to the degree of reduction in CTX concentrations at the start of denosumab treatment.

Switching from alendronic acid treatment (median duration of use 3 years) to denosumab was shown to result in an additional reduction in serum CTX concentrations compared with a group of postmenopausal women with low bone mass who continued alendronic acid treatment. However, changes in serum calcium levels were similar in both groups.

In experimental studies, inhibition of RANK/RANKL simultaneously with binding of osteoprotegerin to the Fc fragment (OPG-Fc) resulted in decreased bone growth and impaired tooth eruption. Therefore, treatment with denosumab may inhibit the growth of bones with open growth plates in children and lead to teething disorders.

Immunogenicity

Denosumab is a human monoclonal antibody, therefore, as with other protein drugs, there is a theoretical risk of immunogenicity. More than 13,000 patients were screened for the production of binding antibodies using a sensitive electrochemiluminescence technique in combination with an immunoassay. Less than 1% of patients treated with denosumab for 5 years had detectable antibodies (including pre-existing, transient and growing). Seropositive patients were further screened for the development of neutralizing antibodies using an in vitro cell culture chemiluminescence assay, and no neutralizing antibodies were detected. There were no changes in the pharmacokinetic profile, toxic profile or clinical response due to antibody formation.

Clinical effectiveness

Treatment of osteoporosis in postmenopause

In women with postmenopausal osteoporosis, Prolia increases bone mineral density (BMD) and reduces the incidence of hip fractures, vertebral and non-vertebral fractures. The effectiveness and safety of denosumab in the treatment of postmenopausal osteoporosis was proven in a 3-year study. The study results show that denosumab significantly, compared with placebo, reduces the risk of vertebral and non-vertebral fractures, and hip fractures in postmenopausal women with osteoporosis. The study included 7808 women, of whom 23% had common vertebral fractures. All three fracture efficacy endpoints reached statistically significant values ​​assessed using a prespecified sequential testing design.

The reduction in the risk of new vertebral fractures with denosumab remained stable and significant for more than 3 years. The risk decreased regardless of the 10-year likelihood of major osteoporotic fractures. The risk reduction was also not affected by a history of frequent vertebral fractures, nonvertebral fractures, age, patients, BMD, level of bone turnover, or previous therapy for osteoporosis.

In postmenopausal women over 75 years of age, denosumab reduced the incidence of new vertebral fractures and, in a post hoc analysis, reduced the incidence of hip fractures.

Reductions in the incidence of nonvertebral fractures were observed regardless of the 10-year incidence of major osteoporotic fractures.

Denosumab significantly increased BMD in all anatomical regions compared to placebo. BMD was determined 1 year, 2 and 3 years after the start of therapy. Similar effects on BMD were noted in the lumbar spine regardless of age, race, body mass index (BMI), BMD, and bone turnover.

Histological studies confirmed normal bone architecture and, as expected, decreased bone turnover compared with placebo. No pathological changes were noted, including fibrosis, osteomalacia, and disorders of bone tissue architecture.

Clinical efficacy in the treatment of bone loss caused by hormone deprivation therapy or aromatase inhibitor therapy

Treatment of bone loss caused by androgen deprivation

The efficacy and safety of denosumab in the treatment of bone loss associated with androgen depletion was demonstrated in a 3-year study of 1,468 patients with non-metastatic prostate cancer.

A significant increase in BMD was determined in the lumbar spine, entire femur, femoral neck, and femoral trochanter 1 month after the first dose. Increases in lumbar spine BMD were independent of age, race, geographic region, BMI, baseline BMD, bone turnover, duration of hormone deprivation therapy, and history of vertebral fracture.

Denosumab significantly reduced the risk of new vertebral fractures over 3 years of use. A reduction in risk was observed 1 year and 2 years after the start of therapy. Denosumab also reduced the risk of more than one osteoporotic fracture of any location.

Treatment of bone loss in women receiving aromatase inhibitor therapy for breast cancer

The efficacy and safety of denosumab in the treatment of bone loss induced by adjuvant aromatase inhibitor therapy was assessed in a 2-year study of 252 patients with nonmetastatic breast cancer. Denosumab significantly increased BMD in all anatomical sites compared with placebo over 2 years. An increase in BMD was observed in the lumbar spine one month after taking the first dose. Positive effects on lumbar spine BMD were observed regardless of age, duration of aromatase inhibitor therapy, BMI, previous chemotherapy, previous use of a selective estrogen receptor modulator (SERM), and time since the onset of menopause.

Relevance

One of the pressing problems in the treatment of metastatic forms of malignant tumors is timely and effective treatment of bone lesions.
Most often, skeletal bones are affected by metastases in breast cancer and prostate cancer (65–75%), somewhat less frequently in thyroid cancer (60%), lung cancer (40%) and prostate cancer (20–25%) [ 1]. The life expectancy of cancer patients is determined by the presence of organ metastases and the sensitivity of the tumor to specific antitumor treatment. At the same time, the clinical manifestations of metastatic bone disease - pain, impaired support function, pathological fractures, various neurological disorders, hypercalcemia - aggravate the condition of patients and significantly reduce the quality of life of cancer patients.

To assess the effectiveness of treatment for bone metastases, the concept of skeletal complications, otherwise known as bone events, is used.

These include pathological bone fractures, compression fractures of the vertebral bodies (with a decrease in the height of the vertebral body by 25% or more between two x-ray examinations), compression of the spinal cord, the appearance or intensification of pain associated with metastases in the bones, the need for radiation therapy, the need for surgery for bone metastases and hypercalcemia. The frequency of these complications varies depending on the nature of the tumor and the intensity of treatment. Most often, within 2 years, bone events are recorded in breast cancer (64%), less often in prostate cancer (49%), in lung cancer and other malignant tumors (46%) [2–5].

The risk of bone events is highest in patients with osteolytic metastases. From an economic point of view, preventing the development of bone complications, reducing their frequency and increasing the time before their development seems obviously more feasible than treating bone complications [6].

The interaction of osteoclasts and osteoblasts normally regulates bone tissue remodeling, but tumor cells disrupt this balance. They produce factors that stimulate bone resorption by osteoclasts and influence the activity of osteoblasts by stimulating (in osteoblastic lesions) or inhibiting (in osteolytic lesions) bone formation. Growth factors released during bone tissue resorption in turn stimulate the growth of tumor cells [7].

Modern treatment of bone metastases is unthinkable without the use of osteomodifying agents (OMAs).

The first class of OMAs to enter clinical practice are bisphosphonates. In their chemical structure, they are an analogue of bone matrix pyrophosphates, resistant to the degrading action of alkaline phosphatase. Bisphosphonates bind to calcium and selectively accumulate in bones. In bone tissue, they are utilized by mature osteoclasts, inhibiting their activity, act only in the zone of bone resorption and only after absorption by osteoclasts, exerting a cytostatic effect on them, and can persist in bone tissue for up to 10 years. Bisphosphonates of the first generations (clodronic acid, pamidronic and alendronic acids) are quite toxic and inconvenient to use [8]. Most practical oncologists prefer zoledronic acid, a 3rd generation bisphosphonate, which acts more selectively on bone metastases and also has an antiangiogenic effect and the ability to induce apoptosis of tumor cells [9–11].

The first representative of a new class of osteomodifiers is the RANK (Receptor Activator of Nuclear Factor NF-κB) ligand blocker denosumab. RANK ligand is a major mediator in the vicious circle of bone destruction in patients with solid tumors and bone metastases.

Denosumab is a targeted drug, which is a fully humanized monoclonal antibody to the RANK ligand; it interrupts the pathogenetic mechanisms of the development and progression of bone metastases [7, 12–14].

Unlike bisphosphonates, denosumab is not included in the bone matrix, does not damage osteoclasts, but reduces their number, and acts in the extracellular space. This causes the rapid disappearance of the antiresorptive effect after discontinuation of the drug [15, 16].

A comprehensive analysis of 3 randomized, double-blind, placebo-controlled, active-controlled phase 3 trials comparing the efficacy of zoledronic acid and denosumab, which included more than 5000 patients with bone metastases from solid tumors, showed that denosumab significantly increased the time to first bone event by 8 .2 months (from 19.4 to 27.6 months) and reduced the risk of a bone event by 17% (hazard ratio [HR] = 0.83, 95% confidence interval [CI] – 0.76–0.90; p <0.0001). The drug was equally effective regardless of the presence or absence of a history of bone complications [17].

In addition, denosumab significantly reduced the level of markers of bone resorption (urinary N-telopeptide and osteospecific alkaline phosphatase), delayed the progression of pain by almost 2 months, and fewer patients required switching from non-opioid analgesics to narcotic ones[18].

Among the advantages of using denosumab over zoledronic acid, it should be noted that there is no negative effect on renal function, therefore no monitoring of renal function and dose adjustment of the drug was required, as well as ease of administration (1 subcutaneous injection per month). The incidence of osteonecrosis of the jaw is the same for both drugs [19].

Thus, when choosing an osteo-modifying agent, the appointment of denosumab should be considered primarily in patients with multiple bone metastases, with a high risk of developing a pathological fracture, with predominant damage to the bones of the axial skeleton, in the presence of pain and the exhaustion of radiation therapy, in cases of impaired renal function , also in the absence of venous access.

Purpose of the study: clinical evaluation of the effectiveness and safety of denosumab in bone metastases of solid tumors.

Methods

We analyzed data from 28 patients treated with denosumab for metastatic bone lesions in solid tumors at the Rostov Oncology Research Institute in 2015–2017. All patients had pathomorphologically confirmed metastatic malignancy (breast cancer, prostate cancer and other tumors) with one or more bone metastases. Selection criteria for denosumab therapy were patient age 18 years and older, functional status according to the ECOG (Eastern Cooperative Oncology Group) scale ≥2. Previous bisphosphonate therapy was allowed, as was radiation therapy or radiopharmaceutical therapy. A mandatory criterion was signed informed consent for treatment.

Denosumab was administered subcutaneously at a dose of 120 mg once every 28 days. Denosumab therapy was carried out alone or combined with chemotherapy or hormonal therapy as indicated, according to the location of the primary tumor. As the process progressed, patients continued to receive denosumab in combination with antitumor therapy. Before treatment and every 2–3 months from the start of denosumab treatment, patients underwent bone examination (osteoscintigraphy, spiral computed tomography or radiography).

The time until the development of the first bone event, the frequency of occurrence of bone events, and the dynamics of pain syndrome were assessed (using a visual analogue scale - VAS).

Statistical data processing was carried out using the Statistica 6.0 software package. When studying the time to the development of the first bone event, the Kaplan–Meier method was used.

The analyzed group included 28 patients aged from 28 to 71 years, the average age was 58.4±2.4 years, 6 (21.4%) men, 22 (78.6%) women were included.

Most patients had metastatic breast cancer - 19 (67.8%), the group also included patients with lung cancer - 5 (17.8%), colorectal cancer - 2 (7.3%), stomach cancer - 1 (3, 6%) and prostate cancer – 1 (3.6%).

All patients had multiple bone metastases, which in more than half of the cases were accompanied by severe pain and limited range of motion (Table 1).

To relieve pain, all patients were treated with non-narcotic analgesics.

In most patients, the presence of bone metastases was combined with damage to soft tissues and internal organs (Table 2).

8 (28.5%) patients had isolated metastases in the bones, 1 (3.6%) had isolated metastases in the bones and soft tissues, 19 (67.9%) patients had visceral metastases.

In 17 (60.7%) patients, denosumab therapy was combined with chemotherapy, in 9 (32.1%) - with hormonal therapy according to indications, according to the location of the primary tumor, 2 (7.3%) patients received denosumab only.

In the 1st line of treatment, 6 (21.5%) patients received denosumab for bone metastases, 22 (78.5%) patients had previously received bisphosphonate therapy, 7 (24.9%) had received radiation and/or radiopharmaceutical therapy.

results

In 22 (78.6%) patients, during therapy with denosumab, reparative changes were noted in the foci of osteolysis according to osteoscintigraphy and x-ray examination; in 6 (21.4%) patients, destructive changes in the bones remained at the same level, which was regarded as stabilization of the process. There was no increase in the degree of metastatic bone lesions during denosumab therapy.

The overall event rate for bone metastases during treatment with denosumab was 7 (25%), which is consistent with the literature (Table 3).

In 10 (35.7%) patients, there was a significant decrease in pain, an increase in range of motion, and they partially refused to take analgesics after the first administration of denosumab.

By the 6th month of therapy, the severity of pain, assessed on the VAS scale, decreased by 50%, and by the 12th month - by 77%.

The duration of denosumab therapy ranged from 3 to 24 months, the median was 16.8±2.3 months (Fig. 1). The time to the first bone event during denosumab therapy ranged from 8 to 18 months, the median was not reached (Fig. 2).

It should be noted that the drug is well tolerated and has a favorable toxicity profile. In 2 (7.1%)

Patients experienced a local reaction in the form of hyperemia and local pain on the first day after drug administration, which resolved independently. In 2 (7.1%) cases, grade 1 influenza-like syndrome was noted. One patient, who initially had concomitant dental pathology, developed osteonecrosis of the lower jaw after 13 months of therapy, the connection of which with denosumab cannot be excluded. No other side effects were noted during treatment with this osteomodifier.

Discussion

Thus, denosumab has demonstrated high clinical efficacy in bone metastases of solid tumors. The median time of denosumab therapy was 16.8±2.3 months, and was not reached before the first bone event. The duration of follow-up and the incidence of bone events are comparable to the results of international studies. Toxic effects noted during denosumab therapy were minimal and did not affect antitumor and osteomodifying therapy.

Conclusion

Thus, denosumab therapy is highly effective without clinically significant toxicity during long-term use in patients with solid tumors with bone metastases.