Materials and methods
The open prospective study included 98 women (mean age 68±9 years, mean duration of postmenopause 17±4 years) with postmenopausal AP, who were observed on an outpatient basis at the National Medical Research Center for Primary Care. In the anamnesis, a fracture of the proximal femur (PHB) was noted in 4, radius - in 8, compression fractures of the vertebrae - in 27. The median 10-year probability of major fractures according to FRAX in patients who had not previously received therapy was 14.9%, fracture femoral neck (FNC) - 3.7% (Table 1).
Table 1. Clinical and instrumental characteristics of the examined patients Note. Here and in the table. 2 NPs - those who had not previously taken anti-osteoporotic therapy; P - previously taken anti-osteoporotic therapy.
All patients received denosumab at a dose of 60 mg once every 6 months subcutaneously (in most cases in the abdominal area) for 12 months or more, as well as calcium and vitamin D supplements according to the instructions [12].
Before starting treatment with Prolia, the concentration of vitamin D (25 (OH)D) in the blood serum was measured. In order to increase the effectiveness and safety of therapy, vitamin D saturation was carried out (50,000 IU per week for 4 weeks) followed by a transition to maintenance intake (800-2000 IU/day) depending on the degree of vitamin D deficiency. The daily calcium intake was at least 1000-1200 mg [13].
Inclusion criteria: signed informed consent; duration of postmenopause (after natural or surgical menopause) ≥1 year; diagnosis of AP, according to WHO criteria: BMD ( T
-criterion) of lumbar vertebrae (LI—LIV) and/or PBC or SBC –2.5
SD
and below;
the presence of low-traumatic fractures of the vertebrae, the spinal vertebrae or the radius with a T
-criterion of –1.5
SD
or lower and a high 10-year risk of major fractures according to FRAX.
Exclusion criteria: other metabolic skeletal diseases; hypocalcemia; malignant neoplasms diagnosed within the last 5 years before the start of therapy; taking other drugs for the treatment of AP after inclusion in the study, except for calcium and vitamin D; taking replacement therapy with female sex hormones; inability to perform densitometry of at least two lumbar vertebrae.
Among the patients there were no persons systematically taking glucocorticosteroids. The following concomitant diseases were identified: type 2 diabetes mellitus - in 8, diseases of the gastrointestinal tract - in 20, hypothyroidism, which requires taking levothyroxine less than 100 mcg / day - in 8, hypertension - in 28, various disorders heart rhythm - in 8, coronary heart disease - in 16, kidney disease with a decrease in creatinine clearance to 27 ml/min - in 3, breast cancer and mastectomy more than 5 years before inclusion in the study - in 6; 3 patients were treated with aromatase inhibitors. Diseases such as diabetes mellitus, hypothyroidism with long-term use of replacement therapy, and a history of therapy for breast cancer could determine the mixed nature of AP.
The maximum observation period was 4 years: 48 people received treatment for 12 months, 29 for 24 months, 11 for 36 months, 10 for 48 months.
Adverse events were assessed after the first administration of the drug, then after 6, 12, 24, 36 and 48 months of treatment based on questionnaires given to patients. In addition, the convenience of the scheme and form of drug administration was assessed using a 4-point system: very convenient, fairly convenient, satisfactory, unsatisfactory.
The patients were divided into 2 groups: 1st - 26 people who had previously received treatment with anti-osteoporotic drugs (15 aminoBP, 6 strontium ranelate, 10 active metabolites of vitamin D), and were transferred to denosumab therapy after consultation at the National Medical Research Center for PM due to the ineffectiveness of the drugs or poor tolerability no earlier than 3 months after the end of previous therapy; 2nd - 72 patients who had not received anti-osteoporotic therapy before denosumab was prescribed.
All patients underwent the following studies:
— examination and anthropometric study;
— dual-energy X-ray bone densitometry of the lumbar spine (LI-LIV) in the posteroanterior projection and POBC using Hologic Delpfi W (USA) and Lunar Expert (USA) devices. Dynamic measurements were carried out once a year on the same device. BMD indicators are unified and adjusted to the indicators used in the Hologic database using correction factors;
- laboratory tests: level of total calcium, creatinine, total alkaline phosphatase (TALP), C-terminal telopeptide of type I collagen (CTx, β-CrossCaps) in blood serum;
— survey about the presence of adverse events.
The 10-year probability of major osteoporotic fractures was assessed using the Russian FRAX model and bone resorption marker CTx once in 72 patients of group 2.
Statistical data processing was carried out using Microsoft Excel applications and the statistical data analysis package SPSS 20.0. Conventional methods of parametric and nonparametric analysis were used. Quantitative variables were described by the number of parameters, the arithmetic mean ( M
), standard deviation from the arithmetic mean (
σ
).
Qualitative variables were described in absolute and relative values (in percentages). Differences were considered statistically significant at p
<0.05. When comparing qualitative indicators, statistical analysis methods were used: Pearson's χ2 test, paired and unpaired Student's t-test. For parameters whose distribution differed from normal, nonparametric tests were used: when comparing two groups, paired Spearman correlation analysis was used to determine the two-sided significance of the indicators.
PROLIA
special instructions
It is recommended to take calcium and vitamin D supplements while using Prolia®.
Hypocalcemia can be corrected by taking calcium and vitamin D supplements in adequate doses before starting denosumab therapy. It is recommended to monitor calcium concentrations during therapy in patients predisposed to hypocalcemia, especially in the first weeks after initiation of therapy (see section "Side Effects").
Patients receiving Prolia® may develop infections of the skin and its appendages (mainly inflammation of the subcutaneous tissue), in some cases requiring hospitalization. Such reactions were reported more frequently in the denosumab group (0.4%) than in the placebo group (0.1%) (see Adverse Reactions section). However, the overall incidence of skin infections was comparable in the denosumab and placebo groups. Patients should be instructed to immediately seek medical attention if symptoms and signs of subcutaneous tissue inflammation develop.
Cases of osteonecrosis of the jaw have been reported in patients with advanced cancer receiving 120 mg denosumab every 4 weeks. There are isolated reports of the development of osteonecrosis of the jaw at a dose of 60 mg every 6 months (see section “Side effects”).
Poor oral hygiene and invasive dental procedures (eg, tooth extraction) were risk factors for the development of ONJ in patients receiving Prolia in clinical trials.
Before initiating therapy, it is important to evaluate patients for risk factors for developing ONJ. If risk factors are identified, before treatment with Prolia®, it is recommended to conduct an examination of the oral cavity and teeth with appropriate preventive dental measures. Adequate oral hygiene should be maintained during treatment with Prolia®.
During treatment with Prolia®, invasive dental procedures should be avoided. If such procedures are necessary, the decision on the treatment plan for each patient should be made jointly with the attending physician based on an individual assessment of the benefit/risk ratio.
Patients suspected of developing ONJ, or who have developed ONJ during treatment with Prolia®, should be monitored by a dentist or oral surgeon. In patients with ONJ that develops while using Prolia, a decision may be made to temporarily discontinue treatment until the condition resolves based on an individual assessment of the risk/benefit ratio.
Atypical femur fractures were observed in patients in the Prolia® group. Atypical femoral fractures—subtrochanteric or diaphyseal fractures of the proximal femur—may occur with minimal or no trauma and may be bilateral. On imaging, these fractures usually have a characteristic appearance.
Atypical femoral fractures have also been reported in patients with underlying diseases and conditions (eg, vitamin deficiencies, rheumatoid arthritis, hypophosphatasia) and in patients receiving certain therapies (eg, bisphosphonates, corticosteroids, proton pump inhibitors). These cases have also been observed in the absence of antiresorptive therapy. Patients receiving Prolia® should be instructed to report any new or unusual pain in the thigh, hip, or groin. Patients who experience these symptoms should be evaluated for a femoral fracture and the contralateral hip should also be examined.
Persons allergic to latex should not touch the rubber needle cap (latex derivative).
Prolia® contains the same active substance (denosumab) as Exgiva
®
.
Patients receiving Prolia® should not take Exjiva®.
Instructions for administering Prolia® in a prefilled syringe with a needle guard
Syringe Parts Guide
See fig. 1.
Important:
Read these instructions carefully before using Prolia® in a prefilled syringe with a needle guard:
— It is very important that before you start self-injecting, your doctor or nurse has given you detailed instructions on how to perform the injection.
— Prolia® is administered subcutaneously (subcutaneous injection).
— Tell your doctor if you have an allergy to latex (the needle cap of the pre-filled syringe consists of a latex derivative).
— Do not remove the gray cap from the needle of a prefilled syringe until you are ready to inject.
— Do not use a prefilled syringe if it has been dropped on a hard surface. Use a new prefilled syringe and tell your doctor or nurse.
— Do not attempt to activate the safety device of a pre-filled syringe before injection.
— Do not attempt to remove the clear guard from a pre-filled syringe before injection.
If you have any questions, please contact your doctor or nurse.
Step 1: Preparation
A.
Remove the blister pack with the prefilled syringe from the packaging and prepare everything you need for the injection.
For a more comfortable injection, leave the prefilled syringe at room temperature for about 30 minutes before injecting. Wash your hands thoroughly with soap. Place the prefilled syringe on a clean, well-lit surface. Also prepare wipes moistened with alcohol, cotton swabs or bandages and adhesive tape (not included with the syringe).
— Do not attempt to heat the syringe in hot water or a microwave oven.
— Do not leave the prefilled syringe in direct sunlight.
— Do not shake the prefilled syringe.
— Keep the prefilled syringe out of the reach of children.
IN.
Open the blister pack by pulling the label. To remove the prefilled syringe from the blister pack, grasp the safety device.
Take the syringe as shown in Figure 2 (See Figure 2).
For security:
— Do not touch the plunger
— Do not touch the gray needle cap
WITH.
Check the drug and the prefilled syringe.
— Do not use a prefilled syringe if:
- the product is cloudy or contains foreign particles. The solution should be clear, colorless or light yellow;
- any part is damaged or broken;
- the gray needle cap is missing or loose;
- The last day of the expiration date indicated on the label has expired.
Tell your doctor or nurse about all of the above.
Step 2: Preparing the injection site
A.
Wash your hands thoroughly. Prepare and clean the injection site.
You can use (see Fig. 3):
- Upper thigh
- Abdomen, excluding area around navel, approximately 5 cm
- The outer surface of the shoulder (only if someone else is giving you the injection).
Clean the injection site with a swab soaked in alcohol. Let the skin dry.
- Do not touch the injection site before injection.
- Do not inject in areas where the skin is thin, bruised, red or hard. Avoid injecting into areas with scars or stretch marks.
IN.
Gently pull the gray needle cap away from the syringe without twisting.
WITH.
Pinch the injection site to create a firm surface.
It is important to keep the skin pinched while injecting (see Figure 4).
Step 3: Introduction
A.
Pinch the skin. INSERT the needle into the skin (see Figure 5).
— Do not touch the treated injection area.
IN.
Slowly and smoothly PRESS the plunger until you feel or hear a “click.” Press the piston until it clicks (see Fig. 6).
It is important to press the plunger until it clicks to deliver the entire dose.
WITH.
RELEASE your thumb. Then REMOVE the syringe from the skin (see Fig. 7).
Once you release the plunger, the prefilled syringe guard will cover the needle.
— Do not put the gray needle cap back on the pre-filled syringe.
Step 4: Finish
A.
Dispose of the used prefilled syringe and other associated materials according to local regulations.
Throw away the used prefilled syringe and gray needle cap. Medicines must be disposed of in accordance with local regulations. Ask your doctor or pharmacist how to discard the medicine when it is no longer needed. These measures will help protect the environment. Keep syringes and related materials out of the reach of children.
— Do not reuse a prefilled syringe.
IN
. Examine the injection site.
— If blood appears at the injection site, apply pressure with a cotton swab or bandage.
Do not rub the injection site. If necessary, cover the injection site with a bandage.
Instructions for administering Prolia® in a prefilled syringe
This section provides information on how to properly administer a prefilled syringe injection.
It is very important that before you begin self-injections, your attending physician or nurse instruct you in detail on the technique of performing the injection.
Wash your hands thoroughly before giving the injection.
If you have any questions about the injection technique, please contact your doctor or nurse.
Before starting the injection
:
Read all instructions carefully before using the PZSh.
DO NOT use the PZS if the cap has been removed.
How to use a pre-filled syringe?
Your doctor has prescribed Prolia® PZS for subcutaneous injection. You must inject the entire contents of the syringe (1 ml) once and repeat the injection after 6 months as prescribed by your doctor.
Equipment
For self-injection you will need:
1. new PZS of the drug Prolia®; And
2. swabs or similar materials soaked in alcohol.
What should you do before self-administering Prolia® subcutaneously?
1. Remove the syringe from the refrigerator. DO NOT pick up the PZSh by the piston or protective cap, as this may damage the device.
2. The PZH can be left outside the refrigerator to reach room temperature. This will make the injection more comfortable.
DO NOT heat the PZH in any other way (for example, in a microwave oven or in hot water).
DO NOT leave the syringe in direct sunlight.
3. DO NOT shake the PZS.
4. DO NOT remove the cap from the PZP until you are ready to inject.
5. Check the expiration date of the PZSh. The expiration date is indicated on the packaging as “BEST UNTIL: MM.YYYY”.
DO NOT use PZS if the last day of the expiration month stated on the label has passed.
6. Check the appearance of Prolia®. The solution should be clear, colorless or light yellow. If the solution becomes cloudy or has a different color, the drug should not be used.
7. Choose a comfortable, well-lit place and a clean surface where you can conveniently place all the necessary materials.
8. Wash your hands thoroughly.
How to choose the right injection site?
It is best to inject into the upper thigh and abdomen.
If someone else is giving you the injections, you can use the outside of your upper arm (see Figure 8).
How to give an injection correctly?
1. Disinfect the injection site using a swab soaked in alcohol.
2. To avoid bending the needle, gently pull the cap off the needle immediately without twisting.
DO NOT touch the needle or press the plunger.
3. If small air bubbles are visible inside the PZ, there is no need to remove them before injection.
Injecting the solution with air bubbles is safe.
4. Pinch the skin (without squeezing) between your thumb and forefinger. Insert the needle completely into the skin as your doctor or nurse showed you.
5. Slowly and smoothly press the plunger while holding the skin fold. Press down on the plunger until the syringe is empty.
6. Remove the needle from the skin and release the skin fold.
7. If blood appears at the injection puncture site, carefully wipe it off with a cotton swab or cloth. Do not rub the injection site. If necessary, cover the injection site with a bandage.
8. Use one PZZ for one injection only. DO NOT use any remaining medication in the syringe.
Remember:
If you have problems, seek help or advice from your doctor or nurse.
Disposal of used syringes
- DO NOT put the cap back on a used syringe.
— Keep the used syringe out of the reach of children.
— The used syringe must be disposed of in accordance with local regulations. Ask your doctor or pharmacist how to discard the medicine when it is no longer needed. These measures will help protect the environment.
Results and discussion
During treatment with denosumab, a significant increase in BMD was observed in all measured skeletal areas (Fig. 1).
Rice.
1. Dynamics of BMD during treatment with denosumab. Here and in Fig. 2 * — p≤0.001. Thus, the increase in BMD in the lumbar spine after 12 months was 4.2%, after 24 months - 7.5%, after 36 months - 8.8%. In the ShBK there was an increase in BMD by 3.1, 3.9 and 5.3%, and in the entire PBC - by 2.8, 4.1 and 5%, in the forearm (1/3 of the radius) - by 0.9 , 1.4 and 2.6% respectively. The data obtained are consistent with the results of an axial phase III RCT assessing the effectiveness and safety of denosumab FREEDOM therapy. However, it should be noted that this study included women with T
-criterion of –2.5
SD
or less, but not less than –4
SD
, while in our study there were no restrictions and patients with a lower
T
-criterion were included.
Thus, in the first part of the FREEDOM study, which lasted for 3 years, BMD in the spine increased by 8.8%, in the BCD by 5.2%, and in the POB by 6.4% [14, 15]. The increase in radial bone BMD over 3 years of denosumab treatment was 3.5% ( p
≤0.0001) [7]. In addition, forearm BMD was measured in an extension study that included 115 patients in the FREEDOM placebo group who received calcium and vitamin D alone and subsequently switched to denosumab, which they received for 5 years in the FREEDOM extension study. Despite the decrease in BMD during the placebo period, at the end of the study there was an increase in BMD by 1.5%, which was important confirmation of the cessation of cortical bone loss [16]. Currently, denosumab is the only drug that increases BMD in the area of 1/3 of the forearm, indicating a clinically significant effect of the drug on cortical bone.
For a number of chronic non-infectious diseases and risk factors for their development, tactics are used to achieve target values of the studied indicators. For this purpose, biomarkers of the pathological process and their levels that must be achieved to prevent the development of complications have been identified. Thus, for a cerebral stroke, such a marker is the level of blood pressure, and its target level is 140/90 mmHg. [17]. Clinical guidelines for the treatment of AP currently do not identify special markers or define their target values. This is due to the fact that treatment with the most common antiresorptive drugs, BP, did not cause a constant and significant increase in bone mass, especially in the POBC, and the markers of bone turnover were characterized by very high variability. Currently, in the course of 5-, 6- and 10-year studies of FD, it has been shown that BMD increased maximally in the 3-4th year of treatment, and then remained at the same level or tended to decrease. This is probably due to the slowdown in bone mineralization during long-term use of BP, necessitating a temporary break in treatment [18, 19]. However, a meta-analysis of RCTs on the effectiveness and safety of various drugs for the treatment of AP has proven a statistically significant linear relationship between the increase in BMD in the vertebrae and femur and a decrease in the relative risk of fractures at a low level of injury [20]. The emergence of new antiresorptive (denosumab) drugs for the treatment of AP, which caused a continuous and significant increase in bone mass over 10 years, made it possible to consider BMD as a marker for achieving target values, i.e., transition from the “zone” of AP to the “zone” of osteopenia or overcoming the acceptable level of risk of fractures, which is T
-criterion –2.5
SD
.
Among 98 patients, according to the results of spinal densitometry, BMD according to T
-criterion below –2.5
SD
were detected in 79, the median
T
-criterion was –2.8
SD
.
After 12 months of therapy, this indicator increased in 23 (29%) women, and the median T
-score was –2.4
SD
, which corresponds to osteopenia.
In 56 patients, the T
-criterion for the spine area was low before the start of therapy, the median
T
-criterion was –3.4
SD
, and after 12 months of treatment it increased to a value of –2.9
SD
, but did not enter the “zone” of osteopenia. After 24 months, 25 people showed a transition from the “zone” of AP to the “zone” of osteopenia.
When analyzing the dynamics of BMD of the SBK, out of 47 people with identified AP in this skeletal area, 12 moved into the “zone” of osteopenia after 12 months of treatment. In the remaining 35 patients with the lowest BMD before treatment, median T
-criterion was –3.0
SD
, and after 12 months of therapy –2.8
SD
, which was also regarded as positive dynamics.
The study included 11 patients who at the first visit, according to densitometry, had osteopenia, but had a history of low-energy fractures, as well as a high risk of major fractures according to FRAX. Among them, 5 people had previously received anti-osteoporotic therapy and were switched to denosumab treatment. In 6 patients who had not previously received treatment, median T
-criteria before the start of the study was –1.5
SD
, –1.4
SD
, and after a year of therapy this indicator at both points was –1.2
SD
.
Achievement of target BMD was assessed over an 8-year period of treatment with denosumab in the FREEDOM study and concluded that many women with AP achieved non-osteoporotic T
-criteria (from 11 to 82%). Based on the results obtained, the authors called for the use of tactics to achieve target values in the treatment of AP [21].
An assessment of the dynamics of BMD after 12 months of therapy in 26 women who had previously taken anti-osteoporotic therapy showed a similar increase in bone mass as in the group of untreated patients, i.e., an additional positive effect was obtained when switching to denosumab (Table 2).
Table 2. Dynamics of BMD in 72 patients who did not receive and 26 who received anti-osteoporotic therapy before the start of the study. The data obtained confirm the results of studies that showed a more significant increase in BMD when patients were transferred from tablet BP or anabolic therapy with teriparatide to denosumab [22, 23].
A significant decrease in serum CTx concentration was noted 6 months after the start of denosumab therapy by 54% ( p
<0.001) and after 12 months - by 72% (
p
<0.001). Subsequently, when monitoring the CTx concentration once a year for 48 months, this level was maintained. These data are consistent with the results of the FREEDOM studies, in which the reduction in CTx concentrations reached 86 and 72% (after 1 and 36 months, respectively) and DECIDE (74% after 1 year of treatment) [8, 11] (Fig. 2).
Rice.
2. Dynamics of CTx levels during treatment with denosumab. In addition, a decrease in the level of total calcium in the blood was recorded after 6 months by 3.6% and after 12 months by 7.6% ( p
≤0.001). It should be noted that when assessing calcium metabolism before the start of therapy, 12 people showed slight and clinically insignificant hypercalcemia, which was not detected after 12 months of treatment. Subsequently, throughout the entire period of treatment, total calcium levels remained within normal limits. The hypocalcemic effect of denosumab in this case may indicate the manifestation of its pronounced antiresorptive effect. The decrease in the level of TAP in the blood did not reach statistical significance throughout the treatment. This is apparently due to the fact that ALP includes several isoenzymes, in addition to bone, reflecting the rate of bone remodeling. The average creatinine level did not change throughout treatment. In patients with reduced glomerular filtration of the kidneys, there was no increase in creatinine concentration in the blood. Currently, Prolia is the only drug for the treatment of AP approved for use in patients even with severe renal impairment. Due to its unique targeted mechanism of action, Prolia is not excreted in the urine and does not necessitate dose adjustment in chronic kidney disease. Special studies have shown that the degree of renal failure does not affect the pharmacokinetics and pharmacodynamics of the drug, and this provides an advantage to prescribing Prolia in this population [24].
Among the 98 patients who received the first injection of Prolia, no independent refusal to continue treatment was noted. The different number of patients after 24 months or more is associated with the period of analysis of the material, and not with the cessation of therapy, therefore in this article we do not draw conclusions about patients’ compliance with the prescribed treatment regimen.
The adverse events encountered were assessed as mild to moderate in severity. They are mainly associated with the musculoskeletal system: arthralgia was noted in 3 patients, the appearance or intensification of back pain - in 16, pain in the bones of the extremities - in 7. It should be noted that similar pain sensations in these patients were periodically observed before the start of therapy and Upon detailed questioning, women could not with complete confidence associate these manifestations with taking denosumab. In 2 patients, dermatitis was observed at a distance from the injection site 1 and 3 months after the first injection of denosumab, which resolved spontaneously. Both patients did not have a history of allergies and the cause of dermatitis could not be identified. All noted adverse events did not require discontinuation of the drug. During the observation period, 3 patients had fractures: one had a fracture of the radius in a typical place 2 months after the first injection, the second had a fracture of the ankle 3.5 months after the first injection, the third had deformities of 2 vertebrae 46 months after the start. treatment with denosumab. All patients were diagnosed with severe AP with a history of fractures, and new fractures were associated with low bone strength, and not with insufficient effect of the drug.
According to the survey, 86 patients found the drug administration regimen very convenient, 8 – quite convenient, 6 – satisfactory.